Source: https://www.lens.org/lens/patent/188-743-076-902-373/fulltext
Timestamp: 2019-04-20 10:38:58+00:00

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Continuation of application No. 14/101,030, filed on Dec. 9, 2013, now abandoned , which is a continuation of application No. 13/277,789, filed on Oct. 20, 2011, now Pat. No. 8,603,506 , which is a continuation of application No. 11/876,478, filed on Oct. 22, 2007, now Pat. No. 8,052,983 , which is a continuation of application No. 10/757,656, filed on Jan. 14, 2004, now abandoned , which is a division of application No. 10/117,709, filed on Apr. 5, 2002, now Pat. No. 7,211,267 , and which is a division of application No. 14/753,544 .
Continuation of application No. 13/838,559, filed on Mar. 15, 2013, now Pat. No. 8,658,189 .
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 This application is a continuation of U.S. application Ser. No. 14/101,030, filed on Dec. 9, 2013, pending, which is a continuation of U.S. application Ser. No. 13/277,789, filed on Oct. 20, 2011, now U.S. Pat. No. 8,603,506, which is a continuation of U.S. application Ser. No. 11/876,478, filed on Oct. 22, 2007, now U.S. Pat. No. 8,052,983, which is a continuation of U.S. application Ser. No. 10/757,656, filed on Jan. 14, 2004, abandoned, which is a divisional application of U.S. application Ser. No. 10/117,709, filed on Apr. 5, 2002, now U.S. Pat. No. 7,211,267, which claims the benefit of U.S. Provisional Application No. 60/281,916, filed Apr. 5, 2001, and U.S. Provisional Application No. 60/325,489, filed Sep. 26, 2001. The application is also a continuation of U.S. application Ser. No. 13/838,559, filed on Mar. 15, 2013, now U.S. Pat. No. 8,658,189. All of the aforementioned applications are incorporated herein by reference in their entireties.
 For the purposes of this specification, acne includes all known types of acne. Some types of acne include, for example, 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 scorbutica, acne scrofulosorum, acne urticata, acne varioliformis, acne venenata, propionic acne, acne excoriee, gram negative acne, steroid acne, nodulocystic acne and acne rosacea. Acne rosacea is characterized by inflammatory lesions (erythema) and permanent dilation of blood vessels (telangectasia).
 Examples of chemically modified non-antibiotic tetracyclines (CMTs) include 4-de(dimethylamino)tetracycline (CMT-1), tetracyclinonitrile (CMT-2), 6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-3), 7-chloro-4-de(dimethylamino)-tetracycline (CMT-4), tetracycline pyrazole (CMT-5), 4-hydroxy-4-de(dimethylamino)-tetracycline (CMT-6), 4-de(dimethylamino-12α-deoxytetracycline (CMT-7), 6-deoxy-5α-hydroxy-4-de(dimethylamino)tetracycline (CMT-8), 4-de(dimethylamino)-12α-deoxyanhydrotetracycline (CMT-9), 4-de(dimethylamino)minocycline (CMT-10).
 The tetracycline compounds are administered without administering a bisphosphonate compound. Bisphosphonates compounds are related to inorganic pyrophosphonic acid. The bisphosphonates include, as non-limiting examples, alendronate ((4-amino-1-hydroxybutylidene) bisphosphonic acid), clodronate (dichloromethane diphosphonic acid), etidronate ((1-hydroxyethylidene) diphosphanic acid) and pamidronate ((3-amino-1-hydroxypropylidene) bisphosphonic acid); also risedronate ([-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid), tiludronate, i.e., tiludronic acid ([(4-chlorophenyl)thio]methylene]bisphosphonic acid) and zolendronate.
 To a solution of one millimole of 4-dedimethylamino-7-dimethylamino-6-demethyl-6-deoxytetracycline in 25 ml of concentrated sulfuric acid at 0° C. was added 1.05 mmole of potassium nitrate. The resulting solution was stirred at ice bath temperature for 15 minutes and poured in one liter of cold ether with stifling. The precipitated solid was allowed to settle and the majority of solvent decanted. The remaining material was filtered through a sintered glass funnel and the collected solid was washed well with cold ether. The product was dried in a vacuum desiccator overnight.
 To 1 mmole of a 4-dedimethylamino-6-deoxytetracycline in 25 ml of concentrated sulfuric acid at 0° C. was added 1 mmole of potassium nitrate with stifling. The reaction solution was stirred for 15 minutes and then poured into 100 g of chopped ice. The aqueous solution was extracted 5 times with 20 ml of butanol each time. The butanol extracts were washed three times with 10 ml of water each time, and concentrated in vacuo to a volume of 25 ml. The light yellow crystalline solid which precipitated was filtered, washed with 2 ml of butanol and dried in vacuo at 60° C. for 2 hours. This solid was a mixture of the two mononitro isomers.
 To 980 mg of the nitration product from 4-dedimethylamino-6-deoxytetracycline (a mixture of the 2 isomers) in 25 ml of methanol was added enough triethylamine to dissolve the solid. The filtered solution (pH 9.0) was adjusted to pH 5.2 with concentrated sulfuric acid. A crystalline yellow solid (236 mg) was obtained (29% yield). The material at this point was quite pure and contained only small amounts of the 7-isomer. Final purification was accomplished by liquid partition chromatography using a diatomaceous earth packed column and the solvent system: chloroform:butanol:0.5 M phosphate buffer (pH 2) (16:1:10).
 A solution of 1.0 mmole of -8-chloro-4-dedimethylamino-6-deoxy-6-demethyl-7-dimethyl amino-9-diazoniumtetracycline hydrochloride in 15 ml of water was added to a solution of 1.15 mmole of potassium ethyl xanthate in 15 ml of water. The mixture was stirred at room temperature for one hour. The solid that separated was filtered and dried in a vacuum desiccator.
 Phototoxicity Assay: Duplicate plates were prepared for each test material by seeding 104 3 T3 cells per well in μl of complete medium 24 hours before treatment. Prior to treatment, the medium was removed, and the cells washed once with 125 μl prewarmed HBSS. Fifty μl of prewarmed HBSS were added to each well. Fifty μl of test article dilutions were added to the appropriate wells and the plates returned to the incubator for approximately one hour. Following the 1 hr incubation, the plates designated for the photoirritation assay were exposed (with the lid on) to 1.7±0.1 mW/cm2 UVA light for 50±2 minutes at room temperature resulting in an irradiation dose of 5 J/cm2. Duplicate plates designated for the cytotoxicity assay were kept in the dark room temperature for 50±2 minutes. After the 50 minute exposure period the test article dilutions were decanted from the plates and the cells washed once with 125 μl HBSS. One hundred μl of medium were added to all wells and the cells incubated as above for 24±1 hours.
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.
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.
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 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. In a further embodiment, the following provisos apply: 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. The method according to claim 1, wherein said doxycycline is doxycycline monohydrate.
3. The method according to claim 2, wherein said doxycycline monohydrate is administered in an amount of 40 milligrams per day.
4. The method according to claim 3, wherein said doxycycline monohydrate is administered by sustained release.
5. A method according to claim 4, wherein said doxycycline monohydrate is administered once a day.
6. The method according to claim 2, wherein said doxycycline monohydrate is administered in a dose of 20 mg twice a day.
8. The method according to claim 7, wherein said doxycycline is doxycycline monohydrate.
9. The method according to claim 8, wherein said doxycycline monohydrate is administered in an amount of 40 milligrams per day.
10. The method according to claim 9, wherein said doxycycline monohydrate is administered by sustained release.
11. A method according to claim 10, wherein said doxycycline monohydrate is administered once a day.
12. The method according to claim 8, wherein said doxycycline monohydrate is administered in a dose of 20 mg twice a day.
14. The method according to claim 13, wherein said doxycycline is doxycycline monohydrate.
15. The method according to claim 14, wherein said doxycycline monohydrate is administered by sustained release.
16. A method according to claim 15, wherein said doxycycline monohydrate is administered once a day.
17. The method according to claim 14, wherein said doxycycline monohydrate is administered in a dose of 20 mg twice a day.
18. The method according to claim 1, wherein said doxycycline is doxycycline hyclate.
19. The method according to claim 18, wherein said doxycycline hyclate is administered in an amount of 40 milligrams per day.
20. The method according to claim 19, wherein said doxycycline hyclate is administered by sustained release.
21. A method according to claim 20, wherein the acne is acne rosacea.
22. The method according to claim 18, wherein said doxycycline hyclate is administered in a dose of 20 mg twice a day.
23. The method according to claim 7, wherein said doxycycline is doxycycline hyclate.
24. The method according to claim 23, wherein said doxycycline hyclate is administered in an amount of 40 milligrams per day.
25. The method according to claim 24, wherein said doxycycline hyclate is administered by sustained release.
26. A method according to claim 25, wherein said acne is acne rosacea.
27. The method according to claim 23, wherein said doxycycline hyclate is administered in a dose of 20 mg twice a day.
28. The method according to claim 13, wherein said doxycycline is doxycycline hyclate.
29. The method according to claim 28, wherein said acne is acne rosacea.
30. The method according to claim 28, wherein said doxycycline hyclate is administered by sustained release.
31. A method according to claim 28, wherein said acne is acne rosacea.
32. The method according to claim 28, wherein said doxycycline hyclate is administered in a dose of 20 mg twice a day.

References: application No. 14
 application No. 13
 application No. 11
 application No. 10
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 application No. 13
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 application No. 60
 § 1
 §42
 §42
 §42
 Application No. 60
 Application No. 60