CA2103836C - 7-(substituted)-9-[(substituted glycyl)-amido]-6-demethyl-6-deoxytetracyclines - Google Patents

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

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CA2103836C
CA2103836C CA002103836A CA2103836A CA2103836C CA 2103836 C CA2103836 C CA 2103836C CA 002103836 A CA002103836 A CA 002103836A CA 2103836 A CA2103836 A CA 2103836A CA 2103836 C CA2103836 C CA 2103836C
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amino
methyl
ethyl
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CA2103836A1 (en
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Phaik-Eng Sum
Ving J. Lee
Raymond T. Testa
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Wyeth Holdings LLC
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/30—Nitrogen atoms non-acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Abstract

The invention provides compounds of the formula (see formula I) wherein R, R3, R4 and W are defined in the specification.
These compounds are useful as antibiotic agents.

Description

31,927 Title: 7-(SUBSTITUTED)-9-[(SUBSTITUTED
GLYCYL)AMIDO]-6-DEMETHYL-6-DEOXYTETRACYCLINES
BACKGROUND OF THE INVENTION
1. Field of the Invention The invention relates to novel [4S-(4alpha, l2aalpha)]-4-(dimethylamino)-7-(substituted)-9-[(sub-stituted glycyl)amido]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecar-boxamides herein after called 7-(substituted)-9-[(sub-stituted glycyl)amido]-6-demethyl-6-deoxytetracyclines, which exhibit antibiotic activity againsts a wide spectrum of organisms including organisms which are resistant to tetracyclines and are useful as antibiotic agents.
The invention also relates to novel 9-[(haloacyl)amido]-7-(substituted)-6-demethyl-6-deoxytetracycline intermediates useful for making the novel compounds of the present invention and to novel methods for producing the novel compounds and intermediate compounds.
SUMMARY OF THE INVENTION
This invention is concerned with novel 7-(substituted)-9-[(substituted glycyl)amido]-6-de-methyl-6-deoxytetracyclines, represented by formula I
and II, which have antibacterial activity; with methods of treating infectious diseases in warm blooded animals employing these new compounds; with pharmaceutical preparations containing these compounds; with novel intermediates compounds and processes for the production of these compounds. More particularly, this invention is concerned with compounds of formula I and II which have enhanced antibacterial activity against tetracycline reisitant strains as well as a high level of activity against strains which are normally susceptible to tetracyclines.
to R N<CH3>2 OH
15 \
R3 ~~
H / \ NH2 R4 \N ~ 0 R N<CH3>2 OH
\ ~ Rs R
~~ H / \ NHCH2N~R~
R~ 'N OH

,.., In formula I and II, R is a halogen selected from bromine, chlorine, fluorine and iodine: or R = -NRiR2 and when R = -NRiR2 and R1 - hydrogen, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl:
and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, to 1-methylpropyl or 2-methylpropyl;
and when R1 - n-propyl, R2 - n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl:
and when R1 - 1-methylethyl, R2 - n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R1 - n-butyl, R2 - n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R1 - 1-methylpropyl, R2 - 2-methylpropyl:
2o R3 is selected from hydrogen: straight or branched (C4-C8)alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl;
a-mercapto(C1-C4)alkyl group selected from mercaptomethyl, a-mercaptoethyl, a-mercapto-1-methylethyl and a-mercaptopropyl:
a-hydroxy(C1-C4)alkyl group selected from hydroxymethyl, a-hydroxyethyl, a-hydroxy-1-methylethyl and a-hydroxypropyl; carboxyl(C1-C$)alkyl group;
(C6-C10)aryl group selected from phenyl, a-naphthyl and ~9-naphthyl: substituted(C6-C10)aryl group (substitution selected from hydroxy, halogen, (C1-C4)alkoxy, trihalo(C1-C3)alkyl, nitro, amino, cyano, (C1-C4)alkoxycarbonyl, (C1-C3)alkylamino and carboxy);
(C~-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl:
substituted (C~-C9)aralkyl group [substitution selected from halo, (C1-C4)alkyl, vitro, hydroxy, amino, mono-or di-substituted (C1-C4)alkylamino, (Cl-C4)alkoxy, (C1-C4)alkylsulfonyl, cyano and carboxy]:

R4 is selected from hydrogen and (C1-C6)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl:

when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the S~stituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D);

W is selected from hydroxylamino; (C~-C12) straight or branched alkyl monosubstituted amino group substitution selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the diastereomers and enantiomers of said branched alkyl monosubstituted amino group:

(C1-C4) straight or branched fluoroalkylamino group selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3,3,2,2-pentafluoropropyl, 2,2-difluoropropyl, 4,4,4-trifluorobutyl and 3,3-di-fluorobutyl; (C3-C8)cycloalkyl monosubstituted amino group substitution selected from cyclopropyl, traps-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 enantiomers of said (C3-C8)cycloalkyl monosubstituted amino group; [(C4-C10)cycloalkyl]alkyl monosubstituted amino group substitution selected from (cyclopropyl)-methyl, (cyclopropyl)ethyl, (cyclobutyl)methyl, (traps-2-methylcyclopropyl)methyl, and (cis-2-methylcyclobutyl)methyl; (C3-C10)alkenyl and alkynyl monosubstituted amino group substitution selected from allyl, 3-butenyl, 2-butenyl (cis or traps), 2-penten 1 y , propynyl, 4-octenyl, 2,3-dimethyl-2-butenyl, 3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexenyl; (C6-C10)aryl monosubstituted amino group substitution selected from phenyl and naphthyl:
(C~-C10)aralkylamino group substitution selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropyl: substituted (C6-C10)aryl monosubstituted amino group [substitution selected from (C1-C5)acyl, (C1-C5)acylamino, (C1-C4)alkyl, mono or disubstituted (C1-C$)alkylamino, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkylsulfonyl, amino, carbo xy, cyano, halogen, hydroxy, vitro and trihalo(C1-C3)alkyl]; straight or branched symmetrical disubstituted (C6-C14)alkylamino group substitution selected from dibutyl, diisobutyl, di-sec-butyl, dipentyl, diisopentyl, di-sec-pentyl, dihexyl, diiso-hexyl and di-sec-hexyl; symmetrical disubstituted (C6-C14)cycloalkylamino group substitution selected from dicyclopropyl, dicyclobutyl, dicyclopentyl, di(dicyclopropyl)methyl, dicyclohexyl and dicycloheptyl: straight or branched unsymmetrical disubstituted (C3-C14)alk lamino y group wherein the total number of carbons in the substitution is more than 14; unsymmetrical disubstituted (C4-C14)cycloalkylamino group wherein the total number of carbons in the substitution is no more than 14:

(C2-C8)azacycloalkyl and substituted (C2-C8)azacyclo-alkyl group substitution selected from 4-methylpiperi-dine, 4-hydroxypiperidine, 4-(hydroxymethyl)piperidine , 4-(aminomethyl)piperidine, cis-3,4-dimethylpyrroli-dinyl, 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, 2-azabicyclo[2.2.2]oct-2-yl and the diastereomers and enantiomers of said (C2-C$)azacyclo-alkyl and substituted (C2-C$)azacycloalkyl group;

substituted 1-azaoxacycloalkyl group substitution selected from 2-(C1-C3)alkylmorpholinyl, 3-(C1-C3)alkylisoxazolidinyl, tetrahydrooxazinyl and 3,4-dihydrooxazinyl: [l,n]-diazacycloalkyl and substituted [l,n]-diazacycloalkyl group selected from piperazinyl, 2-(C1-C3)alkylpiperazinyl, 4-(C1-C3)alkyl-piperazinyl, 2,4-dimethylpiperazinyl, 4-(C1-C4)alkoxy-piperazinyl, 4-(C6-C10)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-2-yl and the diastereomers or enantiomers of said [1,n]-diazacycloalkyl and substituted [l,n]-diazacycloalkyl group:
1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiamorpholinyl, 2-(C1-C3)alkyl-thiomorpholinyl and 3-(C3-C6)cycloalkylthiomorpholinyl:
N-azolyl and substituted N-azolyl group selected from 1-imidazolyl, 2-(C1-C3)alkyl-1-imidazolyl, 3-(C1-C3)alkyl-1-imidazolyl, 1-pyrrolyl, 2-(C1-C3)-alkyl-1-pyrrolyl, 3-(C1-C3)alkyl-1-pyrrolyl, 1-pyrazolyl, 3-(C1-C3)alkyl-1-pyrazolyl, indolyl, 1-(1,2,3-triazolyl), 4-(C1-C3)alkyl-1-(1,2,3-tri-azolyl), 5-(C1-C3)alkyl-1-(1,2,3-triazolyl), 4-(1,2,4-triazolyl, 1-tetrazolyl, 2-tetrazolyl and benzimidazolyl: (heterocycle)amino group 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 substituted (heterocycle)amino group (substitution selected from straight or branched (C1-C6)alkyl): (heterocycle)methylamino group selected from 2- or 3-furylmethylamino, 2- or 3-thienylmethyl-amino, 2-, 3- or 4-pyridylmethylamino, 2- or 5-pyrida-zinylmethylamino, 2-pyrazinylmethylamino, 2-(imidazol-yl)methylamino, (benzimidazolyl)methylamino, and (benzothiazolyl)methylamino and substituted (hetero-cycle)methylamino group (substitution selected from straight or branched (C1-C6)alkyl); carboxy(C2-C4)-alkylamino group selected from aminoacetic acid, a-aminopropionic acid, ~-aminopropionic acid, a-butyric _, _ acid, ~-aminobutyric acid and the enantiomers of said carboxy(C2-C4)alkylamino group; 1,1-disubstituted hydrazino group selected from 1,1-dimethylhydrazino, N-aminopiperidinyl, 1,1-diethylhydrazino, and N-aminopyrroli- dinyl: (C1-C4)alkoxyamino group substitution selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 2-methylpropoxy and 1,1-dimethylethoxy; (C3-C8)cycloalkoxyamino group l0 selected from cyclopropoxy, trans-1,2-dimethylcyclopropoxy, cis-1,2-dimethyl-cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, bicyclo[2.2.1]hept-2-yloxy, bicyclo[2.2.2]oct-2-yloxy and the diastereomers and enantiomers of said (C3-C$)cycloalkoxyamino group;
(C6-C10)aryloxyamino group selected from phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino;
(C~-Cil)arylalkoxyamino group substitution selected from benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxy and phenylpropoxy;
[~ or 7-(C1-C3)acylamido]alkylamino group substitution selected from 2-(formamido)ethyl, 2-(acetamido)ethyl, 2-(propionylamido)ethyl, 2-(acetamido)propyl, 2-(formamido)propyl and the enantiomers of said [~ or 7-(C1-C3)acylamido]alkylamino group; ~ or 7-(C1-C3)alkoxyalkylamino group substitution selected from 2-methoxyethyl, 2-ethoxyethyl, 2,2-diethoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3,3-diethoxypropyl and the enantiomers of said ~ or 7-'(C1-C3)alkoxyalkylamino group; ~, 7, or b (C2-C4)hydroxyalkylamino group substitution selected from 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and 4-hydroxybutyl;
or R3 and W taken together are selected from -(CH2)n(R5)N-, n= 3 - 4, and -CH2CH(OH)CH2(R5)N-wherein R5 is selected from hydrogen and (C1-C3)acyl, the acyl selected from formyl, acetyl, propionyl and z~Q~s3s (C2-C3)haloacyl selected from chloroacetyl, bromoacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl:
R6 is selected from hydrogen: straight or branched (Cl-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl: (C6-C10)aryl group selected from phenyl, a-naphthyl or ~9-naphthyl: (C~-C9)aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or 1o 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:
or Z Z
Z - N, 0, S or S~
such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrroli-dinyl, 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:
Z1 Z~
or I ~Z
~'Z
or Z~ - N, 0, S or a such as imidazolyl, pyrazolyl, benzimidazolyl, oxazo-lyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazo-lyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimid-azolyl, or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom:

21~383G
-g-N
0 \0 N \0 o r N ~0 A A
(A is selected from hydrogen; straight or branched (C1-C4)alkyl: C6-aryl: substituted C6-aryl (substitution selected from halo,(C1-C4)alkoxy, trihalo(C1-C3)alkyl, nitro, amino, cyano, (C1-C4)-alkoxycarbonyl, (C1-C3)alkylamino or carboxy); (C -C )-aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl) such as 7-butyrolactam, 7-butyrolactone, imidazolidinone or N-aminoimidazolidinone, or a six membered aromatic ring with one to three N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C1-C3) alkylthiopyri-dazinyl, or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom such as 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-dioxo-thiomorpholinyl; or -(CH2)nCOOR$ where n=0-4 and R$ is selected from hydrogen: straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C6-C10)aryl group selected from phenyl, a-naphthyl, or p-naphthyl;
R~ is selected from hydrogen: straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C6-C10)aryl group selected from phenyl, a-naphthyl or p-naphthyl; (C~-Cg)aralkyl group such as 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:
~ /~ o r Z Z_ Z - N, 0, S or Se such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrroli-dinyl, 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:
Zt Z1 or ~ ~Z
Z
Z or Z~ = N, 0, S or Se such as imidazolyl, pyrazolyl, benzimidazolyl, oxazo-lyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazo-lyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimid-azolyl, or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom:
N
or 0 0 ~ N 0 N 0 A A
(A is selected from hydrogen; straight or branched 21~3$3~

(C1-C4)alkyl; C6-aryl; substituted C6-aryl (substitution selected from halo,(Cl-C4)alkoxy, trihalo(C1-C3)alkyl, nitro, amino, cyano, (C1-C4)-alkoxycarbonyl, (C1-C3)alkylamino or carboxy); (C~-C9)-aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl) such as 7-butyrolactam, 7-butyrolactone, l0 imidazolidinone or N-aminoimidazolidinone, or a six membered aromatic ring with one to three N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C1-C3)alkylthiopyrida-zinyl, or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom such as 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 -(CH2)nCOOR$ where n=0-4 and R8 is selected from hydrogen; straight or branched (C1-C3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl: or (C6-C10)aryl selected from phenyl, a-naphthyl or ~-naphthyl; with the proviso that R6 and R~ cannot both be hydrogen;
or R6 and R~ taken together are -(CH2)2B(CH2)2 ' wherein B is selected from (CH2)n and n=0-1, -NH, -N(Cl-C3)alkyl [straight or branched], -N(C1-C4)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.
Preferred compounds are compounds according to the above formula I and II wherein:
R is a halogen selected from bromine, chlorine, fluorine and iodine; or R = -NR1R2 and when R = -NR1R2 and R1 - hydrogen, 21~383~

R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl:

and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl:

R3 is selected from hydrogen; straight or branched (C4-C8)alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl:

l0 a-hydroxy(C1-C4)alkyl group selected from hydroxymethyl, a-hydroxyethyl, a-hydroxy-1-methylethyl and a-hydroxypropyl:

carboxyl(C1-C8)alkyl group: (C6-C10)aryl group selected from phenyl, a-naphthyl and ~-naphthyl:

substituted (C6-C10)aryl group (substitution selected from hydroxy, halogen, (C1-C4)alkoxy, (C1-C4)alkoxycar-bonyl and carboxy); (C~-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl:

substituted (C~-C9)aralkyl group [substitution selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl-sulfonyl, cyano and carboxy];

R4 is selected from hydrogen and (C1-C4)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl:

when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D);

W is selected from hydroxylamino: (C~-C12) straight or branched alkyl monosubstituted amino group substitution selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the diastereomers and enantiomers of said branched alkyl monosubstituted amino group:

(C3-C8)cycloalkyl monosubstituted amino group substitution selected from cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,, cyclooctyl, and the diastereomers and 21~D3836 enantiomers of said (C3-C$)cycloalkyl monosubstituted amino group; (C1-C4) straight or branched fluoroalkyl-amino group selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2,2-difluoropropyl and 3,3-difluorobutyl, [(C4-C10)cycloalkyl]alkyl monosub-stituted amino group substitution selected from (cyclopropyl)methyl, (cyclopropyl)ethyl, (cyclobutyl)methyl, (traps-2-methylcyclopropyl)methyl, and (cis-2-methylcyclobutyl)methyl; (C3-C10)alkenyl and alkynyl monosubstituted amino group substitution selected from allyl, 3-butenyl, 2-butenyl (cis or traps), 2-pentenyl, propynyl, 4-octenyl, 2,3-dimethyl-2-butenyl and 3-methyl-2-butenyl; (C6-C10)aryl monosubstituted amino group substitution selected from phenyl and naphthyl; (C~-C10)aralkylamino group substitution selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropyl: straight or branched symmetrical disubstituted (C6-C14)alk lamino y group substitution selected from dibutyl, diisobutyl, di-s-butyl, dipentyl, diisopentyl and di-s-pentyl; symmetrical disubstituted (C6-C14)cycloalkylamino group substitution selected from dicyclopropyl, dicyclobutyl, dicyclopentyl and di(dicyclopropyl)methyl; straight or branched unsymmetrical disubstituted (C3-C14)alkylamino group wherein the total number of carbons in the substitution is no more than 14; unsymmetrical disubstituted (C4-C14)cycloalkylamino group wherein the total number of carbons in the substitution is no more than 14; (C2-C8)azacycloalkyl and substituted (C2-C8)azacycloalkyl group substitution selected from 4-methylpiperidine, 4-hydroxypiperidine, 4-(hydroxymethyl)piperidine, 4-(aminomethyl)piperidine, cis-3,4-dimethylpyrrolidinyl, traps-3,4-dimethylpyrro-lidinyl, 2-azabicyclo [2.2.1]hept-2-yl, 7-azabicyclo-[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl and the diastereomers and enantiomers of said (C2-C$)azac clo-y 21~038~~

alkyl and substituted (C2-C8)azacycloalkyl group;
substituted 1-azaoxacycloalkyl group substitution selected from 2-(C1-C3)alkylmorpholinyl, 3-(C1-C3)alkylisoxazolidinyl and tetrahydrooxazinyl:
[l,n]-diazacycloalkyl and substituted [i,n]-diazacycloalkyl group selected from piperazinyl, 2-(C1-C3)alkylpiperazinyl, 4-(C1-C3)-alkylpiperazinyl, 2,4-dimethylpiperazinyl, 4-(C1-C4)- alkoxypiperazinyl, 4-(C6-C10)ar.yloxypiperazinyl, 4-hydroxypiperazinyl, 2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl, 2,5-diaza-5,7-dimethylbicyclo[2.2.2]oct-2-yl and the diastereomers or enantiomers of said [l,n]-diazacyclo-alkyl and substituted [l,n]-di- azacycloalkyl group:
1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C1-C3)alkyl-thiomorpholinyl and 3-(C3-C6)cycloalkylthiomorpholinyl:
N-azolyl and substituted N-azolyl group selected from 1-imidazolyl, 1-pyrrolyl, 1-pyrazolyl, 3-(C1-C3)alkyl-pyrazolyl, indolyl, 1-(1,2,3-triazolyl), 4-(1,2,4-tri-azolyl), 1-tetrazolyl, 2-tetrazolyl and benzimidazolyl:
(heterocycle)methylamino group selected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3-or 4-pyridylmethylamino, 2- or 5-pyridazinylmethyl-amino, 2-pyrazinylmethylamino, 2-(imidazolyl)methyl-amino, (benzimidazolyl)methylamino, and (benzothiazol-yl)methylamino and substituted (heterocycle)methylamino group (substitution selected from straight or branched (C1-C6)alkyl); carboxy(C2-C4)alkylamino group selected from aminoacetic acid, a-aminopropionic acid, ~-aminopropionic acid, a-butyric acid, and p-aminobutyric acid and the enantiomers of said carboxy(C2-C4)alkylamino group; 1,1-disubstituted hydrazino group selected from 1,1-dimethylhydrazino, N-aminopiperidinyl and 1,1-diethylhydrazino:
(C1-C4)alkoxyamino group substitution selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 2-methylpropoxy and 1,1-dimethylethoxy;

-,~~~383~
(C3-C$)cycloalkoxyamino group selected from cyclopropoxy, trans-1,2-dimethylcyclopropoxy, cis-1,2-dimethylcyclopropoxy, cyclobutoxy, and the diastereomers and enantiomers of said (C3-C8)-cycloalkoxyamino group;
(C6-C10)aryloxyamino group selected from phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino:
(C~-C11)arylalkoxyamino group substitution selected l0 from benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxy and phenylpropoxy: [~ or 7-(C1-C3)acylamido]alkylamino group substitution selected from 2-(formamido)ethyl, 2-(acetamido)ethyl, 2-(propionylamido)ethyl, 2-(acetamido)propyl, 2-(formamido)propyl and the enantiomers of said [p or 7-(C1-C3)acylamido]-alkylamino group: ~ or 7-(C1-C3)alkoxyalkylamino group substitution selected from 2-methoxyethyl, 2-ethoxyethyl, 2,2-diethoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3,3-diethoxypropyl and the enantiomers of said ~ or 7-(C1-C3)alkoxyalkylamino group; ~, 7 or s (C2-C4) hydroxyalkylamino group substitution selected from 2-hydroxyethyl, 3-hydroxypropyl, and 4-hydroxybutyl:
or R3 and W taken together are selected from -(CH2)n(R5)N-, n= 3 - 4, and -CH2CH(OH)CH2(R5)N- wherein R5 is selected from hydrogen and (C1-C3)acyl, the acyl selected from formyl, acetyl, propionyl and (C2-C3)-haloacyl selected from chloroacetyl, bromoacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl;
R6 is selected from hydrogen: straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C6-C10)aryl group selected from phenyl, a-naphthyl or ~-naphthyl; (C~-C9)aralkyl group such as 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:
or Z Z
Z - N, 0, S or S~
such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrroli-dinyl, 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:
Z~ Z~
or ~ ~Z
'Z
Z or Z~ ~ N, 0, S or Se such as imidazolyl, pyrazolyl, benzimidazolyl, oxazo-lyl, benzoxazolyl, indazolyl, thi,azolyl, benzothiazo-lyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimid-azolyl, or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom:
0 \0 N \ ~r 0 A A
(A is selected from hydrogen; straight or branched (Cl-C4)alkyl; C6-aryl: (C~-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl) such as 7-butyrolactam, 7-butyrolactone, imidazolidinone or N-aminoimidazolidinone; or -(CH2)nCOOR$ where n=0-4 and R$ is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;
or (C6-C10)aryl group selected from phenyl, a-naphthyl, , or p-naphthyl;
R~ is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, l0 n-propyl or 1-methylethyl: (C6-C10)aryl group selected from phenyl, a-naphthyl or ~-naphthyl: (C~-C9)aralkyl group such as 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:
or Z Z
Z - N, 0, S or Se such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrroli-dinyl, 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:
Z~ Z~
I ~~ o r I ~ Z
Z
Z or Z~ - N, 0, S or Se such as imidazolyl, pyrazolyl, benzimidazolyl, oxazo-lyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazo-z~o3s3~

lyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimid-azolyl, or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom:
N
N/~~ o r N~ 0 A A
(A is selected from hydrogen: straight or branched (C1-C4)alkyl: C6-aryl: (C~-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl) such as 7-butyrolactam, 7-butyrolactone, imidazolidinone or N-aminoimidazolidinone: or -(CH2)nCOOR$ where n=0-4 and R$ is selected from hydrogen: straight or branched (C1-C3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl: or (C6-C10)aryl selected from phenyl, a-naphthyl or ~-naphthyl: with the proviso that R6 and R~ cannot both be hydrogen:
or R6 and R~ taken together are -(CH2)2B(CH2)2 ' wherein B is selected from (CH2)n and n=0-1, -NH, -N(C1-C3)alkyl [straight or branched], -N(C1-C4)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.
Particularly preferred compounds are compounds according to formula I and II wherein:
R is a halogen selected from bromine, chlorine, ~~o3s~s fluorine and iodine; or R = -NR1R2 and when R = -NR1R2 and R1 - hydrogen, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
R3 is selected from hydrogen; straight or branched l0 (C4-C6)alkyl group selected from butyl, isobutyl, pentyl and hexyl: (C6-C10)aryl group selected from phenyl, a-naphthyl and p-naphthyl; (C~-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;
R4 is selected from hydrogen and (C1-C3)alkyl selected from methyl, ethyl, propyl and isopropyl;
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D);
W is selected from (C~-C12) straight or branched alkyl monosubstituted amino group substitution selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the diastereomers and enantiomers of said branched alkyl monosubstituted amino group; (C1-C4) straight or branched fluoroalkylamino group selected from 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 2,2-di-fluoropropyl; (C3-C8)cycloalkyl monosubstituted amino group substitution selected from cyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the diastereomers and enantiomers of said (C3-C8)cycloalkyl monosubstituted amino group;
[(C4-C10)cycloalkyl]alkyl monosubstituted amino group substitution selected from (cyclopropyl)methyl, (cyclo-propyl)ethyl and (cyclobutyl)methyl; (C3-C10)alkenyl and alkynyl monosubstituted amino group substitution selected from allyl, propynyl, 3-butenyl, 2-butenyl 2~0383fi (cis or traps) and 2-pentenyl; (C~-C10)aralkylamino group substitution selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropyl: straight or branched symmetrical disubstituted (C6-C14)alkylamino group substitution selected from dibutyl, diisobutyl, di-s-butyl, and dipentyl: symmetrical disubstituted (C6-C14)cyclo-alkylamino group substitution selected from l0 dicyclopropyl, dicyclobutyl, dicyclopentyl and dicyclopropylmethyl: straight or branched unsymmetrical disubstituted (C3-C14)alkylamino group wherein the total number of carbons in the substitution is no more than 14; unsymmetrical disubstituted (C4-C14)cyclo-alkylamino group wherein the total number of carbons in the substitution is no more than 14;
(C2-C$)azacycloalkyl and substituted (C2-C8)azacyclo-alkyl group substitution selected from 4-methylpiperi-dine, 4-hydroxypiperidine, 4-(hydroxymethyl)piperidine, 4-(aminomethyl)piperidine, cis-3,4-dimethylpyrroli-dinyl, traps-3,4-dimethylpyrrolidinyl, and the diastereomers and enantiomers of said (C2-C8)azacyclo-alkyl and substituted (C2-C8)azacycloalkyl group:
substituted 1-azaoxacycloalkyl group substitution selected from 2-(C1-C3)alkylmorpholinyl and 3-(C1-C3)alkylisoxazolidinyl: [l,n]-diazacycloalkyl and substituted [l,n]-diazacycloalkyl group selected from piperazinyl, 2-(C1-C3)alkylpiperazinyl, 4-(C1-C3)-alkylpiperazinyl, 2,4-dimethylpiperazinyl, 4-hydroxypiperazinyl, and the enantiomers of said [l,n]-diazacycloalkyl and substituted [l,n]-diazacyclo-alkyl group:
1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C1-C3)alkyl thiomorpholinyl:
(heterocycle)methylamino group selected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3-or 4-pyridylmethylamino, 2- or 5-pyridazinylmethyl-21fl3$~fl amino, 2-pyrazinylmethylamino, 2-(imidazolyl)methyl-amino and the substituted (heterocycle)methylaminno group (substitution selected from straight or branched (C1-C6)alkyl): 1,1-disubstituted hydrazino group selected from 1,1-dimethylhydrazino, N-aminopiperidinyl and 1,1-diethylhydrazino;
(C1-C4)alkoxyamino group substitution selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 2-methylpropoxy and 1,1-dimethylethoxy;
(C~-C11)arylalkoxyamino group substitution selected from benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxy and phenylpropoxy;
[~ or 7-(C1-C3)acylamido]alkylamino group substitution selected from 2-(formamido)ethyl, 2-(acetamido)ethyl, 2-(propionylamido)ethyl, 2-(acetamido)propyl and 2-(formamido)propyl and the enantiomers of said [/9 or 7-(C1-C3)acylamido]alkylamino group;
p or 7-(C1-C3)alkoxyalkylamino group substitution selected from 2-methoxyethyl, 2-ethoxy-hyl, 2,2-diethoxyethyl, 2-methoxypropyl, 3-methoxy-opyl, 3-ethoxypropyl and 3,3-diethoxypropyl and the enantiomers of said ~ or 7-(C1-C3)alkoxyalkyl- amino group; ~, 7, or 6 (C2-C4) hydroxyalkylamino group selected from 3-hydroxypropyl and 4-hydroxybutyl:
or R3 and W taken together are selected from -(CH2)n(R5)N-, n= 3 - 4, and -CH2CH(OH)CH2(R5)N-wherein R5 is selected from hydrogen and (C1-C3)acyl, the acyl selected from formyl, acetyl, propionyl and (C2-C3)haloacyl selected from trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl;
R6 is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C6-C10)aryl group selected from phenyl, a-naphthyl or p-naphthyl; (C~-C9)aralkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocycle group selected from a five 21U3'$3G

member~d aromatic or saturated ring with one N, O, S or Se heteroatom optionally having a benzo or pyrido ring fused thereto:
or Z Z
Z = N, 0, S or S~
such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrroli-dinyl, 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:
Z~ Z~
/ or I /Z
Z '' Z or Z~ = N, 0, S or Se such as imidazolyl, pyrazolyl, benzimidazolyl, oxazo-lyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazo-lyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimid-azolyl; or -(CH2)nCOOR$ where n=0-4 and R8 is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;
or (C6-C10)aryl group selected from phenyl, a-naphthyl, or p-naphthyl;
R~ is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C6-C10)aryl group selected from phenyl, a-naphthyl or /9-naphthyl; (C~-C9)aralkyl group such as 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:
~ /~ o r Z Z
Z - N, 0, S or Ss such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrroli-dinyl, 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:
Z~ Z~
/> o r I / Z
Z
Z or Z~ - N, 0, S or Se such as imidazolyl, pyrazolyl, benzimidazolyl, oxazo-lyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazo-lyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimid-azolyl: or -(CH2)nCOOR8 where n=0-4 and R$ is selected from hydrogen: straight or branched (C1-C3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl;
or (C6-C10)aryl selected from phenyl, a-naphthyl or ~9-naphthyl; with the proviso that R6 and R~ cannot both be hydrogen:
or R6 and R~ taken together are -(CH2)2B(CH2)2 ' wherein B is selected from (CH2)n and n=0-l, -NH, -N(C1-C3)alkyl [straight or branched], -N(C1-C4)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 ~~03836 complexes.
Compounds of special interest are compound according to formula I and II wherein:
R is a halogen selected from bromine, chlorine and iodine; or R = -NR1R2 and when R = -NR1R2 and R1 - methyl or ethyl, R2 - methyl or ethyl, R3 is selected from hydrogen;
l0 R4 is selected from hydrogen and (C1-C2)alkyl selected from methyl and ethyl;
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D):
W is selected from (C~-C12) straight or branched alkyl monosubstituted amino group substitution selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the diastereomers and enantiomers of said branched alkyl monosubstituted amino group: (C2)fluoroalkylamino group selected from 2,2,2-trifluoroethyl and 3,3,3-tri-fluoropropyl:
(C3-C8)cycloalkyl monosubstituted amino group substitution selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the diastereomers and enantiomers of said (C3-C8)cycloalkyl monosubstituted amino group; [(C4-C5)cycloalkyl]alkyl monosubstituted amino group substitution selected from (cyclopropyl)-methyl and (cyclopropyl)ethyl; (C3-C4)alkenyl and alkynyl monosubstituted amino group substitution selected from allyl and propynyl; (C2-C~)azacycloalkyl and substituted (C2-C~)azacycloalkyl group substitution selected from 4-methylpiperidine, 4-hydroxypiperidine and 4-(hydroxymethyl)piperidine; substituted 1-azaoxacycloalkyl group substitution selected from 2-(C1-C3)alkylmorpholinyl; [l,n]-diazacycloalkyl and substituted [l,n]-diazacycloalkyl group selected from piperazinyl and 4-(C1-C3)alkylpiperazinyl;

2~o~s~~

1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C1-C3)alkylthiomorpholinyl; (heterocycle)methylamino group selected from 2- or 3-thienylmethylamino and 2-, 3- or 4-pyridylmethylamino; 1,1-disubstituted hydrazino group selected from 1,1-dimethylhydrazino and N-amino-piperidinyl. [,B or 7-(C1-C3)acylamido]alkylamino group substitution selected from 2-(acetamido)ethyl: p or ,~-(C1-C3)alko alk lamino xy y group substitution selected from 2-methoxyethyl, 2-ethoxyethyl, 2,2-diethoxyethyl, 2-methoxypropyl and 3-methoxypropyl; ~, 7 or d (C2-C4)hydroxyalkylamino selected from 4-hydroxybutyl and 3-hydroxypropyl; or R3 and W taken together are selected from -(CH
) (R5)N-, n= 3, and R5 is selected n from hydrogen and trifluoroacetyl;

R6 is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;

R~ is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; with the proviso that R6 and R~ cannot both be hydrogen;

or R6 and R~ taken together are -(CH2)2B(CH2)2 ' wherein B is selected from (CH
) and n=0-1, -NH, n -N(C1-C3)alkyl [straight or branched], -N(C1-C4)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.

Also included in the present invention are compounds useful as intermediates for producing the above compounds of formula I and II. Such intermediates include those having the formula III:

R N<CH3)2 OH
R3 ~ ( H
N / \ NH2 to R 4 O H

is wherein:
Y is selected from (CH2)nX, n= 0-5, X is halogen selected from bromine, chlorine, fluorine or iodine:
R is a halogen selected from bromine, chlorine, fluorine and iodine; or R = -NR1R2 and when R = -NR1R2 and R1 - hydrogen, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl:
and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R1 - n-propyl, R2 - n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl:
and when R1 - 1-methylethyl, R2 - n-butyl, 1-methylpropyl or 2-methylpropyl:
and when R1 - n-butyl, R2 - n-butyl, 1-methylpropyl or 2-methylpropyl:
and when R1 - 1-methylpropyl, R2 - 2-methylpropyl;
R3 is selected from hydrogen: straight or branched (C4-C8)alkyl group selected from butyl, isobutyl, ,~pentyl, hexyl, heptyl and octyl:

a-mercapto(C1-C4)alkyl group selected from mercaptomethyl, a-mercaptoethyl, a-mercapto-1-methylethyl and a-mercaptopropyl:
a-hydroxy-(C1-C4)alkyl group selected from hydroxymethyl, a-hydroxyethyl, a-hydroxy-1-methylethyl and a-hydroxypropyl: carboxyl(C1-C8)alkyl group:
(C6-C10)aryl group selected from phenyl, a-naphthyl and ~-naphthyl: substituted(C6-C10)aryl group (substitution l0 selected from hydroxy, halogen, (C1-C4)alkoxy, trihalo(C1-C3)alkyl, vitro, amino, cyano, (C1-C4)alkoxycarbonyl, (C1-C3)alkylamino and carboxy);
(C7-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;
substituted (C7-C9)aralkyl group [substitution selected from halo, (C1-C4)alkyl, vitro, hydroxy, amino, mono-or di-substituted (C1-C4)alkylamino, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, cyano and carboxy];
R4 is selected from hydrogen and (C1-C6)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D); and the pharmacologically acceptable organic and inorganic salts or metal complexes:
Preferred compounds are compounds according to the above formula III wherein:
y is selected from (CH2)nX, n= 0-5, X is halogen selected from bromine, chlorine, fluorine or iodine;
R is a halogen selected from bromine, chlorine, fluorine and iodine; or R = -NR1R2 and when R = -NR1R2 and R1 - hydrogen, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl:
and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl:
R3 is selected from hydrogen; straight or branched (C4-C8)alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl:
a-hydroxy(Cl-C4)alkyl group selected from hydroxymethyl, a-hydroxyethyl, a-hydroxy-1-methylethyl and a-hydroxypropyl:
carboxyl(Cl-C8)alkyl group; (C6-C10)aryl group selected to from phenyl, a-naphthyl and ~-naphthyl;
substituted(C6-Cl0)aryl group (substitution selected from hydroxy, halogen, (Cl-C4)alkoxy, (Cl-C4)alkoxy-carbonyl and carboxy): (C~-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenyl-propyl: substituted (C~-C9)aralkyl group [substitution selected from halo, (Cl-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, cyano and carboxy];
R4 is selected from hydrogen and (Cl-C4)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl:
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D): and the pharmacologically acceptable organic and inorganic salts or metal complexes.
Particularly preferred compounds are compounds according to formula III wherein:
Y is selected from (CH2)nX, n= 0-5, X is halogen selected from bromine, chlorine, fluorine or iodine;
R is a halogen selected from bromine, chlorine, fluorine and iodine; or R = -NR1R2 and when R = -NR1R2 and Rl - hydrogen, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

2~0~'8~~

R3 is selected from hydrogen: straight or branched (C4-C6)alkyl group selected from butyl, isobutyl, pentyl and hexyl: (C6-C10)aryl group selected from phenyl, a-naphthyl and ~-naphthyl: (C~-C9)aralkyl grou P
selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;
R4 is selected from hydrogen and (C1-C3)alkyl selected from methyl, ethyl, propyl and isopropyl:
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D): and the pharmacologically acceptable organic and inorganic salts or metal complexes.
Compounds of special interest are compound according to formula III wherein:
Y is selected from (CH2)nX, n= 0-5, X is halogen selected from bromine, chlorine, fluorine or iodine:
R is a halogen selected from bromine, chlorine and iodine; or R = -NR1R2 and when R = -NR1R2 and k~' - methyl or ethyl, R2 - methyl or ethyl, R3 is selected from hydrogen;
R4 is selected from hydrogen and (C1-C2)alkyl selected from methyl and ethyl;
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D): and the pharmacologically acceptable organic and inorganic salts or metal complexes.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The novel compounds of the present invention may be readily prepared in accordance with the following schemes.
The preferred method for producing 7-(substituted)-9-[(substituted glycyl)amido]-6-de-2~03~3~

methyl-6-deoxytetracyclines or the mineral acid salts, 3_, is shown in scheme I. This method uses common intermediates which are easily prepared by reacting commercially available haloacyl halides of the formula:

wQ
l0 Y
wherein Y, R3 and R4 are as defined hereinabove and Q
is halogen selected from bromine, chlorine, iodine and fluorine; with 9-amino-7-(substituted)-6-demethyl-6-deoxytetracycline or its mineral acid salt, 1_, to give straight or branched 9-[(haloacyl)amido]-7-(substi-tuted)-6-demethyl-6-deoxytetracyclines or mineral acid salts, 2_, in almost quantitative yield. The above intermediates, straight or branched 9-[(haloacyl)-amido]-7-(substituted)-6-demethyl-6-deoxytetracyclines or mineral acid salts ,, react with a wide variety of nucleophiles, especially amines, having the formula WH, wherein W is as defined hereinabove, to give a new 7-(substituted)-9-[(substituted glycyl)amido]-7-(sub-stituted)-6-demethyl-6-deoxytetracyclines or the mineral acid salts, 3 of the present invention.

,..

Scheme I
R NCCH3)2 OH
I / \ ~I~ NH2 HEN

~mlnsrol acid salt R
Y~ Q
R
R N<CH3)2 OH
0 \

R~''~ H I / \ I NH2 2 0 lf' \ N I __ R4 OH ~0 OH OH IO IO

- ~ mtn~ral ocld salt WH
R N<CH3)z OH
0 \

R H ( / \ ( NH2 R4 ~N OH

- ~ min~rol acid salt In accordance with scheme I, 9-amino-7-(sub-stituted)-6-demethyl-6-deoxytetracycline or its mineral acid salt, _1, is mixed with a) a polar-aprotic solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone, herein after called DMPU, hexamethylphosphoramide herein after called HMPA, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane or equivalent l0 thereof;
b) an inert solvent such as acetonitrile, methylene chloride, tetrahydrofuran, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethane, diethyl ether, t-butyl methyl ether, isopropyl ether or equivalent thereof;
c) a base such as sodium carbonate, sodium bicarbonate, sodium acetate, potassium carbonate, potassium bicarbonate, triethylamine, cesium carbonate, lithium carbonate or bicarbonate equivalents; and d) a straight or branched haloacyl halide of the formula:

Y
wherein Y, R3, R4 and Q are as hereinabove defined, such as bromoacetyl bromide, chloroacetyl chloride, 2-bromopropionyl bromide or equivalent thereof; the halo, Y, and halide, Q, in the haloacyl halide can be the same or different halogen and is selected from bromine, chlorine, iodine and fluorine; Y is (CH2)nX, n= 0-5, X is halogen;
e) for 0.5 to 5 hours at from room temperature to the reflux temperature of the reaction;
to form the corresponding 9-[(haloacyl)amido-7-(sub-stituted)-6-demethyl-6-deoxytetracycline, 2 , or its mineral acid salt.

21U~836 The intermediate, 9-[(haloacyl)amido]-7-(substituted)-6-demethyl-6-deoxytetracycline or its mineral acid salt, 2, is treated, under an inert atmosphere of helium, argon or nitrogen, with a) a nucleophile WH such as an amine, substituted amine or equivalent thereof for example methylamine, dimethylamine, ethylamine, n-butylamine, propylamine or n-hexylamine;
b) a polar-aprotic solvent such as DMPU, HIKPA
dimethylformamide, dimethylacetamide, N-methylpyrrolidone or 1,2-dimethoxyethane;
c) for from 0.5 - 2 hours at room temperature or under reflux temperature to produce the desired ~-(substituted)-9-[(substituted glycyl)amido]-6-de-methyl-6-deoxytetracycline, 3_, or its mineral acid salt.
Scheme II

R NCCH3)2 OH
\
R H I / \ I NH2 w OH 0 OH 0 0 l-R NCCH3)z OH
R3 o H ~ / \ ( NHCHZN~R~
R4 N ~~~0~~ R
w OH 0 OH 0 0 ~1438~~

In accordance with Scheme II, compounds of formula 3 are N-alkylated in the presence of formaldehyde and either a primary amine such as methylamine, ethylamine, benzylamine, methyl glycinate, (L or D)alanine, (L or D)lysine or their substituted congeners: or a secondary amine such as morpholine, pyrrolidine, piperidine or their substituted congeners to give the corresponding Mannich base adduct, The 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines may be obtained as metal complexes such as aluminum, calcium, iron, magnesium, manganese and complex salts: inorganic and organic salts and corresponding Mannich base adducts using methods known to those skilled in the art (Richard C. Larock, Comprehensive Organic Transformations, VCH Publishers, 411-415, 1989). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hygroscopicity and solubility. Preferably, the 7-(substituted)-9-[(sub-stituted glycyl)amido]-6-demethyl-6-deoxytetracyclines are obtained as inorganic salt such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric or sulfate:

or organic salt such as acetate, benzoate, citrate, cysteine or other amino acids, fumarate, glycolate, maleate, succinate, tartrate, alkylsulfonate or arylsulfonate. Depending on the stochiometry of the acids used, the salt formation occurs with the C(4)'-dimethylamino group (1 equivalent of acid) or with both the C(4)-dimethylamino group and the W group (2 equivalents of acid). The salts are preferred for oral and parenteral administration.

Some of the compounds of the hereinbefore described Schemes have centers of asymmetry at the carbon bearing the W substituent. The compounds may, therefore, exist in at least two (2) stereoisomeric ~_ forms. The present invention encompasses the racemic mixture of stereoisomers as well as all stereoisomers of the compounds whether free from other stereoisomers or admixed with stereoisomers in any proportion of enantiomers. The absolute configuration of any compound may be determined by conventional X-ray crystallography.
The stereochemistry centers on the tetracycline unit (i.e. C-4, C-4a, C-5a and C-12a) remain intact throughout the reaction sequences.
BIOLOGICAL ACTIVITY
Methods for in Vitro antibacterial evaluation (Table I) The minimum inhibitory concentration (MIC), the lowest concentration of the antibiotic which inhibits growth of the test organism, is determined by the agar dilution method using 0.1 ml Muller-Hinton II
agar (Baltimore Biological Laboratories) per well. An inoculum density of 1-5 x 105 CFU/ml, and an antibio-tic concentrations range of 32-0.004 microgram/ml is used. MIC is determined after the plates are incubated for 18 hours at 35oC in a forced air incubator. The test organisms comprise strains that are sensitive to tetracycline and genetically defined strains that are resistant to tetracycline, due to inability to bind bacterial ribosomes (tetM).
E. coli in Vitro Protein Translation System (Table II) An in vitro, cell free, protein translation system using extracts from E. coli strain MRE600 (tetracycline sensitive) and a derivative of MRE600 containing the tetM determinant has been developed based on literature methods [J. M. Pratt, Coupled Transcription-translation in Prokaryotic Cell-free Systems, Transcription and Translation, a Practical Approach, (B.D. Hames and S.J. Higgins, eds) p.
179-209, IRL Press, Oxford-Washington, 1984].

21x3836 Using the system described above, the tetra-cycline compounds of the present invention are tested for their ability to inhibit protein synthesis i~
vitro. Briefly, each 10 microliter reaction contains S30 extract (a whole extract) made from either tetracycline sensitive cells or an isogenic tetracycline resistant (tetM) strain, low molecular weight components necessary for transcription and translation (i.e. ATP and GTP), a mix of 19 amino acids (no methionine), 35S labeled methionine, DNA template (either pBR322 or pUC119), and either DMSO (control) or the novel tetracycline compound to be tested ("novel TC") dissolved in DMSO.
The reactions are incubated for 30 minutes at 37 C. Timing is initiated with the addition of the S30 extract, the last component to be added. After 30 minutes, 2.5 ~1 of the reaction is removed and mixed with 0.5 ml of 1N NaOH to destroy RNA and tRNA. Two ml of 25% trichloroacetic acid is added and the mixture incubated at room temperature for 15 minutes. The trichloroacetic acid precipitated material is collected on Whatman GF/C filters and washed with a solution of 10% trichloroacetic acid. The filters are dried and the retained radioactivity, representing incorporation of 35S-methionine into polypeptides, is counted using standard liquid scintillation methods.
The percent inhibition (P. I.) of protein synthesis is determined to be:
3 0 p,t.=100- ~ Retained radioactivity of novel TC containing sample Retained radioactivity of the DMSO control reaction In Vivo Antibacterial Evaluation The therapeutic effects of tetracyclines are determined against an acute lethal infection with Staphylococcus aureus strain Smith (tetracycline 21038~~

sensitive). Female, mice, strain CD-1(Charles River Laboratories), 20+2 grams, are challenged by an intraperitoneal injection of sufficient bacteria (suspended in hog mucin) to kill non-treated controls within 24-48 hours. Antibacterial agents, contained in 0.5 ml of 0.2% aqueous agar, are administered subcutaneously or orally 30 minutes after infection.
When an oral dosing schedule is used, animals are deprived of food for 5 hours before and 2 hours after infection. Five mice are treated at each dose level.
The 7 day survival ratios from 3 separate tests are pooled for calculation of median effective dose (ED50)' Testing Results ' The claimed compounds exhibit antibacterial activity against a spectrum of tetracycline sensitive and resistant Gram-positive and Gram-negative bacteria, especially, strains of E_. coli, S_. aureus and E_.
faecalis, containing tetM and tetD resistance determinants; and E_. co i containing the tetB and tetD
resistance determinants. Notable are compounds D, G, and K, as shown in Table I, which demonstrated excellent in vitro activity against tetracycline resistant strains containing the tetM resistance determinant (such as S. aureus UBMS 88-5, S_. aureus UBMDS 90-1 and 90-2, _E. coli UBMS 89-1 and 90-4) and tetracycline resistant strains containing tetB
resistance determinants (such as E_. coli UBMS 88-1 and E_. coli TN10C tetB). These compounds also have good activity against _E. coli tetA, E_. coli tetC and E_. coli tetD and are equally as effective as minocycline against susceptible strains and are superior to that of minocycline against a number of recently isolated bacteria from clinical sources (Table I).
Minocycline and compounds B, C, D, G and H
are assayed in vitro for their ability to inhibit protein synthesis taking place on either wild type or tetM protected ribosomes using a coupled transcription z~~~s~s and translation system. All compounds are found to effectively inhibit protein synthesis occuring on wild type ribosomes, having equivalent levels of activity.
Minocycline is unable to inhibit protein synthesis occurring on tetM protected ribosomes. In contrast, compounds B, C, D, G and H are effective at inhibiting protein synthesis occurring on tetM protected ribosomes (Table II).
to Compounds B, C, D, G and H bind reversibly to its target (the ribosome) since bacterial growth resumes when the compound is removed from the cultures by washing of the organism. Therefore, the ability of these compounds to inhibit bacterial growth appears to be a direct consequence of its ability to inhibit protein synthesis at the ribosome level.
The activity of compound G against tetracycline susceptible organisms is also demonstrated Len vivo in animals infected with S_. aureus Smith with ED50's between 1-2 mg/kg when administered intravenously, and ED50's of 4-8 mg/kg when given orally.
The improved efficacy of compounds D, G and K
is demonstrated by the in vitro activity against isogenic strains into which the resistance determinants, such as tetM and tetB, were cloned (Table I); and the inhibition of protein synthesis by tetM
ribosomes (Table II).
As can be seen from Table I and II, compounds of the invention may also be used to prevent or control important veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure, ear, nose and troat infections, wound infections, mastitis and the like.

2f 03$3 COMPOUND LEGEND FOR TABLES
A [7S-(7alpha,l0aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a, 12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1-(trifluoroacetyl)-2-pyrrolidinecarboxamide dihydrochloride B [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-9-[[[(2-(methoxyethyl)-amino]acetyl]amino]-1,11-dioxo-2-naphthacene-carboxamide dihydrochloride C [4S-(4alpha,l2aalpha)]-9-[[[(2,2-Diethoxy-ethyl)amino]acetyl]amino]-4,7-bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-1,11-dioxo-2-naphthacene-carboxamide dihydrochloride D [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-1,11-dioxo-9-[[(2-pro-penylamino)acetyl]amino]-2-naphthacenecarbox-amide dihydrochloride E [4S-(4alpha,l2aalpha)]-4,7-bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-1,11-dioxo-9-[[[(2-pyridinylmethyl)amino]acetyl]amino-2-naphtha-cenecarboxamide dihydrochloride F [7S-(7alpha,l0aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-thiomorpholineacet-amide dihydrochloride G [7S-(7alpha,l0aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-methyl-1-piperidine-acetamide dihydrochloride -- 21~383~

H [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahxdroxy-9-[[[(3-methoxypropyl)-amino]acetyl]amino]-1,11-dioxo-2-naphthacene-carboxamide dihydrochloride I 7[7S-(7alpha,l0aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-methyl-1-piperazine-acetamide dihydrochloride J [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-9-[[(heptylamino)acetyl]amino]-1,4,4a, 5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-hydroxy-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride K [4S-(4alpha,l2aalpha)]-9-[[(Cyclopropyl-methyl)amino]acetyl]amino]-4,7-bis(dimethyl amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-1,11-dioxo-2-naphthacene-carboxamide dihydrochloride L [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-1,11-dioxo-9-[[(undecyl-amino)acetyl]amino]-2-naphthacenecarboxamide dihydrochloride M [4S-(4alpha,l2aalpha)]-9-[(Bromoacetyl)-amino]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, 11-dioxo-2-naphthacenecarboxamide dihydro-chloride N Tetracycline O Minocycline 21.0383 fi P [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-12,12a-tetrahydroxy-9-[[[(2-hydroxyethyl)-amino]acetyl]amino]-1,11-dioxo-2-naphthacene-carboxamide monohydrochloride Q [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-12,12a-tetrahydroxy-9-[[[(2-hydroxyethyl)-methylamino]acetyl]amino-1,11-dioxo-2-naphthacenecarboxamide R [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-4-amino-1-amino)-1,4,4a,5,5a,6,11,12a-octa-hydro-3,10,12,12a-tetrahydroxy-9-[[[(4-(hydroxybutyl)amino]acetyl]amino]-1,11-dioxo 2-naphthacenecarboxamide S [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-12,12a-tetrahydroxy-1,11-dioxo-9-[[[2,2,2-trifluoroethyl)amino]acetyl]amino-2-naphtha-cenecarboxamide T [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-9-[[[(2-fluoroethyl)amino]acetyl]-amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide U [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,i1,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[[[2-(1-piperidinyl)ethyl]amino]acetyl]-amino]-2-naphthacenecarboxamide V [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-12,12a-tetrahydroxy-9-[[[methyl-2-propynyl-amino]acetyl]amino]-1,11-dioxo-2-naphtha-cenecarboxamide zlo3s3s W [4S-(4alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-12,12a-tetrahydroxy-hydroxy-1,11-dioxo-9-[[(1-piperidinylamino)acetyl]amino]-2-naphthacenecarboxamide X [4S-(4-alpha,l2aalpha)]-4,7-Bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10, 12,12a-tetrahydroxy-1,11-dioxo-9-[[[(phenyl methoxy)amino]acetyl]amino]-2-naphthacene carboxamide M If1 If1 If1 O If1 tA O
~f1 N

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~~o3s3s Table II
In Vitro Transcription and Translation Sensitivity to Tetracycline Compounds % Inhibition Compound Conc. Wild Type S30 TetM S30 B 1.0 mg/ml 98 97 0.25 mg/ml 96 95 0.06 mg/ml 92 91 C 1.0 mg/ml 98 96 0.25 mg/ml 95 g4 0.06 mg/ml 88 65 D 1.0 mg/ml 99 98 0.25 mg/ml 98 g6 0.06 mg/ml 93 83 G 1.0 mg/ml 99 99 0.25 mg/ml 97 92 0.06 mg/ml 90 83 H 1.0 mg/ml 99 98 0.25 mg/ml 96 94 0.06 mg/ml 88 85 O 1.0 mg/ml 98 68 0.25 mg/ml 89 43 0.06 mg/ml 78 0 When the compounds are employed as anti-bacterials, they can be combined with one or more phar-maceutically acceptable carriers, for example, sol-vents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for exam-ple, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing for example, from about 20 to 50% ethanol and the like, or parenterally in the form of sterile injectable solutions or suspensions contain-ing from about 0.05 to 5% suspending agent in an iso-tonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
An effective amount of compound from 2.0 mg/kg of body weight to 100.0 mg/kg of body weight should be administered one to five times per day via any typical route of administration including but not limited to oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), topical or rectal, in dosage unit formulations containing conventional non-toxic pharma-ceutically acceptable carriers, adjuvants and vehicles.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the parti-cular condition, and the host undergoing therapy.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellu-lose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfac-tants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the pre-paration of pharmaceutical compositions may be advanta-l0 geously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for exam-ple, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and admini-stration are solid com ositions p , particularly tablets and hard-filled or liquid-filled capsules. Oral ad-ministration of the compounds is preferred.
These active compounds may also be admini-stered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for inject-able use include sterile aqueous solutions or disper-sions and sterile powders for the extemporaneous pre-paration of sterile injectable solutions or disper-sions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserve against the contaminating action of micoorganisms such as bac-terial and fungi. The carrier can be a solvent or dis-persion medium containing, for example, water, ethanol, polyol (e. g., glycerol, propylene glycol and liquid 21Q~S'3~

polyethylene glycol), suitable mixtures thereof, and vegetable oil.

The invention will be more fully described in conjunction with the following specific examples which are not be construed as limiting the scope of the in-vention.

Example 1 [4S-(4alpha.l2aalpha)]-9-[(Chloroacetyl)aminol-4.7-bisidimethylamino)-1.4.4a.5.5a.6.11.12a-octahydro-3.-10.12.12a-tetrahydroxy-1.11-dioxo-2-naphthacenecarbox-amide dihydrochloride To a room temperature solution of 0.334 g of 9-amino-4,7-bis(dimethyamino)-6-demethyl-6-deoxytetra-cycline disulfate, 6 ml of 1,3-dimethyl-3,4,5,6-tetra-hydro-2(iH)-pyrimidinone, hereinafter called DMPU, and 2 ml of acetonitrile is added 0.318 g of sodium carbonate. The mixture is stirred for 5 minutes followed by the addition of 0.068 g of chloroacetyl chloride. The reaction is stirred for 30 minutes, filtered, and the filtrate added dropwise to 100 ml of diethyl ether, containing 1 ml of 1M hydrochloric acid in diethyl ether. The resulting solid is collected and dried to give 0.340 g of the desired intermediate.

MS(FAB): m/z 549 (M+H).

Example 2 [4S-(4alpha.l2aalpha)1-9-[(Bromoacetyl)amino]-4.7-bis(dimethylamino)-1.4.4a.5.5a.6.11,12a-octahydro-3.-10.12,12a-tetrahydrox~-1.11-dioxo-2-naphthacenecarbox-amide monohydrobromide The title compound is prepared by the procedure of Example 1, using 6.68 g of 9-amino-4,7-bis(dimethylamino)-6-demethyl-6-deoxytetracycline disulfate, 50 ml of DMPU, 30 ml of acetonitrile, 6.68 g of sodium carbonate and 0.215 g of bromoacetyl bromide.

5.72 g of the desired intermediate is obtained.

MS(FAB): m/z 593 (M+H).

.....
21!D3836 Example 3 [4S-l4alpha,l2aalpha))-9-f(2-Bromo-1-oxooropvl)amino,]-4,7-bis(dimethylamino)-1.4.4a,5.5a,6.11,,12a-octahydro-3 10.12.12a-tetrahydroxy-1.11-dioxo-2-naphthacene-carboxamide sulfate The title compound is prepared by the procedure of Example 1, using 1.00 g of 9-amino-4,7-bis(dimethylamino)-6-demethyl-6-deoxytetracycline di-sulfate, 1.0 g of sodium carbonate and 0.648 g of 2-bromopropionyl bromide to give 0.981 g of the desired product.
MS(FAB): m/z 607 (M+H).
Example 4 14S-(4alpha,l2aalpha))-9-[(4-Bromo-1-oxobutvl)amino>
4~7-bis(dimethylamino)-1.4.4a.5.5a.6,11,12a-octahydro 3,10,12,12a-tetrahydroxy-1.11-dioxo-2-naphthacene carboxamide dihydrochloride The title compound is prepared by the procedure of Example 1, using 1.34 g of 9-amino-4,7-bis(dimethylamino)-6-demethyl-6-deoxytetracycline disulfate, 1.3 of sodium carbonate, 24 ml of DMPU, 8 ml of acetonitrile and 0.389 g of 4-bromobutyryl chloride to give 1.45 g of the desired product.
Example 5 (7S-(7alpha.l0aalpha))-N-[9-(Aminocarbonyl)-4.7-bis(di-methylamino)-5.5a.6.7.10.10a.12-octahydro-1.8.10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1-trifluoro-acetyl)-2-pvrrolidinecarboxamide dihydrochloride The title compound is prepared by the procedure of Example 1, using 0.334 g of 9-amino-4,7-bis(dimethylamino)-6-demethyl-6-deoxytetracycline disulfate, 10 ml of DMPU, 2 ml of acetonitrile, 0.34 g of sodium carbonate and 7.5 ml of O.1M (S)-(-)-N-(tri-fluoroacetyl)prolyl chloride to give 0.292 g of the desired product.
MS(FAB): m/z 666 (M+H).

20383 ~

Example 6 f4S-(4alpha.l2aalpha)1-9-[([(Cyclopropylmethyl)aminol-acetvllaminol-4,7-bis(dimethylamino)-1 4 4a 5 5a 6 11 12a-octahvdro-3,10.12.12a-tetrahydroxv-1 11-dioxo-2-nabhthacenecarboxamide dihydrochloride A mixture of 0.20 g of product from Example 2, 0.50 g of (aminomethyl)cyclopropane and 5 ml of DMPU, under Argon, is stirred at room temperature for 1 hour. The excess amine is removed 'fin vacuo and the residue diluted with a small volume of methyl alcohol.
The diluted reaction solution is added dropwise to a misture of diethyl ether and 5 ml of 2-propanol. 1M
Hydrochloric acid in diethyl ether is added until a solid is formed. The resulting solid is collected and dried to give 0.175 g of the desired product.
MS(FAB): m/z 584 (M+H).
Substantially following the methods described in detail herein above in Example 6, the compounds of this invention listed below in Examples 7 - 16 are prepared.

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~1 U ... I ,c ~ ,c ..
b s.~ ~1.. ~1 ,o x o i ~~~ i i i ~
~ ~o~~ c~x ~
a ~

1 . on i c ,, ~.os c .~o cn v cn cn +~ b cn -~I ~n In ro ~ o c r-1 o c .~ ,o ~ r.~ r-1 x b s~ -~

~r -.~ ~r ~ v >.-~ ~r >~ , ~
-~ N ~ 1 la ro O
,-~1 ,+~ , ro ~.o a A .Q a '-' ,~,~ a ro M a e"'y ro .Gi '~ QI ~.. .Q
r~ M N l'~
v Fi v .>r, O e-I
x ~ r~ oo Ol ~-1 2~o3s~s m s z z cn v v ~
' ~i N f'~ ~ ~ v e-i ri pp 'd' e~

~O ~0 N 00 N

~0 ~D tp C1 la E .C w N

O N c'~ e-1 i r-I

U a! ' .C

I -'i ~ O

ro s~, ~.I a~

ro .L." 'fir N 'fir rl rl -~ ~
~

1~ ! G! 1 Cl~ U
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, ~

s~
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r1 1 O

~ I ~

ro ' I I 1 ',~, rl ,?~ 1 1 1 ?, I 1 al I -r~
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a, ro ~ ~ ,c .c O o, .~ ' O O ~ s~
s~ a~ N o, b b V~ ~1 ro r--I ~ ~ ~.1 .-I ~0 f'1 S~.I 1 ro 'Cf ~ i I ' U ~, a~ a~ b o ' ' b b ~ ~1 v ~ o o 1 ~ :a .~

olnroro oro~lro ~ 1+~>.xo ~~x ~>.x~x o :~" C." ro ~ .~ O -r1 ,C
1 In d .G."r~ O ?~
O ' .C U
,C i." O
r~

.-I .-1 ~ 't~ '!~~-I 'O ro .-. ' U ro ( -r1 ~J
r-I ro ro .Li O
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d b Q, 1 N.~.U N N U 1 ~ 1 U U2f ~ O 1 ,U 1 O

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' ' O O r-1 ro ro ro O r-1 ?~
.d ro ~-1 ~
i.~ 1.~

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O CO b .-1 -r1 O O
d 'O

o, c, 1 ro I I ro ' ro o -.~ ' ro o ~I
1 ' ~, ' 1 I c >~ :~ >.

a rl ur-1 1~ N 1~ 1~ N e-~
O e-1 ~., .-1 N 'j.,' N N ,L.," ~-~I 'O
ro rl rl ,L,"

?i 1 ' ~ ' w-1 I
i.l )~ ro 1 .-i ..-I
I I -rl 1 ~ I ~
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~-' ~ ~ ~ ~I r, ~ o ~ ~ +~ o ...
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o - , ~ ~
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b -r.lb ro -r.l ~c ro i ~o b +~ s~ +~ b ~c ~ ro .a -r.l b ro ~

ro .c .c I ~ ,~ x ' >..c b a~ w .c ' x U ro ' ~.
1 ~ a~
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O 1 O N N N ' O
' Ul 01 ' ,?~ U
e-I N ' O
t1, e-i G) ~"., Tl ',!~'O ~.1 ~.1 ~ 1~ ,.-1-..~ ~I ~ ~I ro ro ,~ 1 ro +m a~
I 1 ro .a, .~., ~ +~ -~, .r.l ~.1 ro ro ' ' ' ' ' ' d' I
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?~ ''r d~ 1 GW.I J~ I ~
i.1 U U

ro~r~lx ro roo ro ro 'ro~oa~
I 1 'roar 'roroa~
o roxa~o ~'., .C'.. ~"., ~"." ~C d' I f~ C'., d' N -ri ' O d' N U
O O N r-1 ri ]r.. .r, L', .-1 -i w.. w a~w w n, ' ~
O ' ' ' r~ ro s~ ~ ~1 ~
I ~ a~ ~, .c 1 a~
.c r-1 r-I r-1 r-~ .-W -~I
r-1 sl' .~" r-I ' ?~
.-1 ''Cf .~ ' ,C
'tf er ' U
r1 U U U
U

roe, ro roro ro ro 1 Nw.N
'~,>.o I 1 1 o~,l Nro Na~ro o t~ r ~ ~ er ..
C ... rI ... ~ I ,C
t~ r-1 r- r-1 .C ,~ .-1 b .C .-, ,~ .C
~ ~r ,- ~-,-1 ~- ,- .- O ' o ' >. O N w ' ro O ' ro ~ '+~ o ~ v .~
b 1 .c: 1 1 1 I s~ o ro >. .s~ ~
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~

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.~.1 ~oroa~a~~ ~a~ ~r~
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'-'UID~d"Cf u~~0~1 uF. uroc'lu~," uroMuN
U'Cf ~~1 tr"

N r1 d' lf1 ~G
~k ~ ri ri ri ri 21fl38~ 6 Example 17 (4S-(4alpha.l2aalpha)]-4,7-Bis(dimethylamino) 1.4.4a.5.5a.6,11,12a-octahydro-3.10 12.12a-tetrahydroxy-9-L[((2-hydroxyethyl)amino]acetvll-amino]-1.11-dioxo-2-naphthacenecarboxamide monohydrochloride To a solution of 0.10 g of product from Example 7A in 2 ml of 1,3-dimethyl-2-imidazolidinone is added 0.70 ml of 2-amino-1-ethanol. The solution is stirred at room temperature for 20 minutes, added to 100 ml of diethyl ether and the resulting precipitate collected to give 0.055 g of the desired product.
MS(FAB):m/z 574 (M+H).
Substantially following the method described in detail hereinabove in Example 17, the compounds of this invention listed below in Examples 18-24 are prepared.

,,.., _ 5 6 _ 2 .. ... ... .., ., x x m x x ~ ~r ~: .~.~ ~, W
N

''' O N N ~D l~
\

U~ 00 O rl l~ N
~i ,'F'.,tn 1G t0 In ~O

N

,C~ ,~

to x O O N N N

I
O I I
O

i~ Itt r-1 r-1 rl ~.1 O rl U rl O I to d to ro !~ ..
tV

ro ?~ !~" O rl i~ ~.. O ro I
r-I
.1".

at .c ro s~ O 1 O ~ ~ N
~-~

Qi ~ ~il rl C; N to GI rl '-' ''~ .ri 'Cf Ol ~ ~ ro ~ O O W ,~' I
.N
r-I

F. .G ~ N '~
~ ~ G7 r~

-1 I , ,- N C) ~, i ~

d' ri si~ ,S~ N W ro to x ar w aJ

row o :r C I
'O

0 ~ ~ I
~

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~ r '~' '~
'~

ro ro N I ~ I to ~
N , N +~ '-' O .~ O b +~ O .s~ .J~
1 .i~ O

N .N

U ~--~ Q ~ t.1 ',firU I >:, a.J i~
O O to to I
I O

O ~'-1 tV d 'd ~ O ~-1 ~ O U Cl x 't3 't~
O O
U

I 1 ~a~b ~~-o I 1 ~I~ ~~a~,x >~>,xro -.~ ro I -r.l .0 -r.l ro -..1 o ~
ro -'.I 1 r.l . ro ~.~ .o o b N 01 .-~ 'Cy ro 'Cf N r1 't~ ~1 't~
~ d' 'Cf .-. N O
ro ~
v ri 1 rl v W v 1 v t-1 1 v ~, 'O Tf ro rl 'O ~ v --.~1 ,~ x ~ o .--~ -rl ,~ --~ -~I
+~ o ,~ x ,~ ~ a~ o o ~
~-I ~
~

w ~.1 0 m ro c>a ~ ~ ~ v i~ i .1.~ ro I I
~ i .--I ~I
ro ~

r.i I - to 1 ... I
d at x ro ro . .
~
ro I~ 1p 't~ I~ N 01 I~ 10 't~ c'~ t~
ro ro I O O r-1 N
N ~-~1 .-I r-1 x . ~,, ~ . r-I t ~,, ~ .R ~ ?W ~
U ~ I I
?~
O

d ro ,J~ d' ?, d' ~ .C d .C er O O O O ~ ~ -?, ?i ,G
~

1 Inrocc I ~.Ixc 1 ~,ro~~a I+~~Ix I
r-Ix+~s.~

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~ U ~ 'C3 4a O O ~
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to -.
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b ~-I
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ra ,c ro +~ .a . ~, .s~ ro x o .c ~ .~ ., ~ ~ sa at . >, >. ~
~ c I ?W Cl~ ro l3, d I f~., il~
~ r-I ~ U ~ ro ro ro .C
~ :~
~ d ro .c .c ~-I In ~-, . ro ~ rl ~
ro ~ x I ro ~n In ro ro x ..~
U

ro~N.N w b .~,a., ~d~NN~ row ro o .~, .tab o ro ro , ,-~ ro ~n +~ ro - r.l ro ro at ro at :Q . +~ 1 m In +~
+~ -r.l .~ .sr N r-'1 ~ N O U t-1 N ri ~ N N N
~ ~ N ,C; ~ ~
O O
to to W

-I I N .-. r-I ro ~ I N , ~-I ~I
I aJ ro w .-- ro ro ro +~
+~ at ro .c we-i r-1 ~d' I n wrl N ro ~~d' ~d' N U I I
U

ro o , ~ ro ~ ro ro o , ro ro 1 o a~ ~--~ s~ .--- , ~ ro ro ~I
at ro .G >~ O ~"., d' ,l~ ~ O ~; ,O
,~ O N O O ~ ( ~ d' d' N
N Cl, ~ G

~ ~ ~ ~ G ~
~ ~ O ' ~ U ~ ~
~

!~ rl ~ ~ .-1 ~
I U .-i ~ .
~I
c~

roroM~-~ ro I Nrorororor,o,~ ro ro I I
I N.-I
Nro d' rl ( d' .~. dW -i I d .. d~
x 'O r-I .-. I r-1 r~ .-.
,L," r-I ~--) j~, 'r9r0 O v0 ~rl+~ ~~r0 O ~O v0 1 >r O ~N
~~ O

I .~ to I s~ O I .C ii i >; I
to r1 >r .O x +~ ~ :~
O O
,:~ ~--~
O

~ ~ d ~ ~
~ ~ ~ ~
~

'>r ?i ' .F. O 9r .F, ~
~ U 1~
'.~ ca '-' ~, ~.. a ro M ~-' ~. a ro a ~'.. ~ ,C'~ ~. .Gi b ro ro ro f'7 M
~r a ro CO 01 O ~ N
r1 rl N N N

-5~- 21fl3836 ..
x x oa + +

W
N

~i M

In ~O

p -rl il) 1n E~ is N N
i~ I

O
Cl ro s~ ar a U ~

I I
p r-~

)~

.-i I 1 -~
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cb ~~1 i~ I
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~
b .l -I .l ro - ~
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N ~-1 U

rl S

.- .-- r., r., I ro I a~
~
ro ~n N . >.-.
. b ~+~
x -~1 -~1 ~1 r-1 x o -~1 x a~
o ~a~~ x ~~ ~:~
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U

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O

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~~:NC

b tV ~. .. u1 In +~ .1 +r U
ro U

~ ro -~

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ro .
~..o ~

z w u, ~r ~r 1 s~
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+~

ro r-1 -?~ ro U
,C U

ro ro d' d- N ~1, N ro 11, G~

ro ro , ~
. -~1.c ~
O
ro N N e-1 ri ~ ~ a.!

f-t C:

e-I r-1 1 1 N I .C
N
LL

. ~ ~ r-1 .w-1 e-i N

roo roo ,--ro ,N
I

.C O 1 s~
s~ O ,C s;
O ~

~ ~ _ ~
~

~ ?i O ~
I N

ro ~.c-~I ro ro~o, ro I

d' d' r-1 r-1 I ( 1~
b -~oa~ ->,000 I 1 xNxc ~s~r.-, N tI~ ~
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_ u~~ u~~~
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QI
C~ d' Id ~k N N
=7 ~10~8~6 Example 25 C4S-l4-alpha,l2aalpha), -4.7-Bis,~ dimethvlamino) 1.4,4a.5,5a,6,11.12a-octahydro-3,10,12,12a-tetrahydroxy-1.11-dioxo-9-[LLiphenylmethoxy)-amino]acetyl> amino]-2-naphthacenecarboxamide To 0.50 g of O-benzylhydroxylamine and 2.5 ml of 1,3-dimethyl-2-imidazolidinone is added 0.80 g of sodium bicarbonate. The mixture is stirred at room temperature for 2 hours, filtered and the filtrate added to 0.10 g of product from 7A. The reaction solution is stirred at room temperature for 2 hours and then added to 100 ml of diethyl ether. The resulting precipitate is collected and dried to give 0.90 g of the desired product.
MS(FAB): m/z 636 (M+H).

Claims (24)

1. A compound of the formula:

wherein:
R is a halogen selected from bromine, chlorine, fluo-rine and iodine; or R = -NR1R2 and when R = -NR1R2 and R1 - hydrogen, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl:
and when R1 - n-propyl, R2 - n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R1 - 1-methylethyl, R2 - n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R1 - n-butyl, R2 - n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R1 - 1-methylpropyl, R2 - 2-methylpropyl:
R3 is selected from hydrogen; straight or branched (C4-C8)alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl: .alpha.-mercapto(C1-C4)alkyl group selected from mercaptomethyl, .alpha.-mercaptoethyl, .alpha.-mercapto-1-methylethyl and .alpha.-mercaptopropyl:
.alpha.-hydroxy(C1-C4)alkyl group selected from hydroxymethyl, .alpha.-hydroxyethyl, .alpha.-hydroxy-1-methylethyl and .alpha.-hydroxypropyl: carboxyl(C1-C8)alkyl group;
(C6-C10)aryl group selected from phenyl, .alpha.-naphthyl and .beta.-naphthyl: substituted(C6-C10)aryl group (substitution selected from hydroxy, halogen, (C1-C4)alkoxy, trihalo(C1-C3)alkyl, nitro, amino, cyano, (C1-C4)alkoxycarbonyl, (C1-C3)alkylamino and carboxy);
(C7-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl; substi-tuted (C7-C9)aralkyl group [substitution selected from halo, (C1-C4)alkyl, nitro, hydroxy, amino, mono-or di-substituted (C1-C4)alkylamino, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, cyano and carboxy]:
R is selected from hydrogen and (C1-C6)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D);
W is selected from hydroxylamino; (C7-C12) straight or branched alkyl monosubstituted amino group substitution selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the diastereomers and enantiomers of said branched alkyl monosubstituted amino group; (C1-C4) straight or branched fluoroalkylamino group selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 3,3,3,2,2-pentafluoropropyl,
2,2-difluoropropyl, 4,4,4-trifluorobutyl and 3,3-di-fluorobutyl; (C3-C8)cycloalkyl monosubstituted amino group 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 enantiomers of said (C3-C8)cycloalkyl monosubstituted amino group: [(C4-C10)cycloalkyl]alkyl monosubstituted amino group substitution selected from (cyclopropyl)-methyl, (cyclopropyl)ethyl, (cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl, and (cis-2-methylcyclobutyl)methyl: (C3-C10)alkenyl and alkynyl monosubstituted amino group substitution se-lected 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: (C6-C10)aryl monosubstituted amino group substitution selected from phenyl and naphthyl;
(C7-C10)aralkylamino group substitution selected from benzyl, 2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropyl: substituted (C6-C10)aryl monosubstituted amino group [substitution selected from (C1-C5)acyl, (C1-C5)acylamino, (C1-C4)alkyl, mono or disubstituted (C1-C8)alkylamino, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkylsulfonyl, amino, carboxy, cyano, halogen, hydroxy, nitro and trihalo(C1-C3)alkyl]: straight or branched symmetrical disubstituted (C6-C14)alkylamino group substitution selected from dibutyl, diisobutyl, di-s-butyl, dipentyl, diisopentyl, di-s-pentyl, dihexyl, diisohexyl and di-s-hexyl: symmetrical disubstituted (C6-C14)cycloalkylamino group substitution selected from dicyclopropyl, dicyclobutyl, dicyclopentyl, di(dicyclopropyl)methyl, dicyclohexyl and dicycloheptyl; straight or branched unsymmetrical disubstituted (C3-C14)alkylamino group wherein the total number of carbons in the substitution is more than 14; unsymmetrical disubstituted (C4-C14)cycloalkylamino group wherein the total number of carbons in the substitution is no more than 14;
(C2-C8)azacycloalkyl and substituted (C2-C8)azacyclo-alkyl group substitution selected from 4-methylpiperi-dine, 4-hydroxypiperidine, 4-(hydroxymethyl)piperidine, 4-(aminomethyl)piperidine, cis-3,4-dimethylpyrroli-dinyl, 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, 2-azabicyclo[2.2.2]oct-2-yl and the diastereomers and enantiomers of said (C2-C8)azacyclo-alkyl and substituted (C2-C8)azacycloalkyl group; sub-stituted 1-azaoxacycloalkyl group substitution selected from 2-(C1-C3)alkylmorpholinyl,
3-(C1-C3)alkylisoxazolidinyl, tetrahydrooxazinyl and 3,4-dihydrooxazinyl; [1,n]-diazacycloalkyl and substi-tuted [1,n]-diazacycloalkyl group selected from piperazinyl, 2-(C1-C3)alkylpiperazinyl, 4-(C1-C3)alkyl-piperazinyl, 2,4-dimethylpiperazinyl, 4-(C1-C4)alkoxy-piperazinyl, 4-(C6-C10)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-2-yl and the diastereomers or enantiomers of said [1,n]-diazacycloalkyl and substi-tuted [1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C1-C3)alkyl- thiomorpholinyl and 3-(C3-C6)cycloalkylthiomorpholinyl; N-azolyl and sub-stituted N-azolyl group selected from 1-imidazolyl, 2-(C1-C3)alkyl-1-imidazolyl, 3-(C1-C3)alkyl-1-imidazolyl, 1-pyrrolyl, 2-(C1-C3)-alkyl-1-pyrrolyl, 3-(C1-C3)alkyl-1-pyrrolyl, 1-pyrazolyl, 3-(C1-C3)alkyl-1-pyrazolyl, indolyl, 1-(1,2,3-triazolyl), 4-(C1-C3)alkyl-1-(1,2,3-tri-azolyl), 5-(C1-C3)alkyl-1-(1,2,3-triazolyl), 4-(1,2,4-triazolyl, 1-tetrazolyl, 2-tetrazolyl and benzimidazolyl; (heterocycle)amino group 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 substituted (heterocycle)amino group (substitution selected from straight or branched (C1-C6)alkyl); (heterocycle)methylamino group selected from 2- or 3-furylmethylamino, 2- or 3-thienylmethyl-amino, 2-, 3- or 4-pyridylmethylamino, 2- or 5-pyrida-zinylmethylamino, 2-pyrazinylmethylamino, 2-(imidazol-yl)methylamino, (benzimidazolyl)methylamino, and (benzothiazolyl)methylamino and substituted (hetero-cycle)methylamino group (substitution selected from straight or branched (C1-C6)alkyl); carboxy(C2-C4)-alkylamino group selected from aminoacetic acid, .alpha.-aminopropionic acid, .beta.-aminopropionic acid, .alpha.-butyric acid, .beta.-aminobutyric acid and the enantiomers of said carboxy(C2-C4)alkylamino group; 1,1-disubstituted hydrazino group selected from 1,1-dimethylhydrazino, N-aminopiperidinyl, 1,1-diethylhydrazino, and N-amino-pyrrolidinyl; (C1-C4)alkoxyamino group substitution selected from methoxy, ethoxy, n-propoxy, 1-methyl-ethoxy, n-butoxy, 2-methylpropoxy and 1,1-dimethyl-ethoxy; (C3-C8)cycloalkoxyamino group selected from cyclopropoxy, trans-1,2-dimethylcyclo- propoxy, cis-1,2-dimethylcyclopropoxy, cyclobutoxy, cyclo-pentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, bicyclo[2.2.1]hept-2-yloxy, bicyclo[2.2.2]oct-2-yloxy and the diastereomers and enantiomers of said (C3-C8)cycloalkoxyamino group; (C6-C10)aryloxyamino group selected from phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino; (C7-C11)arylalkoxyamino group substitution selected from benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)-methoxy and phenylpropoxy;

[.beta. or 7-(C1-C3)acylamido]alkylamino group substitution selected from 2-(formamido)ethyl, 2-(acetamido)ethyl, 2-(propionylamido)ethyl, 2-(acetamido)propyl, 2-(formamido)propyl and the enantiomers of said [.beta. or 7-(C1-C3)acylamido]alkylamino group; .beta. or 7-(C1-C3)alkoxyalkylamino group substitution selected from 2-methoxyethyl, 2-ethoxyethyl, 2,2-diethoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3,3-diethoxypropyl and the enantiomers of said .beta. or 7-(C1-C3)alkoxyalkylamino group; .beta.,7, or 6 (C2-C4)hydroxyalkylamino group substitution selected from 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and 4-hydroxybutyl;
or R3 and W taken together are selected from -(CH2)n(R5)N-, n= 3 - 4, and -CH2CH(OH)CH2(R5)N- where-in R5 is selected from hydrogen and (C1-C3)acyl, the acyl selected from formyl, acetyl, propionyl and (C2-C3)haloacyl selected from chloroacetyl, bromoacetyl, trifluoroacetyl, 3,3,3-trifluoropropionyl and 2,3,3-trifluoropropionyl:
R6 is selected from hydrogen; straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C6-C10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; (C7-C9) 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:
Z - N, O, S or Se or a five membered aromat-ic ring with two N, O, S or Se heteroatoms optionally having a benzo or pyrido ring fused thereto:
Z or Z1 = N, O, S or Se or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom:
(A is selected from hydrogen straight or branched (C1-C4)alkyl: C6-aryl; substituted C6-aryl (substitu-tion selected from halo,(C1-C4)alkoxy, trihalo(C1-C3)alkyl, nitro, amino, cyano, (C1-C4)-alkoxycarbonyl, (C1-C3)alkylamino or carboxy): (C7-C9)-aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl) or a six membered aromatic ring with one to three N heteroatoms or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adja-cent appended O heteroatom; or -(CH2) n COOR8 where n=0-4 and R8 is selected from hydrogen: straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C6-C10)aryl group se-lected from phenyl, a-naphthyl, or p-naphthyl:
R7 is selected from hydrogen: straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; (C6-C10)aryl group selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl; (C7-C9)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:
Z = N, O, S or Se or a five membered aromat-ic ring with two N, O, S or Se heteroatoms optionally having a benzo or pyrido ring fused thereto:

Z or Z1 = N, O, S, or Se or a five membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O heteroatom:
(A is selected from hydrogen: straight or branched (C1-C4)alkyl: C6-aryl; substituted C6-aryl (substitu-tion selected from halo,(C1-C4)alkoxy, trihalo(C1-C3)alkyl, nitro, amino, cyano, (C1-C4)-alkoxycarbonyl, (C1-C3)alkylamino or carboxy); (C7-C9)-aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl) or a six membered aromatic ring with one to three N heteroatoms or a six membered saturated ring with one or two N, O, S or Se heteroatoms and an adjacent appended O
heteroatom or -(CH2) n COOR8 where n=0-4 and R8 is selected from hydro-gen; straight or branched (C1-C3)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C6-C10)aryl selected from phenyl, .alpha.-naphthyl or .beta.-naphthyl: with the proviso that R6 and R7 cannot both be hydrogen;
or R6 and R7 taken together are -(CH2)2B(CH2)2-, where-in B is selected from (CH2)n and n=0-1, -NH, -N(C1-C3)alkyl [straight or branched], -N(C1-C4)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 com-plexes.

2. The compound according to Claim 1, where-in:
R is a halogen selected from bromine, chlorine and io-dine: or R = -NR1R2 and when R = -NR1R2 and R1 - methyl or ethyl, R2 - methyl or ethyl, R3 is selected from hydrogen;
R4 is selected from hydrogen and (C1-C2)alkyl selected from methyl and ethyl:
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D);
W is selected from (C7-C12) straight or branched alkyl monosubstituted amino group substitution selected from heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the diastereomers and enantiomers of said branched alkyl monosubstituted amino group;
(C2)fluoroalkyl-amino group selected from 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl;

(C3-C8)cycloalkyl monosubstituted amino group substitu-tion selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the diastereomers and enantiomers of said (C3-C8)cycloalkyl monosubstituted amino group: [(C4-C5)cycloalkyl]alkyl monosubstituted amino group substitution selected from (cyclopropyl)-methyl and (cyclopropyl)ethyl; (C3-C4)alkenyl and alkynyl monosubstituted amino group substitution se-lected from allyl and propynyl: (C2-C7)azacycloalkyl and substituted (C2-C7)azacycloalkyl group substitution selected from 4-methylpiperidine, 4-hydroxypiperidine and 4-(hydroxymethyl)piperidine: substituted 1-azaoxacycloalkyl group substitution selected from 2-(C1-C3)alkylmorpholinyl: [1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl group selected from piperazinyl and 4-(C1-C3)alkylpiperazinyl:
1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C1-C3)alkylthiomorpholinyl: (heterocycle)methylamino group selected from 2- or 3-thienylmethylamino and 2-, 3- or 4-pyridylmethylamino: 1,1-disubstituted hydrazino group selected from 1,1-dimethylhydrazino and N-amino-piperidinyl; [.beta. or ~-(C1-C3)acylamido]alkylamino group substitution selected from 2-(acetamido)ethyl; .beta. or ~-(C1-C3)alkoxyalkyl- amino group substitution selected from 2-methoxyethyl, 2-ethoxyethyl, 2,2-diethoxyethyl, 2-methoxypropyl and 3-methoxypropyl: .beta., ~ or .delta.
(C2-C4)hydroxyalkylamino selected from 4-hydroxybutyl and 3-hydroxypropyl: or R3 and W taken together are selected from -(CH2)n(R5)N-, n= 3, and R5 is selected from hydrogen and trifluoroacetyl:
R6 is selected from hydrogen: straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl:
R7 is selected from hydrogen: straight or branched (C1-C3)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl; with the proviso that R6 and R7 cannot both be hydrogen;
or R6 and R7 taken together are -(CH2)2B(CH2)2-, where-in B is selected from (CH2)n and n=0-1, -NH, -N(C1-C3)alkyl [straight or branched], -N(C1-C4)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 com-plexes.

3. A compound of the formula:
wherein:
Y is selected from (CH2) n X, n= 0-5, X is halogen se-lected from bromine, chlorine, fluorine or iodine;
R is a halogen selected from bromine, chlorine, fluo-rine and iodine; or R = -NR1R2 and when R = -NR1R2 and R1 - hydrogen, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;
and when R1 - methyl or ethyl, R2 - methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl:
and when R1 - n-propyl, R2 = n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl:
and when R1 - 1-methylethyl, R2 = n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R1 = n-butyl, R2 = n-butyl, 1-methylpropyl or 2-methylpropyl;
and when R1 = 1-methylpropyl, R2 = 2-methylpropyl;
R3 is selected from hydrogen: straight or branched (C4-C8)alkyl group selected from butyl, isobutyl, pentyl, hexyl, heptyl and octyl; .alpha.-mercapto(C1-C4)alkyl group selected from mercaptomethyl, .alpha.-mercaptoethyl, .alpha.-mercapto-1-methylethyl and .alpha.-mercaptopropyl;
.alpha.-hydroxy-(C1-C4)alkyl group selected from hydroxymethyl, .alpha.-hydroxyethyl, .alpha.-hydroxy-1-methylethyl and .alpha.-hydroxypropyl: carboxyl(C1-C8)alkyl group;
(C6-C10)aryl group selected from phenyl, .alpha.-naphthyl and .beta.-naphthyl; substituted(C6-C10)aryl group (substitution selected from hydroxy, halogen, (C1-C4)alkoxy, trihalo(C1-C3)alkyl, nitro, amino, cyano, (C1-C4)alkoxycarbonyl, (C1-C3)alkylamino and carboxy);
(C7-C9)aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl: substi-tuted (C7-C9)aralkyl group [substitution selected from halo, (C1-C4)alkyl, nitro, hydroxy, amino, mono- or di-substituted (C1-C4)alkylamino, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, cyano and carboxy];
R4 is selected from hydrogen and (C1-C6)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D): and the pharmacologi-cally acceptable organic and inorganic salts or metal complexes.

4. The compound according to Claim 3, where-in:
Y is selected from (CH2)n X, n= 0-5, X is halogen se-lected from bromine, chlorine, fluorine or iodine;
R is a halogen selected from bromine, chlorine and io-dine; or R = -NR1R2 and when R = -NR1R2 and R1 - methyl or ethyl, R2 - methyl or ethyl, R3 is selected from hydrogen;
R4 is selected from hydrogen and (C1-C2)alkyl selected from methyl and ethyl;
when R3 does not equal R4 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the substituent W) maybe be either the racemate (DL) or the individual enantiomers (L or D); and the pharmacologi-cally acceptable organic and inorganic salts or metal complexes.
5. The compound according to Claims 1 or 2 wherein said salts or complexes comprise: hydrochlo-ric, hydrobromic, hydroiodic, phosphoric, nitric, sulfate, acetate, benzoate, citrate, cysteine, fumarate, glycolate, maleate, succinate, tartrate, alkylsulfonate, arylsulfonate, aluminum, calcium, iron, magnesium or manganese.
6. The compound according to Claim 1, [4S-(4alpha,12aalpha)]-9-[[[(Cyclopropylmethyl)amino]-acetyl]amino]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride;

[4S-(4alpha,l2aalpha)]-9-[[[(2,2-diethoxyethyl)amino]-acetyl]amino]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,-12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride:
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[2-(methoxyethyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride:
[4S-(4alpha,l2aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(2-propenylamino)acetyl]amino]-2-naphthacene-carboxamide dihydrochloride;
[4S-(4alpha,l2aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3-,10,12,12a-tetrahydroxy-9-[[[(3-methoxypropyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride;
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,-10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-thiomorpholineacetamide dihydrochloride;
[7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,-10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-methyl-1-piperidineacetamide dihydrochloride:
[7S-(7alpha,l0aalpha)]-N-[9-(Aminocarbonyl)-4,7-bis(di-methylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,-10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-4-methyl-1-piperazineacetamide dihydrochloride:
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[(heptylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride;
[4S-(4alpha,l2aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(undecylamino)acetyl]amino]-2-naphthacene-carboxamide dihydrochloride;

[4S-(4alpha,l2aalpha)]-4,7-bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[[(2-pyridinylmethyl)amino]acetyl]amido]-2-naphthacenecarboxamide dihydrochloride;
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[(2-hydroxyethyl)amino]acetyl]-amino]-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride:
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[(2-hydroxyethyl)methylamino]acetyl]amino-1,11-dioxo-2-naphthacenecarboxamide;
[4S-(4alpha,12aalpha))-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[(4-(hydroxybutyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide:
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[[2,2,2-trifluoroethyl)amino]-2-naphthacene-carboxamide;
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-9-[[[(2-fluoroethyl)amino]acetyl]amino]-1,4,4a,5,5a,6,-11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide;
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[[[2-(1-piperidinyl)ethyl]amino]acetyl]amino]-2-naphthacenecarboxamide;
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[[methyl-2-propynylamino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide;
[4S-(4alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-hydroxy-1,11-dioxo-9-[[(1-piperidinylamino)acetyl]-amine]-2-naphthacenecarboxamide; or [4S-(4-alpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[[(phenylmethoxy)-amino]acetyl]amino]-2-naphthacenecarboxamide.
7. A method of producing a compound, or its organic and inorganic salt or metal complex, of the formula:

according to Claim 1, which comprises reacting a 9-[(haloacyl)amido]-7-(substituted)-6-demethyl-6-deoxy-tetracycline, or its organic and inorganic salt or met-al complex, of the formula:

according to Claim 3, with a nucleophile of the formula WH, wherein W is as defined in Claim 1, in a polar-aprotic solvent and in an inert atmosphere.
8. A method of producing a compound, or its organic and inorganic salt or metal complex, of the formula:

according to Claim 3 excluding the compounds where R3 and R4 are both hydrogen which comprises reacting a 9-amino-7-(substituted)-6-demethyl-6-deoxytetracycline, or its organic and inorganic salt or metal complex, of the formula:

with a straight or branched haloacyl halide of the for-mula:

wherein Y is as defined in Claim 3, R3 and R4 are as defined in Claim 1 excluding the compounds where R3 and R4 are both hydrogen and Q is halogen selected from bromine, chlorine, iodine and fluorine, in an inert solvent, in a polar-aprotic sol-vent and in the presence of a base.
9. Use of a pharmacologically effective amount of a compound according to Claim 1 for the prevention, treatment or control of bacterial infections in warm-blooded animals.
10. A pharmaceutical composition of matter comprising a pharmacologically effective amount of a compound according to Claim 1 in association with a pharmaceutically acceptable carrier.
11. A veterinary composition which comprises a pharmacologically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.
12. Use of a pharmacologically effective amount of a compound according to Claim 1 for the prevention, treatment or control of bacterial infections in warm-blooded animals caused by bacteria having the TetM and TetK resistant determinants.
13. A compound according to Claim 1, wherein R6 is a (C7-C9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl.
14. A compound according to Claim 1, wherein R6 is a five membered aromatic or saturated ring with one N, O, S or Se heteroatom selected from pyrroylyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl and selenazolyl.
15. A compound according to Claim 1, wherein R6 is a five membered aromatic ring with two N, O, S, or Se heteroatoms selected from imidazolyl, pyrazolyl, benzinidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl and pyridylimidazolyl.
16. A compound according to Claim 1, wherein R6 is 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 and N-aminoimidazolidinone.
17. A compound according to Claim 1, wherein R6 is a six membered aromatic ring with one to three N heteroatoms selected from pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl and (C1-C3) alkylthiopyridazinyl.
18. A compound according to Claim 1, wherein R6 is 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 and 2-dioxothiomorpholinyl.
19. A compound according to Claim 1, wherein R7 is a (C7-C9) aralkyl group selected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl.
20. A compound according to Claim 1, wherein R7 is a five membered aromatic or saturated ring with one N, O, S or Se heteroatom selected from pyrroylyl, N-methylindolyl, indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl and selenazolyl.
21. A compound according to Claim 1, wherein R7 is a five membered aromatic ring with two N, O, S, or Se heteroatoms selected from imidazolyl, pyrazolyl, benzinidazolyl, oxazolyl, benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridyl and pyridylimidazolyl.
22. A compound according to Claim 1, wherein R7 is 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 and N-aminoimidazolidinone.
23. A compound according to Claim 1, wherein R7 is a six membered aromatic ring with one to three N heteroatoms selected from pyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsym-triazinyl, pyrimidinyl and (C1-C3) alkylthiopyridazinyl.
24. A compound according to Claim 1, wherein R7 is 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 and 2-dioxothiomorpholinyl.
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Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494903A (en) * 1991-10-04 1996-02-27 American Cyanamid Company 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
USRE40183E1 (en) 1991-10-04 2008-03-25 Wyeth Holdings Corporation 7-Substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
SG47520A1 (en) * 1992-08-13 1998-04-17 American Cyanamid Co New method for the production of 9-amino-6-demethyl-6-deoxytetracycline
US5284963A (en) * 1992-08-13 1994-02-08 American Cyanamid Company Method of producing 7-(substituted)-9-[(substituted glycyl)-amidol]-6-demethyl-6-deoxytetra-cyclines
US5420272A (en) * 1992-08-13 1995-05-30 American Cyanamid Company 7-(substituted)-8-(substituted)-9-](substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
US5442059A (en) * 1992-08-13 1995-08-15 American Cyanamid Company 9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
US5371076A (en) * 1993-04-02 1994-12-06 American Cyanamid Company 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines
AU1279095A (en) * 1994-02-17 1995-09-04 Pfizer Inc. 9-(substituted amino)-alpha-6-deoxy-5-oxy tetracycline derivatives, their preparation and their use as antibiotics
US5675030A (en) * 1994-11-16 1997-10-07 American Cyanamid Company Method for selective extracting a 7-(hydrogen or substituted amino)-9- (substituted glycyl) amido!-6-demethyl-6-deoxytetracycline compound
US5843925A (en) * 1994-12-13 1998-12-01 American Cyanamid Company Methods for inhibiting angiogenesis, proliferation of endothelial or tumor cells and tumor growth
AU753370B2 (en) * 1998-01-23 2002-10-17 Trustees Of Tufts College Pharmaceutically active compounds and methods of use thereof
CN102336680A (en) * 1999-09-14 2012-02-01 塔夫茨大学信托人 Methods of preparing substituted tetracyclines with transition metal-based chemistries.
US8106225B2 (en) * 1999-09-14 2012-01-31 Trustees Of Tufts College Methods of preparing substituted tetracyclines with transition metal-based chemistries
US6946118B1 (en) 1999-09-14 2005-09-20 Orapharma, Inc. Formulations for treating or preventing mucositis
IL151971A0 (en) * 2000-03-31 2003-04-10 Tufts College 7-and 9-carbamate, urea, thiourea, thiocarbabamate, and heteroaryl-amino substituted tetracycline compounds
US20020132798A1 (en) * 2000-06-16 2002-09-19 Nelson Mark L. 7-phenyl-substituted tetracycline compounds
WO2001098236A2 (en) * 2000-06-16 2001-12-27 Trustees Of Tufts College 7-phenyl-substituted tetracycline compounds
EP3461808A1 (en) 2000-07-07 2019-04-03 Trustees of Tufts College 9-substituted minocycline compounds
US7094806B2 (en) 2000-07-07 2006-08-22 Trustees Of Tufts College 7, 8 and 9-substituted tetracycline compounds
CN102336679A (en) * 2000-07-07 2012-02-01 塔夫茨大学信托人 7-substituted tetracycline compounds
US7553828B2 (en) 2001-03-13 2009-06-30 Paratek Pharmaceuticals, Inc. 9-aminomethyl substituted minocycline compounds
EP1955996A1 (en) * 2001-03-13 2008-08-13 Paratek Pharmaceuticals, Inc. 7, 9-Substituted tetracycline compounds
WO2002072506A2 (en) * 2001-03-13 2002-09-19 Paratek Pharmaceuticals, Inc. 7-pyrollyl tetracycline compounds and methods of use thereof
EP1241160A1 (en) * 2001-03-13 2002-09-18 Glaxo Group Limited Tetracycline derivatives and their use as antibiotic agents
EP2332549A1 (en) 2001-07-13 2011-06-15 Paratek Pharmaceuticals, Inc. Novel tetracyclines and their use in medicine
US20060194773A1 (en) * 2001-07-13 2006-08-31 Paratek Pharmaceuticals, Inc. Tetracyline compounds having target therapeutic activities
WO2003055441A2 (en) 2001-08-02 2003-07-10 Paratek Pharmaceuticals, Inc. Medicaments
EP2322501B1 (en) * 2002-01-08 2015-08-05 Paratek Pharmaceuticals, Inc. 4-dedimethylamino tetracycline compounds
CN102531948A (en) * 2002-03-08 2012-07-04 帕拉特克药品公司 Amino-methyl substituted tetracycline compounds
EP2481723A3 (en) 2002-03-21 2013-02-13 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US20040029843A1 (en) * 2002-06-20 2004-02-12 Orapharma, Inc. Rapidly disintegrating formulations for treating or preventing mucositis
CN1700922A (en) 2002-07-12 2005-11-23 帕拉特克药品公司 3, 10, and 12a substituted tetracycline compounds
EP1633774B1 (en) 2003-06-18 2010-02-17 Tranzyme Pharma Inc. Macrocyclic antagonists of the motilin receptor
EP2298323A3 (en) * 2003-07-09 2011-05-11 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US20060287283A1 (en) * 2003-07-09 2006-12-21 Paratek Pharmaceuticals, Inc. Prodrugs of 9-aminomethyl tetracycline compounds
UA83266C2 (en) * 2003-12-08 2008-06-25 Уайет Oxazole derivatives of tetracyclines
WO2005070878A1 (en) * 2004-01-15 2005-08-04 Paratek Pharmaceuticals, Inc. Aromatic a-ring derivatives of tetracycline compounds
EP2284152A3 (en) 2004-10-25 2011-10-05 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US7858601B2 (en) 2004-10-25 2010-12-28 Paratek Pharmaceuticals, Inc. 4-substituted tetracyclines and methods of use thereof
US7534766B2 (en) 2004-11-05 2009-05-19 Wyeth Glucuronide metabolites and epimers thereof of tigecycline
WO2006084265A1 (en) 2005-02-04 2006-08-10 Paratek Pharmaceuticals, Inc. 11a, 12-DERIVATIVES OF TETRACYCLINE COMPOUNDS
AU2006214543A1 (en) 2005-02-15 2006-08-24 Wyeth 9-substituted tetracyclines
AR057324A1 (en) * 2005-05-27 2007-11-28 Wyeth Corp TIGECICLINE AND METHODS TO PREPARE 9-AMINOMINOCICLINE
AR057034A1 (en) * 2005-05-27 2007-11-14 Wyeth Corp METHODS TO PURIFY TIGECICLINE
AR057649A1 (en) 2005-05-27 2007-12-12 Wyeth Corp SOLID CRYSTALINE TIGECICLINE FORMS AND METHODS TO PREPARE THE SAME
AR057033A1 (en) * 2005-05-27 2007-11-14 Wyeth Corp TIGECICLINE AND METHODS TO PREPARE 9-NITROMINOCICLINE
AR057032A1 (en) * 2005-05-27 2007-11-14 Wyeth Corp TIGECICLINE AND PREPARATION METHODS
US20070093455A1 (en) * 2005-07-21 2007-04-26 Paul Abato 10-substituted tetracyclines and methods of use thereof
WO2007075794A2 (en) * 2005-12-22 2007-07-05 Wyeth Oral formulations comprising tigecycline
CA2631632A1 (en) * 2005-12-22 2007-07-05 Wyeth Methods of treating gastrointestinal tract infections with tigecycline
CN101489987A (en) * 2006-04-17 2009-07-22 特瓦制药工业有限公司 Isolation of tetracycline derivatives
DE202007019460U1 (en) * 2006-04-24 2012-10-24 Teva Pharmaceutical Industries Ltd. Crystalline tigecycline forms
US8198470B2 (en) * 2006-04-24 2012-06-12 Teva Pharmaceutical Industries Ltd. Crystalline form II of tigecycline and processes for preparation thereof
EP2537934A3 (en) 2006-05-15 2013-04-10 Paratek Pharmaceuticals, Inc. Methods of regulating expression of genes or of gene products using substituted tetracycline compounds
TW200815020A (en) * 2006-06-15 2008-04-01 Serenex Inc Stabilized tetracycline compositions
EP2086926A2 (en) * 2006-11-29 2009-08-12 Teva Pharmaceutical Industries Ltd. Crystalline forms of tigecycline and processes for preparation thereof
MX2008009727A (en) * 2006-11-30 2009-01-09 Teva Pharma Processes for preparation of 9-haloacetamidominocyclines.
FR2912133B1 (en) * 2007-02-01 2009-04-24 Univ Grenoble 1 NOVEL INDOLIC DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND USES THEREOF IN PARTICULAR AS ANTIBACTERIANS
WO2008106234A1 (en) * 2007-03-01 2008-09-04 Teva Pharmaceutical Industries Ltd. Processes for purification of tigecycline
WO2009032326A1 (en) * 2007-09-07 2009-03-12 Dr. Reddy's Laboratories Ltd. New tetracycline derivatives as antiinfective agents
CA2706475C (en) 2007-11-29 2016-05-03 Actelion Pharmaceuticals Ltd Phosphonic acid derivates and their use as p2y12 receptor antagonists
CN102177134B (en) * 2008-08-08 2014-04-16 麻州四期制药公司 C7-fluoro substituted tetracycline compounds
CA2761241C (en) 2009-05-08 2018-02-27 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
NO2470500T3 (en) 2009-08-28 2018-03-03
WO2013013504A1 (en) * 2011-07-26 2013-01-31 山东亨利医药科技有限责任公司 Tigecycline derivative
MX364400B (en) 2012-08-31 2019-04-24 Tetraphase Pharmaceuticals Inc Tetracycline compounds.
WO2018075767A1 (en) 2016-10-19 2018-04-26 Tetraphase Pharmaceuticals, Inc. Crystalline forms of eravacycline

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE26271E (en) * 1967-09-26 Reductive alkylation process
US2482055A (en) * 1948-02-11 1949-09-13 American Cyanamid Co Aureomycin and preparation of same
US2997471A (en) * 1958-08-18 1961-08-22 Bristol Myers Co Tetracycline derivatives
US3007965A (en) * 1959-02-13 1961-11-07 American Cyanamid Co New tetracyclines produced by streptomyces aureofaciens
US3043875A (en) * 1959-10-22 1962-07-10 Pfizer & Co C Halogenated tetracycline derivatives and processes for their preparation
FR1430859A (en) * 1960-05-23 1966-05-25
US3338963A (en) * 1960-10-28 1967-08-29 American Cyanamid Co Tetracycline compounds
US3862225A (en) * 1961-08-18 1975-01-21 Pfizer D-ring substituted tetracyclines
US3509184A (en) * 1961-08-18 1970-04-28 Pfizer & Co C Anthracyclidine-acetic acid derivatives
US3772363A (en) * 1961-08-18 1973-11-13 Pfizer 3,4,10-trioxo octahydroanthracene-2-aminoacetic acids and derivatives thereof
US3697552A (en) * 1961-08-18 1972-10-10 Pfizer Anthracyclidine-acetic acid derivatives
US3829453A (en) * 1961-08-18 1974-08-13 Pfizer Octahydroanthracene-2-aminoacetic acids and esters and mixed anhydrides thereof
US3502696A (en) * 1961-08-18 1970-03-24 Pfizer & Co C Antibacterial agents
US3360557A (en) * 1963-05-10 1967-12-26 American Cyanamid Co 9-hydroxytetracyclines and a process of preparing same
USRE26253E (en) * 1963-05-17 1967-08-15 And z-alkylamino-g-deoxytetracycline
US3341585A (en) * 1966-05-06 1967-09-12 American Cyanamid Co Substituted 7-and/or 9-amino-6-deoxytetracyclines
US3515731A (en) * 1966-06-17 1970-06-02 Pfizer & Co C Antibacterial agents
US3849493A (en) * 1966-08-01 1974-11-19 Pfizer D-ring substituted 6-deoxytetracyclines
US3345410A (en) * 1966-12-01 1967-10-03 American Cyanamid Co Substituted 7- and/or 9-amino tetracyclines
US3360561A (en) * 1967-06-19 1967-12-26 American Cyanamid Co Nitration of tetracyclines
US3518306A (en) * 1968-02-19 1970-06-30 American Cyanamid Co 7- and/or 9-(n-nitrosoalkylamino)-6-demethyl-6-deoxytetracyclines
US4806529A (en) * 1982-11-18 1989-02-21 Trustees Of Tufts College, Tufts University Tetracycline activity enhancement
US5281628A (en) * 1991-10-04 1994-01-25 American Cyanamid Company 9-amino-7-(substituted)-6-demethyl-6-deoxytetracyclines
ES2168254T3 (en) * 1991-10-04 2002-06-16 American Cyanamid Co NEW 7-SUBSTITUTES-9- (AMINO SUBSTITUTED) -6-DESMETIL-6-DEOXITETRACICLINES.
US5284963A (en) * 1992-08-13 1994-02-08 American Cyanamid Company Method of producing 7-(substituted)-9-[(substituted glycyl)-amidol]-6-demethyl-6-deoxytetra-cyclines

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