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(12) Patent Application Publication (10) Pub. No.: US 2004/0038904 A1 Ogden (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2004/0038904 A1 Ogden (43) Pub US 2004.0038904A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0038904 A1 Ogden (43) Pub. Date: Feb. 26, 2004 (54) METHOD OF TREATING MULTIPLE Related U.S. Application Data SCLEROSIS (60) Provisional application No. 60/382,159, filed on May 21, 2002. (76) Inventor: Angela Ogden, Long Valley, NJ (US) Publication Classification Correspondence Address: (51) Int. Cl." ........................ A61K 38/08; A61K 31/704 Pharmacia & Upjohn Company (52) U.S. Cl. ................................................. 514/16; 514/34 Global Intellectual Property 301 Henrietta Street (57) ABSTRACT Kalamazoo, MI 49001 (US) The present invention provides for use of an anthracycline, (21) Appl. No.: 10/438,131 Such as doxorubicin, alone or in combination with a pro tective agent, Such as deXraZOxane, for treating multiple (22) Filed: May 14, 2003 Sclerosis. US 2004/0038904 A1 Feb. 26, 2004 METHOD OF TREATING MULTIPLE SCLEROSIS 0009 Anthracyclines are members of a very important class of antineoplastic agents that has been used clinically CROSS-REFERENCE TO RELATED for decades in a wide range of human tumors. Examples of APPLICATION commonly used anthracyclines include doxorubicin, dauno rubicin, epirubicin, and idarubicin. This class of agents also 0001. This application claims the benefit of U.S. provi possesses antibacterial activities. sional application Serial No. 60/382,159, filed May 21, 0010 Doxorubicin is effective as an anti-tumor agent 2002, under 35 U.S.C. S119 (e)(1). against a variety of neoplasms. Such as acute leukemias and BACKGROUND OF THE INVENTION malignant lymphomas. It is also very effective in the treat ment of Solid tumors, particularly when administered as part 0002) 1. Field of the Invention of a combination regimen. Doxorubicin is commercially available under the trade names Adriamycin RDF(E)/PFSCR 0003. The present invention relates to treatment of mul (doxorubicin hydrochloride injection, USP) from Pharmacia tiple Sclerosis, and more specifically to the use of anthracy & Upjohn, Doxil(R) (doxorubicin HCl liposome injection) clines, alone or in combination with a protective agent, to from Alza, Lipodox(R) from Pfizer, DaunoXome(R) from treat multiple Sclerosis. Nexter, MTC doxo (doxorubicin magnetic targeted par ticles) from FeRX/Elan, and Rubex(R) (doxorubicin hydro 0004 2. Description of the Related Art chloride for injection) from Bristol-Myers Squibb Oncol 0005) Multiple Sclerosis (MS) is a disease of the central ogy/Immunology. Chemically, doxorubicin hydrochloride is nervous System that affects the brain and Spinal cord. It (8 S, 10 S)-10-(3-amino-2,3,6-trideoxy-(alpha)-L-lyxo-hex strikes an estimated 250,000 people in the United States and opyranosyl)oxy-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-tri is the major acquired neurologic disease in young adults. hydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. Common signs and Symptoms of MS include fatigue, psy 0011 Epirubicin is used to treat some kinds of cancers of chological and cognitive changes, weakneSS or paralysis of the breast, lung, lymph System, Stomach, and ovaries. Epi limbs, numbness, vision problems, Speech difficulties, rubicin hydrochloride is commercially available under the muscle Spasticity, difficulty with balance when walking or trade name Ellence(R) (Pharmacia & Upjohn). Chemically, Standing, bowel and bladder dysfunction, and Sexual dyS epirubicin hydrochloride is (8S-cis)-10-(3-amino-2,3,6- function. Approximately half the people with this disease trideoxy-(alpha)-L-arabino-hexopyranosyl)oxy-7,8,9,10 have relapsing-remitting MS in which there are unpredict tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-meth able attacks where the clinical symptoms become worse oxy-5,12-naphthacenedione hydrochloride. (exacerbation) which are separated by periods of remission where the symptoms stabilize or diminish. The other half 0012 Daunorubicin is used to treat acute nonlympho have chronic progressive MS without periods of remission. cytic leukemia (myelogenous, monocytic, erythroid) of adults and in acute lymphocytic leukemia of children and 0006. At present there are no cures for MS. Many medi adults. Daunorubicin hydrochloride is commercially avail cations are available to relieve Symptoms in progressive MS. able under the trade name Cerubidine from Bedford. Chemi For example, corticosteroids are used to reduce inflamma cally, daunorubicin hydrochloride is (1 S.3 S)-3-Acetyl-1, tion in nerve tissue and Shorten the duration of flare-ups, 2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11 Muscle relaxants Such as tizanidine (Zanaflex) and baclofen dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-(alpha)-L- (Lioresal) are oral treatments for muscle Spasticity; Antide lyxo-hexopyranoside hydrochloride. pressant medication fluoxetine (Prozac), the antiviral drug amantadine (Symmetrel) or a medication for narcolespy 0013 Examples of other anthracyclines or of anthracy called modafinil (Provigil) are used to reduce fatigue. cline derivatives developed or explored for use as antine oplaxtic agents include 4' deoxy-4'-iododoxorubicin (U.S. 0007. A few other drugs are available for MS that are not Pat. No. 4,438,105), nemorubicin (U.S. Pat. No. 4,672,057), directly related to Symptom management and but may act to AR522 (liposome annamycin, Aronex, CLIN. CANC. RES. alter the course of the disease. These drugs include beta Jan. 11, 1995 (1369-1374), L 377202 (Chemical Name: interferons (Betaferon, AvoneX, Rebif) and glatiramer (4R)-1-(4-carboxy-1-oxobutyl)-4-hydroxy-L-prolyl-L-ala acetate (Copaxone). These drugs may have an impact on the nyl-L-seryl-(2R)-2-cyclohexylglycyl-L-glutaminyl-L-seryl frequency and Severity of relapses, and the number of L-leucine), Merck & Co), and GPX-100 (anthracycline, lesions as Seen on MRI scans. Some of the drugs appear to Gem Pharm). have an effect of Slowing the progression of disability. U.S. Pat. No. 4,617,319 discloses a method of treating multiple 0014. Despite the effectiveness of anthracyclines as clini Sclerosis using 1,4-dihydroxy-5,8-bis(2-hydroxyethylami cal antineoplastic agents, it is known that, like many other no)ethylaminoanthraquinone, which is also known by the antineoplastic agents, anthracyclines have Serious Side generic name mitoxantrone. Mitoxantrone is a Synthetic effects Such as cardiotoxicity, bone-marrow depression and anthracenedione and is the active ingredient of the antine gastrointestinal tract mucositis, which Significantly limit oplastic drug Novantrone(R). their clinical usefulneSS. 0008. None of these existing therapies are proven satis 0.015 U.S. Pat. No. 6,057,361 discloses a method of factory because of limited efficacy and for Significant tox reducing anthracycline toxicity by administration of dime icity. In addition, many of these therapies are required to be Sna and analogues and derivatives thereof. administered frequently and Some are very expensive. Thus, 0016 U.S. Pat. No. 6,147,094,361 discloses a method of there clearly exists a need for novel and effective methods of reducing anthracycline-induced cardiotoxicity by adminis treating MS. tration of manganese compounds. US 2004/0038904 A1 Feb. 26, 2004 0017 U.S. Pat. No. 5,242,901 discloses a method of peutically effective amount of one or more anthracyclines in reducing anthracycline-induced cardiotoxicity by adminis combination with administration of an effective amount of a tration of a protective agent Such as deXraZoxane. protective agent. One example of the protective agent is bisdioxopiperazine. Another example of the protective agent 0018 U.S. Pat. No. 5,744,455 discloses a human anti neoplastic composition comprising an anthracycline in is a is a compound of formula (I): admixture with deXraZoxane. 0019 U.S. Pat. No. 4,257,063 discloses a pharmaceutical (I) composition useful for aiding regression and palliation of 1. ( )m ( )n a. Sarcoma, lymphosarcoma, and leukaemia in humans which R1S y R2 comprises an amount therapeutically effective in aiding Said R3 regression and palliation of deXraZoxane. 0020 Franz X, et al. disclose an experimental study on the effect of mitoxantrone in combination with deXraZOxane 0030 or a pharmaceutically acceptable salt thereof, on experimental autoimmune encephalomyelitis in Lewis wherein in formula (I): Rats. (Franz X et al. Combination therapy with the cardio 0031 R is hydrogen, lower alkyl or protector deXraZOxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomycli tis in Lewis Rats. Neurology 54 (Supplement 3): A60-61 (2000)) Dexrazoxane is currently marketed under the trade name Zinecard TM by Pharmacia, Inc. as a cardioprotective agent. Chemically, dexrazoxane is (S)-4,4'-(1-methyl-1,2- ethanediyl)bis-2,6-piperazinedione. 0021 Surprisingly and unexpectedly, it has been found 0032 R and R are each individually SOM", that anthracyclines can be used to treat MS, either alone or PO-M', or POS-M"; in combination with administration of protective agent. 0033 R and Rs are each individually hydrogen, hydroxy or sulfhydryl; SUMMARY OF INVENTION 0034 m and n are individually 0, 1, 2, 3 or 4, with 0022. It is an object of the invention to provide a novel the proviso that if m or n is 0, then R is hydrogen; method of treating multiple Sclerosis. and 0023. It is another object of the invention to provide a 0035) M is hydrogen or an alkali metal ion; or method of treating multiple Sclerosis wherein the toxic effects of the active therapeutic agent are reduced or mini 0036 Still another example of the protective agent is a mized.
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