RU2173680C2 - Hydroxyethylaminosulfoneamides, intermediate compounds, pharmaceutical composition, method of inhibition retroviral proteases, method of treatment of retroviral infections, method of treatment of aids - Google Patents

Abstract

FIELD: organic chemistry, medicine, virology, pharmacy. SUBSTANCE: invention relates to derivatives of hydroxyethylaminosulfoneamides of the formulas (I)

, (II)

, (III)

where R means phenyl-C₁-C₈-alkoxy-carbonyl where phenyl can be substituted with C₁-C₈-alkoxy-group, quinolinylcarbonyl, mono- or di-C₁-C₈-alkylamino-C₁-C₈-alkanoyl; R′ means H, C₁-C₈-alkyl; R¹ means H, C₁-C₈-alkyl, C₂-C₈-alkenyl,

amino acid side-chain, for example, glycine; R¹ and R^2″ both mean H; R² means phenyl-C₁-C₈-alkyl; R³ means H, C₁-C₈-alkyl, C₁-C₈-alkoxy-C₁-C₈-alkyl, C₂-C₈-alkenyl; R⁴ means C₁-C₈-alkyl, phenyl, methoxyphenyl; R⁶ is H; x = 1, 2; t = 0 or 1. Compounds of formulas (I), (II), (III) relate to inhibitors of retroviral protease and can be used in pharmaceutical composition for inhibition of HIV protease and in method of inhibition of HIV infection also. EFFECT: improved method of inhibition of protease and treatment of infection, valuable medicinal properties of compounds. 61 cl, 2 dwg, 25 tbl, 33 ex

Description

 The invention relates to retroviral protease inhibitors, and more particularly to new compounds, compositions and methods for inhibiting retroviral proteases. In particular, the present invention relates to sulfonamide-containing hydroxyethylamine protease inhibiting compounds, compositions and method for inhibiting retroviral proteases, such as human immunodeficiency virus / HIV / protease, and treating retroviral infection, for example, HIV infection. The present invention also relates to methods for producing such compounds, as well as intermediates useful in such methods.

 During the replication cycle of retroviruses, gag and gag-pol gene products act as proteins. These proteins are then processed by a virus encoded protease / or proteinase /, giving viral enzymes and structural proteins of the viral core. In the most typical case, gag precursor proteins are processed to form core proteins, and pol precursor proteins are processed into viral enzymes, such as reverse transcriptase and retroviral protease. It has been shown that the precise processing of precursor proteins by a retroviral protease is necessary for the assembly of infectious virions. For example, it has been shown that frameshift mutations in the protease region of the pol gene of the HIV gene prevent the processing of the gag of the precursor protein. It was also shown by site-directed mutagenesis of the aspartic acid residue in HIV protease that the processing of the gag of the precursor protein could not be carried out. Therefore, attempts have been made to inhibit virus replication by inhibiting the action of retroviral proteases.

 Inhibition of retroviral proteases may involve a substance that simulates a transition state. A retroviral protease is brought into contact with a compound that binds to the enzyme, competing with gag and gag-pol proteins and thereby inhibiting the replication of structural proteins and, more importantly, the retroviral protease itself. In this way, retrovirus proteases can be effectively inhibited.

Crystal Structure of a C₂ Symmetric Inhibitor Complexed to HIV-I Protease", Science 249, 527 /1990/.Several classes of compounds have been proposed, in particular for inhibiting proteases such as HIV protease. Such compounds include hydroxyethylamine isosteres and reduced amide isosteres. See, for example, EP 0346847; EP 0342541; Roberts et al., "Rational Design of Peptide-Based Proteinase Inhibitors", Science 248, 358/1990 /; and Erickson et al., "Design Activity and 2.8

Crystal Structure of a C ₂ Symmetric Inhibitor Complexed to HIV-I Protease ", Science 249, 527/1990 /.

 Several classes of compounds are known to be useful as inhibitors of the proteolytic enzyme renin. See, for example, US N 4,599198; IR, 2184730; GB 2,209,752; EP 0 264 795; GB 2200115 and US SIR H725. Of these, GB 2200115, GB 2209752, EP 0264795, US SIR H725 and US 4,599,198 describe urea-containing hydroxyethylamines as renin inhibitors. GB 2200115 also describes sulfamoyl-containing hydroxyethylamines as renin inhibitors, and EP 0264795 describes some sulfonamide-containing hydroxyethylamines as renin inhibitors. However, it is known that although renin and HIV proteases are classified as aspartyl proteases, it cannot be predicted in advance whether effective renin inhibitors will be effective HIV protease inhibitors.

 This invention relates to compounds and compositions that inhibit the virus. More specifically, the invention relates to compounds and compositions that inhibit retroviral proteases, a method for inhibiting retroviral proteases, methods for producing compounds and intermediates useful in these methods. The compounds of this invention are sulfonamide-containing hydroxyethylamine compounds having inhibitory activity.

или его фармацевтически приемлемые соли, пролекарство или эфир, где
R обозначает водород, алкоксикарбонил, аралкоксикарбонил, алкилкарбонил, циклоалкилкарбонил, циклоалкилалкоксикарбонил, циклоалкилалканоил, алканоил, аралканоил, ароил, арилоксикарбонил, арилоксикарбонилалкил, арилоксиалканоил, гетероциклилкарбонил, гетероциклилоксикарбонил, гетероциклилалканоил, гетероциклилалкоксикарбонил, гетероаралканоил, гетероаралкоксикарбонил, гетероарилоксикарбонил, гетероароил, алкил, алкенил, алкинил, циклоалкил, арил, аралкил, арилоксиалкил, гетероарилоксиалкил, гидроксиалкил, аминокарбонил, аминоалканоил и моно- и дизамещенные аминокарбонил и моно- и дизамещенные аминоалканоилрадикалы, в которых заместители выбраны из алкила, арила, аралкила, циклоалкила, циклоалкилалкила, гетероарила, гетероаралкила, гетероциклоалкила, гетероциклоалкилалкила, или, если радикалы аминокарбонил и аминоалканоил являются дизамещенными, заместители вместе с атомом азота, к которому они присоединены, образуют радикал гетероциклоалкил или гетероарил;
R' обозначает водород, радикалы, описанные для R³, или R''SO₂-, где R'' обозначает радикалы, описанные для R³; или R и R' вместе с азотом, к которому они присоединены, образуют радикалы гетероциклоалкил и гетероарил;
R¹ обозначает водород; -CH₂SO₂NH₂, -CH₂CO₂CH₃, -CO₂CH₃, -CONH₂, -CH₂C(O)NHCH₃, -C(OH₃)₂(SH), -C(CH₃)₂(SCH₃), -C(CH₃)₂(S[O]CH₃), -C(CH₃)₂(S[O] ₂CH₃), алкил, галогеналкил, алкенил, алкинил, циклоалкил и аминокислотные боковые цепи, выбранные из таких боковых цепей, как аспарагин, S-метилцистеин и его сульфоксидные /SO/ и сульфоновые /SO₂/ производные, изолейцин, аллоизолейцин, аланин, лейцин, трет-лейцин, фенилаланин, орнитин, гистидин, норлейцин, глутамин, треонин, глицин, аллотреонин, серин, O-алкилсерин, аспарагиновая кислота, β-цианоаланин и валин;
R^1' и R^1'' независимо друг от друга обозначают водород и радикал, описанный для R¹, или R^1' и R^1'', вместе с R¹ и атомами углерода, с которыми соединены R¹, R^1' и R^1'', обозначают циклоалкил;
R² обозначает алкил, арил, циклоалкил, циклоалкилалкил и аралкил, иногда замещенные группой, выбранной из радикалов, таких как алкил и галоген, -NO₂, -CN, -CF₃, -OR⁹ и -SR⁹, где R⁹ обозначает водород и алкил и галоген;
R³ обозначает водород, алкил, галогеналкил, алкенил, алкинил, гидроксиалкил, алкоксиалкил, циклоалкил, циклоалкилалкил, гетероциклоалкил, гетероарил, гетероциклоалкилалкил, арил, аралкил, гетероаралкил, аминоалкил и моно- и дизамещенный аминоалкил, где заместители выбраны из таких радикалов, как алкил, арил, аралкил, циклоалкил, циклоалкилалкил, гетероарил, гетероаралкил, гетероциклоалкил и гетероциклоалкилалкил, или в случае дизамещенного аминоалкила заместители вместе с атомом азота, к которому они присоединены, образуют гетероциклоалкил или гетероарил;
R⁴ обозначает радикалы, описанные для R³, за исключением водорода;
R⁶ обозначает водород и алкил;
x = 0, 1 или 2;
t = 0 или 1;
Y обозначает O, S и NR¹⁵, где R¹⁵ обозначает водород и радикалы, описанные для R³.In accordance with this invention, a retroviral protease inhibiting compound of the formula

or its pharmaceutically acceptable salts, prodrug or ester, where
R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaralkoksikarbonil, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, amino anoyl and mono- and disubstituted amino-carbonyl and mono- and disubstituted aminoalkanoyl radicals in which the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, aminoalkylaminoalkylalkyl, the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;
R ′ is hydrogen, the radicals described for R ³ , or R ″ SO ₂ -, where R ″ is the radicals described for R ³ ; or R and R ', together with the nitrogen to which they are attached, form heterocycloalkyl and heteroaryl radicals;
R ¹ is hydrogen; -CH ₂ SO ₂ NH ₂ , -CH ₂ CO ₂ CH ₃ , -CO ₂ CH ₃ , -CONH ₂ , -CH ₂ C (O) NHCH ₃ , -C (OH ₃ ) ₂ (SH), -C ( CH ₃ ) ₂ (SCH ₃ ), —C (CH ₃ ) ₂ (S [O] CH ₃ ), —C (CH ₃ ) ₂ (S [O] ₂ CH ₃ ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl and amino acid side chains selected from side chains such as asparagine, S-methylcysteine and its sulfoxide / SO / and sulfonic / SO ₂ / derivatives, isoleucine, alloisoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allotreonin, serine, O-alkylserine, aspartic acid, β-cyanoalanine and valine;
R ^{1 ′} and R ^{1 ″} independently of one another are hydrogen and the radical described for R ¹ , or R ^{1 ’} and R ^{1 ″} , together with R ¹ and the carbon atoms to which R ¹ , R ^{1 ′} are connected and R ^{1 ″} is cycloalkyl;
R ² is alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, sometimes substituted by a group selected from radicals such as alkyl and halogen, —NO ₂ , —CN, —CF ₃ , —OR ⁹ and —SR ⁹ , where R ⁹ is hydrogen and alkyl and halogen;
R ³ is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroalkyl, substituted amino, and substituted monoalkyl radicals such as , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl and heterocycloalkylalkyl, or in the case of a disubstituted aminoalkyl, the substituents together with the nitrogen atom to which they are attached form a heterocycloal keel or heteroaryl;
R ⁴ is the radicals described for R ³ , with the exception of hydrogen;
R ⁶ is hydrogen and alkyl;
x is 0, 1 or 2;
t is 0 or 1;
Y is O, S and NR ¹⁵ , where R ¹⁵ is hydrogen and the radicals described for R ³ .

где R обозначает водород, алкоксикарбонил, аралкоксикарбонил, алкилкарбонил, циклоалкилкарбонил, циклоалкилалкоксикарбонил, циклоалкилалканоил, алканоил, аралканоил, ароил, арилоксикарбонил, арилоксикарбонилалкил, арилоксиалканоил, гетероциклилкарбонил, гетероциклилоксикарбонил, гетероциклилалканоил, гетероциклилалкоксикарбонил, гетероаралканоил, гетероаралкоксикарбонил, гетероарилоксикарбонил, гетероароил, алкил, алкенил, циклоалкил, арил, аралкил, арилоксиалкил, гетероарилоксиалкил, гидроксиалкил, аминокарбонил и моно- и дизамещенные аминокарбонил и моно- и дизамещенные аминоалканоилрадикалы, в которых заместители выбраны из таких радикалов, как алкил, арил, аралкил, циклоалкил, циклоалкилалкил, гетероарил, гетероаралкил, гетероциклоалкил, гетероциклоалкилалкил, или в случае дизамещенного аминоалканоила заместители вместе с атомом азота, с которым они соединены, могут образовывать гетероциклоалкил или гетероарил;
R' обозначает водород и радикалы, описанные для R³, или R и R' вместе с атомом азота, к которому они присоединены, обозначают гетероциклоалкил и гетероарил;
R¹ обозначает водород; -CH₂SO₂NH₂, -CH₂CO₂CH₃, -CO₂CH₃, -CONH₂, -CH₂C(O)NHCH₃, -C(CH₃)₂(SH), -C(CH₃)₂(SCH₃), -C(CH₃)₂(S[O]CH₃), -C(CH₃)₂(S[O] ₂CH₃), алкил, галогеналкил, алкенил, алкинил, циклоалкил и аминокислотные боковые цепи, выбранные из таких боковых цепей, как аспарагин, S-метилцистеин и его сульфоксидные /SO/ и сульфоновые /SO₂/ производные, изолейцин, аллоизолейцин, аланин, лейцин, трет-лейцин, фенилаланин, орнитин, гистидин, норлейцин, глутамин, треонин, глицин, аллотреонин, серин, O-метилсерин, аспарагиновая кислота, β-цианоаланин и валин;
R² обозначает алкил, арил, циклоалкил, циклоалкилалкил и аралкил, иногда замещенные группой, выбранной из таких радикалов, как алкил и галоген, -NO₂, -C≡N, CF₃, -OR⁹, -SR⁹, где R⁹ обозначает водород и алкил;
R³ обозначает алкил, галогеналкил, алкенил, алкинил, гидроксиалкил, алкоксиалкил, циклоалкил, циклоалкилалкил, гетероциклоалкил, гетероарил, гетероциклоалкилалкил, арил, аралкил, гетероаралкил, аминоалкил и моно- и дизамещенный аминоалкил, в которых заместители выбраны из таких радикалов, как алкил, арил, аралкил, циклоалкил, циклоалкилалкил, гетероарил, гетероаралкил, гетероциклоалкил и гетероциклоалкилалкил, или в случае дизамещенного аминоалкила заместители вместе с атомом азота, к которому они присоединены, образуют гетероциклоалкил или гетероарил;
R⁴ обозначает радикалы, описанные для R³.A group of the most preferred compounds described by formula I are represented by formula II

wherein R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaralkoksikarbonil, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl , aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl and mono- and diza further aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals in which the substituents are selected from radicals such as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroamino, together with a diamino connected, may form heterocycloalkyl or heteroaryl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen atom to which they are attached are heterocycloalkyl and heteroaryl;
R ¹ is hydrogen; -CH ₂ SO ₂ NH ₂ , -CH ₂ CO ₂ CH ₃ , -CO ₂ CH ₃ , -CONH ₂ , -CH ₂ C (O) NHCH ₃ , -C (CH ₃ ) ₂ (SH), -C ( CH ₃ ) ₂ (SCH ₃ ), —C (CH ₃ ) ₂ (S [O] CH ₃ ), —C (CH ₃ ) ₂ (S [O] ₂ CH ₃ ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl and amino acid side chains selected from side chains such as asparagine, S-methylcysteine and its sulfoxide / SO / and sulfonic / SO ₂ / derivatives, isoleucine, alloisoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allotreonin, serine, O-methylserine, aspartic acid, β-cyanoalanine and valine;
R ² is alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, sometimes substituted by a group selected from radicals such as alkyl and halogen, —NO ₂ , —C≡N, CF ₃ , —OR ⁹ , —SR ⁹ , where R ⁹ denotes hydrogen and alkyl;
R ³ is alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroalkyl, aminoalkyl and mono and disubstituted alkyl radicals such as aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl and heterocycloalkylalkyl, or in the case of a disubstituted aminoalkyl, the substituents together with the nitrogen atom to which they are attached form heterocycloalkyl or heteroaryl;
R ⁴ denotes the radicals described for R ³ .

A more preferred group of compounds of formula II consists of compounds in which:
R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaralkoksikarbonil, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl and mono- and disubstituted aminocarbonyl and aminoalkanoyl in which the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, or, in the case of a disubstituted amino, form heterocycloalkyl or heteroaryl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen atom to which they are attached are heterocycloalkyl and heteroaryl;
R ¹ is CH ₂ C (O) NHCH ₃ , C (CH ₃ ) ₂ (SCH ₃ ), C (CH ₃ ) ₂ (S [O] CH ₃ ), C (CH ₃ ) ₂ (S [O] ₂ CH ₃ ), alkyl, alkenyl and alkynyl and amino acid side chains selected from side chains such as asparagine, valine, threonine, allotreonin, isoleucine, tert-leucine, S-methylcysteine and its sulfonic and sulfoxide derivatives, alanine, alloisoleucine;
R ² is alkyl, cycloalkylalkyl and aralkyl, sometimes substituted with halogen and radicals of the formula —OR ⁹ and —SR ⁹ , where R ⁹ is alkyl; and
R ³ and R ^{4 are} independently alkyl, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl and heteroalkyl.

Of greatest interest are the compounds of formula II, in which:
R is alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaralkoksikarbonil, heteroaryloxycarbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl and mono- and disubstituted aminocarbonyl and aminoalkanoyl in which the substituents are selected from such radicals, ak alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or in case of a disubstituted aminoalkanoyl radical, said substituents along with the nitrogen atom to which they are attached form heterocycloalkyl or heteroaryl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen atom to which they are attached are heterocycloalkyl or heteroaryl;
R ¹ is CH ₂ C (O) NHCH ₃ , C (CH ₃ ) ₂ (SCH ₃ ), C (CH ₃ ) ₂ (S [O] CH ₃ ), C (CH ₃ ) ₂ (S [O] ₂ CH ₃ ), methyl, propargyl, t-butyl, isopropyl and sec-butyl and amino acid side chains selected from the group consisting of side chains such as asparagine, valine, S-methylcysteine, alloisoleucine, isoleucine and β-cyanoalanine;
R ² is CH ₃ SCH ₂ CH ₂ -, isobutyl, n-butyl, benzyl, 4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl;
R ³ is isoamyl, n-butyl, isobutyl and cyclohexyl; and
R ⁴ is phenyl, substituted phenyl and methyl.

в которой R обозначает водород, алкоксикарбонил, аралкоксикарбонил, алкилкарбонил, циклоалкилкарбонил, циклоалкилалкоксикарбонил, циклоалкилалканоил, алканоил, аралканоил, ароил, арилоксикарбонил, арилоксикарбонилалкил, арилоксиалканоил, гетероциклилкарбонил, гетероциклилоксикарбонил, гетероциклилалканоил, гетероциклилалкоксикарбонил, гетероаралканоил, гетероаралоксикарбонил, гетероарилоксикарбонил, гетероароил, алкил, алкенил, циклоалкил, арил, аралкил, арилоксиалкил, гетероарилоксиалкил, гидроксиалкил, аминокарбонил, аминоалканоил и моно- и дизамещенные аминокарбонил и аминоалканоил, в которых заместители выбраны из таких радикалов, как алкил, арил, аралкил, циклоалкил, циклоалкилалкил, гетероарил, гетероаралкил, гетероциклоалкил, гетероциклоалкилалкил, или в случае дизамещенного аминоалканоила эти заместители вместе с атомом азота, к которому они присоединены, образуют гетероциклоалкил или гетероарил;
R' обозначает водород и радикалы, описанные для R³, или R и R' вместе с атомом азота, к которому они присоединены, обозначают гетероциклоалкил и гетероарил;
R¹ обозначает водород, - CH₂SO₂NH₂, -CH₂CO₂CH₃, -CO₂CH₃, -CONH₂, -CH₂C(O)NHCH₃, -C(CH₃)₂(SH), -C(CH₃)₂(SCH₃), -C(CH₃)₂(S[O]CH₃), -C(CH₃)₂(S[O] ₂CH₃), алкил, галогеналкил, алкенил, алкинил, циклоалкил и аминокислотные боковые цепи, выбранные из таких боковых цепей, как аспарагин, S-метилцистеин и его сульфоксидные /SO/ и сульфонамидные /SO₂/ производные, изолейцин, аллоизолейцин, аланин, лейцин, трет-лейцин, фенилаланин, орнитин, гистидин, норлейцин, глутамин, треонин, глицин, аллотреонин, серин, аспарагиновая кислота, β-цианоаланин и валин;
R² обозначает алкил, арил, циклоалкил, циклоалкилалкил и аралкил, иногда замещенные группой, выбранной из радикалов алкила и водорода, -NO₂, -C≡N, CF₃, -OR⁹, -SR⁹, где R⁹ обозначает водород и алкил;
R³ обозначает алкил, галогеналкил, алкенил, алкинил, гидроксиалкил, алкоксиалкил, циклоалкил, циклоалкилалкил, гетероциклоалкил, гетероарил, гетероциклоалкилалкил, арил, аралкил, гетероаралкил, аминоалкил и моно- и дизамещенный аминоалкил, в которых заместители выбраны из таких радикалов, как алкил, арил, аралкил, циклоалкил, циклоалкилалкил, гетероарил, гетероаралкил, гетероциклоалкил и гетероциклоалкилалкил, или в случае дизамещенного аминоалкила эти заместители вместе с атомом азота, к которому они присоединены, образуют гетероциклоалкил или гетероарил;
R⁴ обозначает радикалы, описанные для R³.Another group of preferred compounds of formula I are compounds of formula III

wherein R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaraloksikarbonil, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, amino anoyl and mono- and disubstituted aminocarbonyl and aminoalkanoyl in which the substituents are selected from radicals such as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or in the case of amino-substituted to which they are attached, form heterocycloalkyl or heteroaryl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen atom to which they are attached are heterocycloalkyl and heteroaryl;
R ¹ is hydrogen, —CH ₂ SO ₂ NH ₂ , —CH ₂ CO ₂ CH ₃ , —CO ₂ CH ₃ , —CONH ₂ , —CH ₂ C (O) NHCH ₃ , —C (CH ₃ ) ₂ (SH ), -C (CH ₃ ) ₂ (SCH ₃ ), -C (CH ₃ ) ₂ (S [O] CH ₃ ), -C (CH ₃ ) ₂ (S [O] ₂ CH ₃ ), alkyl, halogenated , alkenyl, alkynyl, cycloalkyl and amino acid side chains selected from side chains such as asparagine, S-methylcysteine and its sulfoxide / SO / and sulfonamide / SO ₂ / derivatives, isoleucine, alloisoleucine, alanine, leucine, tert-leucine, phenylalanine , ornithine, histidine, norleucine, glutamine, threonine, glycine, allotreonin, serine, aspartic acid, β-cyanoalanine and valine;
R ² is alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, sometimes substituted by a group selected from alkyl and hydrogen radicals, —NO ₂ , —C≡N, CF ₃ , —OR ⁹ , —SR ⁹ , where R ⁹ is hydrogen and alkyl;
R ³ is alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroalkyl, aminoalkyl, and mono and disubstituted alkyl radicals such as aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl and heterocycloalkylalkyl, or in the case of disubstituted aminoalkyl, these substituents together with the nitrogen atom to which they are attached form a heterocyclo alkyl or heteroaryl;
R ⁴ denotes the radicals described for R ³ .

A more preferred group of compounds of formula III consists of compounds in which
R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaralkoksikarbonil, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl and mono- and disubstituted e aminocarbonyl and aminoalkanoyl in which the substituents are selected from radicals such as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, or, in the case of a disubstituted aminoalkyl, these are substituted with nitrogen, heterocycloalkyl or heteroaryl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen atom to which they are attached are heterocycloalkyl and heteroaryl;
R ¹ is hydrogen, alkyl and alkenyl and amino acid side chains selected from the group consisting of amino acids such as asparagine, valine, threonine, allotreonin, isoleucine, tert-leucine, S-methylcysteine and its sulfonic and sulfoxide derivatives, alanine and alloisoleucine ;
R ² is alkyl, cycloalkyl and aralkyl, sometimes substituted with halogen and radicals of the formula —OR ⁹ and —SR ⁹ , where R ⁹ is hydrogen and alkyl and halogen radicals;
R ³ and R ^{4 are} independently alkyl, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylakyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

Most preferred are compounds of formula III in which
R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaralkanoilkarbonil, heteroaryloxycarbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl and mono- and disubstituted aminocarbonyl and aminoalkanoyl in which the substituents are selected from such p dicalite as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or in case of a disubstituted aminoalkanoyl radical, said substituents along with the nitrogen atom to which they are attached form heterocycloalkyl or heteroaryl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen atom to which they are attached are heterocycloalkyl and heteroaryl;
R ¹ is hydrogen, methyl, propargyl, t-butyl, isopropyl, and sec-butyl and amino acid side chains selected from the group consisting of amino acids such as asparagine, valine, S-methylcysteine, alloisoleucine, threonine, serine, aspartic acid β-cyanoalanine and allotreonin;
R ² is CH ₃ SCH ₂ CH ₂ -, isobutyl, n-butyl, benzyl, 4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl; and
R ³ is alkyl, cyclohexyl, isobutyl, isoamyl and n-butyl;
R ⁴ is methyl, phenyl and substituted phenyl, in which the substituents are selected from substituents such as halogen, alkoxyhydroxy, nitro and amino.

в которой R обозначает водород, алкоксикарбонил, аралкоксикарбонил, алкилкарбонил, циклоалкилкарбонил, циклоалкилалкоксикарбонил, циклоалкилалканоил, алканоил, аралканоил, ароил, арилоксикарбонил, арилоксикарбонилалкил, арилоксиалканоил, гетероциклилкарбонил, гетероциклилоксикарбонил, гетероциклилалканоил, гетероциклилалкоксикарбонил, гетероаралканоил, гетероаралкоксикарбонил, гетероарилоксикарбонил, гетероароил, алкил, алкенил, циклоалкил, арил, аралкил, арилоксиалкил, гетероарилоксиалкил, гидроксиалкил, аминокарбонил, аминоалканоил и моно- и дизамещенные аминокарбонил аминоалканоил, в которых заместители выбраны из таких радикалов, как алкил, арил, аралкил, циклоалкил, циклоалкилалкил, гетероарил, гетероаралкил, гетероциклоалкил, гетероциклоалкилалкил, или в случае дизамещенного аминоалканоила эти заместители вместе с атомом азота, с которым они соединены, образуют гетероциклоалкил или гетероарил;
R' обозначает водород и радикалы, описанные для R³, или R и R' вместе с азотом, к которому они присоединены, обозначают гетероциклоалкил и гетероарил;
R¹ обозначает водород, -CH₂SO₂NH₂, -CH₂CO₂CH₃, -CO₂CH₃, -CONH₂, -CH₂C(O)NHCH₃, -C(CH₃)₂(SH), -C(CH₃)₂(SCH₃), -C(CH₃)₂(S[O]CH₃), -C(CH₃)₂(S[O] ₂CH₃), алкил, галогеналкил, алкенил, алкинил, циклоалкил и аминокислотные боковые цепи, выбранные из таких аминокислот, как аспарагин, S-метилцистеин и его сульфоксидные /SO/ и сульфоновые /SO₂/ производные, изолейцин, аллоизолейцин, аланин, лейцин, трет-лейцин, фенилаланин, орнитин, гистидин, норлейцин, глутамин, треонин, глицин, аллотреонин, серин, аспарагиновая кислота, β-цианоаланин и валин;
R^1' и R^1'' независимо друг от друга обозначают водород и радикалы, описанные для R¹, или одни из R^1' и R^1'', вместе с R¹ и атомами углерода, с которыми R¹, R^1' и R^1'' соединены, обозначают циклоалкил;
R² обозначает алкил, арил, циклоалкил, циклоалкилалкил и аралкил, иногда замещенные группой, выбранной из радикалов, таких алкил и галоген, -NO₂, -C≡N, CF₃, -OR⁹ и SR⁹, где R⁹ обозначает водород или алкил;
R³ обозначает алкил, галогеналкил, алкенил, алкинил, гидроксиалкил, алкоксиалкил, циклоалкил, циклоалкилалкил, гетероциклоалкил, гетероарил, гетероциклоалкилалкил, арил, аралкил, аминоалкил и моно- и дизамещенный аминоалкилы, в которых заместители выбраны из таких радикалов, как алкил, арил, аралкил, циклоалкил, циклоалкилалкил, гетероарил, гетероаралкил, гетероциклоалкил и гетероциклоалкилалкил, или в случае дизамещенного аминоалкила эти заместители вместе с атомом азота, к которому они присоединены, образуют гетероциклоалкил или гетероарил; и
R⁴ обозначает радикалы, описанные для R³.Another preferred group of compounds of formula I are compounds of formula IV

wherein R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, tsikloalkilalkanoil, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, ariloksikarbonilalkil, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, geterotsiklilalkanoil, heterocyclylalkoxycarbonyl, geteroaralkanoil, geteroaralkoksikarbonil, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, amino canoyl and mono- and disubstituted aminocarbonyl aminoalkanoyl in which the substituents are selected from radicals such as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl, or, in the case of disubstituted amino, they are connected to form heterocycloalkyl or heteroaryl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen to which they are attached are heterocycloalkyl and heteroaryl;
R ¹ is hydrogen, —CH ₂ SO ₂ NH ₂ , —CH ₂ CO ₂ CH ₃ , —CO ₂ CH ₃ , —CONH ₂ , —CH ₂ C (O) NHCH ₃ , —C (CH ₃ ) ₂ (SH ), -C (CH ₃ ) ₂ (SCH ₃ ), -C (CH ₃ ) ₂ (S [O] CH ₃ ), -C (CH ₃ ) ₂ (S [O] ₂ CH ₃ ), alkyl, halogenated , alkenyl, alkynyl, cycloalkyl and amino acid side chains selected from such amino acids as asparagine, S-methylcysteine and its sulfoxide / SO / and sulfonic / SO ₂ / derivatives, isoleucine, alloisoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allotreonin, serine, aspartic acid, β-cyanoalanine and valine;
R ^{1 ″} and R ^{1 ″} independently of one another are hydrogen and the radicals described for R ¹ , or one of R ^{1 ″} and R ^{1 ″} , together with R ¹ and carbon atoms with which R ¹ , R ^{1 ″} and R ^{1 ″ are} connected, cycloalkyl;
R ² is alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl, sometimes substituted by a group selected from radicals such as alkyl and halogen, —NO ₂ , —C≡N, CF ₃ , —OR ⁹ and SR ⁹ , where R ⁹ is hydrogen or alkyl;
R ³ is alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, aminoalkyl, and mono- and disubstituted aminoalkyls, in which are alkyl radicals such as aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkyl, or in the case of disubstituted aminoalkyl, these substituents together with the nitrogen atom to which they are attached form a heterocycloalkyl or heter oaryl; and
R ⁴ denotes the radicals described for R ³ .

A more preferred group of compounds of formula IV consists of compounds in which
R is arylalkanoyl, heteroaroyl, aryloxyalkanoyl, aryloxycarbonyl, alkanoyl, aminocarbonyl, monosubstituted aminoalkanoyl or disubstituted aminoalkanoyl or mono- or dialkylaminocarbonyl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen to which they are attached are heterocycloalkyl or heteroaryl;
R ¹ , R ^{1 '} and R ^1'' independently represent hydrogen and alkyls having about 1 to 4 carbon atoms, alkenyl, alkynyl, aralkyl and radicals represented by the formula -CH ₂ C (O) R''or - C (O) R ″, in which R ″ is R ³⁸ , —NR ³⁸ R ³⁹ and OR ³⁸ , where R ³⁸ and R ^{39 are} independently hydrogen or alkyl having about 1 to 4 carbon atoms;
R ² is alkyl, cycloalkylalkyl and aralkyl, sometimes substituted with halogen and radicals of the formula —OR ⁹ and —SR ⁹ , where R ⁹ is hydrogen and alkyl;
R ³ and R ^{4 are} independently alkyl, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl and heteroalkyl.

Of greatest interest are compounds of formula IV, in which:
R is arylalkanoyl, aryloxycarbonyl, aryloxyalkanoyl, alkanoyl, aminocarbonyl, monosubstituted aminoalkanoyl or disubstituted aminoalkanoyl or mono- or dialkylaminocarbonyl;
R ′ is hydrogen and the radicals described for R ³ , or R and R ′ together with the nitrogen to which they are attached are heterocycloalkyl or heteroaryl;
R ¹ , R ^{1 '} , R ^1''are independently hydrogen, methyl, ethyl, benzyl, phenylpropyl and propargyl;
R ² is CH ₃ SCH ₂ CH ₂ -, isobutyl, n-butyl, benzyl, 4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl;
R ³ is alkyl, cyclohexyl, isobutyl, isoamyl and n-butyl;
R ⁴ is methyl, phenyl and substituted phenyl, in which the substituents are selected from halogen, alkoxy, amino, and nitro groups.

 As used herein, the term “alkyl”, alone or in combination, means straight or branched chain alkyl containing from 1 to 10, preferably from 1 to 8, carbon atoms. Examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like. The term "alkenyl", alone or in combination, means a straight or branched chain hydrocarbon radical having one or more double bonds and containing from 2 to about 18 carbon atoms, preferably from 2 to about 8 carbon atoms. Examples of suitable alkenyls are ethenyl, propenyl, alkyl, 1,4-butadienyl, etc. The term "alkynyl", alone or in combination, means a straight chain hydrocarbon radical having one or more triple bonds and containing from 2 to about 10 carbon atoms. Examples of alkynyls are ethynyl, propynyl / propargyl /, butynyl and the like. The term "alkoxy", alone or in combination, means an alkyl ether radical in which the term alkyl has the meaning described above. Examples of suitable alkyl ester radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. The term “cycloalkyl”, alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl in which each cyclic part of the molecule contains from about 3 to 8 carbon atoms and is cyclic. The term “cycloalkylalkyl” means an alkyl described above which is substituted by a cycloalkyl radical containing from about 3 to 8, preferably from 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term “aryl”, alone or in combination, means a phenyl or naphthyl radical which sometimes carries one or more substituents selected from radicals such as alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, etc. . such as phenyl, p-tolyl, 4-methoxyphenyl, 4- (tert-butoxy) phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 2-naphthyl, 2-naphthyl, etc. The term "aralkyl", alone or in combination, means alkyl as described above, in which one hydrogen atom is replaced by aryl as described above, such as benzyl, 2-phenylethyl, and the like. . The term "aralkoxycarbonyl", alone or in combination, means a radical of the formula -C (O) -O-aralkyl, in which the term "aralkyl" has the meaning given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl. The term "aryloxy" means a radical of the formula aryl-O-, in which the term "aryl" has the meaning given above. The term "alkanoyl", alone or in combination, means an acyl radical derived from an alkane carboxylic acid. Examples of alkanoyl are acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl and the like. The term “cycloalkylcarbonyl” means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid, for example cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl and the like, or from a benzene-fused monocyclic cycloalkanecarboxylic acid, which is optionally substituted, such as, for example, alkane 2,3,4-tetrahydro-2-naphthoyl-1,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term “aralkanoyl” means an acyl radical derived from an aryl substituted alkane carboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnoxamoyl, 4. P. The term "aroyl" means an acyl radical derived from aromatic carboxylic acid. Examples of such radicals are aromatic carboxylic acids, optionally substituted benzoic or naphthoic acid, for example benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6 - (benzyloxycarbonyl) -2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxyformamido) -2-naphthoyl, etc. The heterocyclyl or heterocycloalkyl moieties, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkyl and the like. represent a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted on one or more carbon atoms by a halogen, alkyl, alkoxy group, oxo group, etc. P. and / or / on a secondary nitrogen atom (i.e. = NH-) alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl, or on a tertiary nitrogen atom / i.e. = N- / oxide group, and which is attached via a carbon atom. The heteroaryl moiety of heteroaroyl, heteroaryloxycarbonyl or heteroaralkoxycarbonyl or similar groups is an aromatic monocyclic, bicyclic or tricyclic heterocycle that contains a heteroatom and is sometimes substituted as described above depending on the definition of heterocyclyl. Examples of such heterocyclyl and heteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, etc.), pyridylpyrilyl, pyrylpyrilyl , furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl (e.g. 2-indolyl, etc.), quinolinyl (e.g. 2-quinolinyl, 3-quinolinyl, 1-oxide-2-quinolinyl, etc.), isoquinolinyl (e.g. 1-isoquinolinyl, 3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g. 1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-te trahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxaline, β-carbolinyl, 2-benzofurancarbonyl, 1-, 2-, 4- or 5-benzimidazolyl, and t .P. The term “cycloalkylalkoxycarbonyl” means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH in which cycloalkylalkyl has the meaning given above. The term “aryloxyalkanoyl” means an acyl radical of the formula aryl-O-alkanoyl in which aryl and alkanoyl are as defined above. The term “heterocyclyloxycarbonyl” means an acyl group derived from heterocyclyl-O-COOH, where heterocyclyl has the meaning given above. The term “heterocyclylalkanoyl” is an acyl radical derived from a heterocyclyl substituted alkane carboxylic acid, where heterocyclyl has the meaning given above. The term “heterocyclylalkoxycarbonyl” means an acyl radical derived from heterocyclyl substituted alkane-O-COOH, where heterocyclyl has the meaning given above. The term “heteroaryloxycarbonyl” means an acyl radical derived from a carboxylic acid represented by the formula heteroaryl-O-COOH, where heteroaryl has the meaning given above. The term "aminocarbonyl", alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid in which the amino group may be a primary, secondary or tertiary amino group containing substituents such as hydrogen, alkyl, aryl, aralkyl, cycloalkyl , cycloalkylalkyl, etc. The term “aminoalkanoyl” means an acyl group derived from an amino-substituted alkane carboxylic acid in which the amino group may be a primary, secondary or tertiary amino group containing substituents such as hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like The term “halogen” means fluoro, chloro, bromo and iodo. The term “haloalkyl” means an alkyl radical, as defined above, in which one or more hydrogens is replaced by halogen. Examples of such haloalkyl radicals are chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and others. The term "leaving (cleavable) group" usually refers to groups easily replaced by a nucleophile, such as amine, thiol or alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups are, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, and the like. Preferred leaving groups will be indicated as necessary.

 Methods for preparing compounds of formula I are set forth below. It should be noted that the main method relates to the preparation of compounds having a specific stereochemistry, for example, absolute stereochemistry with respect to the hydroxyl group is designated as / R /. However, such methods are generally applicable for the same compounds of the opposite configuration, for example, having stereochemistry with respect to the hydroxyl group / S /. In addition, compounds having / R / stereochemistry can be used to prepare compounds having / S / stereochemistry. For example, / R / compound can be converted to / S / compound using well known methods.

Obtaining compounds of formula I
The compounds of this invention represented by formula I can be prepared using the following basic method. This method is schematically shown in schemes 1 and 2 (see the end of the description).

в которой P обозначает аминозащищающую группу, а R² имеет описанное выше значение, восстанавливают до соответствующего спирта при помощи подходящего восстанавливающего агента. Пригодные аминозащищающие группы хорошо известны специалистам и могут представлять собой карбобензоксигруппу, т-бутоксикарбонил и др. Предпочтительной аминозащищающей группой является карбобензоксигруппа. Предпочтительным N-замещенным хлоркетоном является N-бензилоксикарбонил-L-фенилаланинхлорметилкетон. Предпочтительным восстанавливающим агентом является боргидрид. Реакцию восстановления проводят при температуре от -10^oC до приблизительно 25^oC, предпочтительно при приблизительно 0^oC, в подходящей системе растворителей, такой как, например, тетрагидрофуран и т.п. N-защищенные хлоркетоны коммерчески доступны, например в Bachem. Inc., Torrance, California. В другом случае, хлоркетоны можно получить способом, изложенным в S.J. Fittkau. J. Pract. Chem., 315, 1037 /1973/, с последующей N-защитой при помощи хорошо известных специалистам способов.An N-protected amino acid chloroketone derivative having the formula

in which P represents an amino protecting group and R ² has the meaning described above, is reduced to the corresponding alcohol using a suitable reducing agent. Suitable amino protecting groups are well known to those skilled in the art and may be a carbobenzoxy group, t-butoxycarbonyl, etc. A preferred amino protecting group is a carbobenzoxy group. A preferred N-substituted chloro ketone is N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone. A preferred reducing agent is borohydride. The reduction reaction is carried out at a temperature of from -10 ^° C to about 25 ^° C, preferably at about 0 ^° C, in a suitable solvent system, such as, for example, tetrahydrofuran and the like. N-protected chloro ketones are commercially available, for example from Bachem. Inc., Torrance, California. Alternatively, chloroketones can be prepared by the method described in SJ Fittkau. J. Pract. Chem., 315, 1037 (1973), followed by N-protection using methods well known to those skilled in the art.

в которой P и R² имеют описанные выше значения. Подходящими системами растворителей для получения аминоэпоксида являются этанол, метанол, изопропанол, тетрагидрофуран, диоксан и др. в том числе их смеси. Подходящими основаниями для получения эпоксида из восстановленного хлоркетона являются гидроксид калия, гидроксид, натрия, т-бутоксид калия, DBU и т.п. Предпочтительным из них является гидроксид калия.The halogen derivative of the alcohol can be used directly as described below, or preferably it is then reacted, preferably at room temperature, with a suitable base in a suitable solvent system to form an N-protected aminoepoxide of the formula

in which P and R ² have the meanings described above. Suitable solvent systems for the production of aminoepoxide are ethanol, methanol, isopropanol, tetrahydrofuran, dioxane and others, including mixtures thereof. Suitable bases for producing epoxide from reduced chlorketone are potassium hydroxide, hydroxide, sodium, potassium t-butoxide, DBU, and the like. Of these, potassium hydroxide is preferred.

в которой P³ обозначает карбоксилзащищающую группу, например метил, этил, бензил, трет-бутил и т.п.; R² имеет описанное выше значение; и P¹ и P² независимо друг от друга выбраны из таких аминозащищающих групп /но не только из них/, как арилалкил, замещенный арилалкил, циклоалкенилалкил и замещенный циклоалкенилалкил, аллил, замещенный аллил, ацил, алкоксикарбонил, аралкоксикарбонил и силил. Примерами арилалкила являются /но не ограничены ими/ бензил, о-метилбензил, тритил и бензгидрил, которые необязательно могут быть замещены галогеном, C₁-C₈-алкилом, алкокси-, гидрокси-, нитро-, амино-, алкиламино-, ациламиногруппой, алкиленом и ацилом или их солями, такими как соли фосфония или аммония. Примерами арильных групп являются фенил, нафталенил, инданил, антраценил, дуренил, 9-(9-фенилфторенил) и фенантренил, циклоалкенилалкил или замещенный циклоалкиленилалкил, содержащие C₆-C₁₀-циклоалкилы. Подходящие ацильные группы представляют собой карбобензоксигруппу, т-бутоксикарбонил, изобутоксикарбонил, бензоил, замещенный бензоил, бутирил, ацетил, трифторацетил, трихлорацетил, фталоил и т.п.Alternatively, a protected aminoepoxide may be prepared as described in PCT Patent Application Serial No. PCT / US93 / 04804, incorporated herein by reference and incorporated herein by reference, starting from an L-amino acid that reacts with a suitable amino-protecting group in a suitable solvent to form an amino protected L-amino acid ester of the formula

in which P ³ denotes a carboxyl-protecting group, for example methyl, ethyl, benzyl, tert-butyl and the like; R ² has the meaning described above; and P ¹ and P ^{2 are} independently selected from amino protecting groups / but not only from / such as arylalkyl, substituted arylalkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl and Examples of arylalkyl are / but not limited to / benzyl, o-methylbenzyl, trityl and benzhydryl, which optionally may be substituted with halogen, C ₁ -C ₈ -alkyl, alkoxy, hydroxy, nitro, amino, alkylamino, acylamino alkylene and acyl or their salts, such as phosphonium or ammonium salts. Examples of aryl groups are phenyl, naphthalenyl, indanyl, anthracenyl, durenyl, 9- (9-phenyl fluorenyl) and phenanthrenyl, cycloalkenylalkyl or substituted cycloalkenylalkyl containing C ₆ -C ₁₀ cycloalkyls. Suitable acyl groups are carbobenzoxy, t-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl and the like.

In addition, P ¹ and / or / P ² protecting groups can form a heterocyclic ring with nitrogen to which they are attached, for example, 1,2-bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl and the like. These heterocyclic groups may further include adjacent aryl and cycloalkyl rings. In addition, heterocyclic groups may be mono-, di- or trisubstituted, for example nitrophthalimidyl. The term silyl refers to a silicon atom optionally substituted with one or more alkyls, aryls, and aralkyls.

 Suitable silyl protecting groups are / but not limited to / trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and diphenylmethylsilyl. Silylation of amino groups to obtain mono- or bisdisilylamino groups can give derivatives of amino alcohol, amino acids, amino acid esters and amides. In the case of amino acids, amino acid esters and amides, the reduction of the carbonyl group provides the desired mono- or bissilylamino alcohol. Silylation of an amino alcohol can give an N, N, O-trisilyl derivative. Removal of silyl from the silyl ester group is easily achieved by treatment, for example, with metal hydroxide or ammonium fluoride, either as a separate reaction step or in situ during the preparation of the aminoaldehyde reagent. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyldimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or their combination with imidazole or DMF. Methods of silylation of amines and removal of silyl protecting groups are well known in the art. Methods for the preparation of these amino group-containing derivatives from the corresponding amino acids, amides or amino acid esters are also well known to those skilled in the art of organic chemistry, in particular in the field of the chemistry of amino acids / amino acid esters or amino alcohols.

Preferably, P ¹ and P ² independently of one another are aralkyl or substituted aralkyl. More preferably, each of P ¹ and P ² is benzyl.

в которой P¹, P² и R² имеют описанное выше значение. Так, раствор спирта в дихлорметане добавляют к охлажденному /-75^o ... -68^oC/ раствору оксалилхлорида в дихлорметане и DMSO в дихлорметане и перемешивают в течение 35 минут.The amino protected L-amino acid ester is then reduced to the corresponding alcohol. For example, an amino-protected L-amino acid ester can be reduced with diisobutylaluminum hydride at -78 ^° C in a suitable solvent, such as toluene. Preferred reducing agents are lithium aluminum hydride, lithium borohydride, sodium borohydride, borane, lithium tri-tert-butoxyaluminum hydride, borane / THF complex (tetrahydrofuran). The most preferred reducing agent is diisobutylaluminium hydride (DiBAL-H) in toluene. The resulting alcohol is then converted, for example by the Swern oxidation method, into the corresponding aldehyde of the formula

in which P ¹ , P ² and R ² have the meaning described above. Thus, a solution of alcohol in dichloromethane is added to a cooled / -75 ^o ... -68 ^o C / solution of oxalyl chloride in dichloromethane and DMSO in dichloromethane and stirred for 35 minutes.

Suitable oxidizing agents are, for example, a sulfur trioxide / pyridine and DMSO complex, oxalyl chloride and DMSO, acetyl chloride or anhydride and DMSO, trifluoroacetyl chloride or anhydride and DMSO, methanesulfonyl chloride / DMSO or tetrahydrothiafen-S-trihydromide, toluide, toluide DMSO, phosphorus pentachloride and DMSO dimethyl phosphoryl chloride; and DMSO and isobutyl chloroformate and DMSO. Oxidation conditions are described by Rutz et al. [Angew. Chem. 99, p. 1186, / 1987 /, Angew. Chem. Int. Ed. Eng. 26, p. 1141, 1987 / using oxalyl chloride and DMSO at -78 ^o C.

 The preferred oxidation method described in this invention is the use of a complex of sulfur trioxide with pyridine, triethylamine and DMSO at room temperature. This system provides very good yields of the desired chiral protected aminoaldehyde, applicable without purification, i.e. the need for purification of kilograms of intermediate products by chromatography is eliminated and large-scale operations become less dangerous. The reaction at room temperature also eliminates the need for a low temperature reactor, which makes the process more suitable for commercial production.

The reaction can be carried out in an inert atmosphere, for example in an atmosphere of nitrogen or argon, or in normal or dry air, at atmospheric pressure or in a sealed reaction vessel at elevated pressure. A nitrogen atmosphere is preferred. Examples of amine bases are, for example, tributylamine, triisopropylamine, N-methylpiperidine, N-methylmorpholine, azabicyclononan, diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, N, N-dimethylaminopyridine or mixtures of these bases. Triethylamine is preferred. In addition to pure DMSO, a mixture of DMSO with non-protic or halogenated solvents such as tetrahydrofuran, ethyl acetate, toluene, xylene, dichloromethane, ethylene dichloride, etc. can be used as a solvent. Bipolar aprotic cosolvents include acetonitrile, dimethylformamide, dimethyl acetamide and its cyclic analog, N-methylpyrrolidone, sulfolane and the like. In addition to N, N-dibenzylphenylalaninol, the phenylalaninol derivatives discussed above can be used as the aldehyde precursor to obtain the corresponding N-monosubstituted (either P ¹ or P ² = H) or N, N-disubstituted aldehyde.

 In addition, to obtain such aldehydes, hydride reduction of an amide or ether derivative of phenylalanine with nitrogen, protected by alkyl, benzyl or cycloalkenyl, substituted phenylalanine or a cycloalkyl-containing analog of a phenylalanine derivative can be carried out. Hydride transfer is an additional method for the synthesis of aldehyde under conditions in which condensation of the aldehyde can be avoided (for example, Oppenhauer oxidation).

Aldehydes of this method can also be obtained by methods of reducing protected phenylalanine and analogues of phenylalanine or their amide or ester derivatives, for example, sodium amalgam with HCl in ethanol, or lithium, or sodium, or potassium, or calcium in ammonia. The reaction is carried out at a temperature of from about −20 ^° C. to about 45 ^° C., preferably from 5 ^° C. to about 25 ^° C. Two additional methods for the preparation of protected nitrogen aldehyde include oxidation of the corresponding alcohol with bleach in the presence of a catalytic amount of 2.2 free radical, 6,6-tetramethyl-1-pyridyloxy, and in the second method for the oxidation of alcohol to aldehyde, a catalytic amount of tetrapropylammonium perruthenate is used in the presence of N-methylmorpholine-N-oxide.

 Alternatively, the acid chloride derivative of the protected phenylalanine or phenylalanine derivative described above can be reduced with hydrogen and a catalyst, such as Pd on barium carbonate or barium sulfate, with or without an additional catalyst moderator / sulfur / thiol / Rosenmund reduction / .

Эти диастереомеры можно разделить, например, при помощи хроматографии, или, альтернативно, они могут разделиться после реакции в последующих стадиях. Для соединений, имеющих /S/-стереохимию, вместо D-аминокислоты можно использовать L-аминокислоту.The aldehyde obtained by Swern oxidation is then reacted with a halogenmethyl lithium reagent generated in situ by the reaction of an alkyl lithium or allyl lithium compound with a dihalogenomethane of the formula X ¹ CH ₂ X ² in which X ¹ and X ² are independently I, Br or Cl . For example, a solution of aldehyde and chloromethane in THF is cooled to -78 ^° C and a solution of n-butyllithium in hexane is added. The resulting product is a mixture of diastereomers of the corresponding amino-protected epoxides of the formulas

These diastereomers can be separated, for example, by chromatography, or, alternatively, they can be separated after the reaction in subsequent stages. For compounds having / S / stereochemistry, an L-amino acid can be used instead of the D-amino acid.

The addition of chloromethyllithium or bromomethyllithium to a chiral aminoaldehyde is highly selective for diastereomers. Preferably, chloromethyllithium or bromomethyllithium is prepared in situ by the reaction of dihalogenomethane and n-butyl lithium. Suitable methyleneating halogenmethanes are chloroiodomethane, dibromomethane, diiodomethane, bromofluoromethane and the like. The sulfonate ester of the product of the addition of, for example, hydrobromic acid to formaldehyde is also a methyleneating agent. Tetrahydrofuran is the preferred solvent, but other solvents such as toluene, dimethoxyethane, ethylene dichloride, methylene chloride can be used as pure solvents or as a mixture. Bipolar aprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone are useful as solvents or as part of a solvent mixture. The reaction can be carried out in an inert atmosphere, such as nitrogen or argon. N-butyllithium can be replaced by other organometallic reagents such as methyl lithium, tert-butyl lithium, sec-butyl lithium, phenyl lithium, phenyl sodium and the like. The reaction can be carried out at a temperature between about -80 ^° C and 0 ^° C, but preferably between about -80 ^° C and -20 ^° C. The most preferred temperature is between -40 ^° C and -15 ^° C. Reagents can be added only once. but under certain conditions multiple additions are preferred. The reaction is preferably carried out at atmospheric pressure, but under certain conditions, for example in an environment with high humidity, preferably elevated pressure.

 Alternative methods for converting to epoxides according to this invention include substituting other types of charged methyleneation precursors, followed by treating them with a base to form a similar anion. Examples of these types of molecules are tosylate or triflate trimethyl sulfoxonium, tetramethyl ammonium halide, methyl diphenyl sulfoxonium halide, where the halide is chloride, bromide or iodide.

 The conversion of the aldehydes of the present invention to their epoxy derivative can also be carried out in several stages. For example, adding a thioanisole anion, obtained, for example, from a butyl or aryl lithium reagent, to a protected aminoaldehyde, oxidizing the resulting protected amino sulfo alcohol with well-known oxidizing agents such as hydrogen peroxide, tert-butyl hypochloride, sodium peroxide or periodate to form sulfoxide. Alkylation of the sulfoxide with, for example, methyl iodide or bromide, methyltosylate, methyl mesylate, methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride and the like, in the presence of an organic or inorganic base. Alternatively, the protected amino sulfoalcohol can be alkylated, for example, with the above alkylating agents to form sulfonium salts, which are then converted to the desired epoxides using tert-amine or mineral bases.

 The required epoxides under the most preferred conditions were formed diastereoselectively in a proportion of 85:15 / S: R /. This product can be purified chromatographically to form a diastereomerically and enantiomerically pure product, but it is more convenient to use it without purification to obtain retroviral protease inhibitors. The above method is applicable to mixtures of optical isomers in the same way as for separated compounds. If a specific optical isomer is desired, it can be obtained by selecting starting material, for example, L-phenylalanine, D-phenylalanine, L-phenylalaninol, D-phenylalaninol, D-hexahydrophenylalaninol and the like, or the separation can occur at intermediate or final stages. Chiral excipients, such as one or two equivalents of camphorsulfonic acid, citric acid, camphoric acid, 2-methoxyphenylacetic acid and the like, can be used to form salts, esters or amides of the compounds of this invention. These compounds or derivatives may be crystallized or separated chromatographically using a chiral or achiral column, as is known to those skilled in the art.

в которых P, P¹, P², R² и R³ имеют описанное выше значение. Альтернативно, вместо аминоэпоксида может быть использован галоспирт.The aminoepoxide is then reacted in a suitable solvent system with an equal amount, or preferably an excess, of the desired amine of the formula: R ³ NH ₂ in which R ³ is hydrogen or has the meaning described above. The reaction can be carried out over a wide temperature range, for example from about 10 ^° C. to about 100 ^° C., but it is preferable, although not necessary, to carry out this reaction at a temperature at which the solvent begins to boil. Suitable solvent systems are protic, non-proton and bipolar aprotic organic solvents, such as, for example, systems in which the solvent is alcohol, for example methanol, ethanol, isopropanol and others, ethers, such as tetrahydrofuran, dioxane and the like, and toluene, N, N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. A preferred solvent is isopropanol. Examples of the amines corresponding to the formula R ³ NH ₂ are benzylamine, isoamylamine, cyclohexanomethylamine, naphthylenemethylamine, etc. The resulting product is a 3- (N-substituted amino) -3- (R ² ) -1- (NHR ³ ) derivative. -propan-2-ol (hereinafter referred to as amino alcohol) and can be represented by the formulas

in which P, P ¹ , P ² , R ² and R ³ have the meaning described above. Alternatively, a halo alcohol may be used in place of the amino epoxide.

в которых P, P¹, P², R², R³ и R⁴ имеют описанное выше значение. Эти промежуточные продукты применимы для получения ингибиторных соединений данного изобретения и сами являются также активными ингибиторами ретровирусных протеаз.The amino alcohol described above is then reacted in a suitable solvent with a sulfonyl chloride / R ⁴ SO ₂ Cl / or sulfonyl anhydride in the presence of an acid acceptor. The solvents in which this reaction can take place are methylene chloride, tetrahydrofuran. Suitable acid acceptors are triethylamine, pyridine. Preferred sulfonyl chlorides are methanesulfonyl chloride and benzenesulfonyl chloride. The resulting sulfonamide derivative (sulfamide) can be represented depending on the epoxide used by the formulas

in which P, P ¹ , P ² , R ² , R ³ and R ⁴ have the meaning described above. These intermediates are useful for preparing the inhibitory compounds of this invention and are themselves also active retroviral protease inhibitors.

Sulfonyl halides of the formula R ⁴ SO ₂ X can be prepared by reacting a suitable Grignard reagent or an alkyl lithium reagent with sulfuryl chloride or sulfur dioxide, followed by oxidation with halogen, preferably chlorine. Thiols can also be oxidized to sulfonyl chlorides with chlorine in the presence of water under carefully controlled conditions. In addition, sulfonic acids can be converted to sulfonyl halides using reagents such as PCl ₅ and also to anhydrides using suitable dehydrating agents. Sulfonic acids, in turn, can be obtained using methods well known to those skilled in the art. Such sulfonic acids are also commercially available. To obtain compounds in which -SO ₂ - is replaced by -SO- or -S-, respectively, sulfonyl halides / R ⁴ SOX / or sulfenyl halides / R ⁴ SX / can be used instead of sulfonyl halides, respectively.

в которой t, P, R¹, R^1', R^1'', R², R³ и R⁴ имеют описанные выше значения. Предпочтительными защитными группами в этом случае являются бензилоксикарбонил или т-бутоксикарбонил. Если амин реагирует с производным аминокислоты, например, когда t = 1 и R^1' и R^1'' оба представляют собой H, так что аминокислота является β-аминокислотой, такие β-аминокислоты можно получить в соответствии со способом, изложенным в дополнительной заявке US Serial N 07/345808. Если t = 1 один из R^1' и R^1'' представляет собой H и R¹ представляет собой H, так что аминокислота представляет собой гомо-β-аминокислоту, такие гомо-β-аминокислоты можно получить по способу, изложенному в дополнительной заявке US Serial N 07/853561. Если t = 0 и R¹ является алкилом, алкенилом, алкинилом, циклоалкилом, -CH₂SO₂NH₂, -CH₂CO₂CH₃, -CO₂CH₃, -CONH₂, -CH₂C(O)NHCH₃, -C(CH₃)₂(SH), -C(CH₃)₂(SCH₃), -C(CH₃)₂(S[O] CH₃), -C(CH₃)₂(S[O₂]CH₃), или аминокислотной боковой цепью, такие материалы хорошо известны и многие из них коммерчески доступны от Sigma-Aldrich.After the sulfonamide derivative is prepared, the amino protecting group P or the amino protecting groups P ¹ and P ² are removed under conditions that do not affect the remainder of the molecule. These methods are well known to those skilled in the art and include hydrolysis, hydrogenolysis, and the like. A preferred method is to remove the protecting group, for example, a carbobenzoxy group, by hydrogenolysis using palladium on carbon in a suitable solvent system such as alcohol, acetic acid and the like. or mixtures thereof. If the protecting group is t-butoxycarbonyl, it can be removed using an inorganic or organic acid, for example HCl or trifluoroacetic acid, in a suitable solvent system, for example, dioxane or methylene chloride. The resulting product is an amine salt. After neutralizing the salt, the amine reacts with an amino acid or corresponding amino acid derivative represented by the formula (PN [CR ^{1 '} R ^1'' ] _t CH (R ¹ ) COOH) in which t, R ¹ , R ^1' and R ^{1 ''} have the values described above, with the formation of the antiviral compounds of this invention having the formula

in which t, P, R ¹ , R ^{1 ′} , R ^{1 ″} , R ² , R ³ and R ⁴ have the meanings described above. Preferred protecting groups in this case are benzyloxycarbonyl or t-butoxycarbonyl. If the amine reacts with an amino acid derivative, for example, when t = 1 and R ^{1 '} and R ^1''are both H, so that the amino acid is a β-amino acid, such β-amino acids can be obtained in accordance with the method described in the additional application US Serial N 07/345808. If t = 1 one of R ^{1 '} and R ^1'' is H and R ¹ is H, so that the amino acid is a homo-β-amino acid, such homo-β-amino acids can be obtained by the method described in the additional application US Serial N 07/853561. If t = 0 and R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, —CH ₂ SO ₂ NH ₂ , —CH ₂ CO ₂ CH ₃ , —CO ₂ CH ₃ , —CONH ₂ , —CH ₂ C (O) NHCH ₃ , -C (CH ₃ ) ₂ (SH), -C (CH ₃ ) ₂ (SCH ₃ ), -C (CH ₃ ) ₂ (S [O] CH ₃ ), -C (CH ₃ ) ₂ (S [O ₂ ] CH ₃ ), or amino acid side chain, such materials are well known and many of them are commercially available from Sigma-Aldrich.

где R имеет описанное выше значение, а L представляет собой подходящую уходящую /отщепляемую/ группу, такую как галоген. Предпочтительно, если R¹ является боковой цепью, природной α-аминокислоты, R представляет собой 2-хинолинкарбонил, производный от N-гидроксисукцинимид-2-хинолинкарбоксилата, т.е. L является гидроксисукцинимидом. Раствор свободного амина /или его соли с уксусной кислотой/ и приблизительно 1,0 эквивалент карбоксилата смешивают в подходящей системе растворителей и иногда обрабатывают (до 5 эквивалентов) основанием, таким как N-метилморфолин, при комнатной температуре. Подходящей системой растворителей являются тетрагидрофуран, метиленхлорид или N,N-диметилформамид и др., в том числе их смеси.The N-protecting group can then be removed, if necessary, using the methods described above and then can be reacted with a carboxylate of the formula

where R has the meaning described above, and L is a suitable leaving / leaving / group, such as halogen. Preferably, if R ¹ is a side chain of a naturally occurring α-amino acid, R is 2-quinolinecarbonyl derived from N-hydroxysuccinimide-2-quinolinecarboxylate, i.e. L is hydroxysuccinimide. A solution of the free amine / or its salt with acetic acid / and approximately 1.0 equivalent of carboxylate are mixed in a suitable solvent system and sometimes treated (up to 5 equivalents) with a base such as N-methylmorpholine at room temperature. A suitable solvent system is tetrahydrofuran, methylene chloride or N, N-dimethylformamide, etc., including mixtures thereof.

может быть введено в дальнейшие стадии синтеза с образованием соединения формулы

и новую защитную группу P¹ избирательно удаляют. После снятия защиты образующийся амин реагирует с образованием производного сульфонамида, описанного выше. Это избирательное снятие защиты и дальнейшее превращение в сульфонамид можно выполнять либо в конце синтеза, либо на какой-либо промежуточной стадии, если желательно.Alternatively, the amino alcohol protected from breaking the epoxy bond can be protected further in place of the newly introduced amino group by the protecting group P ¹ , which is not removed when the first protecting group P is removed. Those skilled in the art can choose the appropriate combination of P and P ¹ . One such option is when P is Cbz and P ¹ is Boc. The resulting compound represented by the formula

can be introduced into further synthesis steps to form a compound of the formula

and the new protecting group P ^{1 is} selectively removed. After deprotection, the resulting amine reacts to form the sulfonamide derivative described above. This selective deprotection and further conversion to sulfonamide can be performed either at the end of the synthesis, or at some intermediate stage, if desired.

Instead of sulfonyl halides, sulfinyl halides / RSOCl / and sulfenyl halides / RSCl / can be used to prepare compounds in which a part of the -SO ₂ - molecule is replaced by -SO- or -S-, respectively.

It is assumed that to obtain compounds of formulas having R ⁶ , these compounds can be obtained after the above method and before the interaction of the sulfonamide derivative or its analogue, for example, interaction with the amino acid PNH (CH ₂ ) _t CH (R ¹ ) COOH, carried out according to the method known to specialists as reductive amination. Thus, sodium cyanoborohydride and a suitable aldehyde or ketone can be reacted with a sulfonamide derivative or its analog at room temperature to reductively aminate any of the compounds of formulas I-IV. It is also proposed that if R ^{3 of} an amino alcohol intermediate is hydrogen, the inhibitory compounds of this invention in which R ³ is alkyl or other substituents in which α-C contains at least one hydrogen can be obtained by reductive amination of the final product reactions between an amino alcohol and an amine or at any other stage of the synthesis to produce such compounds.

 The proposed equivalents of the basic formulas set forth above for antiviral compounds and derivatives, as well as intermediates, are compounds that otherwise correspond to them and have the same basic properties, for example, their tautomers, as well as compounds in which one or more of the R groups are simple variations of the substituents described above, for example, in which R is alkyl with more carbon atoms than the specified alkyl. In addition, if the substituent is hydrogen, then the exact chemical nature of the substituent other than hydrogen in this position, for example, a hydrocarbyl or halogen radical, a hydroxy group, an amino group and the like, is not critical until it does not adversely affect overall activity and / or / the synthesis procedure.

 The above chemical reactions are described, as a rule, in the form of their widest application in the preparation of compounds of this invention. Sometimes these reactions may not be applicable in this form for each compound within the described range of compounds. Specialists will easily understand for which compounds this may be. In all such cases, such reactions can be carried out using generally accepted modifications known to those skilled in the art, for example, using appropriate protection of interfering groups, changing reagents, conventionally modifying the reaction conditions, etc., or by applying other reactions described herein or conventional to obtain the corresponding compounds of this invention. In all preparative methods, all starting materials are known or can be easily obtained from known starting materials.

 Without further elaboration, those skilled in the art will be able, using the preceding description, to use this invention to its fullest extent. Therefore, the following separate preferred options should be understood only as illustrative, but not limiting the invention to any degree.

 All reagents were used without purification in the form in which they were obtained. All H-NMR and C-NMR spectra were obtained either on a Varian VXR-300 or on a VXR-400 nuclear magnetic resonance spectrometer.

 Examples 1-9 illustrate the preparation of intermediates. These intermediates are used to prepare the inhibitory compounds of this invention, illustrated in Examples 10-16. In addition, the intermediates of Examples 2-6 are also retroviral protease inhibitors and, in particular, inhibit HIV protease.

Получение N[3(S)-бензилоксикарбониламино-2(R)-гидрокси-4-фенилбутил] -N-изоамиламина
Часть A:
К раствору 75,0 г /0,226 моля/ N-бензилоксикарбонил-L-фенилаланинхлорметилкетона в смеси 807 мл метанола и 807 мл тетрагидрофурана при -2^oC добавляли 13,17 г /0,348 моля, 1,54 экв./ твердого боргидрида натрия в течение 100 минут. Растворители удаляли при пониженном давлении при 40^oC и остаток растворяли в этилацетате /приблизительно 1 л/. Раствор промывали последовательно 1 М кислым сульфатом натрия, насыщенным раствором бикарбоната натрия и насыщенным раствором хлорида натрия. После высушивания над безводным сульфатом магния и фильтрования раствор удаляли при пониженном давлении. К полученному маслу добавляли гексан /приблизительно 1 л/ и смесь нагревали до 60^oC при интенсивном перемешивании. После охлаждения до комнатной температуры твердый материал собирали и промывали 2 л гексана. Полученный твердый материал перекристаллизовывали из горячего этилацетата и гексана, получая 32,3 г /выход 43%/ N-бензилоксикарбонил-3(S)-амино-1-хлор-4-фенил-2-(S)-бутанола, т.пл. 150-151^oC и M+Li⁺ = 340.Example 1A

Preparation of N [3 (S) -benzyloxycarbonylamino-2 (R) -hydroxy-4-phenylbutyl] -N-isoamylamine
Part A:
To a solution of 75.0 g / 0.226 mol / N-benzyloxycarbonyl-L-phenylalanine chloromethylketone in a mixture of 807 ml of methanol and 807 ml of tetrahydrofuran was added at -2 ^° C. 13.17 g / 0.348 mol, 1.54 equiv / solid sodium borohydride in for 100 minutes. The solvents were removed under reduced pressure at 40 ^o C and the residue was dissolved in ethyl acetate / approximately 1 l /. The solution was washed sequentially with 1 M sodium hydrogen sulfate, saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate and filtering, the solution was removed under reduced pressure. Hexane (approximately 1 L) was added to the resulting oil, and the mixture was heated to 60 ^° C. with vigorous stirring. After cooling to room temperature, the solid material was collected and washed with 2 L of hexane. The resulting solid material was recrystallized from hot ethyl acetate and hexane to give 32.3 g / yield 43% / N-benzyloxycarbonyl-3 (S) -amino-1-chloro-4-phenyl-2- (S) -butanol, mp . 150-151 ^o C and M + Li ⁺ = 340.

Part B:
To a solution of 6.52 g / 0.116 mol, 1.2 eq / potassium hydroxide in 968 ml of absolute alcohol, 32.3 g / 0.097 mol / N-CBZ-3 (S) -amino-1-chloro- was added at room temperature 4-phenyl-2 (S) -butanol. After stirring for 15 minutes, the solvent was removed under reduced pressure and the solid material was dissolved in methylene chloride. After washing with water, drying over magnesium sulfate, filtering and evaporation, 27.9 g of a white solid were obtained. Recrystallization from hot ethyl acetate and hexane gave 22.3 g / yield of 77% / N-benzyloxycarbonyl-3 (S) -amino-1,2 (S) -epoxy-4-phenylbutane; mp. 102-103 ^o C and MH ⁺ 298.

Part C:
A solution of N-benzyloxycarbonyl-3 (S) -amino-1,2 (S) -epoxy-4-phenylbutane / 1.0 g, 3.36 mmol / and isoamylamine / 4.90 g, 67.2 mmol, 20 eq ./ in 10 ml of isopropanol was heated for reflux for 1.5 hours. The solution was cooled to room temperature, concentrated in vacuo, and then poured into 100 ml of stirred hexane, whereby the product crystallized from the solution. The product was isolated by filtration and dried in air, yielding 1.18 g, 95% N - [[3 (S) -phenylmethylcarbamoyl) amino-2 (R) -hydroxy-4-phenylbutyl] N - [(3-methylbutyl)] amine , mp 108.0-109.5 ^° C, MH ⁺ m / z = 371.

Получение N,N-дибензил-3(S)-амино-1,2-(S)-эпокси-4-фенилбутана
Стадия A:
Раствор L-фенилаланина /50,0 г, 0,302 моля/, гидроксида натрия /24,2 г, 0,605 моля/ и карбоната калия /83,6 г, 0,605 моля/ в воде /500 мл/ нагревали до 90^oC. Затем медленно добавляли бензилбромид /108,5 мл, 0,912 моля/ /время добавления приблизительно 25 минут/. Затем смесь перемешивали при 97^oC в течение 30 минут. Раствор охлаждали до комнатной температуры и экстрагировали толуолом /2 х 250 мл/. Объединенные органические слои промывали водой, солевым раствором, сушили над сульфатом магния, фильтровали и концентрировали, получая масляный продукт. Этот неочищенный продукт использовали в следующей стадии без очистки.Example 1B

Preparation of N, N-Dibenzyl-3 (S) -amino-1,2- (S) -epoxy-4-phenylbutane
Stage A:
A solution of L-phenylalanine / 50.0 g, 0.302 mol /, sodium hydroxide / 24.2 g, 0.605 mol / and potassium carbonate / 83.6 g, 0.605 mol / in water / 500 ml / was heated to 90 ^o C. Then benzyl bromide (108.5 ml, 0.912 mol) was added slowly / (the addition time was approximately 25 minutes). The mixture was then stirred at 97 ^° C. for 30 minutes. The solution was cooled to room temperature and was extracted with toluene / 2 x 250 ml /. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give an oil product. This crude product was used in the next step without purification.

Stage B:
The crude benzylated product of the previous step was dissolved in toluene / 750 ml / and cooled to -55 ^o C. a 1.5 M solution of DIBAL-H in toluene / 443.9 ml, 0.666 mol / was added at a speed allowing to maintain the temperature between -55 ^o and -50 ^o C / time of addition - 1 hour /. The mixture was stirred for 20 minutes at -55 ^° C. The reaction was stopped at -55 ^° C by slow addition of methanol / 37 ml /. Then the cold solution was poured into a cold solution / 5 ^o C / 1.5 N HCl / 1.8 l /. Precipitated solid / approx. 138 g / was filtered and washed with toluene. The solid material was suspended in a mixture of toluene / 400 ml / and water / 100 ml /. The mixture was cooled to 5 ^° C., treated with 2.5 N NaOH / 186 ml /, and then stirred at room temperature until the solid material dissolved. The toluene layer was separated from the aqueous phase and washed with water and brine, dried over magnesium sulfate, filtered and concentrated to a volume of 75 ml / 89 g /. Then, ethyl acetate / 25 ml / and hexane / 25 ml / were added to the residue, after which the alcohol product began to crystallize. After 30 minutes, an additional 50 ml of hexane was added to accelerate further crystallization. The solid was filtered and washed with 50 ml of hexane, obtaining approximately 35 g of material. The second part of the material could be isolated by re-filtering the mother liquor. The solids were combined and recrystallized from ethyl acetate / 20 ml / and hexane / 30 ml /, giving a total of two parts, approximately 40 g / 40% of L-phenylalanine / analytically pure alcohol product. The mother liquors were combined and concentrated (34 g). The residue was treated with ethyl acetate and hexane, which gave an additional 7 g / yield of approx. 7% / slightly contaminated solid. Further optimization of product recovery from the mother liquor is possible.

Alternatively, alcohol was obtained from L-phenylalaninol. L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution of potassium carbonate / 484.6 g, 3.506 mol / in 710 ml of water. The mixture was heated to 65 ^° C. under nitrogen. A solution of benzyl bromide / 400 g, 2,339 mol / in 3A ethanol / 305 ml / was added at a speed allowing to maintain the temperature between 60 ^o and 68 ^o C. The two-phase solution was stirred at 65 ^o C for 55 minutes and then cooled to 10 ^o C at vigorous stirring. The oily product was cured to small granules. The product was diluted with 2.0 L of tap water and stirred for 5 minutes to dissolve the inorganic by-products. The product was isolated by filtration under reduced pressure and washed with water to pH 7. The resulting crude product was dried in air overnight to obtain a semi-solid solid / 407 g /, which was recrystallized from 1.1 L of a mixture of ethyl acetate / heptane / 1: 10 by volume / . The product was isolated by filtration (at -8 ^° C), washed with 1.6 L of cold / -10 ^° C / ethyl acetate / heptane / 1: 10 by volume / mixture and dried in air, obtaining 339 g / 88% yield / β S- 2- [bis (phenylmethyl) amino] benzenepropanol; mp. 71.5-73.0 ^o C. If necessary, you can get an additional product from the mother liquor. Other analytical properties were identical to those of the compound obtained as described above.

Stage C:
A solution of oxalyl chloride / 8.4 ml, 0.095 mol / in dichloromethane / 240 ml / was cooled to -74 ^o C. Then a solution of DMSO / 12.0 ml, 0.155 mol / in dichloromethane / 50 ml / was slowly added at a speed allowing to maintain the temperature at -74 ^o C / addition time - approx. 1.25 hours. The mixture was stirred for 5 minutes and a solution of alcohol / 0.074 mol / in 100 ml of dichloromethane was added / the addition time was 20 minutes, the temperature was -75 ... -68 ^o C /. The solution was stirred at -78 ^° C for 35 minutes. Then triethylamine (41.2 ml, 0.295 mol) was added over 10 minutes / temperature -78 ... -68 ^o C /, after which the ammonium salt precipitated. The cold mixture was stirred for 30 minutes and then water (225 ml) was added. The dichloromethane layer was separated from the aqueous phase and washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The residue was diluted with ethyl acetate and hexane and then filtered to further remove the ammonium salt. The filtrate was concentrated to obtain the desired aldehyde product. Aldehyde was used in the next step without purification.

Temperatures higher than -70 ^° C have been reported in the literature for oxidation by Swern. Other Swern modifications and Swern oxidation alternatives are also possible.

Alternative aldehyde was prepared as follows. (200 g, 0.604 mol) was dissolved in triethylamine (300 ml, 2.15 mol). The mixture was cooled to 12 ^o C and a solution of a complex of sulfur trioxide / pyridine / 380 g, 2.39 mol / in DMSO / 1.6 l / was added at a speed allowing to maintain the temperature between 8 ^o and 17 ^o C / time of addition - 1, 0 h / The solution was stirred at ambient temperature under nitrogen for 1.5 hours, after which the reaction was completed by TLC analysis / 33% ethyl acetate / hexane, silica gel /. The reaction mixture was cooled with chilled ice, water and maturities of 1.6 l of cold water / 10-15 ^o C / after 45 minutes. The resulting solution was extracted with ethyl acetate / 2.0 L /, washed with 5% citric acid / 2.0 L / brine / 2.2 L /, dried over MgSO _4/280 g / and filtered. The solvent was removed on a rotary evaporator at 35-40 ^o C and then dried under vacuum, obtaining 198.8 g of α S- [bis- (phenylmethyl) amino] benzenepropanaldehyde as a pale yellow oil / 99.9% /. The resulting crude product was pure enough to be used immediately in the next step without further purification. The analytical data for this compound are consistent with those published in the literature. [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = -92.9 ^o / s 1.87, CH ₂ Cl ₂ /; ¹ H-NMR / 400 MHz, CDCl ₃ / δ, 2.94 and 3.15 (ABX-System, 2H, J _AB = 13.9 Hz, J _AX = 7.3 Hz and J _BX = 6.2 Hz ), 3.56 (t, 1H, 7.1 Hz), 3.69 and 3.82 (AB-System, 4H, J _AB = 13.7 Hz), 7.25 (m, 15H) and 9, 72 (s, 1H); HRMS calculated for / M + 1 / C ₂₃ H ₂₄ NO 330.450, found: 330.1836. Anal calculated for C ₂₃ H ₂₃ ON: C 83.86; H 7.04; N, 4.25. Found: C, 83.64; H 7.42; N, 4.19. HPLC on a chiral stationary phase: / S, S / Pirkle-Whelk-01 column / 250 x 4.6 mm 1.D /, mobile phase: hexane / isopropanol (99.5: 0.5, v / v) , flow rate: 1.5 ml / min, detection by UV detector at 210 nm. Retention time of the target S-isomer: 8.75 min; retention time of the R-enantiomer 10.62 min.

Stage D:
A solution of α S- [bis (phenylmethyl) amino] benzenepropanaldehyde / 191.7 g, 0.58 mol / and chloroiodomethane / 56.4 ml, 0.77 mol / in tetrahydrofuran / 1.8 L / was cooled to -30 .. . -35 ^o C / a lower temperature, such as -70 ^o C, also worked well, but higher temperatures are easier to obtain in large-scale operations / in a stainless steel reactor in a nitrogen atmosphere. Then, a solution of n-butyllithium in hexane (1.6 M, 365 ml, 0.58 mol) was added at a speed allowing the temperature to be kept below -25 ^o C. After addition, the mixture was stirred at -30 ... -35 ^o C for 10 minutes . The following additions of reagents were performed as follows:
(1) Chlorodiodomethane (17 ml) was additionally added, followed by the addition of n-butyllithium / 110 ml / at a temperature below -25 ^o C. After addition, the mixture was stirred at -30 ... -35 ^o C for 10 minutes. This was repeated once.

(2) Chloriodiodomethane (8.5 ml, 0.11 mol) was added, followed by n-butyllithium (55 ml, 0.088 mol) at a temperature below -25 ^o C. After the addition, the mixture was stirred at -30 ... -35 ^o C 10 minutes. This was repeated 5 times.

(3) Chlorodiodomethane (8.5 ml, 0.11 mol) was added, followed by n-butyllithium (37 ml, 0.059 mol) at a temperature below -25 ^o C. After addition, the mixture was stirred at -30 ... -35 ^o C 10 minutes. This was repeated once. External cooling was stopped and the mixture was heated to ambient temperature for 4-16 hours when TLC analysis (silica gel, 20% ethyl acetate / hexane) showed that the reaction was complete. The reaction mixture was cooled to 10 ^° C. and the reaction was quenched with 1452 g of a 16% solution of ammonium chloride (obtained by dissolving 232 g of ammonium chloride in 1220 ml of water), keeping the temperature below 23 ^° C. The mixture was stirred for 10 minutes and the organic and aqueous layers were separated. The aqueous phase was extracted with ethyl acetate / 2 x 500 ml /. The ethyl acetate layer was combined with the tetrahydrofuran layer. The combined solution was dried over magnesium sulfate / 220 g /, filtered and concentrated on a rotary evaporator at 65 ^° C. The brown oil residue was dried at 70 ^° C in vacuo / 0.8 bar / for 1 h, yielding 222.8 g of crude material . / The weight of the crude product was more than 100%. Due to the relative instability of the product on silica gel, the product was usually used in the next step without purification. The ratio of the diastereomers of the crude mixture was determined using proton NMR: (2S) / (2R): 86:14. The minor and major epoxy diastereomers were characterized in this mixture by TLC analysis (silica gel, 10% ethyl acetate / hexane), R _f = 0.29 and 0.32, respectively. An analytical sample of each of the diastereomers was obtained by purification on TLC silica gel (3% ethyl acetate / hexane) and was characterized as follows:
N, N α S-Tris (phenylmethyl) -2S-hydroxyranmethanamine
¹ H-NMR / 400 MHz, CDCl ₃ / δ 2.49 (AB-System, 1H, J _AB = 2.82), 2.76 and 2.77 (AB-System, 1H, J _AB = 4.03 Hz), 2.83 (m, 2H), 2.99 and 3.03 (AB-System, 1H, J _AB = 10.1 Hz), 3.15 (m, 1H), 3.73 and 3, 84 (AB-System, 4H, J _AB = 14.00 Hz), 7.21 (m, 15H); ¹³ C-NMR (400 MHz, CDCl ₃ ) δ 139.55, 129.45, 128.42, 128.14, 129.09, 126.94, 125.97, 60.32, 54.23, 52, 13, 45.99, 33.76; HRMS calculated for C ₂₄ H ₂₆ NO / M + 1 / 344,477, found 344,2003.

N, N, α S-Tris (phenylmethyl) -2R-hydroxyranmethanamine
¹ H-NMR / 300 MHz, CDCl ₃ / δ 2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m, 2H), 2.97 (m, 1H), 3, 14 (m, 1H); 3.85 (AB-System, 4H); 7.25 (m, 15H). HPLC on a chiral stationary phase: Pirkle-Whelk-01 Column / 250 x 4.6 mm 1.D./, mobile phase: hexane / isopropanol (99.5: 0.5, v / v), flow rate: 1.5 ml / min, detection by UV detector at 210 nm. Retention time / 8 / 9.38 min, retention time of the enantiomer / 4 /: 13.75 min.

Alternatively, a solution of the crude aldehyde of 0.074 mol and chloroiodomethane / 7.0 ml, 0.096 mol / in tetrahydrofuran / 285 ml / was cooled to -78 ^o C in a nitrogen atmosphere. A 1.6 M solution of n-butyllithium in hexane / 25 ml, 0.040 mol / was then added at a speed allowing to maintain the temperature at -75 ^o C / time of addition - 15 minutes /. After the first addition, additional chloroiodomethane (1.6 ml, 0.022 mol) was added followed by n-butyllithium (23 ml, 0.037 mol), while maintaining the temperature at -75 ^° C. The mixture was stirred for 15 minutes. Each of the reagents, chloroiodomethane / 0.70 ml, 0.010 mol / and n-butyllithium / 5 ml, 0.008 mol / was added 4 more times during 45 minutes at -75 ^o C. The cooling bath was then removed and the solution was heated to 22 ^o C within 1.5 hours. The mixture was poured into 300 ml of a saturated solution of ammonium chloride in water. The tetrahydrofuran layer was separated. The aqueous phase was extracted with ethyl acetate / 1 x 300 ml /. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a brown oil / 27.4 g /. The product could be used in the next step without purification. The desired diastereoisomer could be purified by recrystallization in a subsequent step. The product could also be purified by chromatography.

Alternatively, a solution of α S- [Bis (phenylmethyl) amino] benzenepropanaldehyde / 178.84 g, 0.54 mol / and bromochloromethane / 46 ml, 0.71 mol / in tetrahydrofuran / 1.8 L / was cooled to -30 .. . -35 ^o C / a lower temperature, such as -70 ^o C, also worked well, but higher temperatures are easier to obtain in large-scale operations / in a stainless steel reactor in a nitrogen atmosphere. Then, a solution of n-butyllithium in hexane (1.6 M, 340 ml, 0.54 mol) was added at a speed allowing the temperature to be kept below -25 ^o C. After addition, the mixture was stirred at -30 ... -35 ^o C for 10 minutes . Further additions of reagents were performed as follows:
(1) bromochloromethane (14 ml) was additionally added, followed by n-butyllithium / 102 ml / at a temperature below -25 ^o C. After the addition, the mixture was stirred at -30 ... -35 ^o C for 10 minutes. This was repeated 1 time.

/ 2 / Additionally bromochloromethane / 7 ml, 0.11 mol / was added followed by n-butyllithium / 51 ml, 0.082 mol / at a temperature below -25 ^o C. After addition, the mixture was stirred at -30 ... -35 ^o C 10 minutes. This was repeated 5 times.

/ 3 / Additionally bromochloromethane / 7 ml, 0.11 mol / was added followed by n-butyllithium / 51 ml, 0.082 mol / at a temperature below -25 ^o C. After addition, the mixture was stirred at -30 ... -35 ^o C 10 minutes. This was repeated 1 time. External cooling was stopped and the mixture was heated to ambient temperature for 4-16 hours when TLC analysis (silica gel, 20% ethyl acetate / hexane) showed that the reaction was complete. The reaction mixture was cooled to 10 ^° C. and the reaction was stopped with 1452 g of a 16% solution of ammonium chloride (obtained by dissolving 232 g of ammonium chloride in 1220 ml of water), keeping the temperature below 23 ^° C. The mixture was stirred for 10 minutes and the organic and aqueous phases were separated. The aqueous phase was extracted with ethyl acetate / 2 x 1500 ml /. The ethyl acetate layer was combined with the tetrahydrofuran layer. The combined solution was dried over magnesium sulfate / 220 g /, filtered and concentrated on a rotary evaporator at 65 ^° C. The brown oil residue was dried at 70 ^° C in vacuum / 0.8 bar / for 1 hour to obtain 222.8 g of crude material .

Получение N-[[3-(фенилметилкарбамоил)амино] -2R-гидрокси-4- фенил]-1-[(2-метилпропил)амино-2-(1,1-диметилэтоксил)карбонил]бутана
К раствору 7,51 г /20,3 ммоля/ N-[[3S-(фенилметилкарбамоил)амино]-2R- гидрокси-4-фенилбутил] -N-(2-метилпропил)] амина в 67 мл безводного тетрагидрофурана добавляли 2,25 г /22,3 ммоля/ триэтиламина. После охлаждения до 0^oC добавляли 4,4 г /20,3 ммоля/ ди-трет-бутилкарбоната и перемешивание продолжали при комнатной температуре в течение 21 часа. Летучие соединения удаляли в вакууме, добавляли этилацетат, затем промывали 5% лимонной кислотой, насыщенным раствором бикарбоната натрия, солевым раствором, сушили над сульфатом магния, фильтровали и концентрировали, получая 9,6 г неочищенного продукта. Хроматографирование на силикагеле с применением смеси 30% этилацетат/гексан дало 8,2 г чистого N-[[3S-фенилметилкарбамоил)амино]-2R-гидрокси-4-фенил]-1-[(2- метилпропил)амино-2-(1,1-диметилэтоксил)карбонил]бутана, масс-спектр m/e = 477 /M+Li/.Example 2

Preparation of N - [[3- (phenylmethylcarbamoyl) amino] -2R-hydroxy-4-phenyl] -1 - [(2-methylpropyl) amino-2- (1,1-dimethylethoxy) carbonyl] butane
To a solution of 7.51 g / 20.3 mmol / N - [[3S- (phenylmethylcarbamoyl) amino] -2R-hydroxy-4-phenylbutyl] -N- (2-methylpropyl)] amine in 67 ml of anhydrous tetrahydrofuran was added 2, 25 g / 22.3 mmol / triethylamine. After cooling to 0 ^° C., 4.4 g / 20.3 mmol / di-tert-butyl carbonate was added and stirring was continued at room temperature for 21 hours. Volatile compounds were removed in vacuo, ethyl acetate was added, then washed with 5% citric acid, saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated to obtain 9.6 g of a crude product. Chromatography on silica gel using 30% ethyl acetate / hexane gave 8.2 g of pure N - [[3S-phenylmethylcarbamoyl) amino] -2R-hydroxy-4-phenyl] -1 - [(2-methylpropyl) amino-2- ( 1,1-dimethylethoxyl) carbonyl] butane, mass spectrum m / e = 477 / M + Li /.

Получение фенилметил[2R-гидрокси-3-[(3-метилбутил)метилсульфонил) амино] -1S-(фенилметил)пропил]карбамата
К раствору N[3(S)-бензилоксикарбониламинно-2(R)-гидрокси-4- фенилбутил] -N-изоамиламина /2,0 г, 5,2 ммоля/ и триэтиламина /723 мкл, 5,5 ммоля/ в дихлорметане /20 мл/ добавляли по каплям метансульфониллхлорид /метансульфохлорид/ /400 мкл, 5,2 ммоля/. Реакционную смесь перемешивали 2 часа при комнатной температуре, затем раствор дихлорметана концентрировали прибл. до 5 мл и вносили в колонку с силикагелем /100 г/. Эту колонку элюировали хлороформом, содержащим 1% этанол и 1% метанол. Фенилметил[2R-гидрокси-3-[(3-метилбутил)(метилсульфонил)амино] - 1S-(фенилметил)пропил]карбамат получали в виде белого твердого вещества. Анал. рассчит. для C₂₄H₃₄N₂O₅S: C 62,31; H 7,41; N 6,06. Найдено: C 62,17; H 7,55; N 5,97.Example 3A

Preparation of Phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) methylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate
To a solution of N [3 (S) -benzyloxycarbonylamino-2 (R) -hydroxy-4-phenylbutyl] -N-isoamylamine / 2.0 g, 5.2 mmol / and triethylamine / 723 μl, 5.5 mmol / in dichloromethane (20 ml) was added dropwise methanesulfonyl chloride / methanesulfonyl chloride / / 400 μl, 5.2 mmol /. The reaction mixture was stirred for 2 hours at room temperature, then the dichloromethane solution was concentrated to approx. up to 5 ml and introduced into a column of silica gel / 100 g /. This column was eluted with chloroform containing 1% ethanol and 1% methanol. Phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (methylsulfonyl) amino] - 1S- (phenylmethyl) propyl] carbamate was obtained as a white solid. Anal calculated for C ₂₄ H ₃₄ N ₂ O ₅ S: C 62.31; H 7.41; N, 6.06. Found: C, 62.17; H 7.55; N, 5.97.

Получение фенилметил[2R-гидрокси-3-[(3-метилбутил)(фенилсульфонил) амино]-1S-(фенилметил)пропил]карбамата
Реакцией N[3(S)-бензилоксикарбониламино-2(R)-гидрокси-4- фенилбутил]-N-изоамиламина /1,47 г, 3,8 ммоля/, триэтиламина /528 мкл, 3,8 ммоля/ и бензолсульфохлорида /483 мкл, 3,8 ммоля/ получают фенилметил[2R-гидрокси-3-[(3-метилбутил)фенилсульфонил)амино]- 1S-(фенилметил)пропил]-карбамат. Колоночная хроматография на силикагеле с элюированием хлороформом, содержащим 1% этанол, дала чистый продукт. Анал. рассчит. для C₂₉H₃₆N₂O₅: C 66,39; H 6,92; N 5,34. Найдено: C 66,37; H 6,93; N 5,26.Example 3B

Preparation of Phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate
The reaction of N [3 (S) -benzyloxycarbonylamino-2 (R) -hydroxy-4-phenylbutyl] -N-isoamylamine / 1.47 g, 3.8 mmol /, triethylamine / 528 μl, 3.8 mmol / and benzenesulfonyl chloride / 483 μl, 3.8 mmol / give phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) phenylsulfonyl) amino] - 1S- (phenylmethyl) propyl] carbamate. Silica gel column chromatography eluting with chloroform containing 1% ethanol gave the pure product. Anal calculated for C ₂₉ H ₃₆ N ₂ O ₅ : C 66.39; H 6.92; N, 5.34. Found: C, 66.37; H 6.93; N, 5.26.

Получение фенилметил[2R-гидрокси-3-/(3-метилбутил)(н-пропансульфонил) амино]-1S-(фенилметил)пропил/карбамата
К раствору N[3(S)-бензилоксикарбониламино-2(R)-гидрокси-4- фенилбутил] -N-изоамиламина /192 мг, 0,5 ммоля/ и триэтиламина /139 мкл, 1,0 ммоль/ в дихлорметане /10 мл/ добавляли по каплям триметилсилилхлорид /63 мкл, 0,5 ммоля/. Смесь перемешивали в течение 1 часа при комнатной температуре, охлаждали до 0^oC на бане со льдом и затем добавляли каплями н-пропансульфохлорид /56 мкл, 0,5 ммоля/. Реакционную смесь перемешивали в течение 1,5 часов при комнатной температуре, затем разбавляли этилацетатом /50 мл/ и промывали последовательно 1 N HCl, водой, насыщенным раствором бикарбоната натрия и насыщенным раствором хлорида натрия /по 25 мл каждого/. Органический раствор сушили над сульфатом магния, фильтровали и концентрировали до масла. Масло перемешивали с метанолом /10 мл/ в течение 16 часов, концентрировали и остаток хроматографировали на силикагеле /50 г/, элюируя колонку 10% этилацетатом с гексаном. Фенилметил[2R-гидрокси-3-[(3-метилбутил)-(н-пропансульфонил)амино] - 1S-(фенилметил)пропил] карбамат перекристаллизовывали из смеси этиловый эфир/гексан, получая белое твердое вещество. Аналит. рассчитано: для C₂₆H₃₈N₂O₅S: C 63,64; H 7,81; N 5,71. Найдено: C 63,09; H 7,74; N 5,64.Example 4

Preparation of Phenylmethyl [2R-hydroxy-3 - / (3-methylbutyl) (n-propanesulfonyl) amino] -1S- (phenylmethyl) propyl / carbamate
To a solution of N [3 (S) -benzyloxycarbonylamino-2 (R) -hydroxy-4-phenylbutyl] -N-isoamylamine / 192 mg, 0.5 mmol / and triethylamine / 139 μl, 1.0 mmol / in dichloromethane / 10 ml / trimethylsilyl chloride (63 μl, 0.5 mmol) was added dropwise. The mixture was stirred for 1 hour at room temperature, cooled to 0 ^° C. in an ice bath, and then n-propanesulfonyl chloride (56 μl, 0.5 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hours at room temperature, then diluted with ethyl acetate / 50 ml / and washed successively with 1 N HCl, water, saturated sodium bicarbonate solution and saturated sodium chloride solution (25 ml each). The organic solution was dried over magnesium sulfate, filtered and concentrated to an oil. The oil was stirred with methanol / 10 ml / for 16 hours, concentrated and the residue was chromatographed on silica gel / 50 g /, eluting with a column of 10% ethyl acetate and hexane. Phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) - (n-propanesulfonyl) amino] - 1S- (phenylmethyl) propyl] carbamate was recrystallized from ethyl ether / hexane to give a white solid. Analit. calculated: for C ₂₆ H ₃₈ N ₂ O ₅ S: C 63.64; H 7.81; N, 5.71. Found: C, 63.09; H 7.74; N, 5.64.

Способ, описанный в примере 2, применяли для получения фенилметил[2S-гидрокси-3-[(3-метилбутил)метилсульфонил)амино] - 1S-(фенилметил)пропил] карбамата.Example 5

The method described in Example 2 was used to prepare phenylmethyl [2S-hydroxy-3 - [(3-methylbutyl) methylsulfonyl) amino] - 1S- (phenylmethyl) propyl] carbamate.

To a solution of N [3 (S) -benzyloxycarbonylamino-2 (S) -hydroxy-4-phenylbutyl] -N-isoamylamine / 192 mg, 0.5 mmol / and triethylamine / 139 μl, 0.55 mmol / in dichloromethane / 8 ml / methanesulfonyl chloride (39 μl, 0.55 mmol) was added dropwise. The reaction mixture was stirred for 16 hours at room temperature, then the dichloromethane solution was introduced into a column of silica gel / 50 g /. The column was eluted with dichloromethane containing 2.5% methanol. Phenylmethyl [2S-hydroxy-3 - [(3-methylbutyl) - (methylsulfonyl) amino] - 1S- (phenylmethyl) propyl] carbamate was obtained as a white solid. Analit. calculated for C ₂₄ H ₃₄ N ₂ O ₅ S • 0.2H ₂ O: C 61.83; H 7.44; N, 6.01. Found: C, 61.62; H 7.40; N, 5.99.

Example 6
According to the methods of the preceding examples 1-5, the intermediates shown in tables 1A and 1B were obtained.

 The following examples 7-9 illustrate the preparation of intermediates of β-amino acids. These intermediates can interact with intermediates of Examples 1-6 to form β-amino acid inhibitor compounds of the present invention.

5-литровую трехгорлую круглодонную колбу, снабженную капельной воронкой с постоянным давлением, обратным холодильником, входным отверстием для азота и механической мешалкой, загружали итаконовым ангидридом /660,8 г, 5,88 моля/ и толуолом /2300 мл/. Раствор нагревали с обратным холодильником и обрабатывали 4-метоксибензиловым спиртом /812,4 г, 5,88 моля/, добавляемым по каплям в течение 2,6 часов. Этот раствор кипятили с обратным холодильником еще 1,5 часа и затем содержимое колбы выливали в три 2-литровые колбы Эрленмейера для кристаллизации. Раствору давали остыть до комнатной температуры, после чего происходила кристаллизация целевого мономера. Продукт выделяли фильтрованием на воронке Бюхнера и сушили на воздухе, получая 850,2 г, 58% материала с т.пл. 83-85^oC. Второй сбор, 17%, был выделен после охлаждения фильтрата в бане со льдом. ¹H-ЯМР /CDCl₃/ 300 МГц, 7,32 (д, J = 8,7 Гц, 2H), 6,91 (д, J = 8,7 Гц, 2H), 6,49 (с, 1H), 5,85 (с, 1H), 5,12 (с, 2H), 3,83 (с, 3H), 3,40 (с, 2H).Example 7
A. Preparation of 4- (4-methoxybenzyl)) itaconate

A 5-liter three-necked round-bottom flask equipped with a dropping funnel with constant pressure, a reflux condenser, a nitrogen inlet and a mechanical stirrer was charged with itaconic anhydride / 660.8 g, 5.88 mol / and toluene / 2300 ml /. The solution was heated under reflux and treated with 4-methoxybenzyl alcohol / 812.4 g, 5.88 mol /, added dropwise over 2.6 hours. This solution was refluxed for another 1.5 hours and then the contents of the flask were poured into three 2 liter Erlenmeyer flasks for crystallization. The solution was allowed to cool to room temperature, after which crystallization of the target monomer took place. The product was isolated by filtration on a Buchner funnel and dried in air, obtaining 850.2 g, 58% of the material with so pl. 83-85 ^o C. The second collection, 17%, was isolated after cooling the filtrate in an ice bath. ¹ H-NMR / CDCl _3/300 MHz 7.32 (d, J = 8,7 Hz, 2H), 6,91 (d, J = 8,7 Hz, 2H), 6,49 (c, 1H ), 5.85 (s, 1H), 5.12 (s, 2H), 3.83 (s, 3H), 3.40 (s, 2H).

5-литровую круглодонную трехгорлую колбу, снабженную обратным холодильником, входным отверстием для азота, капельной воронкой с постоянным давлением и механической мешалкой, загружали 4(4-метоксибензил)итаконатом /453,4 г, 1,81 моля/ и обрабатывали 1,5-диазобицикло[4.3.0]нон-5-еном /275,6 г, 1,81 моля/, /DBN/ добавляемым по каплям так, чтобы температура не повышалась выше 15^oC. К этой перемешиваемой смеси добавляли раствор метилйодида /256,9 г, 1,81 моля/ в 250 мл толуола из капельной воронки в течение 45 минут. Раствору давали нагреться до комнатной температуры и перемешивали дополнительно 3,25 часа.B. Preparation of methyl 4 (4-methoxybenzyl) itaconate

A 5-liter round-bottomed three-necked flask equipped with a reflux condenser, a nitrogen inlet, a constant pressure drop funnel and a mechanical stirrer was charged with 4 (4-methoxybenzyl) itaconate (453.4 g, 1.81 mol) and treated with 1.5- diazobicyclo [4.3.0] non-5-ene / 275.6 g, 1.81 mol /, / DBN / added dropwise so that the temperature does not rise above 15 ^o C. To this stirred mixture was added a solution of methyl iodide / 256, 9 g, 1.81 mol / in 250 ml of toluene from a dropping funnel for 45 minutes. The solution was allowed to warm to room temperature and was stirred for an additional 3.25 hours.

The precipitated DBN hydroiodide was removed by filtration, washed with toluene and the filtrate was poured into a separatory funnel. The solution was washed with saturated aqueous NaHCO _3/2 x 500 mL /, 0,2 N HCl / 1 x 500 ml / brine / 2 x 500 mL /, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. This gave a clear, colorless oil, 450.2 g, 94%, the NMR of which corresponded to the proposed structure. ¹ H-NMR / CDCl _3/300 MHz 7.30 (d, J = 8,7 Hz, 2H), 6,90 (d, J = 8,7 Hz, 2H), 6,34 (c, 1H) 5.71 (s, 1H), 5.09 (s, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 3.38 (s, 2H), ¹³ C-NMR / CDCl ₃ / 170.46, 166.47, 159.51, 133.55, 129.97, 128.45, 127.72, 113.77, 66.36, 55.12, 51.94, 37, 64.

500-миллилитровую склянку Фишера-Портера загружали метил-4(4-метоксибензил)итаконатом /71,1 г, 0,269 моля/, катализатором родий (R,R) DiPAMP /204 кг, 0,269 ммоля, 0,1 мол.%/ и дегазированным метанолом /215 мл/. Через склянку пропускали 5 раз азот и 5 раз водород до конечного давления 40 Psig. Гидрогенизация начиналась сразу же и приблизительно через 1 час поглощение начинало уменьшаться, после 3 часов поглощение водорода прекращалось, колбу продували азотом, открывали и содержимое склянки концентрировали на роторном испарителе, получая коричневое масло, которое поглощалось в кипящем изооктане /прибл. 200 мл, это повторяли дважды/, раствор фильтровали через слой целита /броунмиллерита/ и фильтрат концентрировали в вакууме, получая 66,6 г, 93% прозрачного бесцветного масла. ¹H-ЯМР /CDCl₃/ 300 МГц 7,30 (д, J = 8,7 Гц, 2H), 6,91 (д, J = 8,7 Гц, 2H), 5,08 (с, 2H), 3,82 (с, 3H), 3,67 (с, 3H), 2,95 (ддк, J = 5,7, 7,5, 8,7 Гц, 1H), 2,79 (дд, J = 8,1, 16,5 Гц, 1H), 2,45 (дд, J = 5,7, 16,5 Гц, 1H), 1,23 (д, J = 7,5 Гц, 3H).C. Preparation of methyl 4 (4-methoxybenzyl) -2 (R) methyl succinate

A 500 ml Fischer-Porter flask was charged with methyl 4 (4-methoxybenzyl) itaconate (71.1 g, 0.269 mol), a rhodium (R, R) DiPAMP catalyst / 204 kg, 0.269 mmol, 0.1 mol% / and degassed methanol / 215 ml /. Nitrogen and 5 times hydrogen were passed through the flask to a final pressure of 40 Psig. Hydrogenation started immediately and after about 1 hour, absorption began to decrease, after 3 hours, hydrogen uptake stopped, the flask was purged with nitrogen, it was opened and the contents of the flask were concentrated on a rotary evaporator to obtain a brown oil, which was absorbed in boiling isooctane / approx. 200 ml, this was repeated twice /, the solution was filtered through a layer of celite / brownmillerite / and the filtrate was concentrated in vacuo to obtain 66.6 g, 93% clear colorless oil. ¹ H-NMR / CDCl _3/300 MHz 7.30 (d, J = 8,7 Hz, 2H), 6,91 (d, J = 8,7 Hz, 2H), 5,08 (c, 2H) 3.82 (s, 3H), 3.67 (s, 3H), 2.95 (ddc, J = 5.7, 7.5, 8.7 Hz, 1H), 2.79 (dd, J = 8.1, 16.5 Hz, 1H), 2.45 (dd, J = 5.7, 16.5 Hz, 1H), 1.23 (d, J = 7.5 Hz, 3H).

D. Preparation of methyl 2 (R) methyl succinate
A 3-liter, three-necked round-bottom flask equipped with a nitrogen inlet, a mechanical stirrer, a reflux condenser and a dropping funnel with constant pressure was charged with methyl 4 (4-methoxybenzyl) - (2R) methyl succinate / 432.6 g, 1.65 mol / and toluene / 1200 ml /. The solution was treated with trifluoroacetic acid (600 ml) from a dropping funnel for 0.25 hours with stirring. The solution turned dark purple and the internal temperature rose to 45 ^° C. After stirring for 2.25 hours, the temperature was 27 ^° C. and the solution turned pink. The solution was concentrated on a rotary evaporator. The residue was diluted with water / 2200 ml / and saturated aqueous NaHCO _3/1000 ml /. An additional amount of NaHCO _{3 was} added until the acid was neutralized. The aqueous phase was extracted with ethyl acetate / 2 x 1000 ml / to remove by-products and the aqueous layer was acidified to pH = 1.8 with concentrated HCl. This solution was extracted with ethyl acetate / 4 x 1000 ml /, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator, obtaining a colorless liquid / 251 g /, more than 100%, which was distilled in vacuum through a device with a short liquid path , fraction 1: bath temperature 120 ^o C, @ more than 1 mm, t. 25-29 ^o C; fraction 2: bath temperature 140 ^o C, @ 0.5 mm, so Kip. 95-108 ^o C, 151 g, [α] _d @ 25 ^o C = +1.38 ^o C / c = 15.475, MeOH /, [α] _d = 8.48 ^o C / ne /; fraction 3: bath temperature 140 ^o C, so Kip. 108 ^o C, 36 g, [α] _d @ 25 ^o C = 11.49 ^o C / c = 15.00, MeOH /, [α] _d = +8.98 ^o C / pure /. Fractions 2 and 3 were combined to give 189 g, 78% of the product. ¹ H-NMR / CDCl _3/300 MHz 11.6 (br. A, 1H), 3,72 (c, 3H), 2,92 (MCM, J = 8.7, 6.9, 8.0 Hz , 1H), 2.81 (dd, J = 8.0, 16.8 Hz, 1H), 2.47 (dd, J = 5.7, 16.8 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H).

50-миллилитровую круглодонную колбу, снабженную обратным холодильником, входным отверстием для азота и магнитной мешалкой загружали метил-4-(4-метоксибензил)итаконатом /4,00 г, 16 ммолей/, 12 мл толуола и 6 мл трифторуксусной кислоты. Раствор выдерживали при комнатной температуре 18 часов и затем летучие вещества удаляли в вакууме. Остаток разбавляли этилацетатом и экстрагировали три раза насыщенным водным раствором бикарбоната натрия. Объединенный водный экстракт подкисляли до pH 1 водным бисульфатом калия и затем экстрагировали три раза этилацетатом. Объединенный раствор в этилацетате промывали насыщенным водным раствором хлорида натрия, сушили над безводным сульфатом магния, фильтровали и концентрировали в вакууме. Остаток подвергали вакуумной перегонке, получая 1,23 г, 75% чистого продукта, т.кип. 85-87^oC, @ 0,1 мм. ¹H-ЯМР /CDCl₃/ 300 МГц 6,34 (с, 1H), 5,73 (с, 2H), 3,76 (с, 3H), 3,38 (с, 2H), ¹³C-ЯМР /CDCl₃/ 177,03, 166,65, 129,220, 132,99, 52,27, 37,46.E. Preparation of methyl nitaconate

A 50 ml round bottom flask equipped with a reflux condenser, a nitrogen inlet and a magnetic stirrer was charged with methyl 4- (4-methoxybenzyl) itaconate (4.00 g, 16 mmol), 12 ml of toluene and 6 ml of trifluoroacetic acid. The solution was kept at room temperature for 18 hours and then the volatiles were removed in vacuo. The residue was diluted with ethyl acetate and extracted three times with saturated aqueous sodium bicarbonate. The combined aqueous extract was acidified to pH 1 with aqueous potassium bisulfate and then extracted three times with ethyl acetate. The combined ethyl acetate solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to vacuum distillation to obtain 1.23 g, 75% pure product, b.p. 85-87 ^o C, @ 0.1 mm. ¹ H-NMR / CDCl _3/300 MHz 6.34 (s, 1H), 5,73 (c, 2H), 3,76 (c, 3H), 3,38 (c, 2H), ¹³ C-NMR / CDCl ₃ / 177.03, 166.65, 129.220, 132.99, 52.27, 37.46.

5-литровую круглодонную четырехгорлую колбу, снабженную входным отверстием для азота, обратным холодильником, механической мешалкой, капельной воронкой с постоянным давлением и отверстие для термометра, загружали метил-2(R)-метилсукцинатом /184,1 г, 1,26 моля/, триэтиламином /165,6 г, 218 мл, 1,64 моля, 1,3 экв/ и толуолом /1063 мл/. Раствор нагревали до 85^oC и затем обрабатывали по каплям раствором дифенилфосфорилазида /346,8 г, 1,26 моля/ в течение 1,2 часа. Раствор поддерживали при этой температуре еще в течение 1 часа и затем смесь обрабатывали 4-метоксибензиловым спиртом /174,1 г, 1,26 моля/ в течение 0,33 часа из капельной воронки. Раствор перемешивали при 88^oC еще в течение 2,25 часа и затем охлаждали до комнатной температуры. Содержимое колбы выливали в разделительную воронку и промывали насыщенным водным раствором NaHCO₃ /2 х 500 мл/, 0,2 N HCl /2 х 500 мл/, солевым раствором /1 х 500 мл/, сушили над безводным сульфатом магния, фильтровали и концентрировали в вакууме, получая 302,3 г, 85% целевого продукта в виде слегка коричневого масла. ¹H-ЯМР /CDCl₃/ 300 МГц 7,32 (д, J = 8,4 Гц, 2H), 6,91 (д, J = 8,4 Гц, 2H), 5,2 (шир. м, 1H), 5,05 (с, 2H), 3,83 (с, 3H), 3,70 (с, 3H), 3,35 (м, 2H), 2,70 (м, 2H), 1,20 (д, J = 7,2 Гц, 3H).F. Kuruius Rearrangement of Methyl 2 (R) Methyl Succinate: Preparation of Methyl-N-Moz-α-methyl-β-alanine

A 5-liter round-bottomed four-necked flask equipped with a nitrogen inlet, a reflux condenser, a mechanical stirrer, a constant pressure drop funnel and a thermometer hole was charged with methyl 2 (R) methyl succinate / 184.1 g, 1.26 mol /, triethylamine / 165.6 g, 218 ml, 1.64 mol, 1.3 eq / and toluene / 1063 ml /. The solution was heated to 85 ^° C. and then treated dropwise with a solution of diphenylphosphoryl azide (346.8 g, 1.26 mol) for 1.2 hours. The solution was maintained at this temperature for another 1 hour and then the mixture was treated with 4-methoxybenzyl alcohol / 174.1 g, 1.26 mol / for 0.33 hours from a dropping funnel. The solution was stirred at 88 ^° C. for an additional 2.25 hours and then cooled to room temperature. The contents of the flask were poured into a separatory funnel and washed with saturated aqueous NaHCO _3/2 x 500 mL /, 0,2 N HCl / 2 x 500 ml / brine / ml 1 x 500 /, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum, obtaining 302.3 g, 85% of the target product as a slightly brown oil. ¹ H-NMR / CDCl _3/300 MHz 7.32 (d, J = 8,4 Hz, 2H), 6,91 (d, J = 8,4 Hz, 2H), 5,2 (br. M, 1H), 5.05 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.35 (m, 2H), 2.70 (m, 2H), 1, 20 (d, J = 7.2 Hz, 3H).

5-литровую трехгорлую круглодонную колбу, снабженную обратным холодильником, входным отверстием для азота, механической мешалкой, загружали метил-N-Moz-α-метил β-аланином /218,6 г, 0,78 моля/, ледяной уксусной кислотой /975 мл/ и 12 N HCl /1960 мл/. Затем раствор нагревали с обратным холодильником в течение 3 часов. После того, как раствор охлаждали до комнатной температуры /прибл. 1 час/, водную фазу декантировали из органического остатка /полимера/ и концентрировали водную фазу на роторном испарителе. После добавления ацетона к концентрированному остатку образовалось слегка желтое твердое вещество, которое суспендировали ацетоном, и белое твердое вещество выделяли фильтрованием на воронке Бюхнера. Последние следы ацетона удаляли под вакуумом, получая 97,7 г, 90% чистого продукта, т.пл. 128,5-130,5^oC, @ 25^oC = 9,0^oC /c = 2,535, метанол/. ¹H-ЯМР /D₂O/ 300 МГц 3,29 (дд, J = 8,6, 13,0 Гц, 1H), 3,16 (дд, J = 5,0, 13,0 Гц, 1H), 2,94 (ддк, J = 7,2, 5,0, 8,6 Гц, 1H), 1,30 (д, J = 7,2 Гц, 3H); ¹³C-ЯМР /D₂O/ 180,84, 44,56, 40,27, 17,49.G. Hydrolysmethyl-N-Moz-α-methyl-β-alanine: preparation of α-methyl-β-alanine hydrochloride

A 5 liter three-necked round bottom flask equipped with a reflux condenser, nitrogen inlet, mechanical stirrer was charged with methyl N-Moz-α-methyl β-alanine (218.6 g, 0.78 mol), glacial acetic acid / 975 ml / and 12 N HCl / 1960 ml /. Then the solution was heated under reflux for 3 hours. After the solution was cooled to room temperature / approx. 1 hour /, the aqueous phase was decanted from the organic residue / polymer / and the aqueous phase was concentrated on a rotary evaporator. After adding acetone to the concentrated residue, a slightly yellow solid formed, which was suspended with acetone, and a white solid was isolated by filtration on a Buchner funnel. The last traces of acetone were removed under vacuum, obtaining 97.7 g, 90% of the pure product, so pl. 128.5-130.5 ^o C, @ 25 ^o C = 9.0 ^o C / s = 2.535, methanol /. ¹ H-NMR / D ₂ O / 300 MHz 3.29 (dd, J = 8.6, 13.0 Hz, 1H), 3.16 (dd, J = 5.0, 13.0 Hz, 1H) 2.94 (ddc, J = 7.2, 5.0, 8.6 Hz, 1H); 1.30 (d, J = 7.2 Hz, 3H); ¹³ C-NMR / D ₂ O / 180.84, 44.56, 40.27, 17.49.

Раствор α-метил-β аланин-гидрохлорида /97,7 г, 0,70 моля/ в воде /1050 мл/ и диоксан /1050 мл/ доводили до pH 8,9 раствором 2,9 N NaOH. Перемешиваемый раствор обрабатывали дитретбутилпирокарбонатом /183,3 г, 0,84 моля, 1,2 экв./, добавляя сразу все его количество. pH раствора поддерживали между 8,7 и 9,0 путем периодического добавления 2,5 N NaOH. После 2,5 часов pH стабилизировался и реакция считалась завершенной. Раствор концентрировали на роторном испарителе /температуру поддерживали менее 40^oC/. Избыток ди-трет-бутилпирокарбоната удаляли экстрагированием дихлорметаном и водный раствор затем подкисляли холодной 1 N HCl и сразу же экстрагировали этилацетатом /4 х 1000 мл/. Объединенный этилацетатный экстракт промывали солевым раствором, сушили над безводным сульфатом магния, фильтровали и концентрировали на роторном испарителе, получая густое масло /127,3 г, 90% выход неочищенного продукта/, которое перемешивали с н-гексаном, после чего образовались кристаллы чистого продукта /95,6 г, 68%/, т.пл. 76-78^oC, [α]_d @ 25^oC = -11,8^oC /c = 2,4, EtOH/. Вторую часть получали концентрированием фильтрата и разбавлением гексаном, 15,4 г, объединенный выход 111,05, 78%. ¹H-ЯМР /ацетон D₆/ 300 МГц 11,7 (шир. с, 1H), 6,05 (шир. с, 1H), 3,35 (м, 1H), 3,22 (м, 1H), 2,50 (м, 1H), 1,45 (с, 9H), 1,19 (д, J = 7,3 Гц, 3H); ¹³C-ЯМР /ацетон D₆/ 177,01, 79,28, 44,44, 40,92, 29,08, 15,50. Элементный анализ, рассчитанный для C₉H₁₇NO₄: C 53,19; H 8,42; N 6,89. Найдено: C 53,36; H 8,46; N 6,99.H. Preparation of N-Boc-α-methyl-β-alanine

A solution of α-methyl-β alanine hydrochloride (97.7 g, 0.70 mol) in water / 1050 ml / and dioxane / 1050 ml / was adjusted to pH 8.9 with a solution of 2.9 N NaOH. The stirred solution was treated with ditretbutyl pyrocarbonate / 183.3 g, 0.84 mol, 1.2 eq. /, Adding all at once. The pH of the solution was maintained between 8.7 and 9.0 by periodically adding 2.5 N NaOH. After 2.5 hours, the pH stabilized and the reaction was considered complete. The solution was concentrated on a rotary evaporator (the temperature was kept below 40 ^° C). The excess di-tert-butyl pyrocarbonate was removed by extraction with dichloromethane and the aqueous solution was then acidified with cold 1 N HCl and immediately extracted with ethyl acetate / 4 x 1000 ml /. The combined ethyl acetate extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator to obtain a thick oil / 127.3 g, 90% yield of crude product /, which was stirred with n-hexane, after which crystals of pure product formed / 95.6 g, 68% / mp. 76-78 ^o C, [α] _d @ 25 ^o C = -11.8 ^o C / c = 2.4, EtOH /. The second part was obtained by concentrating the filtrate and diluting with hexane, 15.4 g, combined yield of 111.05, 78%. ¹ H-NMR / acetone D _6/300 MHz 11.7 (br. A, 1H), 6,05 (br. A, 1H), 3,35 (m, 1H), 3,22 (m, 1H) 2.50 (m, 1H); 1.45 (s, 9H); 1.19 (d, J = 7.3 Hz, 3H); ¹³ C-NMR / acetone D ₆ / 177.01, 79.28, 44.44, 40.92, 29.08, 15.50. Elemental analysis calculated for C ₉ H ₁₇ NO ₄ : C 53.19; H 8.42; N, 6.89. Found: C, 53.36; H 8.46; N, 6.99.

I. Preparation of N-4-methoxybenzyloxycarbonyl-α-methyl-β-alanine
A solution of N-4-methoxybenzylcarbonyl-α-methyl-β-alanine methyl ester / 2.81 g, 10.0 mmol / in 30 ml of 25% aqueous methanol was treated with lithium hydroxide / 1.3 eq. / At room temperature for 2 hours. The solution was concentrated in vacuo and the residue was taken up in a mixture of water and ether, the phases were separated and the organic phase was discarded. The aqueous phase was acidified with aqueous potassium hydrogen sulfate to a pH of 1.5 and then extracted three times with ether. The combined ether phase was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.60 g, 97% N-4-methoxybenzyloxycarbonyl-α-methyl-β-alanine / N-Moz-AMBA /, which was purified by recrystallization from a mixture of ethyl acetate and hexane, yielding 2.44 g, 91% pure product, mp. 96-97 ^o C, MH + = 268. ¹ H-NMR / D _6- acetone / 300 MHz 1.16 (3H, d, J = 7.2 Hz, 2.70 (1H, m), 3.31 ( 2H, m), 3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, d, J = 8.7 Hz), 7.13 (2H, d, J = 8 , 7 Hz).

Example 8
By the method of example 7 were obtained are presented in table 2 β-amino acids.

Example 9
According to the method described in example 7, the following β-amino acid compounds were obtained.

Пример 10A

Получение N-[2R-гидрокси-3-[[(4-метоксифенил)сульфонил] (2- метилпропил)амино]-1S-(фенилметил)пропил]-4-пиридинкарбоксамида
К раствору 231 мг /0,57 ммоля/ 2R-гидрокси-3-[(2-метилпропил-(4-метоксифенил)сульфонил] амино- 1S-(фенилметил)пропиламина в 3 мл метиленхлорида при 0^oC добавляли 288 мг /2,85 ммоля/ триэтиламина и затем 112 мг /0,63 ммоля/ гидрохлорида изоникотиноилхлорида. После 19 часов при комнатной температуре растворитель удалялся, добавляли этилацетат, затем промывали насыщенным раствором бикарбоната натрия, солевым раствором, сушили над сульфатом магния, фильтровали и концентрировали, получая 290 мг неочищенного продукта. Его хроматографировали на силикагеле с применением смеси 3-5% изопропанол/метиленхлорид в качестве элюента, получая 190 мг целевого соединения; масс-спектр, рассчит. для C₂₇H₃₄N₃O₅S /M+H/ 512,2219; обнаруженный 512,2280.

Example 10A

Preparation of N- [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] -4-pyridinecarboxamide
To a solution of 231 mg / 0.57 mmol / 2R-hydroxy-3 - [(2-methylpropyl- (4-methoxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine in 3 ml of methylene chloride at 0 ^° C was added 288 mg / 2 85 mmol / triethylamine and then 112 mg / 0.63 mmol / isonicotinoyl chloride hydrochloride After 19 hours at room temperature, the solvent was removed, ethyl acetate was added, then washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated to give 290 mg of crude product It was chromatographed on silica gel using using a mixture of 3-5% isopropanol / methylene chloride as the eluent, to obtain 190 mg of the target compound; mass spectrum calculated for C ₂₇ H ₃₄ N ₃ O ₅ S / M + H / 512.2219; detected 512.2280.

Получение N-[2R-гидрокси-3-[[(4-метоксифенил)сульфонил] (2- метилпропил)амино]-1S-(фенилметил)пропил]-2,6-диметилбензамида
К раствору 83 мг /0,55 ммоля/ 2,6-диметилбензойной кислоты и 125 мг /0,82 ммоля/ N-гидроксибензотриазола в 3 мл безводного DMF при 0^oC добавляли 117 мг /0,61 ммоля/ 1-(3-диметиламинопропил)-3-этилкарболиимидгидрохлорида. После 2 часов при 0^oC добавляли 203 мг /0,50 ммоля/ 2R-гидрокси-3-[(2-метилпропил)(4-метоксифенил)сульфонил]амино- 1S-(фенилметил)пропиламина. После 22 часов при комнатной температуре растворитель удаляли в вакууме, добавляли этилацетат, затем промывали насыщенным раствором бикарбоната натрия, солевым раствором, сушили над сульфатом магния, фильтровали и концентрировали, получая 300 мг неочищенного продукта. Хроматография его на силикагеле с применением смеси 20-50% этилацетат/гексан в качестве элюента дала 37 мг целевого продукта; масс-спектр, рассчитанный для C₃₀H₃₈N₂O₅S /M+H/, 539,2580, обнаружено 539,2632.Example 10B

Preparation of N- [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] -2,6-dimethylbenzamide
To a solution of 83 mg / 0.55 mmol / 2,6-dimethylbenzoic acid and 125 mg / 0.82 mmol / N-hydroxybenzotriazole in 3 ml of anhydrous DMF at 0 ^° C. was added 117 mg / 0.61 mmol / 1- (3 dimethylaminopropyl) -3-ethylcarbolyimide hydrochloride. After 2 hours at 0 ^° C., 203 mg / 0.50 mmol / 2R-hydroxy-3 - [(2-methylpropyl) (4-methoxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine was added. After 22 hours at room temperature, the solvent was removed in vacuo, ethyl acetate was added, then washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated to give 300 mg of a crude product. Chromatography on silica gel using a mixture of 20-50% ethyl acetate / hexane as eluent gave 37 mg of the target product; mass spectrum calculated for C ₃₀ H ₃₈ N ₂ O ₅ S / M + H /, 539.2580, found 539.2632.

Получение N1-[2R-гидрокси-3-[(3-метилбутил)(метилсульфонил)амино]- 1S-(фенилметил)пропил]-2S-[(2-хинолинилкарбонил)амино]-бутандиамида
Часть A:
Раствор фенилметил[2R-гидрокси-3-[(3-метилбутил)(метилсульфонил) амино] -1S-(фенилметил)пропил] карбамата, полученный, как описано в примере 3, /100 мг/ в метаноле /10 мл/ гидрировали над 10% палладием на угле в течение 2 часов, фильтровали через диатомовую землю и концентрировали, получая продукт в виде масла.Example 11A

Preparation of N1- [2R-hydroxy-3 - [(3-methylbutyl) (methylsulphonyl) amino] - 1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide
Part A:
A solution of phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (methylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate, prepared as described in Example 3, (100 mg / in methanol / 10 ml) was hydrogenated over 10% palladium on carbon for 2 hours, filtered through diatomaceous earth and concentrated to give the product as an oil.

Part B:
A solution of N-CBZ-L-asparagine / 61 mg, 0.23 mmol / and N-hydroxybenzotriazole / 33 mg, 0.22 mmol / in DMF / 2 ml / was cooled to 0 ^o C in an ice bath and then EDC / was added 42 mg, 0.22 mmol. The solution was stirred for 30 minutes at 0 ^° C. and then the product of part A / 69 mg, 0.21 mmol / in DMF / 2 ml / was added. After 30 minutes at 0 ^° C., the reaction mixture was warmed to room temperature and stirred for 16 hours. Then the reaction mixture was poured into a 50% saturated sodium bicarbonate solution (100 ml) and the resulting white precipitate was collected by vacuum filtration, washed with water and dried in vacuum. Phenylmethyl [3-amino-1S - [[2R-hydroxy-3 - [(3-methylbutyl) (methylsulfonyl) amino] -1S- (phenylmethyl) amino] carbonyl] -3-oxopropylcarbamate was obtained as a white solid. Analytically calculated for C ₂₈ H ₄₀ N ₄ O ₇ S • 0.5H ₂ O: C 57.42; H 7.06; N, 9.57. Found: C, 57.72; H 7.21; N, 9.24.

Part C:
Solution phenylmethyl [3-amino-1S - [[2R-hydroxy-3 - [(3-methylbutyl) (methylsulfonyl) amino] -1S- (phenylmethyl) amino] carbonyl] -3-oxopropyl carbamate / 135 mg, 0.23 mmol (in methanol / 15 ml) was hydrogenated over 10% palladium-carbon for 6 hours, filtered through diatomaceous earth and concentrated to give the product as an oil.

Part D:
To a solution of the product of part C / 101 mg, 0.23 mmol / in DMF / 5 ml / was added an ester of N-hydroxysuccinimide and 2-quinolinecarboxylic acid (67 mg, 0.25 mmol). The reaction was carried out with stirring at room temperature for 16 hours, then the reaction mixture was poured into a 50% saturated solution of sodium bicarbonate / 60 ml /. The resulting solid was collected by vacuum filtration, washed with water and dried in vacuo. N1- [2R-hydroxy-3 - [(3-methylbutyl) (methylsulphonyl) amino] - 1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide was obtained as a white solid. Analytically calculated for C ₃₀ H ₃₉ N ₅ O ₆ S • 0.1 H ₂ O: C 58.52; H 6.71; N, 11.37. Found: C, 58.34; H 6.35; N, 11.13.

Получение N1-[2R-гидрокси-3-[(3-метилбутил(фенилсульфонил)амино] - 1S-(фенилметил)пропил]-2S-[(2-хинолинилкарбонил) амино]бутандиамида
Часть A:
CBZ-защищенное соединение фенилметил[2R-гидрокси-3-[(3- метилбутил)(фенилсульфонил)амино] -1S- (фенилметил)пропил] карбамат /200 мг, 0,38 ммоля/ подвергали снятию защиты гидрированием над 10% палладием на угле и получали продукт в виде масла.Example 11B

Preparation of N1- [2R-hydroxy-3 - [(3-methylbutyl (phenylsulfonyl) amino] - 1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide
Part A:
The CBZ-protected compound phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate / 200 mg, 0.38 mmol / was deprotected by hydrogenation over 10% palladium on coal and received the product in the form of oil.

Part B:
The free amine from Part A was reacted with N-CBZ-L-asparagine / 109 mg, 0.41 mmol / in the presence of N-hydroxybenzotriazole / 63 mg, 0.41 mmol / in EDC / 77 mg, 0.40 mmol /, giving phenylmethyl [3-amino-1S - [[2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) amino] carbonyl] -3-oxopropyl] carbamate as a white solid. Analit. calculated for C ₂₃ H ₄₂ N ₄ O ₇ S: C 62.05; H 6.63; N, 8.77. Found: C, 61.86; H 6.60; N, 8.64.

Part C:
Part B product (110 mg, 0.17 mmol) was deprotected by hydrogenation over 10% palladium-carbon to give the product as an oil.

Part D:
The resulting free amine was reacted with an ester of N-hydroxysuccinimide and 2-quinoline carboxylic acid (45 mg, 0.17 mmol) to give N1- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] - 1S- ( phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide as a white solid. Analit. calculated for C ₃₅ H ₄₁ N ₅ O ₆ S: C 63.71; H 6.26; N, 10.61. Found: C, 63.69; H 6.42; N, 10.42.

Получение 2S-[[(диметиламино)ацетил] амино] -N-[2R-гидрокси-3-[(3- метилбутил)метилсульфонил) амино]-1S-(фенилметил)пропил]-3,3-диметилбутанамида
Часть A:
К раствору N-CBZ-L-трет-лейцина /100 мг, 0,38 ммоля/ и N-гидроксибензотриазола /52 мг, 0,34 ммоля/ в DMF /3 мл/ добавляли EDC /65 мг, 0,34 ммоля/. Раствор перемешивали 60 минут при комнатной температуре и затем добавляли продукт примера 10, части A /105 мг, 0,32 ммоля/ в DMF /2 мл/. Реакционную смесь перемешивали в течение 16 часов при комнатной температуре, затем выливали в 50%-насыщенный раствор бикарбоната натря /50 мл/. Водную смесь экстрагировали дважды этилацетатом /25 мл/. Объединенные этилацетатные слои промывали водой /25 мл/ и сушили над сульфатом магния. Фильтрование и концентрирование дали масло, которое хроматографировали на силикагеле /50 г/ с элюированием 2,5% метанолом в дихлорметане. Фенилметил[1S-[[[2R-гидрокси-3-[(3-метилбутил)-(метилсульфонил)амино] - 1S-(фенилметил)пропил]амино]-карбонил]-2,2-диметилпропил]карбамат получали в виде липкого твердого вещества. Аналит. рассчит. для C₃₀H₄₅N₃O₆•2H₂O: C 58,55; H 8,09; N 6,83. Найдено: C 58,38; H 7,77; N 7,10.Example 12A

Preparation of 2S - [[(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) methylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide
Part A:
To a solution of N-CBZ-L-tert-leucine / 100 mg, 0.38 mmol / and N-hydroxybenzotriazole / 52 mg, 0.34 mmol / in DMF / 3 ml / was added EDC / 65 mg, 0.34 mmol / . The solution was stirred for 60 minutes at room temperature and then the product of Example 10, parts A / 105 mg, 0.32 mmol / in DMF / 2 ml / was added. The reaction mixture was stirred for 16 hours at room temperature, then poured into a 50% saturated solution of sodium bicarbonate / 50 ml /. The aqueous mixture was extracted twice with ethyl acetate / 25 ml /. The combined ethyl acetate layers were washed with water / 25 ml / and dried over magnesium sulfate. Filtration and concentration gave an oil which was chromatographed on silica gel (50 g), eluting with 2.5% methanol in dichloromethane. Phenylmethyl [1S - [[[2R-hydroxy-3 - [(3-methylbutyl) - (methylsulphonyl) amino] - 1S- (phenylmethyl) propyl] amino] carbonyl] -2,2-dimethylpropyl] carbamate was obtained as a sticky solid matter. Analit. calculated for C ₃₀ H ₄₅ N ₃ O ₆ • 2H ₂ O: C 58.55; H 8.09; N, 6.83. Found: C, 58.38; H 7.77; N, 7.10.

Part B:
A solution of phenylmethyl [1S - [[[2R-hydroxy-3 - [(3-methylbutyl) - (methylsulfonyl) amino] -1S- (phenylmethyl) propyl] amino] carbonyl] -2,2-dimethylpropyl] carbamate / 100 mg, 0.17 mmol (in methanol / 10 ml) was hydrogenated over 10% palladium-carbon for 2 hours. The reaction mixture was filtered through diatomaceous earth and concentrated to an oil.

Part C:
N, N-dimethylglycine / 20 mg, 0.19 mmol /, N-hydroxybenzotriazole / 28 mg, 0.18 mmol / and EDC / 35 mg, 0.18 mmol / were stirred in DMF / 4 ml / at room temperature for 40 minutes . The product from Part B in DMF / 4 ml / was added and the reaction mixture was stirred for 16 hours, then poured into 50% saturated sodium bicarbonate / 50 ml /. The aqueous mixture was extracted three times with dichloromethane / 30 ml /, which in turn was washed with water / 30 ml / and dried over magnesium sulfate. Filtration and concentration gave an oil. It was chromatographed on silica gel / 50 g /, eluting first with 2.5% methanol in dichloromethane / 400 ml / and then 5% methanol in dichloromethane. 2S - [[(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) methylsulfonyl) amino] -1S (phenylmethyl) propyl] - 3,3-dimethylbutanamide was obtained as a white solid . Analit. calculated for C ₂₆ H ₄₆ N ₄ O ₅ S • CH ₂ Cl ₂ : C 56.04; H 8.34; N, 9.87. Found: C, 56.06; H 8.36; N, 9.70.

Получение 2S-[[(диметиламино)ацетил] амино] -N-[2R-гидрокси-3-[(3- метилбутил)(фенилсульфонил)амино] -1S-(фенилметил)пропил] -3,3- диметилбутанамида
Часть A:
К раствору N-CBZ-L-трет-лейцина /450 мг, 1,7 ммоля/ и N-гидроксибензотриазола /260 мг, 1,7 ммоля/ в DMF /10 мл/ добавляли EDC /дихлорэтан/ /307 мг, 1,6 ммоля/. Раствор перемешивали 60 минут при комнатной температуре и затем добавляли продукт примера 11, части A /585 мг, 1,5 ммоля/ в DMF /2 мл/. Реакционную смесь перемешивали в течение 16 часов при комнатной температуре, затем выливали в 50%-насыщенный раствор бикарбоната натрия /200 мл/. Водную смесь экстрагировали трижды этилацетатом /50 мл/. Объединенные этилацетатные слои промывали водой /50 мл/ и насыщенным раствором NaCl /50 мл/, затем сушили над сульфатом магния. Фильтрование и концентрирование дали масло, которое хроматографировали на силикагеле /50 г/ с элюцией 20% этилацетатом в гексане. Феннилметил[1S-[[[2R-гидрокси -3-[(3-метилбутил) (фенилсульфонил)амино]- 1S-(фенилметил)пропил] амино]карбонил]-2,2 -диметилпропил] карбамат получали в виде твердого вещества. Аналит. рассчитано для C₃₅H₄₇N₃O₆S: C 65,91; H 7,43; N 6,59. Определено: C 65,42; H 7,24; N 6,55.Example 12B

Preparation of 2S - [[(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide
Part A:
To a solution of N-CBZ-L-tert-leucine / 450 mg, 1.7 mmol / and N-hydroxybenzotriazole / 260 mg, 1.7 mmol / in DMF / 10 ml / was added EDC / dichloroethane / / 307 mg, 1, 6 mmol. The solution was stirred for 60 minutes at room temperature and then the product of Example 11, parts A / 585 mg, 1.5 mmol / in DMF / 2 ml / was added. The reaction mixture was stirred for 16 hours at room temperature, then poured into a 50% saturated solution of sodium bicarbonate / 200 ml /. The aqueous mixture was extracted three times with ethyl acetate / 50 ml /. The combined ethyl acetate layers were washed with water / 50 ml / and saturated NaCl / 50 ml /, then dried over magnesium sulfate. Filtration and concentration gave an oil which was chromatographed on silica gel (50 g) eluted with 20% ethyl acetate in hexane. Phenylmethyl [1S - [[[2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] - 1S- (phenylmethyl) propyl] amino] carbonyl] -2,2-dimethylpropyl] carbamate was obtained as a solid. Analit. calculated for C ₃₅ H ₄₇ N ₃ O ₆ S: C 65.91; H 7.43; N, 6.59. Determined: C, 65.42; H 7.24; N, 6.55.

Part B:
Solution phenylmethyl [1S - [[[2R-hydroxy-3- [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] amino] carbonyl] -2,2-dimethylpropyl] carbamate / 200 mg, 0 , 31 mmol (in methanol / 15 ml) was hydrogenated over 10% palladium on charcoal for 2 hours. The reaction mixture was filtered through diatomaceous earth and concentrated to an oil.

Part C:
The resulting free amine from part B / 150 mg, 0.3 mmol / was combined with diisopropylethylamine / 114 μl, 0.33 mmol / in dichloromethane / 5 ml /. Bromoacetyl chloride (27 μl, 0.33 mmol) (dropwise) was added to the mixture. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with dichloromethane / 30 ml / and extracted with 1 N HCl and then with saturated NaCl solution (25 ml each). The organic solution was dried over magnesium sulfate and concentrated to a solid. 2S - [[bromoacetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide was pure enough for use in the following stage. This material can also be obtained by replacing bromoacetic anhydride with bromoacetyl chloride; chloroacetyl chloride or chloroacetic anhydride may also be used.

Part D:
The product of Part C was dissolved in dichloromethane (5 ml) and diisopropylethylamine (114 μl, 0.66 mmol) and dimethylamine hydrochloride (53 mg, 0.66 mmol) were added. The reaction was stirred for 18 hours, then concentrated under a stream of nitrogen to approximately 1 ml. The residue was chromatographed on silica gel (50 g) using 2% methanol in dichloromethane. 2S - [(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide was obtained as a solid . Anal calculated for C ₃₁ H ₄₈ N ₄ O ₅ S: C 63.24; H 8.22; N, 9.52. Defined: C 63.03; H 8.01; N, 9.40.

Получение 2S-[[(метиламино)ацетил] амино]-N-[2R-гидрокси-3-[(3- метилбутил)(фенилсульфонил) амино]-1S-(фенилметил) пропил]-3,3-метилбутанамида
2S-[[Бромацетил]амино]-N-[2R-гидрокси -3-[(3-метилбутил) (фенилсульфонил)амино] -1S-(фенилметил)пропил]-3,3-диметилбутанамид /103 мг, 0,16 ммоля/ и 40% водный метиламин /42 мкл, 0,49 ммоля/ соединяли в этаноле /2 мл/ и перемешивали при комнатной температуре в течение 24 часов. Реакционную смесь концентрировали досуха и растирали с эфиром. Твердый материал удаляли фильтрованием, а фильтрат концентрировали до масла. Масло хроматографировали на силикагеле /50 г/ с применением 4% метанола в дихлорметане. 2S-[[(метиламино)ацетил] амино]-N-[2R-гидрокси-3-[(3-метилбутил) (фенилсульфонил) амино]-1S-(фенилметил) пропил]-3,3-диметилбутанамид получали в виде твердого вещества. Анал. рассчит. для C₃₀H₄₆N₄O₅S: C 62,69; H 8,07; N 9,75. Определено: C 62,38; H 8,14; N 9,60.Example 12C

Preparation of 2S - [[(methylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-methylbutanamide
2S - [[Bromoacetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide / 103 mg, 0.16 mmol / and 40% aqueous methylamine / 42 μl, 0.49 mmol / were combined in ethanol / 2 ml / and stirred at room temperature for 24 hours. The reaction mixture was concentrated to dryness and triturated with ether. The solid material was removed by filtration, and the filtrate was concentrated to an oil. The oil was chromatographed on silica gel (50 g) using 4% methanol in dichloromethane. 2S - [[(methylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide was obtained as a solid substances. Anal calculated for C ₃₀ H ₄₆ N ₄ O ₅ S: C 62.69; H 8.07; N, 9.75. Determined: C, 62.38; H 8.14; N, 9.60.

Получение 2S-[[(диметиламино)ацетил] амино] -N-[2R-гидрокси-3-[(3- метилбутил)(фенилсульфонил) амино]-1S-(фенилметил)пропил] -3S-метилпентанамида
Часть A:
К раствору амина /продукта примера 11, части A/ /2,79 г, 7,1 ммоля/ в 27 мл диоксана добавляли сложный эфир N-t-бутилкарбонил-L-изолейцин-N-гидроксисукцинимида и реакцию перемешивали в атмосфере азота в течение 16 часов. Содержимое концентрировали в вакууме и остаток растворяли в этилацетате, промывали 5% водным кислым сульфатом калия, насыщенным раствором бикарбоната натрия и насыщенным раствором хлорида натрия. Органический слой сушили над сульфатом магния, фильтровали и концентрировали, получая 4,3 г неочищенного материала, который хроматографировали с применением смеси этилацетат:гексан /3: 1/, получая 3,05 г, 72% 2S-[[(1,1-диметилэтокси)карбонил] амино]-N-[2R- гидрокси-3-[(3-метилбутил)(фенилсульфонил) амино] -1S-(фенилметил) пропил]- 3S-метилпентанамида.Example 12

Preparation of 2S - [[(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3S-methylpentanamide
Part A:
Nt-butylcarbonyl-L-isoleucine-N-hydroxysuccinimide ester was added to a solution of the amine / product of example 11, part A / 2.79 g, 7.1 mmol / in 27 ml of dioxane, and the reaction was stirred under nitrogen for 16 hours . The contents were concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 4.3 g of crude material, which was chromatographed using ethyl acetate: hexane / 3: 1 / to give 3.05 g, 72% 2S - [[(1,1- dimethylethoxy) carbonyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] - 3S-methylpentanamide.

Part B:
(3.05 g, 5.0 mmol) of the product from Part A was dissolved in 20 ml of 4 N HCl in dioxane and stirred under a nitrogen atmosphere for 1.5 hours. The contents were concentrated in vacuo and triturated with diethyl ether. The crude hydrochloride salt was pumped out to dryness at 1 mm Hg to give 2.54 g of the product as the hydrochloride.

Part C:
(2.54, 5.0 mmol) of the amine hydrochloride was dissolved in 50 ml of tetrahydrofuran and 4-methylmorpholine (1.01 g, 10 mmol) was added to obtain a precipitate. Chloroacetic anhydride (0.865 g, 5.0 mmol) was added to this suspension and stirred for 40 minutes. The contents were concentrated in vacuo and the residue was separated in ethyl acetate / 200 ml / and 5% KHSO ₄ . The organic layer was washed with a solution of saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a crude product. Purification on silica gel using ethyl acetate: hexane / 1: 1 / as an eluent afforded 1.89 g of pure chloroacetamide.

Part D:
To a solution of chloroacetamide (1.89 g, 3.2 mmol) from Part C in 25 ml of tetrahydrofuran was added 4.0 ml of 50% aqueous dimethylamine and the solution was stirred for 1 hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a crude product, which was purified by crystallization from ethyl acetate and isooctane to obtain 1.80 g / 88% yield /, mp. 121-122 ^o C, H-NMR, mass spectrum: calc. 589.3424, determined 589.3405.

Получение 2S-[[(метиламино)ацетил] амино]-N-[2R-гидрокси-3-[(3- метилбутил)(фенилсульфонил) амино]-1S-(фенилметил) пропил-3S-метилпентанамида
К раствору хлорацетамида примера 12D, части C /2,36 г, 4,0 ммоля/ в тетрагидрофуране /25 мл/ добавляли 3 мл водного метиламина /40 вес.%/ и реакцию перемешивали в течение 1 часа. Содержимое концентрировали и остаток разделяли между этилацетатом /100 мл/ и водой /100 мл/. Органический слой сушили над сульфатом магния, фильтровали и концентрировали, получая неочищенный продукт, который очищали перекристаллизацией из смеси этилацетат/гептан; /M + H/ 575, ЯМР: определено 575,3267.Example 12E

Preparation of 2S - [[(methylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl-3S-methylpentanamide
To a solution of chloroacetamide of Example 12D, part C / 2.36 g, 4.0 mmol / in tetrahydrofuran / 25 ml / was added 3 ml of aqueous methylamine / 40 wt.% / And the reaction was stirred for 1 hour. The content was concentrated and the residue was partitioned between ethyl acetate / 100 ml / and water / 100 ml /. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a crude product, which was purified by recrystallization from ethyl acetate / heptane; (M + H / 575); NMR: determined 575.3267.

Получение 2S-[[(диметиламино)ацетил] амино] -N-[2R-гидрокси-3-[(3- метилпропил)(4-метоксифенилсульфонил) амино] -1S-(фенилметил)пропил] -3S- метилпентанамида
Часть A:
К раствору 2R-гидрокси-3- [(2-метилпропил)(4-метоксифенилсульфонил) амино] -1S-пропиламина /1,70 г, 4,18 ммоля/ в 40 мл дихлорметана добавляли эфир N-карбобензилокси-L- изолейцин-N-гидроксисукцинамида /1,51 г, 4,18 ммоля/ и раствор перемешивали в атмосфере азота в течение 16 часов. Содержимое концентрировали в вакууме и остаток перерастворяли в этилацетате. Раствор в этилацетате промывали водным раствором 5% KHSO₄, насыщенным раствором бикарбоната натрия и насыщенным раствором хлорида натрия, сушили над сульфатом магния, фильтровали и концентрировали, получая 2,47 г неочищенного продукта. Продукт очищали хроматографически на силикагеле с применением в качестве элюента смеси гексан/этилацетат /12: 1/, получая 2,3 г /выход 84%/ 2-[(карбобензилокси)амино] -N-[2-гидрокси-3-[(3-метилпропил)(4- метоксифенилсульфонил)амино]-1-(фенилметил)пропил] -3-метилпентанамид, [4-(R^*,S^*,S^*,)].Example 12F

Preparation of 2S - [[(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3S-methylpentanamide
Part A:
To a solution of 2R-hydroxy-3- [(2-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1S-propylamine / 1.70 g, 4.18 mmol / in 40 ml of dichloromethane was added N-carbobenzyloxy-L-isoleucine- ester N-hydroxysuccinamide (1.51 g, 4.18 mmol) and the solution was stirred under nitrogen for 16 hours. The contents were concentrated in vacuo and the residue was redissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous solution of 5% KHSO ₄ , saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 2.47 g of a crude product. The product was purified by silica gel chromatography using hexane / ethyl acetate / 12: 1 / as an eluent to obtain 2.3 g / yield 84% / 2 - [(carbobenzyloxy) amino] -N- [2-hydroxy-3 - [( 3-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1- (phenylmethyl) propyl] -3-methylpentanamide, [4- (R ^* , S ^* , S ^* ,)].

 1.18 g / 1.8 mmol / of the product of Part A was dissolved in 50 ml of methanol, and 250 mg of 10% palladium on carbon was added to the solution under a stream of nitrogen. The suspension was hydrogenated at 50 psi / 50 × 6894, 757 Pa / hydrogen for 20 hours. The contents were purged with nitrogen and filtered through celite / brownmellite / and concentrated in vacuo to give 935 mg of 2S- (amino) -N- [2R-hydroxy-3 - [(3-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1S- ( phenylmethyl) propyl] -3S-methylpentanamide, which was used without further purification.

Part C:
0.935 g / 1.8 mmol / amine from Part B was dissolved in 15 ml of dioxane and 4-methylmorpholine / 190 mg, 1.85 mmol / and then chloroacetic anhydride / 0.315 g, 1.8 mmol / were added to the solution. The reaction mixture was stirred under nitrogen for 3 hours, concentrated in vacuo and redissolved in ethyl acetate. The ethyl acetate solution was washed with 50 ml of 5% aqueous KHSO ₄ , saturated NaHCO ₃ and saturated NaCl, dried over magnesium sulfate, filtered and concentrated to give 613 mg / yield 68% / 2S - [(chloroacetyl) amino] -N- [ 2R-hydroxy-3 - [(3-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3S-methylpentanamide after purification by silica gel chromatography using hexane: ethyl acetate / 1: 1 /.

Part D:
To a solution of chloroacetamide from part C / 673 mg, 1.10 mmol / in 20 ml of tetrahydrofuran was added 5 ml of 50 wt.% Aqueous dimethylamine and the solution was stirred for 1 hour. The solution was concentrated and the residue was redissolved in 50 ml of ethyl acetate and washed with 25 ml of water. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give a crude solid which was purified on a silica gel column using eluent 97: 3 / dichloromethane: methanol / to give 400 mg of 2S - [[(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1- (phenylmethyl) propyl] -3-methylpentanamide.

Получение фенилметилового эфира [2R-гидрокси-3-[[(4-диметиламинофенил)сульфонил] (2-метилпропил)амино] - 1S-(фенилметил)пропил] карбаминовой кислоты
К раствору 100 мг /0,19 ммоля/ фенилметилового эфира [2R-гидрокси-3-[[(4-фторфенил)сульфонил](2-метилпропил)амино]- 1S-(фенилметил)пропил]карбаминовой кислоты в 1 мл пиридина добавляли 53 мл триэтиламина и 120 мкл /0,95 ммоля/ 40% водного диметиламина. После нагревания в течение 24 часов при 100^oC раствор охлаждали, добавляли этилацетат, промывали 5% лимонной кислотой, насыщенным раствором бикарбоната натрия, сушили над сульфатом магния, фильтровали и концентрировали. Оставшееся твердое вещество перекристаллизовывали из этилацетата/гексана, получая 10 мг целевого продукта; масс-спектр m/e = 540 /M+H/.Example 13A

Preparation of [2R-hydroxy-3 - [[((4-dimethylaminophenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid phenylmethyl ester
To a solution of 100 mg / 0.19 mmol / phenylmethyl ether [2R-hydroxy-3 - [[(4-fluorophenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid in 1 ml of pyridine was added 53 ml of triethylamine and 120 μl / 0.95 mmol / 40% aqueous dimethylamine. After heating for 24 hours at 100 ^° C., the solution was cooled, ethyl acetate was added, washed with 5% citric acid, saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The remaining solid was recrystallized from ethyl acetate / hexane to give 10 mg of the expected product; mass spectrum m / e = 540 / M + H /.

Получение 3-пиридилметилового эфира [2R-гидрокси-3-[[(4-метоксифенил)сульфонил] (2 -метилпропил)амино]- 1S-(фенилметил) пропил]-карбаминовой кислоты
Часть A:
Раствор N-бензилоксикарбонил-3S-амино-1,2-S-эпокси-4-фенилбутана /50 г, 0,168 моля/ и изобутиламина /246 г, 3,24 моля/ в 650 мл изопропанола нагревали с обратным холодильником в течение 1,25 часов. Раствор охлаждали до комнатной температуры, концентрировали в вакууме и затем выливали в 1 л перемешиваемого гексана, после чего продукт кристаллизовался из раствора, собирали его и сушили на воздухе, получая 57,6 г N-[3S-бензилоксикарбониламино-2R-гидрокси-4-фенил] -N-изобутиламина, т.пл. 108-109,5^oC, масс-спектр m/e = 371 /M + H/.Example 13B

Preparation of [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester
Part A:
A solution of N-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane (50 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol) in 650 ml of isopropanol was heated under reflux for 1, 25 hours. The solution was cooled to room temperature, concentrated in vacuo, and then poured into 1 L of stirred hexane, after which the product crystallized from the solution, collected and dried in air to obtain 57.6 g of N- [3S-benzyloxycarbonylamino-2R-hydroxy-4- phenyl] -N-isobutylamine, so pl. 108-109.5 ^o C, mass spectrum m / e = 371 / M + H /.

Part B:
The amine from part A / 1.11 g, 3.0 mmol / and triethylamine / 324 mg, 3.20 mmol / in 20 ml of methylene chloride was treated with 715 mg / 3.46 mmol / 4-methoxybenzenesulfonyl chloride. The solution was stirred at room temperature for 6 hours, concentrated, dissolved in ethyl acetate, then washed with 1 N potassium hydrogen sulfate, saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated to obtain a clear oil. It was recrystallized from diethyl ether to give 1.27 g of [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid phenylmethyl ester.

Part C:
A solution of 930 mg / 3.20 mmol / part B product in 30 ml of methanol was hydrogenated in the presence of 70 mg of 10% palladium on a carbon catalyst at 40 psig / 40 • 6894, 757 Pa / for 17 hours, the catalyst was removed by filtration and the solution was concentrated, receiving 704 mg of [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propylamine, mass spectrum m / e = 407 / M + H /, which was used in the next step without purification.

Part D:
To a solution of 2.5 g / 22.9 mmol / 3-pyridylcarbinol in 100 ml of anhydrous acetonitrile was added 8.8 g / 34.4 mmol / N, N-disuccinimidyl carbonate and 5.55 ml / 68.7 mmol / pyridine. The solution was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in ethyl acetate, then washed with saturated sodium bicarbonate, dried with brine over magnesium sulfate, filtered and concentrated to obtain 5.3 g of N-hydroxysuccinimide-3-pyridylmethyl carbonate, mass spectrum m / e = 251 / M + H /, which was used immediately in the next step without purification.

Part E:
To a solution of the amine from part C / 2.87 g, 7.0 mmol / and 1.38 ml of triethylamine in 24 ml of anhydrous methylene chloride was added a solution of 1.65 g / 6.6 mmol / N-hydroxysuccinimide-3-pyridyl carbonate from part D in 24 ml of methylene chloride. The solution was stirred for 1 hour, 100 ml of methylene chloride was added, then washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated to obtain 3.69 g of a crude product. Silica gel chromatography using a 2% methanol / methylene chloride mixture afforded 3.27 g of [2R-hydroxy-3 - [[4-methoxyphenylsulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic 3-pyridylmethyl ester acid, mass spectrum m / e = 548 / M + Li /.

Получение 3-пиридилметилового эфира [2R-гидрокси-3- [(фенилсульфонил)(2-метилпропил)амино] - 1S-(фенилметил)пропил]-карбаминовой кислоты
Часть A:
Раствор N-бензилоксикарбонил-3S-амино-1,2 -S-эпокси-4-фенилбутана /50 г, 0,168 моля/ и изобутиламина /246 г, 3,24 моля/ в 650 мл изопропилового спирта нагревали с обратным холодильником в течение 1,25 часов. Раствор охлаждали до комнатной температуры, концентрировали в вакууме и затем выливали в 1 л перемешиваемого гексана, после чего продукт кристаллизовали из раствора, собирали и сушили на воздухе, получая 57,6 г N-[3S-бензилоксикарбониламино-2R -гидрокси-4-фенил]-N-изобутиламина, т.пл. 108-109,5^oC, масс-спектр m/e = 371 /M + H/.Example 13C

Preparation of [2R-hydroxy-3- [(phenylsulfonyl) (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester
Part A:
A solution of N-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane (50 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol) in 650 ml of isopropyl alcohol was heated under reflux for 1 25 hours. The solution was cooled to room temperature, concentrated in vacuo, and then poured into 1 L of stirred hexane, after which the product was crystallized from the solution, collected and dried in air to obtain 57.6 g of N- [3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl ] -N-isobutylamine, so pl. 108-109.5 ^o C, mass spectrum m / e = 371 / M + H /.

Part B:
The amine from part A (0.94 g, 2.5 mmol) and triethylamine (288 mg, 2.85 mmol) in 20 ml of methylene chloride were treated with 461 mg / 2.61 mmol / benzenesulfonyl chloride. The solution was stirred at room temperature for 16 hours, concentrated, dissolved in ethyl acetate, then washed with 1 N potassium hydrogen sulfate, saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated to give a clear oil. It was recrystallized from diethyl ether and hexane to obtain 0.73 g of [2R-hydroxy-3 - [(phenylsulfonyl) (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] -carbamic acid phenylmethyl ester, m.p. 95-99 ^o C mass spectrum m / e = 511 / M + H /.

Part C:
A solution of 500 mg of [2R-hydroxy-3 - [(phenylsulfonyl) (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] -carbamic acid phenylmethyl ester in 20 ml of methanol was hydrogenated in the presence of 250 mg of 10% palladium on a carbon catalyst with 40 psi for 3 hours, the catalyst was removed by filtration and the solution was concentrated to obtain 352 g of [2R-hydroxy-3 - [(phenylsulfonyl) (2-methylpropyl) amino] - 1S- (phenylmethyl) propylamine, mass spectrum m / e = 377 / M + H /, which was used immediately without purification in the next step.

Part D:
To a solution of 1.24 mmol of 5-norbornene-2,3-dicarboxyimidocarbonochloride / Henklein P., et al., Synthesis 1987, 166-167 / in 1 ml of anhydrous methylene chloride was added a solution of 43 μl / 2.44 mmol / 3-pyridylcarbinol in 129 μl / 1.6 mmol / pyridine in 1 ml of methylene chloride at 0 ^° C. under nitrogen. After 4 hours at room temperature, 150 mg / 0.4 mmol / [2R-hydroxy-3 - [(phenylsulfonyl) (2-methylpropyl) amino] - 1S- (phenylmethyl) propylamine from part C and 100 μl of pyridine were added. After stirring for 15 hours at room temperature, ethyl acetate was added, then washed with 1 N HCl, saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated to obtain 175 mg of the crude product. Silica gel chromatography using 1% methanol / methylene chloride gave 69 mg of pure 3-pyridyl methyl ether [2R-hydroxy-3 - [(phenylsulfonyl) (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid, mass -spectrum m / e = 512.2267 / M + H /; calculated for C ₂₇ H ₃₃ N ₃ O ₅ S: 512.2219.

Получение 3-пиридилметилового эфира [2R-гидрокси-3-[[(4-метоксифенил) сульфонил] (2-метилпиридил)амино] - 1S-(фенилметил)пропил]-карбаминовой кислоты, N-оксида.Example 13D

Preparation of [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpyridyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid, N-oxide 3-pyridylmethyl ester.

To a solution of 211 mg / 0.39 mmol / 3-pyridylmethyl ester of [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] -carbamic acid in 5 ml of methylene chloride at 0 ^° C. was added 500 mg of 50% 3-chloroperbenzoic acid. After stirring at room temperature for 1 hour, ethyl acetate was added, the solution was washed with saturated sodium bicarbonate, 0.2 N ammonium hydroxide solution and brine, dried over magnesium sulfate, filtered and concentrated to give 200 mg of a crude product. It was chromatographed on a C18 reverse phase material (column) using a mixture of 20-40% acetonitrile / water, then 100% acetonitrile, to give 90 mg of the desired product, which was then recrystallized from ethyl acetate / isooctane to obtain 34 mg of the title compound example in pure form. Mass spectrum m / e = 564 / M + Li /.

Получение 3-пиридилметилового эфира [2R-гидрокси-3-[[(4-гидроксифенил)сульфонил] (2-метилпропил)амино] - 1S-(фенилметил)пропил] -карбаминовой кислоты
Часть A:
Раствор 0,98 г (1,85 ммоля) фенилметилового эфира
[2R-гидрокси-3-[[(4-фторфенил)сульфонил] (2-метилпропил)амино] - 1S-(фенилметил)пропил]-карбаминовой кислоты в 3,8 мл безводного DMF добавляли к 22 мг /7,4 ммоля/ 80% гидрида натрия в 2 мл DMF. К этой смеси добавляли 0,40 г /3,7 ммоля/ бензилового спирта. После 2 часов раствор охлаждали до 0^oC, добавляли воду и затем этилацетат. Органический слой промывали 5% лимонной кислотой, насыщенным раствором бикарбоната натрия и солевым раствором и сушили над сульфатом магния. Фильтровали и концентрировали, получая 0,90 г неочищенного материала. Его хроматографировали на основном оксиде алюминия с применением смеси 3% метанол/метиленхлорид, получая 0,70 г циклического карбамата [2R-гидрокси-3-[(2-метилпропил)(4- гидроксифенил)сульфонил] амино-1S-(фенилметил)пропиламина. Масс-спектр m/e = 509 /M + H/.Example 13E

Preparation of [2R-hydroxy-3 - [[(4-hydroxyphenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester
Part A:
A solution of 0.98 g (1.85 mmol) of phenylmethyl ether
[2R-hydroxy-3 - [[(4-fluorophenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid in 3.8 ml of anhydrous DMF was added to 22 mg / 7.4 mmol / 80% sodium hydride in 2 ml of DMF. To this mixture was added 0.40 g / 3.7 mmol / benzyl alcohol. After 2 hours, the solution was cooled to 0 ^° C., water and then ethyl acetate were added. The organic layer was washed with 5% citric acid, saturated sodium bicarbonate and brine, and dried over magnesium sulfate. Filtered and concentrated to give 0.90 g of crude material. It was chromatographed on basic alumina using a 3% methanol / methylene chloride mixture to give 0.70 g of cyclic carbamate [2R-hydroxy-3 - [(2-methylpropyl) (4-hydroxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine . Mass spectrum m / e = 509 / M + H /.

Part B:
To a solution of 0.66 g / 1.28 mmol / cyclic carbamate from Part A in 15 ml of ethanol was added 2.6 ml / 6.4 mmol / 2.5 sodium hydroxide. After 1 hour of heating under reflux, 4 ml of water was added and the solution was refluxed for another 8 hours. Volatiles were removed, ethyl acetate was added and washed with water, brine, dried over magnesium sulfate. It was then filtered and concentrated to give 550 mg of crude 2R-hydroxy-3 - [(2-methylpropyl) (4-hydroxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine.

Part C:
A solution of crude 2R-hydroxy-3 - [(2-methylpropyl) (4-benzyloxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine in 10 ml of ethanol was hydrogenated in the presence of 500 mg of 10% palladium on a carbon catalyst at 50 psig / 50 • 6894, 757 Pa / hydrogen for 2 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 330 mg of 2R-hydroxy-3 - [(2-methylpropyl) (4-hydroxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine, mass spectrum m / e = 393 / M + H /.

Part D:
To a solution of 320 mg / 0.82 mmol / amine from Part C in 6 ml of DMF was added 192 mg / 0.76 mmol / N-hydroxysuccinimide-3-pyridylmethyl carbonate. After 15 hours at room temperature, DMF was removed in vacuo by adding ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to obtain 390 mg of crude material, chromatography on silica gel using a mixture of 50-80% ethyl acetate / hexane gave 180 mg of [2R-hydroxy-3 - [[(4-hydroxyphenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester, mass spectrum m / e = 528 / M + H /.

Получение 5-пиримидилметилового эфира [2R-гидрокси-3-[[(4-метоксифенил)сульфонил] (2-метилпропил)амино] - 1S-(фенилметил)пропил] -карбаминовой кислоты
К раствору 9,5 мг /0,09 ммоля/ 5-пиримидилкарбинола в 1 мл безводного ацетонитрила при комнатной температуре добавляли 24 мг /0,09 ммоля/ N,N-дисукцинимидилкарбоната и 19,1 мкл /0,24 ммоля/ пиридина. После перемешивания в течение 5 часов добавляли 32 мг /0,08 ммоля/ 2R-гидрокси-3-[(2-метилпропил)(4-метоксифенил)сульфонил] амино- 1S-(фенилметил)пропиламина и раствор перемешивали в течение 48 часов. После концентрирования в вакууме добавляли метиленхлорид, затем промывали смесью насыщенного раствора бикарбоната с солевым раствором /1:1/, сушили над сульфатом магния, фильтровали и концентрировали, получая 27 мг неочищенного продукта. Хроматография на силикагеле с применением смеси 2% метанол/метиленхлорид дала 22 мг целевого продукта, масс-спектр m/e = 543 /M + H/.Example 13F

Preparation of [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] - 1S- (phenylmethyl) propyl] carbamic acid 5-pyrimidylmethyl ester
To a solution of 9.5 mg / 0.09 mmol / 5-pyrimidylcarbinol in 1 ml of anhydrous acetonitrile, 24 mg / 0.09 mmol / N, N-disuccinimidyl carbonate and 19.1 μl / 0.24 mmol / pyridine were added at room temperature. After stirring for 5 hours, 32 mg / 0.08 mmol / 2R-hydroxy-3 - [(2-methylpropyl) (4-methoxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine was added and the solution was stirred for 48 hours. After concentration in vacuo, methylene chloride was added, then washed with a mixture of saturated bicarbonate solution with brine / 1: 1 /, dried over magnesium sulfate, filtered and concentrated to obtain 27 mg of a crude product. Chromatography on silica gel using a mixture of 2% methanol / methylene chloride gave 22 mg of the target product, mass spectrum m / e = 543 / M + H /.

Получение фенилметил[3-амино-1S-[[2R-гидрокси-3-[(3- пропил)(фенилсульфонил)амино]-1S-(фенилметил)амино]карбонил]-3- оксопропил]карбамата
Фенилметил[2R-гидрокси-3-[(3-пропил)(фенилсульфонил)амино] - 1S-(фенилметил)пропил] карбамат /200 мг, 0,40 ммоля/ подвергали реакции снятия защитной группы гидрированием над 10% палладием на угле и образующийся свободный амин соединяли с N-CBZ-L-аспарагином /157 мг, 0,42 ммоля/ в присутствии N-гидроксибензотриазола /114 мг, 0,84 ммоля/ и EDC /130 мг, 0,67 ммоля/, получая фенилметил[3-амино-1S-[[2R-гидрокси-3-[(3-пропил)(фенилсульфонил)амино] - 1S-(фенилметиламино] карбонил] -3-оксопропил] карбамат в виде твердого вещества. Анал. рассчит. для C₃₁H₃₈N₄O₇S•0,2H₂O: C 60,61; H 6,30; N 9,12. Определено: C 60,27; H 6,16; N 8,93.Example 14

Preparation of Phenylmethyl [3-amino-1S - [[2R-hydroxy-3 - [(3-propyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) amino] carbonyl] -3-oxopropyl] carbamate
Phenylmethyl [2R-hydroxy-3 - [(3-propyl) (phenylsulfonyl) amino] - 1S- (phenylmethyl) propyl] carbamate (200 mg, 0.40 mmol) was subjected to deprotection by hydrogenation over 10% palladium-carbon and the resulting free amine was combined with N-CBZ-L-asparagine / 157 mg, 0.42 mmol / in the presence of N-hydroxybenzotriazole / 114 mg, 0.84 mmol / and EDC / 130 mg, 0.67 mmol /, obtaining phenylmethyl [ 3-amino-1S - [[2R-hydroxy-3 - [(3-propyl) (phenylsulfonyl) amino] - 1S- (phenylmethylamino] carbonyl] -3-oxopropyl] carbamate as a solid. Anal Calcd for C ₃₁ H ₃₈ N ₄ O ₇ S • 0.2H ₂ O: C 60.61; H 6.30; N 9.12. Defined : C 60.27; H 6.16; N 8.93.

Получение N1[2R-гидрокси-3-[(3 -метилбутил)(фенилсульфонил) амино]-N4- метил-1S-(фенилметил)пропил]-2S-[(2- хинолинилкарбонил)амино]бутандиамида
Часть A:
N2-[(1,1-диметилэтокси) карбонил] -N-метил-L-аспарагин получали из α-бензилового эфира Boc-L-аспарагиновой кислоты /1,0 г, 3,09 ммоля/, метиламина•HCl /209 мг, 3,09 ммоля/, EDC /711 мг, 3,7 ммоля/, 1-гидроксибензотриазола /627 мг, 4,63 ммоля/ и N-метилморфолина /0,7 мл, 6,3 ммоля/ в DMF /20 мл/. После перемешивания в течение ночи при ком. температуре реакционную смесь разбавляли этилацетатом, промывали водой, насыщенным раствором бикарбоната натрия, 5% лимонной кислотой, солевым раствором, сушили над сульфатом магния и концентрировали до масла, масло растворяли в 20 мл сухого этанола и гидрировали в присутствии 10% (вес/вес) палладия на угле при атмосферном давлении и комнатной температуре в течение ночи. Смесь фильтровали через целит и концентрировали до белой твердой пены, 670 мг.Example 15A

Preparation of N1 [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -N4-methyl-1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide
Part A:
N2 - [(1,1-dimethylethoxy) carbonyl] -N-methyl-L-asparagine was obtained from Boc-L-aspartic acid α-benzyl ester (1.0 g, 3.09 mmol), methylamine • HCl / 209 mg , 3.09 mmol /, EDC / 711 mg, 3.7 mmol /, 1-hydroxybenzotriazole / 627 mg, 4.63 mmol / and N-methylmorpholine / 0.7 ml, 6.3 mmol / in DMF / 20 ml /. After stirring overnight at room temperature. temperature, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, 5% citric acid, brine, dried over magnesium sulfate and concentrated to oil, the oil was dissolved in 20 ml of dry ethanol and hydrogenated in the presence of 10% (w / w) palladium on coal at atmospheric pressure and room temperature overnight. The mixture was filtered through celite and concentrated to a white solid foam, 670 mg.

Part B:
A solution of phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] - 1S- (phenylmethyl) propyl] carbamate / 310 mg, 0.59 mmol / in methanol / 10 ml / was hydrogenated over 10% palladium per coal for 3 hours, filtered through diatomaceous earth and concentrated, obtaining the product as an oil / 214 mg /. This free amine (208 mg, 0.53 mmol) was combined with N2 - [(1,1-dimethylethoxy) carbonyl] -N-methyl-L-asparagine (137 mg, 0.76 mmol) and EDC / 130 mg, 0 67 mmol /, yielding 290 mg of N1 (2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -N4-methyl-1S- (phenylmethyl) propyl] -2S - [(1,1-dimethylethoxycarbonyl) amino] butanediamide.

Part C:
N1 [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -N4-methyl-1S- (phenylmethyl) propyl] -2S- [1,1-dimethylethoxycarbonyl) amino] butanediamide / 270 mg, 0, 43 mmol / was stirred in 4 N HCl in dioxane / 5 ml / at room temperature for 0.5 hours. The solvent and excess reagent were evaporated to dryness. The product was dried in vacuo. This material (125 mg, 0.225 mmol) was then reacted with ether of N-hydroxysuccinimide and 2-quinoline carboxylic acid / 61 mg, 0.225 mmol /, N-methylmorpholine / 50 μl, 0.45 mmol / in methylene chloride / 2 ml / for 3 hours. The product N1 [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -N4-methyl-1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide was purified by silica gel chromatography. Anal will calculate. for C ₃₆ H ₄₃ N ₅ O ₆ S • 0.2 H ₂ O: C 63.83; H 6.45; N, 10.34. Defined: C 63.64; H 6.40; N, 10.34.

Получение (4-метоксифенил)метилового эфира [3-[[2-гидрокси-3-[(3-метилбутил)(фенилсульфонил) амино]- 1-(фенилметил)пропил] амино]-2-метил-3-оксопропил]-карбаминовой кислоты, [1S-[1R^*(S^*),2S^*]]
4,10 г /7,8 ммоля/ фенилметилового эфира [2R-гидрокси-3-[(3-метилбутил) (фенилсульфонил)амино]- 1S-(фенилметил)пропил]-карбаминовой кислоты, [R-(R^*, S^*)] гидрогенировали в растворе метанола и этанола с применением каталитического 20% Pd/C при избыточном давлении 50 пси водорода в течение 3 часов. Катализатор отфильтровывали и растворители удаляли в вакууме, получая 3,0 г свободного амина.Example 15B
According to the methods described above, the following compound was also obtained:

Preparation of (4-methoxyphenyl) methyl ester [3 - [[2-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] - 1- (phenylmethyl) propyl] amino] -2-methyl-3-oxopropyl] - carbamic acid, [1S- [1R ^* (S ^* ), 2S ^* ]]
4.10 g / 7.8 mmol / of [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] - 1S- (phenylmethyl) propyl] -carbamic acid phenylmethyl ester, [R- (R ^* , S ^* )] hydrogenated in a solution of methanol and ethanol using a catalytic 20% Pd / C at an excess pressure of 50 psi of hydrogen for 3 hours. The catalyst was filtered off and the solvents removed in vacuo to give 3.0 g of free amine.

 In a separate flask, 2.09 g / 7.8 mmol / N-Moz-AMBA was added to 10 ml of dimethylformamide and 1.58 g / 1.5 equiv. / N-hydroxybenzotriazole and the solution was stirred for 30 minutes. Free amine in 10 ml of dimethylformamide was added thereto, and the reaction mixture was stirred for 20 hours. The solvent was removed by evaporation and the crude material was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with 5% potassium hydrogen sulfate and brine, dried over magnesium sulfate, filtered and concentrated to give 2.58 g of pure product after recrystallization from ethyl acetate, ether and hexane, yield 52%.

Example 16
According to the methods of examples 1-15 were obtained compounds shown in table 3.

Example 17
The compounds of this invention are effective HIV protease inhibitors. Using the enzyme text described below, the compounds shown in the examples described here inhibited the HIV enzyme. Preferred compounds of this invention and their calculated values of IC ₅₀ / inhibitory concentration of 50%, i.e. the concentration at which the inhibitory compound reduces the activity of the enzyme by 50% / are presented in table 16. The method for determining the activity of the enzyme is described below. The substrate is 2-Ile-Nle-Phe (p-NO ₂ ) -Gln-Arg-NH ₂ . Positive control - MVT-101 / Miller M., et al., Science, 246, 1149/1989 //. Test conditions are as follows:
Test buffer: 20 mM sodium phosphate, pH 6.4
20% glycerin
1 mm EDTA
1 mm DTG
0.1% CHAPS
The above substrate was dissolved in DMSO, then diluted 10 times with test buffer. The final substrate concentration in the test was 80 μM.

 The HIV protease was diluted with test buffer to a final enzyme concentration of 12.3 nM based on mol. masses 10780.

 The final concentration of DMSO is 14% and the final glycerol concentration is 18%. The test compound was dissolved in DMSO and DMSO was diluted to 10 x test concentration; 10 μl of the enzyme preparation was added, the materials were mixed and then this mixture was kept at ambient temperature for 15 minutes. The enzyme reaction was initiated by the addition of 40 μl of substrate. An increase in fluorescence was observed at 4 time points / 0.8, 16 and 24 minutes / at ambient temperature. Each determination was performed twice / in two cells /.

 The preceding examples can be repeated with the same success with the replacement of the generally described or specific reagent and / or / applicable conditions for the reagents and the conditions used in the preceding examples.

Example 18
The effectiveness of the compounds shown in table 15 was determined according to the above enzyme test and CEM cell test.

A method for determining the inhibition of HIV infected cells is an automated tetrazolium colorimetric test described by Pauwles et al., J. Virol. Methods, 20, 309-321 / 1988 /. Tests were performed in 96-well plates for tissue culture. CEM cells, a CD4 ⁺ cell line grown in RPM1-1640 medium (Gibco) supplemented with 10% fetal calf serum and then treated with polybrene (2 μg / ml). 80 μl of medium containing 1 • 10 ⁴ cells was poured into each cell of a tissue culture plate. 100 μl of the test compound dissolved in the culture medium (or medium without the test compound as a control) was added to each well to obtain the desired final concentration, and the cells were incubated at 37 ^° C for 1 hour. Frozen HIV-1 culture was diluted with culture medium to a concentration of 5 • 10 ⁴ TCID ₅₀ per ml / TCID ₅₀ = dose of virus that infects 50% of cells in tissue culture / and 20 μl of this virus sample / containing 1000 virus TCID ₅₀ / was added to the cells containing the test compound, and in cells containing only medium / infected control cells /. Several cells received a virus-free culture medium (uninfected control cells). Similarly, intrinsic toxicity of the test compound was determined by adding virus-free medium to several cells containing the test compound. In General, tablets for tissue culture contained the following experimental options (see table A at the end of the description).

 In experiments 2 and 4, the final concentrations of the tested compounds were 1, 10, 100 and 500 μg / ml. A positive drug control included either azidothymidine / AZT / or dideoxyinosine / ddI /. Test compounds were dissolved in DMSO and diluted with tissue culture medium so that the final concentration of DMSO did not exceed 1.5% in any case. DMSO was added to the control cells at a suitable concentration.

After the addition of the virus, the cells were incubated at 37 ^° C. in a humidified atmosphere of 5% CO ₂ for 7 days. Test compounds could be added on days 0, 2, and 5, if desired. On the 7th day after infection, cells in each cell were resuspended and 100 μl of each cell suspension was taken for analysis. 20 μl of a solution of 5 mg / ml 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) was added to each sample 100 μl of cell suspension and the cells were incubated for 4 hours at 27 ^o C in the atmosphere 5% CO ₂ . During this incubation, MTT was metabolically restored by living cells, resulting in the formation of a stained formazan product in the cell. To each sample was added 100 μl of 10% sodium dodecyl sulfate in 0.01 N HCl for cell lysis and the samples were incubated overnight. The absorbance at 590 nm was determined for each sample using a Molecular Device microplate reader. Absorption values for each series of cells were compared to assess the control viral infection, the response of uninfected control cells, and also to evaluate the test compound for its cytotoxicity and antiviral efficacy.

 The compounds of this invention are effective antiviral compounds and, in particular, effective retrovirus inhibitors, as shown above. Thus, the compounds of this invention are effective HIV protease inhibitors. It is anticipated that these compounds will also inhibit other retroviruses, such as lentiviruses, in particular other HIV strains such as HIV-2, human T-cell leukemia virus, respiratory syncytial virus, monkey-like immunodeficiency virus, dog leukemia virus, dog immunodeficiency virus, hepatadavirus, cytomegalovirus and picornavirus. Thus, the compounds of this invention are effective in the treatment and / or / prophylaxis of retroviral infections.

 The compounds of this invention may have one or more asymmetric carbon atoms and therefore are able to exist in the form of optical isomers, as well as in the form of their racemic or non-racemic mixtures. Optical isomers can be obtained by resolution of racemic mixtures according to conventional methods, for example, by formation of diastereoisomeric salts by treatment with optically active acid or base. Examples of suitable acids for this are tartaric, dibenzoyl tartaric, ditoluin tin and camphorsulfonic acid. The mixture of diastereoisomers is then separated by crystallization, followed by the isolation of optical bases from these salts. Another method for the separation of optical isomers involves the use of a chiral chromatographic column that improves the separation of enantiomers. Another available method involves the synthesis of covalent diastereomer molecules by reacting compounds of formula I with optically pure acid in an activated form or with an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional methods, such as chromatography, distillation, crystallization or sublimation, followed by hydrolysis to obtain enantiomers of the pure compound. Optically active compounds of formula I can be prepared by known methods using optically active starting materials. These isomers may be in the form of a free acid, free base, ester or salt.

 The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. These salts include / but are not limited to / the following salts: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, busulfate, butyrate, camphorite, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, hepto-heptano phosphano hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivatate, propionate, propionate, propionate, propionate, propionate, propionate, propionate cyanate, tosylate, mesylate and undecanoate. Also, basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, etc. water or oil soluble or dispersible products.

 Examples of acids that can be used to form pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium, or with organic bases.

 The total daily dose administered to the host as a single dose or as divided doses is, for example, 0.01-10 mg / kg body weight per day, and more usually 0.01-1 mg. The composition of the standard dose may contain such amounts in separate dosages so that you can get a daily dose.

 The amount of active ingredient that can be combined with carrier materials to form a unit dosage form will vary depending on the host being treated and on the route of administration.

 The dosage regimen for treating a disease with the compounds and / or / compositions of this invention is selected in accordance with a variety of factors, including factors such as type, age, weight, gender, diet and treatment conditions of the patient, severity of the disease, route of administration, pharmacological properties such as activity, efficacy, pharmacokinetic and toxicological profiles of the compound used, and also depending on whether the drug delivery system is used or the compound is administered as part of a combination vannogo drug. Therefore, in reality, the reception pattern can vary widely and therefore deviate from the preferred reception pattern described above.

 The compounds of this invention can be administered orally, parenterally, using an inhaler, rectally or topically in unit dosage form containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients, if desired. Topical administration may also include the use of transdermal patches and iontophoresis devices for transdermal administration. The term parenteral here includes subcutaneous injections, intravenous, intramuscular, intrathoracic injections or infusion methods.

 Injectable preparations, for example, injectable aqueous or oily suspensions, may be prepared using suitable dispersing or moisturizing and suspending agents. Such sterile injectable preparations may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable excipients and solvents, water, Ringer's solution and isotonic sodium chloride solution may be used. In addition, sterile fixed oils are used as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injectable preparations.

 Suppositories for rectal administration can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures and melt at the temperature in the rectum to release the drug.

 Solid dosage forms for oral administration may be capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as in normal practice, additional substances other than inert diluents, for example, lubricants, such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. Tablets and pills may have an outer coating.

 Liquid dosage forms for oral administration may be pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in pharmacology, such as water. Such compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, as well as sweetening and flavoring agents.

 Although the compounds of this invention can be administered as a single active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents, or other anti-infectious agents. For example, the compounds of this invention can be administered in combination with AZT, DDI, DDC, or with glucosidase inhibitors, such as N-butyl-1-deoxyjiramycin or its prodrugs, for the prevention and / or / treatment of AIDS. When administered as a combination, these therapeutic agents can be formulated as separate compositions that are given simultaneously or at other times, or these therapeutic agents can be given as a single composition with the compounds of this invention.

 The foregoing is merely an illustration of the present invention and should not limit the invention to the described compounds only. Variations and changes that are obvious to those skilled in the art and which are defined in the appended claims are contemplated within the scope and nature of the invention.

 From the foregoing description, those skilled in the art can easily determine the main characteristics of the invention and, without departing from the scope and scope of the invention, can make various changes and modifications to the invention to adapt it to various conditions and applications.

Claims (60)

1. Derivatives of hydroxyethylaminosulfonamides of the General formula

or their pharmaceutically acceptable salts,
where R is phenyl-C ₁ -C ₈ alkoxycarbonyl, where phenyl may be substituted with C ₁ -C ₈ alkoxy; quinolinylcarbonyl, mono- or di-C ₁ -C ₈ alkylamino-C ₁ -C ₈ alkanoyl; R 'is hydrogen, C ₁ -C ₈ alkyl;
R ¹ is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, -C (O) NH ₂ , CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHCH ₃ , C (CH ₃ ) ₂ (SCH ₃ ), an amino acid side chain such as glycine;
R ^{1 '} and R ^1''are both hydrogen;
R ² is phenyl-C ₁ -C ₈ alkyl;
R ³ is hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy-C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl;
R ⁴ is C ₁ -C ₈ alkyl, phenyl, methoxyphenyl;
R ⁶ is hydrogen;
Y is oxygen;
x is 1 or 2;
t = 0 or 1. 2. The compound according to claim 1, in which R ¹ - C ₁ -C ₄ alkyl. 3. The compound according to claim 1, in which R ¹ - C ₁ -C ₈ alkyl and an amino acid side chain, such as glycine.  4. The compound according to claim 3, in which R is 2-quinolinylcarbonyl. 5. The compound according to claim 1, in which R ¹ is methyl. 6. The compound according to claim 5, in which R is phenyl-C ₁ -C ₈ alkoxycarbonyl.  7. The compound according to claim 5, in which R is benzyloxycarbonyl or p-methoxybenzyloxycarbonyl. 8. The compound according to claim 1, which is a
phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (methylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
N1- [2R-hydroxy-3 - [(3-methylbutyl) (methylsulfonyl) amino] -1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide;
N1- [2R-hydroxy-3 - [(3-methylbutyl) (methylsulfonyl) amino] -1S- (phenylmethyl) propyl] -2S - [(phenylmethyloxycarbonyl) amino] butanediamide;
N1- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide;
N1- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -2S - [(phenylmethyloxycarbonyl) amino] butanediamide;
2S - [[(dimethylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide;
2S - [[(methylamino) acetyl] amino] -N- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3,3-dimethylbutanamide;
N1- [2R-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -N4-methyl-1S- (phenylmethyl) propyl] -2S - [(2-quinolinylcarbonyl) amino] butanediamide;
[3 - [[2-hydroxy-3 - [(3-methylbutyl) (phenylsulfonyl) amino] -1- (phenylmethyl) propyl] amino] -2-methyl-3-oxopropyl] - (4-methoxyphenyl) methyl ether, [1S- (1R * (S *), 2S *]] -. 9. Derivatives of hydroxyethylaminosulfonamides of the general formula

or their pharmaceutically acceptable salts,
where R is phenyl-C ₁ -C ₈ alkoxycarbonyl, where phenyl may be substituted with C ₁ -C ₈ alkoxy, quinolinylcarbonyl, mono- or di-C ₁ -C ₈ alkylamino-C ₁ -C ₈ alkanoyl; R 'is hydrogen, C ₁ -C ₈ alkyl;
R ¹ is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, -C (O) NH ₂ , CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHCH ₃ , C (CH ₃ ) ₂ (SCH ₃ ), an amino acid side chain such as glycine;
R ² is phenyl-C ₁ -C ₈ alkyl;
R ³ is C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy-C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl;
R ⁴ is C ₁ -C ₈ alkyl, phenyl, methoxyphenyl. 10. The compound according to claim 9, in which R is phenyl-C ₁ -C ₈ alkoxycarbonyl.  11. The compound according to claim 9, in which R is 2-quinolinylcarbonyl. 12. The compound according to claim 9, in which R ¹ is C ₁ -C ₈ alkyl. 13. The compound of claim 9, wherein R ¹ is methyl, tert-butyl, isopropyl, and sec-butyl. 14. The compound according to claim 9, in which R ¹ is tert-butyl. 15. The compound according to claim 9, in which R ³ is C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxyalkyl, R ⁴ is C ₁ -C ₈ alkyl. 16. The compound according to claim 9, in which R ⁴ is phenyl. 17. The compound according to claim 9, in which R ³ and R ⁴ independently - C ₁ -C ₈ alkyl. 18. The compound of claim 8, in which R ⁴ is phenyl, methoxyphenyl. 19. The compound according to claim 9, in which R ³ is C ₂ -C ₅ alkyl. 20. The compound according to claim 9, in which R ³ is n-pentyl, n-hexyl, n-propyl, isobutyl, neopentyl, isoamyl and n-butyl. 21. The compound according to claim 9, in which R ³ and R ⁴ independently is C ₂ -C ₅ alkyl. 22. The compound of claim 9, wherein R ³ is isobutyl, n-propyl, n-butyl, isoamyl, and R ⁴ is phenyl and methoxyphenyl. 23. The compound of claim 9, wherein R ³ is isoamyl or isobutyl and R ⁴ is p-methoxyphenyl. 24. The compound of claim 9, wherein R ³ is isobutyl and R ⁴ is phenyl. 25. The compound according to claim 9, in which R ³ is n-butyl and R ⁴ is phenyl. 26. The compound according to claim 9, in which R ⁴ is C ₁ -C ₈ alkyl. 27. The compound according to claim 9, in which R ⁴ is phenyl. 28. The compound according to claim 9, in which R ⁴ is C ₁ -C ₆ alkyl. 29. The compound according to claim 9, in which R ¹ is tert-butyl. 30. The compound of claim 29, wherein R is mono-ylidi-C ₁ -C ₈ alkylamino-C ₁ -C ₈ alkanoyl.  31. The compound according to clause 29, in which R is N, N-dimethylaminoacetyl, N-methylaminoacetyl.  32. A pharmaceutical composition for inhibiting HIV protease, comprising the compound of claim 1 in an amount effective to inhibit the protease, and a pharmaceutically acceptable carrier.  33. A pharmaceutical composition for inhibiting HIV protease, comprising the compound of claim 9 in an amount effective to inhibit the protease, and a pharmaceutically acceptable carrier.  34. A method of inhibiting HIV protease, comprising using the composition of claim 32 in an amount effective to inhibit the protease.  35. A method of inhibiting HIV infection, comprising using the composition of claim 32 in an amount effective to inhibit a protease.  36. A method of inhibiting HIV protease, comprising using the composition of claim 33 in an amount effective to inhibit the protease.  37. A method of inhibiting HIV infection, comprising using the composition of claim 33 in an amount effective to inhibit a protease. 38. Derivatives of hydroxyethylaminosulfonamides of the General formula

or their pharmaceutically acceptable salts,
where R is phenyl-C ₁ -C ₈ alkoxycarbonyl, where phenyl may be substituted with C ₁ -C ₈ alkoxy, quinolinylcarbonyl, mono- or di-C ₁ -C ₈ alkylamino-C ₁ -C ₈ alkanoyl; R 'is hydrogen, C ₁ -C ₈ alkyl;
R ¹ is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, -C (O) NH ₂ , CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHCH ₃ , C (CH ₃ ) ₂ (SCH ₃ ), an amino acid side chain such as glycine;
R ^{1 '} and R ^1''are both hydrogen;
R ² is phenyl-C ₁ -C ₈ alkyl;
R ³ is C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy-C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl;
R ⁴ is C ₁ -C ₈ alkyl, phenyl, methoxyphenyl. 39. The compound of claim 38, wherein R 'is hydrogen and R is phenyl-C ₁ -C ₈ alkoxycarbonyl.  40. The compound of claim 38, wherein R 'is hydrogen and R is 2-quinolinylcarbonyl. 41. The compound according to § 38, in which R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₈ alkenyl, -CH ₂ C (O) NH ₂ , -CH ₂ C (O) NHCH ₃ , - C (O) NH ₂ , -C (CH ₃ ) ₂ (SCH ₃ ). 42. The compound of claim 38, wherein R ¹ is hydrogen, methyl, ethyl, —C (O) NH ₂ . 43. The compound of claim 38, wherein R ¹ is hydrogen. 44. The compound of claim 38, wherein R is phenyl-C ₁ -C ₈ alkoxycarbonyl.  45. The compound of claim 38, wherein R is 2-quinolinylcarbonyl. 46. The compound of claim 38, wherein R ³ and R ^{4 are} independently C ₁ -C ₈ alkyl. 47. The compound of claim 38, wherein R ³ is C ₁ -C ₈ alkyl and C ₂ -C ₈ alkenyl and R ⁴ is phenyl. 48. The compound of claim 38, wherein R ³ is C ₂ -C ₅ alkyl. 49. The compound of claim 38, wherein R ³ is n-propyl, isobutyl, isoamyl and n-butyl, and R ⁴ is phenyl and methoxyphenyl. 50. The compound of claim 38, wherein R ³ is isoamyl and n-butyl and R ⁴ is phenyl and methoxyphenyl. 51. The compound of claim 38, wherein R ³ is isobutyl and n-propyl and R ⁴ is phenyl and methoxyphenyl. 52. The compound of claim 38, wherein R ⁴ is phenyl. 53. The compound of claim 38, wherein R ⁴ is phenyl and p-methoxyphenyl.  54. A pharmaceutical composition for inhibiting HIV protease, comprising the compound of claim 38 in an amount effective to inhibit the protease, and a pharmaceutically acceptable carrier.  55. A method of inhibiting HIV protease, comprising using the composition of claim 54 in an amount effective to inhibit the protease.  56. A method of inhibiting HIV infection, comprising using the composition of claim 54 in an amount effective to inhibit protease. 57. Derivatives of sulfamide of the General formula

or their pharmaceutically acceptable salts,
where P ¹ is phenyl-C ₁ -C ₈ alkoxycarbonyl, phenylcarbonyl, where phenyl may be substituted with one or two substituents selected from halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -SO ₂ CY ₃ groups, -CH ₂ SO ₂ CH ₃ , heteroaryl-C ₁ -C ₈ alkoxycarbonyl, heteroarylcarbonyl, where heteroaryl may be substituted with C ₁ -C ₈ alkyl and contains one or two nitrogen atoms as heteroatoms, C ₁ -C ₈ alkoxycarbonyl, C ₃ -C ₈ cycloalkylcarbonyl;
R ² is hydrogen;
R ² is phenyl-C ₁ -C ₈ alkyl;
R ³ is C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy-C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl;
R ⁴ is C ₁ -C ₈ alkyl, phenyl optionally substituted with halogen, C ₁ -C ₈ alkyl, hydroxy, NO ₂ , C ₁ -C ₈ alkoxy, dimethylamino. 58. The compound of claim 57, which is
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-fluorophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-nitrophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-chlorophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-acetamidophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-aminophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (4-methoxyphenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (4-fluorophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (4-nitrophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(3-methylbutyl) (4-chlorophenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1S- (4-fluorophenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(2-methylpropyl) (4-fluorophenylsulfonyl) amino] -1S- (4-fluorophenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(butyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(cyclohexylmethyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(cyclohexyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
phenylmethyl [2R-hydroxy-3 - [(propyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] carbamate;
pentamide 2S - [[(dimethylamino) acetyl] amino] -N-2R-hydroxy-3 - [(3-methylpropyl) (4-methoxyphenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3S-methyl;
pentamide 2S - [[(methylamino) acetyl] amino] -N-2R-hydroxy-3 - [(4-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3S-methyl;
pentamide 2S - [[(dimethylamino) acetyl] amino] -N-2R-hydroxy-3 - [(4-methylbutyl) (phenylsulfonyl) amino] -1S- (phenylmethyl) propyl] -3S-methyl;
[2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propylamine;
2R-hydroxy-3 - [(2-methylpropyl) (4-hydroxyphenyl) sulfonyl] amino-1S- (phenylmethyl) propylamine;
[2R-hydroxy-3 - [(phenylsulfonyl) (3-methylbutyl) amino] -1S- (phenylmethyl) propylamine;
[2R-hydroxy-3 - [(phenylsulfonyl) (2-methylpropyl) amino] -1S- (phenylmethyl) propylamine;
[2R-hydroxy-3 - [(phenylsulfonyl) (cyclohexylmethyl) amino] -1S- (phenylmethyl) propylamine;
[2R-hydroxy-3 - [(phenylsulfonyl) (cyclohexyl) amino] -1S- (phenylmethyl) propylamine;
4- Pyridinecarboxamide N- [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl];
benzamide N- [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] -2,6-dimethyl;
benzamide N- [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] -2-methyl;
benzamide N- [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] -2-ethyl;
benzamide N- [2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] -2-chloro;
[2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester;
[2R-Hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid N-oxide 3-pyridylmethyl ester;
[2R-hydroxy-3 - [[phenylsulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester;
[2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 4-pyridylmethyl ester;
[2R-Hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid N-oxide 4-pyridylmethyl ester;
[2R-hydroxy-3 - [[(4-chlorophenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester;
[2R-hydroxy-3 - [[(4-nitrophenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester;
[2R-hydroxy-3 - [[(4-fluorophenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester;
[2R-Hydroxy-3 - [[(4-hydroxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 3-pyridylmethyl ester; or
[2R-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methylpropyl) amino] -1S- (phenylmethyl) propyl] carbamic acid 5-pyridylmethyl ester.  59. A pharmaceutical composition for inhibiting HIV protease, comprising the compound of claim 57 in an amount effective to inhibit the protease, and a pharmaceutically acceptable carrier.  60. A method of inhibiting HIV protease, comprising using the composition of claim 59 in an amount effective to inhibit the protease.  61. A method of inhibiting HIV infection, comprising using the composition of claim 59 in an amount effective to inhibit protease.

Images