Antiretroviral hydrazine derivatives

A compound of formula I ##STR46## wherein R.sub.1 and R.sub.9 are each independently of the other hydrogen,

• lower alkoxycarbonyl,
• 2-halo-lower alkoxycarbonyl,
• aryloxycarbonyl wherein aryl has from 6 to 14 carbon atoms,
• aryl-lower alkoxycarbonyl wherein aryl has from 6 to 14 carbon atoms,
• 2-tri-lower alkylsilyl-lower alkoxycarbonyl,
• 2-triarylsilyl-lower alkoxycarbonyl wherein aryl is phenyl or 1- or 2-naphthyl,
• the radical, bonded via the carboxy group, of an amino acid selected from glycine, alanine, valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, b-phenylserine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, d-hydroxylysine, ornithine, a,g-diaminobutyric acid and a,b-diaminopropionic acid in the D-, L- or (D,L)-form, and wherein the a-amino group may be unsubstituted or mono- or di-N-alkylated by lower alkyl, by amino-lower alkyl or by phenyl- or naphthylamino-lower alkyl, or may be N-acylated by lower alkanoyl;
• by aryl-lower alkanoyl wherein aryl is selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl and may be unsubstituted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, sulfo, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower alkylaminosulfonyl, nitro and/or by cyano, wherein phenyl may be present up to three times, and wherein lower alkanoyl may be unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, acetoacetoxy, amino- or benzyloxy-carbonylamino-lower alkanoyloxy, aryl-lower alkanoyloxy wherein aryl has from 6 to 10 carbon atoms, lower alkoxycarbonyloxy, mono- or di-lower alkylaminocarbonyloxy, aryloxycarbonyloxy wherein aryl has from 6 to 10 carbon atoms, aryl-lower alkoxycarbonyloxy wherein aryl has from 6 to 14 carbon atoms, sulfonyloxy, lower alkylsulfonyloxy, phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy or 1- or 2-naphthylsulfonyloxy, carboxy, esterified carboxy selected from lower alkoxycarbonyl, aryloxycarbonyl wherein aryl has from 6 to 10 carbon atoms, aryl-lower alkoxycarbonyl wherein aryl has from 6 to 12 carbon atoms, lower alkanoyl, lower alkylsulfonyl, hydroxy-lower alkoxyphosphoryl and di-lower alkoxyphosphoryl, carbamoyl, carbamoyl substituted by one or two radicals selected from lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, di-lower alkylamino-lower alkyl, aminocarboxy-lower alkyl, hydroxy-lower alkyl and di-lower alkoxy-lower alkyl sulfamoyl, phosphono, oxo and/or by cyano and is branched or unbranched;
• by heterocyclyl-lower alkanoyl selected from morpholinyl-, thiomorpholinyl- and S,S-dioxothiomorpholinyl lower alkanoyl (including -carbonyl), the mentioned heterocyclyl radicals being unsubstituted or substituted by lower alkyl, phenyl, 1- or 2-naphthyl, phenyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenoxy- or naphthyloxy-lower alkyl, phenyl-lower alkoxy- or naphthyl-lower alkoxy-lower alkyl, lower alkanoyloxy-lower alkyl, phenyl- or naphthyl-lower alkanoyloxy-lower alkyl, lower alkoxycarbonyloxy-lower alkyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyloxy-lower alkyl, amino-lower alkyl, carboxy-lower alkyl, hydroxy, lower alkoxy, phenyl- or naphthyl-lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbonyl, phenyl- or naphthyl-lower alkoxycarbonyl, halogen, lower alkanoyl, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl, dialkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, hydroxy- or carboxy-lower alkylcarbamoyl, sulfamoyl, nitro, oxo and/or by cyano;
• by carboxy-lower alkanoyl;
• by lower alkoxycarbonyl-lower alkanoyl;
• by hydroxy-lower alkoxy-lower alkanoyl;
• by amino-lower alkanoyl;
• or by benzyloxy-carbonylamino-lower alkanoyl wherein the amino group is not bonded in the a- or b-position;
• by carbamoyl;
• by phenyl-lower alkylaminocarbonyl;
• by N-di-lower alkylamino-lower alkyl-N-lower alkylaminocarbonyl;
• by N-dihydroxy-lower alkyl-N-lower alkylaminocarbonyl;
• by sulfonyl;
• by lower alkylsulfonyl;
• by arylsulfonyl wherein aryl has from 6 to 10 carbon atoms and is unsubstituted or substituted by lower alkyl or by lower alkoxy;
• by sulfamoyl;
• a carboxy group of the side chain is present in free form or in esterified form as a lower alkyl ester group, as an aryl ester group or as an aryl-lower alkyl ester group, wherein aryl is phenyl, 4-nitrophenyl, naphthyl or biphenylyl, or in amidated form as a carbamoyl, lower alkylcarbamoyl, di-lower alkylaminocarbamoyl, mono- or di-(hydroxy-lower alkyl)-carbamoyl or mono- or di-(carboxy-lower alkyl)-carbamoyl group,
• an amino group of the side chain is present in free form or in alkylated form as mono- or di-lower alkylamino or in acylated form as lower alkanoylamino, as amino-lower alkanoylamino, as aryl-lower alkanoylamino wherein aryl has from 6 to 14 carbon atoms and is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, carboxy, carbamoyl or by sulfamoyl, as a lower alkoxycarbonylamino group, an arylmethoxycarbonylamino group wherein aryl has from 6 to 14 carbon atoms, morpholinocarbonyl, thiomorpholinocarbonyl or as S,S-dioxothiomorpholinocarbonyl and/or
• a hydroxy group of the side chain is present in free form or in etherified or esterified form as a lower alkoxy, aryl-lower alkoxy, lower alkanoyloxy or lower alkoxycarbonyloxy group,
• lower alkylsulfonyl, (2- or 3-morpholinyl)-, (2- or 3-thiomorpholinyl)- or (S,S-dioxothiomorpholin-2- or -3-yl)-, (2- or 3-indolinyl)-, methylsulfonyl,
• phenyl- or 1- or 2-naphthyl-sulfonyl that is unsubstituted or mono- or di-substituted by lower alkyl,
• lower alkoxysulfonyl, or
• benzyloxysulfonyl or 1- or 2-naphthyloxysulfonyl,
• with the result that not more than one of the radicals R.sub.1 and R.sub.9 may be hydrogen, and R.sub.2 and R.sub.8 are each independently of the other hydrogen or the same radicals as R.sub.1 and R.sub.9,
• R.sub.3 is
• cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 7 carbon atoms and is unsubstituted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, nitro and/or by cyano and is bonded to lower alkyl, or
• aryl-lower alkyl wherein aryl is selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl, which may be unsubstituted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, sulfo, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, nitro and/or by cyano, wherein phenyl may be present up to three times, and wherein lower alkyl is unsubstituted or substituted by lower alkyl, heterocyclyl selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, b-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be fully or partially saturated, hydroxy, lower alkoxy, lower alkanoyloxy, acetoacetoxy, amino- or benzyloxycarbonylamino-lower alkanoyloxy, aryl-lower alkanoyloxy wherein aryl has from 6 to 10 carbon atoms, lower alkoxycarbonyloxy, mono- or di-lower alkylaminocarbonyloxy, aryloxycarbonyloxy wherein aryl has from 6 to 10 carbon atoms, aryl-lower alkoxycarbonyloxy wherein aryl has from 6 to 12 carbon atoms, sulfonyloxy, lower alkylsulfonyloxy, phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy or 1- or 2-naphthylsulfonyloxy, amino, mono- or di-lower alkylamino, N-lower alkoxy-N-lower alkylamino, mono- or di-(phenyl- or naphthyl-lower alkyl)-amino, lower alkanoylamino, carboxy, esterified carboxy selected from lower alkoxycarbonyl, aryloxycarbonyl wherein aryl has from 6 to 10 carbon atoms, aryl-lower alkoxycarbonyl wherein aryl has from 6 to 12 carbon atoms, lower alkanoyl, lower alkylsulfonyl, hydroxy-lower alkoxyphosphoryl and di-lower alkoxyphosphoryl, carbamoyl, carbamoyl substituted by one or two radicals selected from lower alkyl, from carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl, from di-lower alkylamino-lower alkyl, from aminocarboxy-lower alkyl, from hydroxy-lower alkyl and from di-lower alkoxy-lower alkyl, or carbamoyl substituted by one radical selected from ethylene, trimethylene, tetramethylene and pentamethylene in which a carbon atom may have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by oxygen and which may be unsaturated, and also sulfamoyl, phosphono, benzofuranyl, oxo and/or by cyano and is unbranched or branched,
• R.sub.4 is hydrogen,
• R.sub.5 is hydroxy and
• R.sub.6 is hydrogen,
• or R.sub.5 and R.sub.5 together are oxo and
• R.sub.7 is
• lower alkyl,
• cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 7 carbon atoms and is unsubstituted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, nitro and/or by cyano and is bonded to lower alkyl,
• bicycloalkyl-lower alkyl wherein bicycloalkyl contains from 5 to 10 carbon atoms,
• tricycloalkyl-lower alkyl wherein tricycloalkyl contains from 8 to 10 carbon atoms,
• aryl-lower alkyl wherein aryl is selected from phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl, which may be unsubstituted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy, N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, halogen, carboxy, lower alkoxycarbonyl, benzyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, sulfo, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl, di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, nitro and/or by cyano, wherein phenyl may be present up to three times, and wherein lower alkyl is unsubstituted or substituted by lower alkyl, heterocyclyl selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, 1-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be fully or partially saturated, hydroxy, lower alkoxy, lower alkanoyloxy, acetoacetoxy, amino- or benzyloxycarbonylamino-lower alkanoyloxy, aryl-lower alkanoyloxy wherein aryl has from 6 to 10 carbon atoms, lower alkoxycarbonyloxy, mono- or di-lower alkylaminocarbonyloxy, aryloxycarbonyloxy wherein aryl has from 6 to 10 carbon atoms, aryl-lower alkoxycarbonyloxy wherein aryl has from 6 to 12 carbon atoms, sulfonyloxy, lower alkylsulfonyloxy, phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy, 1- or 2-naphthylsulfonyloxy, amino, mono- or di-lower alkylamino, N-lower alkoxy-N-lower alkylamino, mono- or di-(phenyl- or naphthyl-lower alkyl)amino, lower alkanoylamino, carboxy, esterified carboxy selected from lower alkoxycarbonyl, aryloxycarbonyl wherein aryl has from 6 to 10 carbon atoms, aryl-lower alkoxycarbonyl wherein aryl has from 6 to 12 carbon atoms, lower alkanoyl, lower alkylsulfonyl, hydroxy-lower alkoxyphosphoryl and di-lower alkoxyphosphoryl, carbamoyl, carbamoyl substituted by one or two radicals selected from lower alkyl, from carboxy-lower alkyl, from lower alkoxycarbonyl-lower alkyl, from di-lower alkylamino-lower alkyl, from aminocarboxy-lower alkyl, from hydroxy-lower alkyl and from di-lower alkoxy-lower alkyl, or carbamoyl substituted by one radical selected from ethylene, trimethylene, tetramethylene and pentamethylene in which a carbon atom may have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by oxygen and which may be unsaturated, and also sulfamoyl, phosphono, benzofuranyl, oxo (which is not bonded to the carbon atom that is linked to the nitrogen atom bonding the radical R.sub.7) and/or by cyano and is unbranched or branched,
• heterocyclyl-lower alkyl wherein heterocyclyl is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, .beta.-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be fully or partially saturated,
• hydroxy-lower alkyl,
• lower alkoxy-lower alkyl,
• phenoxy-lower alkyl or nitrophenoxy-lower alkyl,
• naphthyloxy-lower alkyl,
• lower alkanoyloxy-lower alkyl,
• acetoacetoxy-lower alkyl,
• arylmercapto-lower alkyl wherein aryl has from 6 to 10 carbon atoms,
• amino-lower alkyl,
• mono- or di-lower alkylamino-lower alkyl,
• phenyl- or naphthyl-amino-lower alkyl,
• lower alkanoylamino-lower alkyl,
• piperazinylcarbonyl-lower alkyl substituted at the nitrogen atom by lower alkyl,
• lower alkoxycarbonylamino-lower alkyl,
• phenyl-lower alkoxycarbonylamino-lower alkyl,
• aminocarbonylamino-lower alkyl,
• N-phenyl-lower alkyl-N-lower alkylaminocarbonylamino-lower alkyl,
• halo-lower alkyl,
• carboxy-lower alkyl,
• lower alkoxycarbonyl-lower alkyl,
• 2-halo-lower alkoxycarbonyl-lower alkyl,
• phenyl- or naphthyl-lower alkoxycarbonyl-lower alkyl,
• heterocyclyl-lower alkoxycarbonyl-lower alkyl wherein heterocyclyl is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,
• quinolyl, isoquinolyl, quinoxalinyl, .beta.-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, it also being possible for the mentioned radicals to be fully or partially saturated,
• lower alkylsulfonyl-lower alkyl,
• arylsulfonyl-lower alkyl wherein aryl has from 6 to 10 carbon atoms,
• carbamoyl-lower alkyl,
• lower alkylcarbamoyl-lower alkyl,
• di-lower alkylcarbamoyl-lower alkyl,
• hydroxy-lower alkylcarbamoyl- or di(hydroxy-lower alkyl)carbamoyl-lower alkyl,
• N-lower alkoxy-lower alkoxy-lower alkylcarbamoyl-lower alkyl,
• carboxy-lower alkylcarbamoyl- or di(carboxy-lower alkyl)carbamoyl-lower alkyl,
• carbamoyl-lower alkyl substituted at the nitrogen atom by one radical selected from ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon atom may have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by oxygen, it also being possible for the radical so formed to be fully or partially unsaturated,
• N-lower alkyl-N-heterocyclyl-lower alkylcarbamoyl-lower alkyl wherein heterocyclyl is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, .beta.-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be fully or partially saturated,
• sulfamoyl-lower alkyl,
• N-(phenyl- or naphthyl-lower alkyl)sulfamoyl-lower alkyl,
• sulfamoyl-lower alkyl substituted at the nitrogen atom by one radical selected from ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon atom may have been replaced by nitrogen, lower alkyl-substituted nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by oxygen, it also being possible for the radical so formed to be fully or partially unsaturated,
• oxo-lower alkyl (wherein oxo is not bonded to the carbon atom that is linked to the nitrogen atom that carries R.sub.7),
• cyano-lower alkyl,
• hydroxy-carboxy-lower alkyl,
• a-naphthyloxy-carboxy-lower alkyl,
• hydroxy-lower alkoxycarbonyl-lower alkyl,
• a-naphthyloxy-lower alkoxycarbonyl-lower alkyl,
• lower alkylcarbonyl-halo-lower alkyl,
• a-naphthyloxyethoxycarbonyl-lower alkyl,
• a-naphthyloxy-benzyloxycarbonyl-lower alkyl,
• esterified hydroxy-lower alkoxycarbonyl-lower alkyl wherein the hydroxy group is esterified by lower alkanoyl, cycloalkyl-lower alkanoyl wherein cycloalkyl has from 3 to 7 carbon atoms, bicycloalkyl-lower alkanoyl wherein bicycloalkyl has from 5 to 10 carbon atoms, tricycloalkyl-lower alkanoyl wherein tricycloalkyl has from 8 to 10 carbon atoms, aryl-lower alkanoyl wherein aryl has from 6 to 14 carbon atoms and may be unsubstituted or mono- to tri-substituted by lower alkyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl, di-lower alkoxyphosphoryl, carbamoyl, sulfamoyl, nitro and/or by cyano, lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or by phenyl- or fluorenyl-lower alkoxycarbonyl,
• dihydroxy-carboxy-lower alkyl,
• dihydroxy-lower alkoxycarbonyl-lower alkyl,
• dihydroxy-lower alkoxycarbonyl-lower alkyl esterified by lower alkanoyl, lower alkoxycarbonyl, phenyl- or fluorenyl-lower alkoxycarbonyl, lower alkylsulfonyl or by toluenesulfonyl,
• a-naphthyloxy-di-lower alkylamino-lower alkyl,
• a-naphthyloxy-carbamoyl-lower alkyl,
• a-naphthyloxy-oxo-lower alkyl (wherein oxo is not bonded to the carbon atom that is linked to the nitrogen atom that carries R.sub.7), or
• a-naphthyloxy-cyano-lower alkyl,
• or a salt thereof where salt-forming groups are present.