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Title:  Use of treosulfan and derivatives thereof for treating multiple sclerosis
United States Patent: 
7,235,590
Issued: 
June 26, 2007

Inventors: 
Sass; Gretel (Hamburg, DE)
Assignee: 
Medac Gesellschaft fur Klinische Spezialpraparate mbH (Hamburg, DE)
Appl. No.: 
10/524,144
Filed: 
August 12, 2003
PCT Filed: 
August 12, 2003
PCT No.: 
PCT/EP03/08957
371(c)(1),(2),(4) Date: 
July 26, 2005
PCT Pub. No.: 
WO20/04/016263
PCT Pub. Date: 
February 26, 2004


 

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Abstract

The invention relates to the use of treosulfan and/or derivatives thereof for producing a pharmaceutical composition used in the treatment of multiple sclerosis.

Description of the Invention

This application is a 371 of PCT/EP03/08957 filed on Aug. 12, 2003.

The present invention relates to the use of treosulfan and derivatives thereof for treating Multiple sclerosis.

Multiple sclerosis (MS) is a neurological disease which affects more than a million people worldwide. MS is an inflammatory state which destroys the myelin of the central nervous system (CNS) and causes neurological impairments as well as frequently also serious disabilities. The etiology of MS has so far remained unknown, it being generally assumed that the disease is mediated by some kind of autoimmune process which is possibly triggered by an infection and superimposed by a genetic predisposition. Following a mostly insidious, rarely sub-acute or acute beginning in the 20.sup.th to 40.sup.th year of life, most frequently, a chronic-progressive or polycentric development with a tendency towards remission is observed. The different stages and forms of multiple sclerosis are subdivided into relapsing-remitting (RR) MS (at present approximately 80 85% of MS patients), primary progressive (PP) MS, with more than 50% of the patients with RR-MS finally developing a permanent deterioration with or without superimposed relapses (secondary progressive (SP) form of MS) over time. It is not clear whether the different disease progressions are based on the same or different pathophysiological processes.

For the treatment of the different phases and forms of MS, there are partially clear-cut treatment recommendations which are reflected in an immunomodulatory stepwise therapy of MS (P. Riekmann, "Immunmodulatorische Therapie der Multiplen Sklerose: Konsensusprotokolle im deutschsprachigen Raum und Nordamcrika" (immunomodulatory therapy of Multiple sclerosis: consensus protocols in the German-speaking region and North America) in "Multiple Sklerose: Kausalorientierte, symptomatische und rehabilitative Therapie" (Multiple sclerosis causally oriented, symptomatic and rehabilitative therapy) Springer Verlage Berlin--Heidelburg--New York 2002: 109 188). Corticosteroids have proved suitable for periodic therapy. For relapsing-remitting multiple sclerosis, immunologically effective substances reducing the number of relapses are available in the form of interferon .beta. and glatriamer acetate. Interferon .beta. is also effective in the case of secondary progressive MS insofar as relapses-remissions still occur at this stage.

For the therapy of the purely progressive MS, no drugs are available which have been clearly shown to be effective. Mitoxantrone and cyclophosphamide or methotrexate are used. According to the treatment guidelines of the MS Council for Clinical Practice Guidelines of 2002 (D. S. Goodin et at., Neurology 58 (2002) 169 178), the effectiveness of these substances is considered to be possible. Since cardiac side effects occur in the case of mitoxantrone with a cumulative dosage of 160 mg/m.sup.2 and above (specialist information "Novantron.RTM." (Wyeth Pharma GmbH), January 2002, Bundesverband der Pharmazeutischen Industrie c.V./FachInfo-Service, D-88322 Aulendorf), since damage to the lower urinary tract is possible in the case of cyclophosphamide and methotrexate frequently has gastrointestinal side effects, at least equally effective alternatives with fewer side effects are required.

In view of the still existing problems in the search for suitable active substances for the treatment of MS, it is consequently a task of the present invention to provide a pharmaceutical composition which is suitable for treating MS (including all development forms) and which does not exhibit the disadvantages known in the case of the active agents used so far.

The task is achieved according to the invention by the use of treosulfan or derivatives thereof.

Within the framework of the present invention it has surprisingly enough been found that treosulfan is not only extremely well tolerated but has also led to a clear improvement in the disease development in the case of MS patients.

Using the example of experimental autoimmune encephalomyelitis (EAE) which is recognized as animal model of human MS, the effectiveness of treosulfan was first of all examined. The effectiveness of the treosulfan treatment was investigated in comparison with an untreated control group and a group receiving mitoxantrone. In the first trials, treosulfan was applied on the day of immunisation, in another on day 14 following immunisation. Although it was not possible to reverse the damage that manifested itself by that day, a stabilisation could be observed in the case of the group treated with treosulfan, in contrast to the (untreated) control group in the case of which the disease progressed further. In the case of numerous test animals, however, a noticeable improvement occurred. Moreover, it was worth noting that in the treosulfan group, 7 out of 8 animals were still alive on day 53 whereas in the comparative group only 2 of 8 animals were still alive at that point. In the comparative group which received mitoxantrone, no greater effectiveness was observed than in the treosulfan group.

Treosulfan is (2S,3S)-threitol-1,4-bismethane sulphonate (L-threitol-1,4-bis(methane sulfonate); Chemical Abstracts Registry No. 299-75-2) -- see Original Patent.

According to the invention, derivatives of treosulfan are also included such as e.g. busulfan (1,4-bis(methyl sulphonyloxy) butane), dimethyl busulfan (1,4-bis(methyl sulphonyloxy)-1,4-dimethyl butane; CA Registry No. 55-93-6), pentasulfan (1,5-dimesyl oxypentane; CA Registry No. 2374-22-3), hepsulfam (1,7-heptane diol disulphamate; CA Registry No. 96892-57-8) or similar substances which have led to similar results in initial control trials as treosulfan. To be considered for use are also treosulfan derivatives in which the methyl groups on the sulphur atom have been replaced (for example by (lower) alkyl substituents (linear or branched), in particular with 1 to 7 C atoms, e.g. ethyl, propyl, butyl, pentyl, hexyl and heptyl etc.) or substituted (replacement of one/several hydrogen atoms by one/several substituents such as e.g. isopropyl, tertiary butyl).

Busulfan has previously been used exclusively for conditioning patients before stem cell transplantation (compare Openshaw et al., Biology of Blood and Marrow Transplantation 2000, 6:563 575), with the aim of promoting the accretion of the transplant. In comparison, it has surprisingly enough been found in connection with the present invention that treosulfan and/or its derivatives, including busulfan are suitable directly for the treatment of MS. In comparison with the high risk and complicated approach of stem cell transplantation, the invention represents an independent and successful alternative.

The subject matter of the present invention is consequently the use of treosulfan and derivatives thereof for the preparation of a pharmaceutical composition for the treatment of MS. The above-mentioned substances, for example, are used as derivatives. According to the invention, combinations of treosulfan and/or a derivative thereof with one or several immunomodulatory substances, i.e. combination preparations containing--apart from treosulfan and/or a derivative thereof--one or several substances with an immunomodulatory effect such as e.g. interferon-.beta. (IFN-.beta.) and/or glatriamer acetate, as further active agent.

The pharmaceutical composition is preferably present in the form of a solution suitable for intravenous application (infusion); however, an oral formulation can also be considered for use.

The dosage is 1 to 10 g, preferably 3 to 9 g and particularly preferably 5 to 8 g treosulfan (and/or treosulfan derivative) per m.sup.2 of body surface.

The pharmaceutical composition is used for the treatment of multiple sclerosis, including the treatment of relapsing-remitting, primary progressive and in particular secondary progressive MS.
 


Claim 1 of 30 Claims

1. A method of treating multiple sclerosis (MS) comprising administering at least one compound selected from the group consisting of treosulfan, busulfan, dimethyl busulfan, pentasulfan and hepsulfam to a person in need of such treatment, said method not comprising stem cell transplantation.
 

 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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