IP Library › Granted Patent US 7,014,858

Granted Patent B2

US 7,014,858 · App. 10/272,499 · Granted Mar 21, 2006

Use methods of treating acne and telangiectasia

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Quick Facts

Patent No.: US 7,014,858
App. No.: 10/272,499
Granted: Mar 21, 2006
Kind: B2

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Abstract

A method of treating telangiectasia in a human in need thereof comprising administering to said human a tetracycline compound in an amount that is effective to treat telangiectasia, but has substantially no antibiotic activity.

Claims (367)

1. A method for treating telangiectasia in a human in need thereof comprising administering orally or intravenously to said human a tetracycline compound in a sub-antibacterial amount that reduces telangiectasia, said amount being 10–80% of the antibacterial effective amount, wherein the tetracycline compound is administered long term, wherein the tetracycline compound is administered without a bisphosphonate compound.

2. A method according to claim 1 , wherein said telangiectasia is associated with age, acne rosacea, sun exposure, alcohol use, scleroderma, hereditary hemorrhagic telangiectasia, Ataxia-Telangiectasia, spider angioma, cutis marmorata telangiectasia congenita, Bloom syndrome, Klippel-Trenaunay-Weber syndrome, Sturge-Weber disease, Xeroderma pigmentosa or Nevus flammeus, or any combination thereof.

3. A method according to claim 1 wherein said tetracycline compound is minocycline administered once a day in a dose of 38 mg.

4. A method according to claim 1 , wherein said tetracycline compound is minocycline administered twice a day in a dose of 38 mg.

5. A method according to claim 1 , wherein said tetracycline compound is minocycline administered three times a day in a dose of 38 mg.

6. A method according to claim 1 , wherein said tetracycline compound is minocycline administered four times a day in a dose of 38 mg.

7. A method according to claim 1 , wherein said tetracycline compound is tetracycline administered once a day in a dose of 60 mg/day.

8. A method according to claim 1 , wherein said tetracycline compound is tetracycline administered twice a day in a dose of 60 mg/day.

9. A method according to claim 1 , wherein said tetracycline compound is tetracycline administered three times a day in a dose of 60 mg/day.

10. A method according to claim 1 , wherein said tetracycline compound is tetracycline administered four times a day in a dose of 60 mg/day.

11. A method according to claim 1 , wherein said tetracycline compound is an antibiotic tetracycline compound administered in an amount which results in a serum concentration which is 10–80% of the minimum antibiotic serum concentration.

12. A method according to claim 1 , wherein said tetracycline compound is doxycycline administered in an amount which results in a serum concentration which is 1.0 μg/ml.

13. A method according to claim 1 , wherein said tetracycline compound is minocycline administered in an amount which results in a serum concentration which is 0.8 μg/ml.

14. A method according to claim 1 , wherein said tetracycline compound is tetracycline administered in an amount which results in a serum concentration which is 0.5 μg/ml.

15. A method according to claim 11 , wherein said antibiotic tetracycline compound is doxycycline, minocycline, tetracycline, oxytetracycline, chlortetracycline, demeclocycline or pharmaceutically acceptable salts thereof.

16. A method according to claim 15 , wherein said antibiotic tetracycline compound is doxycycline.

17. A method according to claim 16 , wherein said doxycycline is administered in an amount which provides a serum concentration in the range of about 0.1 to about 0.8 μg/ml.

18. A method according to claim 16 , wherein said doxycycline is administered in an amount of 20 milligrams twice daily.

19. A method according to claim 17 , wherein said doxycycline is administered by sustained release over a 24 hour period.

20. A method according to claim 19 , wherein said doxcycline is administered in an amount of 40 milligrams.

21. A method according to claim 1 , wherein said tetracycline compound is a non-antibiotic tetracycline compound.

22. A method according to claim 21 , 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), or

4-de(dimethylamino)minocycline (CMT-10).

23. A method according to claim 21 , 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.

24. A method according to claim 21 , 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.

25. A method according to claim 21 , 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:

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 consisting 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 salts thereof.

26. A method according to claim 21 , 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;

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.

27. A method according to claim 26 , 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.

28. A method according to claim 1 , wherein said tetracycline compound has a photoirritancy factor of less than the photoirritancy factor of doxycycline.

29. A method according to claim 1 , wherein said tetracycline compound has a photoirritancy factor from about one to about two.

30. A method according to claim 29 , wherein said tetracycline compound has a general formula:

wherein R7, R8, and R9 taken together are, respectively, hydrogen, hydrogen and dimethylamino.

31. A method according to claim 1 , wherein said tetracycline compound has a photoirritancy factor from about 1.0 to about 1.2.

32. A method according to claim 31 , 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:

hydrogen

amino

hydrogen

palmitamide

and

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

hydrogen

acetamido

hydrogen

dimethylaminoacetamido

hydrogen

nitro

hydrogen

amino

and

wherein R8, and R9 taken together are, respectively, hydrogen and nitro.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 12, 2011

From: COLLAGENEX PHARMACEUTICALS, INC.

To: GALDERMA LABORATORIES INC.

Reel/Frame 027369/0215 →