Methods of treating acne
View Patent ↗A method of treating acne in a human in need thereof comprising administering systemically to said human a tetracycline compound in an amount that is effective to treat acne but has substantially no antibiotic activity, without administering a bisphosphonate compound.
1. A method of treating acne in a human in need thereof comprising administering systemically to said human a tetracycline compound in an amount that is effective to treat acne but has substantially no antibiotic activity, without administering a bisphosphonate compound, wherein said tetracycline compound is a non-antibiotic tetracycline compound, or a pharmaceutically acceptable salt of a non-antibiotic tetracycline compound.
2. A method according to claim 1 , wherein said acne is acne vulgaris, cystic acne, acne atrophica, bromide acne, chlorine acne, acne conglobata, acne cosmetica, acne detergicans, epidemic acne, acne estivalis, acne fulminans, halogen acne, acne indurata, iodide acne, acne keloid, acne mechanica, acne papulosa, pomade acne, premenstral acne, acne pustulosa, acne rosacea, acne scorbutica, acne scrofulosorum, acne urticata, acne varioliformis, acne venenata, propionic acne, acne excoriee, gram negative acne, steroid acne, or nodulocystic acne.
3. A method according to claim 1 , wherein said non-antibiotic tetracycline compound is:
4-de(dimethylamino)tetracycline (CMT-1),
tetracyclinonitrile (CMT-2),
6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-3),
4-de(dimethylamino)-7-chlorotetracycline (CMT-4),
tetracycline pyrazole (CMT-5)
4-hydroxy-4-de(dimethylamino)tetracycline (CMT-6),
4-de(dimethylamino)-12α-deoxytetracycline (CMT-7),
6-α-deoxy-5-hydroxy-4-de(dimethylamino)tetracycline (CMT-8),
4-de(dimethylamino)-12α-deoxyanhydrotetracycline (CMT-9),
4-de(dimethylamino)minocycline (CMT-10),
or pharmaceutically acceptable salts thereof.
4. A method according to claim 1 , wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
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 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, and pharmaceutically acceptable salts thereof.
5. A method according to claim 1 , wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
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 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.
6. A method according to claim 1 wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
wherein: R7, R8, and R9 taken together in each case, have the following meanings:
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
wherein: R7, R8, and R9 taken together in each case, have the following meanings:
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
wherein: R8 is hydrogen or halogen and R9 is selected from the group consisting of nitro, (N,N-dimethyl)glycylamino, and ethoxythiocarbonylthio; and
wherein: R7, R8; and R9 taken together in each case, have the following meanings:
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 salts thereof.
7. A method according to claim 1 , wherein the non-antibiotic tetracycline compound is selected from the group consisting of:
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;
R a and R b are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and 1-methylethyl with the proviso that R a and R b cannot both be hydrogen;
R c and R d are, independently, (CH 2 ) n CHR e wherein n is 0 or 1 and R e is selected from the group consisting of hydrogen, alkyl, hydroxy, lower(C 1 -C 3 ) alkoxy, amino, or nitro; and,
W is selected from the group consisting of (CHR e ) m wherein m is 0-3 and said R e is as above, NH, N(C 1 -C 3 ) straight chained or branched alkyl, O, S and N(C 1 -C 4 ) straight chain or branched alkoxy; and,
pharmaceutically acceptable salts thereof.
8. A method according to claim 7 , wherein the non-antibiotic tetracycline compound selected from the group consisting of structures S-Z has 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.
9. A method according to claim 1 , wherein said tetracycline compound has a general formula:
wherein R7, R8, and R9 taken together are, respectively, hydrogen, hydrogen and dimethylamino or a pharmaceutically acceptable salt thereof.
10. A method according to claim 1 , wherein said tetracycline compound is selected from the group consisting of:
wherein R7, R8, and R9 taken together in each case, have the following meanings:
R7
R8
R9
hydrogen
hydrogen
amino
hydrogen
hydrogen
palmitamide
and
wherein R7, R8, and R9 taken together in each case, have the following meanings:
R7
R8
R9
hydrogen
hydrogen
acetamido
hydrogen
hydrogen
dimethylaminoacetamido
hydrogen
hydrogen
nitro
hydrogen
hydrogen
amino
and
wherein R8, and R9 taken together are, respectively, hydrogen and nitro and pharmaceutically acceptable salts thereof.
11. A method according to claim 1 , wherein said systemic administration is oral administration, intravenous injection, intramuscular injection, subcutaneous administration, transdermal administration or intranasal administration.