7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines

A compound of the formula:

• ##STR24## wherein:
• R is a halogen selected from bromine, chlorine, fluorine and iodine;
• or R=--NR.sup.1 R.sup.2 and R.sup.1 is selected from hydrogen, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl or 1-methylpropyl and R.sup.2 is selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl with the proviso that when R=--NR.sup.1 R.sup.2 and R.sup.1 =hydrogen, R.sup.2 =methyl, ethyl, n-propyl, 1-methyl-ethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
• and when R.sup.1 =methyl or ethyl, R.sup.2 =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
• and when R.sup.1 =n-propyl, R.sup.2 =n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
• and when R.sup.1 =1-methylethyl, R.sup.2 =n-butyl, 1-methylpropyl or 2-methylpropyl;
• and when R.sup.1 =n-butyl, R.sup.2 =n-butyl, 1-methylpropyl or 2-methylpropyl;
• and when R.sup.1 =1-methylpropyl, R.sup.2 =2-methylpropyl;
• R.sup.3 is selected from hydrogen;
• straight or branched (C.sub.4 -C.sub.8)alkly group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl;
• .alpha.-mercapto(C.sub.1 -C.sub.4)alkyl group selected from mercaptomethyl, .alpha.-mercaptoethyl, .alpha.-mercapto-1-methylethyl and .alpha.-mercaptopropyl;
• .alpha.-hydroxy(C.sub.1 -C.sub.4) alkyl group selected from hydroxymethyl, .alpha.-hydroxyethyl, .alpha.-hydroxy-1-methylethyl and .alpha.-hydroxypropyl;
• carboxyl(C.sub.1 -C.sub.8)alkyl group;
• (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.naphthyl and .beta.-naphthyl;
• substituted (C.sub.6 -C.sub.10)aryl group with substitution selected from hydroxy, halogen, (C.sub.1 - C.sub.4) alkoxy, trihalo(C.sub.1 -C.sub.3)alkyl, nitro, amino, cyano, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.3)alkylamino and carboxy;
• (C.sub.7 -C.sub.9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;
• substituted (C.sub.7 -C.sub.9)aralkyl group with substitution selected from halo, (C.sub.1 -C.sub.4)alkyl, nitro, hydroxy, amino, mono- or di-substituted (C.sub.1 -C.sub.4)alkylamino, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)akkylsulfonyl, cyano and carboxy;
• R.sup.4 is selected from hydrogen and (C.sub.1 -C.sub.6)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;
• when R.sup.3 does not equal R.sup.4 the stereo-chemistry of the carbon bearing the substituent W maybe be either the racemate (DL) or the individual enatiomers (L or D);
• W is selected from hydroxylamino;
• (C.sub.7 -C.sub.12) straight or branched alkyl monosubstituted amino group with substitution selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the diastereomers and enantiomers of said branched alkyl monosubstituted amino group;
• (C.sub.1 -C.sub.4) straight or branched fluoroalkylamino group selected from trifluoromethylamino, 2,2,2-trifluoroethylamino, 3,3,3-trifluoropropylamino, 3,3,3,2,2-pentafluoropropylamino, 2,2-difluoropropylamino, 4,4,4-trifluorobutylamino and 3,3,-difluorobutylamino;
• (C.sub.3 -C.sub.8)cycloalkyl monosubsituted amino group with substitution selected from cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclo- propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.2]oct-2-yl and the diastereomers and enatiomers of said (C.sub.3 -C.sub.8 -cycloalkyl monosubstituted amino group;
• [(C.sub.4 -C.sub.10)cycloalkyl]alkyl monosubstituted amino group with substitution selected from (cyclopropylmethyl, (cyclopropyl)ethyl, (cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl, and (cis-2-methylcyclobutyl)methyl;
• (C.sub.3 -C.sub.10)alkenyl and alkynyl monosubstituted amino group with substitution selected from allyl, 3-butenyl, 2-butenyl (cis or trans), 2-pentenyl, propynyl, 4-octenyl, 2,3-dimethyl- 2-butenyl, 3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexenyl;
• (C.sub.6 -C.sub.10)aryl monosubstituted amino group with substitution selected from phenyl and naphthyl;
• (C.sub.7 -C.sub.10)aralkylamino group selected from benzylamino, 2-phenylethylamino, 1-phenylethylamino, 2-(naphthyl)-methylamino, 1-(naphthylmethylamino and phenylpropylamino;
• substituted (C.sub.6 -C.sub.10)aryl monosubsituted amino group with substitution for the (C.sub.6 -C.sub.10)aryl group selected from (C.sub.1 -C.sub.5)acyl, (C.sub.1 -C.sub.5)acylamino, (C.sub.1 -C.sub.4)alkyl, mono or disubstituted (C.sub.1 -C.sub.8)alkylamino, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkoxycarbonyl, (C.sub.1 -C.sub.4)alkylsulfonyl, amino, carboxy, cyano, halogen, hydroxy, nitro and trihalo(C.sub.1 -C.sub.3)alkyl;
• straight or branched symmetrical disubstituted (C.sub.6 -C.sub.14)alkylamino group with substitution selected from dibutyl, diisobutyl, di-s-butyl, dipentyl, diisopentyl, di-s-pentyl, dihexyl, diisohexyl and di-s-hexyl;
• symmetrical disubstituted (C.sub.6 -C.sub.14)cycloalkylamino group with substitution selected from dicyclopropyl, dicyclobutyl, dicyclopentyl, di(dicyclopropyl)methyl, dicyclohexyl and dicycloheptyl;
• straight or branched unsymmetrical disubstituted (C.sub.3 -C.sub.14)alkylamino group wherein the total number of carbons in the substitution is no more than 14;
• unsymmetrical disubstituted (C.sub.4 -C.sub.14)cycloalkylamino group wherein the total number of carbons in the substitution is no more than 14;
• (C.sub.2 -C.sub.8)azacycloalkyl and substituted (C.sub.2 -C.sub.8)azacycloalkyl group selected from 4-methylpiperidine, 4-hydroxypiperidine, 4-(hydroxymethyl)piperidine, 4-(aminomethyl)piperidine, cis-3,4-dimethylpyrrolidinyl, trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo [2.1.1.]hex2-yl, 5azabicyclo[2.1.1]hex-5-6l, 2-azabicylco[2.2.l]hept-2-yl, 7-azabicyclo[2.2.1]-hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl and the diastereomers and enantiomers of said (C.sub.2 -C.sub.8)azacycloalkyl and substituted (C.sub.2 -C.sub.8)azacycloalkyl group;
• substituted 1-azaoxacycloalkyl group selected from 2-(C.sub.1 -C.sub.3)alkylmorpholinyl, 3-(C.sub.1 -C.sub.3)alkylisoxazolidinyl, tetrahydrooxazinyl and 3,4-dihydrooxazinyl;
• [l,n]-diazacycloalkyl and substituted [l,n]-diazacycloalkyl group selected from piperazinyl, 2-(C.sub.1 -C.sub.3)alkylpiperazinyl, 4-(C.sub.1 -C.sub.3)alkyl- piperazinyl, 2,4-dimethylpiperazinyl, 4-(C.sub.1 -C.sub.4)alkoxypiperazinyl, 4-(C.sub.6 -C.sub.10)aryloxypiperazinyl, 4-hydroxypiperazinyl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl, 2,3-diaza-3-methylbicyclo[2.2.2.]oct-2-yl, 2,5-diaza-5,7-dimethyl-bicyclo[2.2.2]oct-2yl and the diastereomers or enantiomers of said [l,n]-diazacycloalkyl and substituted [l,n ]diazacycloalkyl group;
• 1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C.sub.1 -C.sub.3)alkylthiomorpholinyl and 3-(C.sub.3 -C.sub.6)cycloalkylthiomorpholinyl;
• N-azolyl and substituted N-azolyl group selected from 1-imidazolyl, 2-(C.sub.1 -C.sub.3)alkyl-1-imidazolyl, 3-(C.sub.1 -C.sub.3)alkyl-1-imidazolyl, 1-pyrrolyl, 2-(C.sub.1 -C.sub.3)-alkyl-1-pyrrolyl, 3-(C.sub.1 -C.sub.3)alkyl-1-pyrrolyl, 1-pyrazolyl, 3-(C.sub.1 -C.sub.3)alkyl-1-pyrazolyl, indolyl, 1-(1,2,3-triazolyl), 4-(C.sub.1 -C.sub.3)alkyl-1(1,2,3-triazolyl), 5-(C.sub.1 -C.sub.3)alkyl-1(1,2,3-triazolyl), 4-(1,2,4-triazolyl, 1-tetrazolyl, 2-tetrazolyl an benzimidazolyl;
• (heterocycle)amino group and substituted (heterocycle) amino said heterocycle selected from 2- or 3-furanyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 5-pyridazinyl, 2-pyrazinyl, 2-(imidazolyl), (benzimidazolyl), and (benzothiazolyl) and substitution selected from straight or branched (C.sub.1 -C.sub.6)alkyl;
• (heterocycle)methylamino group selected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3- or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino, 2-pyrazinylmethylamino, 2-(imidazolyl)methylamino, (benzimidazolyl)methylamino, and (benzothiazolyl)methylamino and substituted (heterocycle)methylamino group as defined hereinabove with substitution selected from straight or branched (C.sub.1 -C.sub.6)alkyl;
• carboxy(C.sub.2 -C.sub.4)alkylamino group selected from aminoacetic acid, .alpha.-aminopropionic acid, .beta.-aminopropionic acid, .alpha.-butyric acid, .beta.-aminobutyric acid and the enantiomers of said carboxy(C.sub.2 -C.sub.4)alkylamino group;
• 1,1,-di-substituted hydrazino group selected from 1,1-dimethylhydrazino, N-aminopiperidinyl, 1,1-diethylhydrazino, and N-aminopyrrolidinyl;
• (C.sub.1 -C.sub.4)alkoxyamino group selected from methoxyamino, ethoxyamino, n-propoxyamino, 1-emthylethoxyamino, n-butoxyamino, 2-methylpropoxyamino and 1,1-dimethylethoxyamio;
• (C.sub.3 -C.sub.8)cycloalkoxyamino group selected from cyclopropoxyamio, trans-1,2-dimethylcyclopropoxyamino, cis-1,2-dimethylcyclopropoxyamino, cyclobutoxyamino, cyclopentoxyamino, cyclohexoxyamino, cycloheptoxyamino, cyclooctoxyamino, bicyclo[2.2.1]hept-2-yloxyamino, bicyclo[2.2.2]oct-2-yloxy amino and the diastereomers and enantiomers of said (C.sub.3 -C.sub.8)cycloalkoxyamino group;
• (C.sub.6 -C.sub.10)aryloxyamino group selected from phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino;
• (C.sub.7 -C.sub.11)arylalkoxyamino group selected from benzyloxy amino, 2-phenylethoxyamino, 1-phenylethoxyamino, 2-(naphthyl)methoxyamino, 1-(naphthyl)methoxyamino and phenylpropoxyamino;
• [.beta.or .gamma.-(C.sub.1 -C.sub.3)acylamido]alkylamino group selected from 2-(formamido)ethylamino, 2-(acetamido)ethylamino, 2-(propionylamido)ethylamino, 2-(acetamido)propylamino, 2-(formamido)propylamino and the enantiomers of said [.beta.or .gamma.-(C.sub.1 -C.sub.3)acylamido]alkylamino group;
• .beta.or .gamma.-(C.sub.1 -C.sub.3)alkoxyalkylamino group selected from 2-methoxyethylamino, 2-ethoxyethylamino, 2,2-diethoxyethylamino, 2-methoxypropylamino, 3-methoxypropylamino. 3-ethoxypropylamino, 3,3-diethoxypropylamino and the enantiomers of said .beta. or .gamma.-(C.sub.1 -C.sub.3)alkoxyalkylamino grop;
• .beta., .gamma., or .delta. (C.sub.2 -C.sub.4)hydroxyalkylamino group selected from 2-hydroxyethylamino, 2-hydroxypropylamino, 3-hydroxypropylamino and 4-hydroxybutylamino;
• or R.sup.3 and W taken together are selected from --(CH.sub.2).sub.n)R.sup.5)N--, n=3-4, and --CH.sub.2 CH(OH)CH.sub.2 (R.sup.5)N-- wherein R.sup.5 is selected from hydrogen and (C.sub.1 -C.sub.3)acyl, the acyl selected from formyl, acetyl, propionyl and (C.sub.2 -C.sub.3)haloacyl selected from chloroacetyl, bromoacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,2-trifluoropropionyl;
• R.sup.6 is selected from hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl group selected from emthyl, ethyl, n-propyl or 1-methylethyl;
• (C.sub.6 -C.sub.10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
• (C.sub.7 -C.sub.9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl;
• a heterocycle grup selected from a five membered aromatic or saturated ring with one N, O, S or Se heteroatom optionally having abenzo orpyrido ring fused thereto selected from pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolindinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a five membered aromatic ring with two N, O, S or Se heteroatoms optionally having a benzo or pyrido ring fused thereto selected from imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom selected from .gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or N-aminoimidazolidinone, or a six membered aromatic ring with one to three N heteroatoms selected from pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsymtriazinyl, pyrimidinyl or (C.sub.1 -C.sub.3) alkylthiopyridazinyl, or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom selected from 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
• or --(CH.sub.2).sub.m COOR.sup.8 where m=0-4 and R.sup.8 is selected from hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;
• or (C.sub.6 -C.sub.10)aryl group selected from phenyl, .beta.-naphthyl, or .beta.-naphthyl;
• R.sup.7 is selected from hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;
• (C.sub.6 - C.sub.10)aryl group selected from phenyl, .beta.-naphthyl or .beta.-naphthyl;
• (C.sub.7 -C.sub.9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl;
• a heterocycle group selected from a five membered aromatic or saturated ring with one N, O, S or Se heteroatom optionally having a benzo or pyrido ring fused thereto selected from pyrroly, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolindinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a five membered aromatic ring with two N, O, S or Se heteroatoms optionally having a benzo or pyrido ring fused thereto selected from imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom selected from .gamma.-butyrolactam, .gamma.-butyrolactone, imidazolidinone or A-aminoimidazolidinone, or a six membered aromatic ring with one to three N heteroatoms selected from pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsymtriazinyl, pyrimidinyl or (C.sub.1 -C.sub.3)alkylthiopyridazinyl, or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom selected from 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl, 2-dioxothiomorpholinyl;
• or --(CH.sub.2).sub.m COOR.sup.8 where m=0-4 and R.sup.8 is selected from hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl;
• or (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl;
• with the proviso that R.sup.6 and R.sup.7 cannot both be hydrogen;
• or R.sup.6 and R.sup.7 taken together are --(CH.sub.2).sub.2 B(CH.sub.2).sub.2 --, wherein B is selected from (CH.sub.2)q and q=0-1, --HN, --N(C.sub.1 -C.sub.3)alkyl straight or branched, --N(C.sub.1 -C.sub.4)alkoxy, oxygen, sulfur or substituted congeners selected from (L or D)proline, ethyl(L or D)prolinate, morpholine, pyrrolidine or piperidine;
• and the pharmacologically acceptable organic and inorganic salts or metal complexes.