IP Library › Patent Application 12288807

Patent Application

App. No. 12/288,807

Novel 4-Dedimethylaminotetracycline derivatives

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Patent No.: US None
App. No.: 12/288,807

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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.

Claims (282)

1 . A tetracycline compound of the formulae:

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(NH 2 )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.

2 . A tetracycline compound of the formulae:

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(NH 2 )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.

3 . A 4-dedimethylamino tetracycline compound selected from:

wherein: R7, R8, and R9 taken together in each case, have the following meanings:

azido

hydrogen

dimethylamino

hydrogen

azido

hydrogen

amino

hydrogen

azido

hydrogen

nitro

dimethylamino

hydrogen

amino

acylamino

hydrogen

acylamino

amino

hydrogen

nitro

hydrogen

(N,N-dimethyl)glycylamino

amino

hydrogen

amino

hydrogen

ethoxythiocarbonylthio

dimethylamino

hydrogen

acylamino

dimethylamino

hydrogen

diazonium

dimethylamino

chloro

amino

hydrogen

chloro

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

dimethylamino

hydrogen

and

wherein: R7, R8, and R9 taken together in each case, have the following meanings:

azido

hydrogen

dimethylamino

hydrogen

azido

hydrogen

amino

hydrogen

azido

hydrogen

nitro

dimethylamino

hydrogen

amino

acylamino

hydrogen

acylamino

amino

hydrogen

nitro

hydrogen

(N,N-dimethyl)glycylamino

amino

hydrogen

amino

hydrogen

ethoxythiocarbonylthio

dimethylamino

hydrogen

acylamino

hydrogen

diazonium

hydrogen

dimethylamino

diazonium

hydrogen

ethoxythiocarbonylthio

hydrogen

dimethylamino

chloro

amino

chloro

amino

acylamino

chloro

acylamino

hydrogen

chloro

amino

chloro

hydrogen

acylamino

chloro

hydrogen

monoalkylamino

chloro

amino

nitro

chloro

amino

and

wherein: R8 is hydrogen or halogen and R9 is selected from the group consi051205650512sting of nitro, (N,N-dimethyl)glycylamino, and ethoxythiocarbonylthio; and

wherein: R7, R8, and R9 taken together in each case, have the following meanings:

amino

hydrogen

nitro

hydrogen

azido

hydrogen

dimethylamino

hydrogen

azido

hydrogen

amino

hydrogen

azido

hydrogen

nitro

bromo

hydrogen

dimethylamino

hydrogen

amino

acylamino

hydrogen

acylamino

amino

hydrogen

nitro

hydrogen

(N,N-dimethyl)glycylamino

amino

hydrogen

amino

diethylamino

hydrogen

ethoxythiocarbonylthio

dimethylamino

hydrogen

methylamino

dimethylamino

hydrogen

acylamino

dimethylamino

chloro

amino

chloro

amino

acylamino

chloro

acylamino

hydrogen

chloro

amino

chloro

hydrogen

acylamino

chloro

hydrogen

monoalkylamino

chloro

amino

nitro

chloro

amino

and pharmaceutically acceptable and unacceptable salts thereof.

4 - 21 . (canceled)