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US 2003/0195174 A1Published application
Novel 4-dedimethylaminotetracycline derivatives
AssigneeCollaGenex Pharmaceuticals, Inc.
InventorsRobert A. Ashley, Joseph J. Hlavka
Life of this patent
Estimating the term…
Abstract
The present invention provides new chemically modified 4-dedimethylaminotetracycline compounds that can be substituted with aryl, alkenyl, or alkynyl groups. The 7, 8, and/or 9 positions and methods for preparing such compounds. Other tetracycline compounds include the 4-dedimethylaminotetracycline derivatives with an oxime group, NH-Alkyl, or N—NH-Alkyl group substituted at the C4 position as well as C2 Mannich derivatives. The present invention also provides a method of treating a mammal suffering from conditions or diseases by administering to the mammal an effective amount of the new chemically modified tetracycline compounds.
Claims36
A tetracycline compound of the formulae:
- 20
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH2)CO;
- R is hydrogen or lower alkyl;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- with the following provisos:
- when either R7 and R9 are hydrogen then R8 must be halogen;
- and
- when R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or diethylamino, then R8 must be halogen;
- and
- when R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is hydrogen, amino, nitro, halogen or diethylamino, then R8 is halogen;
- and
- when R6-a is methyl, R6 is hydroxyl, R5, R7 and R9 are all hydrogen, then R8 must be halogen;
- and
- when R6-a, R6 and R5 are all hydrogen, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen;
- and
- when R6-a is methyl, R6 is hydrogen, R5 is hydroxyl, R9 is methylamino and R7 is dimethylamino, then R8 must be halogen;
- and
- when R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen.
21 more elements
A tetracycline compound of the formulae:
- 21
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, and di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R4 is selected from the group consisting of NOH, N—NH—A, and NH—A, where A is a lower alkyl group;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, di(lower alkyl)amino and RCH(NH2)CO;
- R is hydrogen or lower alkyl;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- with the following provisos:
- when R4 is NOH, N—NH-alkyl or NH-alkyl and R7, R6-a, R6, R5, and R9 are all hydrogen, then R8 must be halogen;
- and
- when R4 is NOH, R6-a is methyl, R6 is hydrogen or hydroxyl, R7 is halogen, R5 and R9 are both hydrogen, then R8 must be halogen;
- and
- when R4 is N—NH-alkyl, R6-a is methyl, R6 is hydroxyl and R7, R5, R9 are all hydrogen, then R8 must be halogen;
- and
- when R4 is NH-alkyl, R6-a, R6, R5 and R9 are all hydrogen, R7 is hydrogen, amino, mono(lower alkyl)amino, halogen, di(lower alkyl)amino or hydroxyl, then R8 must be halogen;
- and
- when R4 is NH-alkyl, R6-a is methyl, R6 and R9 are both hydrogen, R5 is hydroxyl, and R7 is mono(lower alkyl)amino or di(lower alkyl)amino, then R8 must be halogen;
- and
- when R4 is NH-alkyl, R6-a is methyl, R6 is hydroxy or hydrogen and R7, R5, and R9 are all be hydrogen, then R8 must be halogen.
20 more elements
A 4-dedimethylamino tetracycline compound selected from:
- 12 R7 R8 R9 22 wherein:
- R7, R8, and R9 taken together in each case, have the following meanings:
- azido hydrogen hydrogen dimethylamino hydrogen azido hydrogen hydrogen amino hydrogen hydrogen azido hydrogen hydrogen nitro dimethylamino hydrogen amino acylamino hydrogen hydrogen hydrogen hydrogen acylamino amino hydrogen nitro hydrogen hydrogen (N,N-dimethyl)glycylamino amino hydrogen amino hydrogen hydrogen ethoxythiocarbonylthio dimethylamino hydrogen acylamino dimethylamino hydrogen diazonium dimethylamino chloro amino hydrogen chloro amino amino chloro amino acylamino chloro acylamino amino chloro hydrogen acylamino chloro hydrogen monoalkylamino chloro amino nitro chloro amino dimethylamino chloro acylamino dimethylammo chloro dimethylamino hydrogen hydrogen dimethylamino dimethylamino hydrogen hydrogen and 23 24 25 26 wherein:
- R7, R8, and R9 taken together in each case, have the following meanings:
- azido hydrogen hydrogen dimethylamino hydrogen azido hydrogen hydrogen amino hydrogen hydrogen azido hydrogen hydrogen nitro dimethylamino hydrogen amino acylamino hydrogen hydrogen hydrogen hydrogen acylamino amino hydrogen nitro hydrogen hydrogen (N,N-dimethyl)glycylamino amino hydrogen amino hydrogen hydrogen ethoxythiocarbonylthio dimethylamino hydrogen acylamino hydrogen hydrogen diazonium hydrogen hydrogen dimethylamino diazonium hydrogen hydrogen ethoxythiocarbonylthio hydrogen hydrogen dimethylamino chloro amino amino chloro amino acylamino chloro acylamino hydrogen chloro amino amino chloro hydrogen acylamino chloro hydrogen monoalkylamino chloro amino nitro chloro amino and 27 wherein:
- R8 is hydrogen or halogen and R9 is selected from the group consisting of nitro, (N,N-dimethyl)glycylamino, and ethoxythiocarbonylthio;
- and 28 29 wherein:
- R7, R8, and R9 taken together in each case, have the following meanings:
- amino hydrogen hydrogen nitro hydrogen hydrogen azido hydrogen hydrogen dimethylamino hydrogen azido hydrogen hydrogen amino hydrogen hydrogen azido hydrogen hydrogen nitro bromo hydrogen hydrogen dimethylamino hydrogen amino acylamino hydrogen hydrogen hydrogen hydrogen acylamino amino hydrogen nitro hydrogen hydrogen (N,N-dimethyl)glycylamino amino hydrogen amino diethylamino hydrogen hydrogen hydrogen hydrogen ethoxythiocarbonylthio dimethylamino hydrogen methylamino dimethylamino hydrogen acylamino dimethylamino chloro amino amino chloro amino acylamino chloro acylamino hydrogen chloro amino amino chloro hydrogen acylamino chloro hydrogen monoalkylamino chloro amino nitro chloro amino and pharmaceutically acceptable and unacceptable salts thereof.
6 more elements
A tetracycline compound of the formulae:
- 30 31
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH2)CO;
- R is hydrogen or lower alkyl;
- Ra and Rb are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and 1-methylethyl with the proviso that Ra and Rb cannot both be hydrogen;
- Rc and Rd are, independently, (CH2)nCHRe wherein n is 0 or 1 and Re is selected from the group consisting of hydrogen, alkyl, hydroxy, lower(C1-C3) alkoxy, amino, or nitro;
- and,
- W is selected from the group consisting of (CHRe)m wherein m is 0-3 and said Re is as above, NH, N(C1-C3) straight chained or branched alkyl, O, S and N(C1-C4) straight chain or branched alkoxy;
- and,
- pharmaceutically acceptable and unacceptable salts thereof
11 more elements
A tetracycline compound of the formulae:
- STRUCTURE C STRUCTURE D STUCTURE E STRUCTURE F
- wherein:
- R7 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH2)CO;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE C STRUCTURE D STUCTURE E STRUCTURE F
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE C STRUCTURE D STUCTURE E STRUCTURE F
- wherein:
- R7 and R9 are selected from the group consisting of an aryl, alkene alkyne, or mixures thereof;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- and
- pharmaceutically acceptable and unacceptable salts thereof.
25 more elements
A tetracycline compound of the formulae:
- STRUCTURE G STRUCTURE H STRUCTURE I STRUCTURE J
- wherein:
- R7 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R4 is selected from the group consisting of NOH, N—NH—A, and NH—A, where A is a lower alkyl group;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, di(lower alkyl)amino and RCH(NH2)CO;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE G STRUCTURE H STRUCTURE I STRUCTURE J
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R4 is selected from the group consisting of NOH, N—NH—A, and NH—A, where A is a lower alkyl group;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- and
- pharmaceutically acceptable and unacceptable salts thereof,
- or
- STRUCTURE G STRUCTURE H STRUCTURE I STRUCTURE J
- wherein:
- R7 and R9 are selected from the group consisting of an aryl, alkenyl, alkynyl;
- or mixtures thereof;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R4 is selected from the group consisting of NOH, N—NH—A, and NH—A, where A is a lower alkyl group;
- and
- R8 is selected from the group consisting of hydrogen and halogen;
- and
- pharmaceutically acceptable and unacceptable salts thereof,
30 more elements
A tetracycline compound of the formulae:
- STRUCTURE K
- wherein:
- R7 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, di(lower alkyl)amino and RCH(NH2)CO;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE K
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE K
- wherein:
- R7 and R9 are selected from the group consisting of an aryl, alkenyl, alkynyl and mixtures thereof;
- and
- R8 is selected from the group consisting of hydrogen and halogen;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- and
- STRUCTURE L STRUCTURE M STRUCTURE N STRUCTURE O
- wherein:
- R7 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- and pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE L STRUCTURE M STRUCTURE N STRUCTURE O
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE L STRUCTURE M STRUCTURE N STRUCTURE O
- wherein:
- R7 is and R9 are selected from the group consisting of an aryl, alkenyl, alkynyl and mixtures thereof;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, di(lower alkyl)amino and RCH(NH2)CO;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- and
- STRUCTURE P
- wherein:
- R9 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- and
- R8 is selected from the group consisting of hydrogen and halogen;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- and
- STRUCTURE Q STRUCTURE R
- wherein:
- R7 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, di(lower alkyl)amino and RCH(NH2)CO;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE Q STRUCTURE R
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- and
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURE Q STRUCTURE R
- wherein:
- R7 and R9 are selected from the group consisting of an aryl, alkenyl, alkynyl;
- and mixtures thereof,
- R8 is selected from the group consisting of hydrogen and halogen;
- and
- pharmaceutically acceptable and unacceptable salts thereof.
74 more elements
A tetracycline compound of the formulae:
- STUCTURES S-Z
- wherein:
- R7 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of hydrogen, amino, azido, nitro, acylamino, hydroxy, ethoxythiocarbonylthio, mono(lower alkyl) amino, halogen, diazonium, di(lower alkyl)amino and RCH(NH2)CO;
- Ra and Rb are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and 1-methylethyl with the proviso that Ra and Rb cannot both be hydrogen;
- Rc and Rd are, independently, (CH2)nCHRe wherein n is 0 or 1 and Re is selected from the group consisting of hydrogen, alkyl, hydroxy, lower(C1-C3) alkoxy, amino, or nitro;
- and,
- W is selected from the group consisting of (CHRe)m wherein m is 0-3 and said Re is as above, NH, N(C1-C3) straight chained or branched alkyl, O, S and N(C1-C4) straight chain or branched alkoxy;
- and,
- pharmaceutically acceptable and unacceptable salts thereof;
- or
- STRUCTURES S-Z
- wherein:
- R7 is selected from the group consisting of hydrogen, amino, nitro, mono(lower alkyl) amino, halogen, di(lower alkyl)amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano, and hydroxyl;
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- R9 is selected from the group consisting of an aryl, alkenyl and alkynyl;
- Ra and Rb are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and 1-methylethyl with the proviso that Ra and Rb cannot both be hydrogen;
- Rc and Rd are, independently, (CH2)nCHRe wherein n is 0 or 1 and Re is selected from the group consisting of hydrogen, alkyl, hydroxy, lower(C1-C3) alkoxy, amino, or nitro;
- and,
- W is selected from the group consisting of (CHRe)m wherein m is 0-3 and said Re is as above, NH, N(C1-C3) straight chained or branched alkyl, O, S and N(C1-C4) straight chain or branched alkoxy;
- and
- pharmaceutically acceptable and unacceptable salts thereof,
- or
- STRUCTURES S-Z
- wherein:
- R7 and R9 are selected from the group consisting of an aryl, alkenyl, alkynyl and mixtures thereof,
- R6-a is selected from the group consisting of hydrogen and methyl;
- R6 and R5 are selected from the group consisting of hydrogen and hydroxyl;
- R8 is selected from the group consisting of hydrogen and halogen;
- Ra and Rb are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and 1-methylethyl with the proviso that Ra and Rb cannot both be hydrogen;
- Rc and Rd are, independently, (CH2)nCHRe wherein n is 0 or 1 and Re is selected from the group consisting of hydrogen, alkyl, hydroxy, lower(C1-C3) alkoxy, amino, or nitro;
- and,
- W is selected from the group consisting of (CHRe)m wherein m is 0-3 and said Re is as above, NH, N(C1-C3) straight chained or branched alkyl, O, S and N(C1-C4) straight chain or branched alkoxy;
- and,
- pharmaceutically acceptable and unacceptable salts thereof.
37 more elements
A 4-dedimethylamino tetracycline compound:
- 32
- wherein:
- R7, R8, and R9 are trimethylammonium, hydrogen, and hydrogen, respectively.
Dependencies are inferred from the claim text.