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

A compound of the formula:

• ##STR27## wherein:
• R is seIected from the group consisting of hydrogen;
• straight or branched (C.sub.1 -C.sub.8)alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, beptyl and octyl;
• .alpha.-mercapto(C.sub.1 -C.sub.4)alkyl group selected from the group consisting of mercaptomethyl, .alpha.-mercaptoethyl, .alpha.-mercapto-1-methylethyl, .alpha.-mercaptopropyl and .alpha.-mercaptobutyl;
• .alpha.-hydroxy(C.sub.1 -C.sub.4)alkyl group selected from the group consisting of hydroxymethyl, .alpha.-hydroxyethyl, .alpha.-hydroxy-1-methylethyl, .alpha.-hydroxypropyl and .alpha.-hydroxybutyl;
• carboxyl (C.sub.1 -C.sub.8) alkyl group;
• (C.sub.6 -C.sub.10) aryl group selected from the group consisting of phenyl, .alpha.-naphthyl and .beta.-naphthyl;
• substituted (C.sub.6 -C.sub.10) aryl group wherein the substitution is selected from the group consisting of 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 the group consisting of benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;
• and substituted (C.sub.7 -C.sub.9) aralkyl group wherein the substitution is selected from the group consisting of 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)alkylsulfonyl, cyano and carboxy];
• R.sup.1 is selected from the group consisting of hydrogen and (C.sub.1 -C.sub.6)alkyl selected from the group consisting of methyl, ethyl propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;
• when R does not equal R.sup.1 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the W substituent) maybe be either the racemate (DL) or either of the individual enantiomers (L or D);
• W is selected from amino;
• hydroxylamino;
• (C.sub.1 -C.sub.12) straight or branched alkyl monosubstituted amino group wherein the substitution is selected from the group consisting of methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1-methyl-l-ethylpropyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl;
• diastereomers and enantiomers of said branched alkyl monosubstituted amino group;
• (C.sub.3 -C.sub.8)cycloalkyl monosubstituted amino group wherein the substitution is selected from the group consisting of cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hept-2-yl, and bicyclo[2.2.2oct-2-yl and the diastereomers and enantiomers of said (C.sub.3 -C.sub.8)cycloalkyl monosubstituted amino group;
• [(C.sub.4 -C.sub.10)cycloalkyl]alkyl monosubstituted amino group wherein the substitution is selected from the group consisting of (cyclopropyl)methyl, (cyclopropyl)ethyl, (cyclobutyl) methyl, (trans-2-methylcyclopropyl)methyl, and (cis-2-methylcyclobutyl)methyl;
• (C.sub.3 -C.sub.10)alkenyl monosubstituted amino group wherein the substitution is selected from the group consisting of allyl, 3-butenyl, cis 2-butenyl trans 2-butenyl, 2-pentenyl, 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 wherein the substitution is selected from the group consisting of phenyl and naphthyl;
• (C.sub.7 -C.sub.10)aralkylamino group wherein aralkyl is selected from the group consisting of benzyl, 2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropyl;
• substituted (C.sub.6 -C.sub.10)aryl monosubstituted amino group wherein the substitution is selected from the group consisting of (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.2 -C.sub.14)alkylamino group wherein the substitution is selected from the group consisting of dimethyl, diethyl, diisopropyl, di-n-propyl, di-n-butyl and diisobutyl;
• symmetrical disubstituted (C.sub.3 -C.sub.14)cycloalkylamino group wherein the substitution is selected from the group consisting of dicyclopropyl, dicyclobutyl, dicyclopentyl, dicylohexyl 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 not more than 14;
• unsymmetrical disubstituted (C.sub.4 -C.sub.14)cycloalkylamino group wherein the total number of carbons in the substitution is not more than 14;
• (C.sub.2 -C.sub.8) azacycloalkyl;
• substituted (C.sub.2 -C.sub.8)azacycloalkyl group wherein the substitution is selected from the group consisting aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl, 2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl, trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo[2.1.1]hex-2-yl, 5-azabicyclo[2.1.1]hex-5-yl, 2-azabicyclo [2.2.1]hept-2-yl, 7-azabicyclo-[2.2.1]hept-7-yl, and 2-azabicyclo[2.2.2oct-2-yl;
• diastereomers and enantiomers of said (C.sub.2 -C.sub.8)azacycloalkyl and substituted (C.sub.2 -C.sub.8)azacycloalkyl group 1-azaoxacycloalkyl group selected from the group consisting of morpholinyl and 1-aza-5-oxocycloheptane;
• substituted 1-azaoxacycloalkyl group wherein the substitution is selected from the group consisting of 2-(C.sub.1 2203 -C.sub.3)alkylmorpholinyl, 3-(C.sub.1 -C.sub.3)alkylisoxazolidinyl, tetrahydrooxazinyl and 3,4-dihydrooxazinyl;
• [1,n]-diazacycloalkyl or substituted [1,n]-diazacycloalkyl group selected from the group consisting of piperazinyl, 2-(C.sub.1 -C.sub.3)alkylpiperazinyl, 4-(C.sub.1 -C.sub.3)alkylpiperazinyl, 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-di-aza-5-methylbicyclo[2.2.1]hept-2-yl, 2,3-diaza-3-methylbicyclo[2.2.2oct-2-yl, and 2,5-diaza-5,7-dimethylbicyclo[2.2.2oct-2-yl, and the diastereomers and enantiomers of said [1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl groups;
• 1-azathiacycloalkyl or substituted 1-azathiacycloalkyl group selected from the group consisting of thiomorpholinyl, 2-(C.sub.1 -C.sub.3)alkylthiomorpholinyl and 3-(C.sub.3 -C.sub.6)cycloalkylthiomorpholinyl;
• N-azolyl or substituted N-azolyl group selected from the group consisting of 1-imidazolyl, 2-(C.sub.1 -C.sub.3)alkyl-l-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-l-(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 and benzimidazolyl;
• (heterocycle)amino group selected from the group consisting of 2- or 3-furanylamino, 2- or 3-thienylamino, 2-, 3- or 4-pyridylamino, 2- or 5-pyridazinylamino, 2-pyrazinylamino, 2-(imidazolyl)amido, (benzimidazolyl)amino, and (benzothiazolyl)amino;
• substituted (heterocycle)-amino group wherein (heterocycle) amino is as defined above with substitution selected from straight or branched (C.sub.1 -C.sub.6)alkyl;
• (heterocycle)methylamino group selected from the group consisting of 2- or 3-furylmethylamino, 2- or 3-thienylmethyl- amino, 2-, 3- or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino, 2-pyrazinylmethylamino, 2-(imidazolyl)methylamino, (benzimidazolyl)methylamino, and (benzothiazolyl) methylamino;
• substituted (heterocycle)methylamino group as defined above 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 the group consisting of aminoacetic acid, .alpha.-aminopropionic acid, .beta.-aminopropionic acid, .alpha.-butyric acid, and .beta.-aminobutyric acid;
• enantiomers of said carboxy (C.sub.2 -C.sub.4)alkylamino group;
• (C.sub.1 -C.sub.4)alkoxycarbonylamino group wherein alkoxycarbonyl is selected from methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, propoxycarbonyl, isoproproxycarbonyl, 1,1-dimethylethoxycarbonyl, n-butoxycarbonyl, and 2-methylpropoxycarbonyl;
• (C.sub.1 -C.sub.4)alkoxyamino group wherein alkoxy is selected from the group consisting of methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 2-methylpropoxy, and 1,1-dimethyl ethoxy;
• (C.sub.3 -C.sub.8)cycloalkoxyamino group wherein cycloalkoxy is selected from the group consisting of cyclopropoxy, trans-1,2-dimethylcyclopropoxy, cis-1,2-dimethylcyClopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, bicyclo[2.2.1]hept-2-yloxy, and bicyclo[2.2.2oct-2-yloxy;
• diastereomers and enantiomers of said (C.sub.3 -C.sub.8)cycloalkoxyamino group;
• (C.sub.6 -C.sub.10)aryloxyamino group selected from the group consisting of phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino;
• and (C.sub.7 -C.sub.11)arylalkoxyamino group wherein arylalkoxy is selected from the group consisting of benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 2- (naphthyl) methoxy, 1- (naphthyl) methoxy and phenylpropoxy;
• R.sup.2 is selected from the group consisting of hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl group selected from the group consisting of methyl, ethyl, n-propyl and 1-methylethyl;
• (C.sub.6 -C.sub.10)aryl group selected from the group consisting of phenyl, .alpha.-naphthyl and .beta.-naphthyl;
• (C.sub.7 -C.sub.9)aralkyl group;
• 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 the group consisting of ##STR28## a five membered aromatic ring with two N, O, S or Se heteroatoms optionally having a benzo or pyrido ring fused thereto selected from the group consisting of ##STR29## a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom selected from the group consisting of ##STR30## wherein A is selected from the group consisting of hydrogen;
• straight or branched (C.sub.1 -C.sub.4)alkyl;
• C.sub.6 -aryl;
• substituted C.sub.6 -aryl wherein the substitution is selected from the group consisting of halo, (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 or carboxy;
• and (C.sub.7 -C.sub.9)-aralkyl group selected from the group consisting of benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl;
• a six membered aromatic ring with one to three N heteroatoms;
• a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom;
• and --(CH.sub.2).sub.n COOR.sup.4 where n=0-4 and R.sup.4 is selected from the group consisting of hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl group selected from the group consisting of methyl, ethyl, n-propyl and 1-methylethyl;
• and (C.sub.6 -C.sub.10)aryl group , selected from the group consisting of phenyl, .alpha.-naphthyl, and .beta.-naphthyl;
• R.sup.3 is selected from the group consisting of hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl group selected from the group consisting of methyl, ethyl, n-propyl and 1-methylethyl;
• (C.sub.6 -C.sub.10)aryl group selected from the group consisting of phenyl, .alpha.-naphthyl and .beta.-naphthyl;
• (C.sub.7 -C.sub.9)aralkyl group;
• 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 the group consisting of ##STR31## a five membered aromatic ring with two N, O, S or Se heteroatoms optionally having a benzo or pyrido ring fused thereto selected from the group consisting of ##STR32## a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom selected from the group consisting of ##STR33## wherein A is selected from the group consisting of hydrogen;
• straight or branched (C.sub.1 -C.sub.4)alkyl;
• C.sub.6 -aryl;
• substituted C.sub.6 -aryl wherein the substitution is selected from the group consisting of halo,(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 carboxyl;
• aand (C.sub.7 -C.sub.9)-aralkyl group selected from the group consisting of benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl;
• a six membered aromatic ring with one to three N heteroatoms;
• a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom;
• and --(CH.sub.2).sub.n COOR.sup.4 where n=0-4 and R.sup.4 is selected from the group consisting of hydrogen;
• straight or branched (C.sub.1 -C.sub.3)alkyl selected from the group consisting of methyl, ethyl, n-propyl and 1-methylethyl;
• and (C.sub.6 -C.sub.10)aryl selected from phenyl, .alpha.-naphthyl and .beta.-naphthyl;
• with the proviso that R.sup.2 and R.sup.3 cannot both be hydrogen;
• or R.sup.2 and R.sup.3 taken together are --(CH.sub.2).sub.2 B(CH.sub.2).sub.2 --, wherein B is selected from the group consisting (CH.sub.2).sub.n where n=0-1, --NH, straight or branched --N(C.sub.1 -C.sub.3)alkyl, --N(C.sub.1 -C.sub.4)alkoxy, oxygen, sulfur and substituted congeners selected from the group consisting of (L or D)proline, ethyl(L or D)prolinate, morpholine, pyrrolidine or piperidine;
• and the pharmacologically acceptable organic and inorganic salts or metal complexes.