US 2002/0160987 A1 · Novel 4-dedimethylaminotetracycline derivatives · patentgrep

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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.

Claims21

Dependent claims

A tetracycline compound of the formulae:

11
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 4-dedimethylamino tetracycline compound selected from:

13
wherein:
R7, R8, and R9 taken together in each case, have the following meanings:
10 R7 R8 R9 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 dimethylamino chloro dimethylamino hydrogen hydrogen dimethylamino dimethylamino hydrogen hydrogen
and
14
wherein:
R7, R8, and R9 taken together in each case, have the following meanings:
11 R7 R8 R9 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
15
wherein:
R8 is hydrogen or halogen and R9 is selected from the group consisting of nitro, (N,N-dimethyl)glycylamino, and ethoxythiocarbonylthio;
and
16
wherein:
R7, R8, and R9 taken together in each case, have the following meanings:
12 R7 R8 R9 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.

16 more elements

A tetracycline compound of the formulae:

17
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 STRUCTURE 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 STRUCTURE 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 STRUCTURE E STRUCTURE F
wherein:
R7 and R9 are selected from the group consisting of an aryl, alkene alkyne, 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;
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.

73 more elements

A tetracycline compound of the formulae:

STRUCTURES 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

Dependencies are inferred from the claim text.

Facts

Application: 09/911,861Filed 24 Jul 2001
Priority: 18 Nov 1998
Published: 31 Oct 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07D 295/13
With the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings:…
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes

Family

Application09/195,013Continuation in part · filed 18 Nov 1998
Application09/479,604Continuation in part · filed 7 Jan 2000
Application09/573,654Continuation in part · filed 18 May 2000
Application09/911,861Continuation in part · filed 24 Jul 2001
US 6,506,740 B1Related patent
US 6,638,922 B2Related patent
US 2002/0160987 A1This patent

From the US filing history. Foreign family members aren’t listed.

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