Title: Use of treosulfan and
derivatives thereof for treating multiple sclerosis
United States Patent: 7,235,590
Issued: June 26, 2007
Inventors: Sass; Gretel
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
July 26, 2005
PCT Pub. No.:
PCT Pub. Date: February 26,
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
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
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
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
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,
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
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
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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