Process for the production of 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines

A method of producing a compound of the formula:

• ##STR25## 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-mthylpropyl 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)alkyl 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) alkylsulfonyl, 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 substitutent W may 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-trifluoro-propylamino, 3,3,3,2,2-pentafluoropropylamino, 2,2-difluoropropyl-amino, 4,4,4-trifluorobutylamino and 3,3-difluorobutylamino;
• (C.sub.3 -C.sub.8) cycloalkyl monosubstituted amino group with substitution selected from cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, 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 (cyclopropyl)methyl, (cyclopropyl)ethyl, (cycobutyl)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-(naphthyl)methylamino and phenylpropylamino;
• substituted (C.sub.6 -C.sub.10) aryl monosubstituted 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 di-substituted (C.sub.3 -C.sub.14) alkylamino groups 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-dimethyl-pyrrolidinyl, 2-azabicyclo [2.1.1]hex2-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, 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, tetrahydroox-azinyl and 3,4-dihydrooxazinyl;
• [1,n]-diazacycloalkyl and substituted [1,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) aryl-oxypiperazinyl, 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-dimethylbicyclo [2.2.2]oct-2yl and the diastereomers or enantiomers of said [1,n]-diazacycloalkyl and substituted [1,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-trizaolyl), 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 and 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, .alpha.-aminobutyric acid and the enantiomers of said carboxy(C.sub.2 -C.sub.4) alkkylamino 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, ethoxymino, n-propoxyamino, 1-methylethoxyamino, n-butoxyamino, 2-methylpropoxyamino, and 1,1-dimethylethoxyamino;
• (C.sub.3 -C.sub.8) cycloalkoxyamino group selected from cyclopropoxyamino, 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) aralalkoxyamino 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-methoxethylamino, 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 group;
• .beta., .gamma., or .delta. (C.sub.2 -C.sub.4)hydroxyalkylamino group selected from 2-hydroxyethylamino, 2-hydroxypropylamino, 3-hydroxypropylamino and 4-hydroxybutylamino;
• which comprises reating a 9-[(haloacyl)amido]-7-(substituted)-6-demethyl-6-deoxytetracycline of the formula:
• ##STR26## wherein R.sup.3 and R.sup.4 are as defined hereinabove and Y is selected from (CH.sub.2).sub.n X, n=0-5, X is halogen selected from bromine, chlorine, fluorine, or iodine;
• with a nucleophile of the formula WH, wherein W is as defined hereinabove, in a polar aprotic solvent and in an inert atmosphere.