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1. WO2004098603 - UTILISATION D'ACIDES AMINOALCANEPHOSPHONIQUES SUBSTITUES POUR TRAITER LA SCLEROSE EN PLAQUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

USE OF SUBSTITUTED AMINOALKANEPHOSPHONIC ACIDS IN THE TREATMENT OF MULTIPLE SCLEROSIS

The present invention relates to a new pharmaceutical use of substituted
aminoalkanephosphonic acids.

More particularly the invention relates to a new pharmaceutical use for compounds of formula I



wherein
Ri is hydroxy or (C1-4)alkyl,
R2 is (C1-4)alkyl,
R3 is hydrogen, (C1-4) alkyl, fluorine, chlorine, bromine, trifluoromethyl, cyano or nitro, and X is (C1-6)alkylene, (C1-6)alkylidene, (C1-6)alkylene(C3.6)cycloalkylene or (C1.6)alkylene- (C3-6)cycloalkylidene,

and their pharmaceutically acceptable salts, hereafter referred to as "the compounds".

The compounds as well as their production process are known e.g. from WO 98/17672.

This application also discloses the use of the compounds for the treatment of pathological conditions which respond to blockade of excitatory amino acid receptors, such as AMPA receptors, NMDA, kainate receptors and glycine binding sites of NMDA receptors, for example of neurodegenerative disorders, stroke, epilepsy, anxiety and pain.

In accordance with the present invention, it has now surprisingly been found that the compounds are also useful in the treatment of multiple sclerosis and related demyelinating diseases, e.g. neuromyelitis optica.

The activity of the compounds in the treatment of multiple sclerosis is evidenced, for example, in the following model of experimental autoimmune encephalomyelitis (EAE), the primary animal model for the indication multiple sclerosis (MS), an autoimmune disease of the central nervous system.

Female Dark Agouti rats (DA-rats) are kept in a climate-controlled room with 12 hr light/dark cycles, housed in sawdust-lined cages with 4 to 5 rats per cage, and given standard rodent chow and water ad libitum. Severely paralyzed animals are especially provided with easier access to food and water. The rats are allowed at least one week to adapt to their surroundings, then they are randomly distributed into experimental groups (10 per group) and individually numbered with a tail mark. Rats are 8-9 weeks old (about 135 g) at the time of immunization on day 0. For optimal EAE induction, the immunization procedure utilizes freshly isolated brain and spinal cord (40:60 ratio) from adult DA rats as a source of syngeneic encephalitogenic neuroantigens. The central nervous system (CNS) tissue samples, also referred to as DA-b/sc, are stored in Eppendorf tubes at -70° C until needed.

Rats are lightly anesthetized with isoflurane and immunized by a single intradermal (i.d.) injection at the dorsal root of the tail with 200 μl inoculum containing 1 part (volumervolume) CNS tissue emulsified in the appropriate diluent to 1 part incomplete Freund's adjuvant (IFA) supplemented with Mycobacterium tuberculosis strain H37RA (Difco, Detroit, Ml). The IFA-mycobacterium mixture is hereafter designated CFA (complete Freund's adjuvant). More specifically, DA-b/sc is emulsified in 'syringe A' containing 0.9% NaCI using a Polytron PT 3100 homogenizer (Kinematica, Lucerne, Switzerland) at 28,000 rpm for about 3 min. The antigen emulsion is gradually added to CFA in 'syringe B' while homogenizing. All solutions are kept on ice and not allowed to overheat with high speed mixing.

Adjuvant control animals are injected with CFA alone (1.6 mg M. tuberculosis per rat) and treated with the vehicle. Animals in the other experimental groups are injected with the neuroantigen-CFA emulsion (65 mg DA-b/sc and 1.6 mg mycobacterium per rat) and treated with vehicle alone or vehicle containing the test compound. The study is usually terminated on day 63, nine weeks after immunization on day 0.

Clinical EAE scoring: The animals are examined daily for neurological signs and body weight change. Clinical grades of EAE are assessed using a disease scale from 0 to 4:
0 = no disease
1 = complete loss of tail tonus
2 = weakness of hindlimb(s) or ataxia
3 = complete paralysis of either both hindlimbs or forelimbs
4 = moribund condition with paralysis of both forelimbs and hindlimbs;
[disease-related mortality]

Scores of 3-4 are often accompanied by urinary incontinence. EAE-related mortality is recorded with a maximum score of 4. Other recorded data include day of EAE onset and % disease incidence per group.

Compound application: The compounds are applied for 14 to 21 days, starting on day 0 (prophylactic treatment) or on day 12 post-immunization (therapeutic treatment). The compounds are applied bid or tid and are given orally, intraperitoneally, or subcutaneously.

Statistical analysis: Since disease severity and duration are both key parameters to consider in drug testing, clinical scores are analysed as area under the curve (AUC) of scores over time.

In this EAE model, 10 to 20% of the antigen-immunized control animals can die due to disease-related causes. To account for this relevant information in the statistical analysis, the method of Gould was applied [Gould AL. A new approach to the analysis of clinical drug trials with withdrawals. Biometrics 1980; 36:721-7]. Animals in each group were ranked by their AUC value (increasing disease severity). Deceased rats were positioned according to the time of death, thereby giving them higher ranks than the survivors. Ranks were compared using non-parametric Wilcoxon Mann-Whitney tests (StatXact V3, Cytel Software Corp.). Probabilities (p) < 0.05 are considered statistically significant.

In this model, the compounds ameliorate the severity of EAE symptoms. With the compound {[(7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-ylmethyl)-amino]-methyl} -phosphonic acid, for example, an effect is seen at 2 X 10 mg/kg, i.p..

Suitable compounds for the treatment of multiple sclerosis include {[(7-nitro-2,3-dioxo-1 ,2,3,4-tetrahydro-quinoxaline-5-ylmethyl)-amino]-methyl}-phosphonic acid, (R)-N-(2,3-dioxo-7-nitro-1 ,2,3,4-tetrahydroquinoxaline-5-ylmethyl)-α-(ethylamino)-ethylphosphonic acid, (S)-N-(7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-ylmethyl)-α-aminoethylphosphonic acid and their pharmaceutically acceptable salts.

The present invention also provides pharmaceutical compositions comprising a compound of formula I in association with at least one pharmaceutical carrier or diluent, for use in the treatment of multiple sclerosis and related demyelinating diseases, e.g. neuromyelitis optica. Such compositions may be manufactured in conventional manner. Unit dosage forms for the treatment multiple sclerosis and related demyelinating diseases, e.g. neuromyelitis optica may contain for example from about 2.5 mg to about 500 mg of the compound of formula I.

The invention further provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of multiple sclerosis and related demyelinating diseases, e.g. neuromyelitis optica.

The invention furthermore provides a method for the treatment of multiple sclerosis and related demyelinating diseases, e.g. neuromyelitis optica in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of formula I.