WO1999051226A1 - Use of aminothiazole derivatives for preparing medicines for treating diseases causing demyelinization - Google Patents

Abstract

The invention concerns the use of aminothiazole for preparing pharmaceutical compositions for fighting against diseases causing demyelenization.

Description

Use of aminothiazole derivatives for the preparation of medicaments for the treatment of diseases resulting in demyelination.

The present invention relates to the use of certain aminothiazoles for the preparation of medicaments for the treatment of diseases causing the destruction of myelin.

These pathologies have the common characteristic of being of inflammatory or autoimmune origin and of causing the loss of myelin in the central nervous system. We can distinguish mainly between chronic pathologies like multiple sclerosis and acute pathologies like acute disseminated encephalomyelitis and acute hemorrhagic leukoencephalitis. Among these pathologies, multiple sclerosis is the most widespread and leads to very serious sensory and visual motor dysfunctions.

At present, no effective therapy is available for these diseases and treatments are limited to symptomatic treatments aimed at improving spastic hypertonia, fatigue and pain or, as the origin of these pathologies is often reputed to be autoimmune, aimed at suppressing the immunological response.

It is known that PAF (Platelet Activating Factor) antagonists have, among many possible uses, a possible activity on multiple sclerosis (DW Howat et al., Agents and Action, 1989, 27, 3/4; Lydia Vêla er al .,

Journal of Neuroimmunology, 1991, 33, 81-86; B. Brochet et al., Rev. Neurol.

(Paris), 1992, 148, 4, 299-301; B. Brochet et al., Journal of Neurology, Neurosurgery and Psychiatry, 1995, 58, 360-362).

Several patent applications describe the use of PAF antagonists in indications such as inflammation; pain ; asthma; gastric ulcers; respiratory diseases; regulation of platelet coagulation; hypotension; immune system diseases; skin diseases such as hives, dermatitis; multiple sclerosis ; rheumatoid arthritis; transplant rejection and any disease in which PAF is involved. Patent applications claim the use of benzimidazole derivatives (WO

92/03422 and WO 92/03423) as PAF antagonists.

Patent EP 0 462 264 claims variously substituted sulfur and nitrogen or oxygen and nitrogen heterocycles. These heterocycles are described as PAF antagonists useful in particular for the treatment of asthma, certain allergic or inflammatory conditions, cardiovascular diseases including

Partherosclerosis, thrombosis, hypotension or arrhythmias, ischemia cerebral or cardiac, and various renal pathologies including glomerulonephritis or as a contraceptive agent.

It is moreover well known that very numerous aminothiazole derivatives have been described in the literature for their use in therapy in very varied fields and pathologies.

It has now been found according to the present invention that certain aminothiazole derivatives exert a beneficial action with respect to diseases causing the destruction of myelin. These aminothiazole derivatives have been described, inter alia, in EP 0 462 264 and are provided with a PAF antagonist activity.

Among the very numerous indications for the PAF antagonists mentioned above, it has been demonstrated according to the present invention that a particular group of aminothiazole derivatives are useful for the preparation of medicaments intended for the treatment of diseases causing the destruction of myelin and in particular, multiple sclerosis.

Thus, the subject of the present invention is the use of aminothiazole compounds described and claimed in EP 0 462 264 or of a pharmaceutically acceptable salt and solvate thereof, for the preparation of pharmaceutical compositions intended for combating diseases causing demyelinization. According to an advantageous aspect, the invention relates to the use of the foropafant or N, N-dimethyl-N'-pyridin-3-yl-methyl-N '- [4- (2,4,6-triisopropylphenyl) thiazol-2 -yl] ethane-1, 2-diamine or one of its pharmaceutically acceptable salts and solvates also described in the literature under the reference SR 27417A. Foropafant fumarate is particularly preferred. The activity of the compounds of EP 0 462 264 for the use according to the invention was sought in the experimental allergic encephalitis (EAE) model induced in the Lewis rat by the intraplantar administration of basic myelin protein (MBP). (fragment 68-84) in a complete Freund's adjuvant (FCA) enriched in mycobacterium tuberculosis according to the protocol published by Martin and Near (Journal of Neuroimmunology, 1995, 241-245).

EAE is an autoimmune and inflammatory disease of the central nervous system with demyelinating lesions reminiscent of human multiple sclerosis. In this experimental model, representative compounds according to the invention, administered orally since the zero day of induction of the disease, very significantly attenuate the disease, measured both on the variations in weight of the animals (the animals suffer from significant weight loss) and severity of the pathology (diseased animals show paralysis of the hind legs). The weight loss of the treated animals is significantly lower than that of the animals treated by the vehicle alone. Likewise, the severity of the disease is statistically lower in the groups of animals treated with foropafant.

Another major event recognized in multiple sclerosis is the loss of integrity of the blood brain barrier under attack by the immune system. This pathological effect is also highlighted in the EAE model. It has been verified that the degradation of the blood-brain barrier is significantly reduced or even non-existent (the barrier not exhibiting any permeability anomaly) in animals treated with compounds representative of the invention compared with control animals.

The results of these studies show that the compounds claimed in EP 0 462 264 and its pharmaceutically acceptable salts and solvates, play a favorable role in this pathology of neurological dysfunction and can thus find clinical application in the treatment of diseases causing demyelinating lesions, such as multiple sclerosis.

The compounds and their pharmaceutically acceptable salts and solvates are preferably administered orally. In the pharmaceutical compositions of the present invention for oral administration, the active principle can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, to animals and humans for the treatment of the aforementioned conditions. Suitable unit dosage forms include, for example, possibly scored tablets, capsules, powders, granules and oral solutions or suspensions.

When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle. A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules. A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color. Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters. The amount of active ingredient to be administered depends as always on the degree of progression of the disease as well as on the age and weight of the patient. Nevertheless, the unit doses generally comprise from 0.1 to 100 mg, better still from 0.25 to 50 mg, preferably from 0.5 to 20 mg of active principle.

The preferred compound for the use according to the present invention, the foropafant is used in unit doses of 0.5 to 10 mg, advantageously from 1 to 5, preferably from 1 to 3 mg, for example 1 - 1, 5 - 2 - 2.5 - 3 mg of active ingredient. These unit doses are normally administered one or more times a day, preferably one to three times a day, the overall dose in humans being variable between 0.5 and 50 mg per day, for example from 1 to 20 mg per day. , advantageously from 2 to 10 mg per day. According to another of its aspects, the present invention relates to a synergistic association comprising a compound of EP 0 462 264 or one of its pharmaceutically acceptable salts or solvates, and at least one compound chosen from immunosuppressive agents, such as interferon β-1b; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; interleukin-1 inhibitors.

More particularly, the invention relates to a combination comprising the foropafant, or one of its pharmaceutically acceptable salts or solvates and at least one compound chosen from roquimex (1, 2-dihydro-4-hydroxy-N, 1-dimethyl- 2-oxo-3-quinolinecarboxanilide), myloran (product from Autoimmune containing bovine myelin), antegren (human monoclonal antibody from Elan / Athena

Neurosciences), the recombinant interferon β-1a. Other possible combinations are those consisting of a compound of EP 0 462 264 or one of its pharmaceutically acceptable salts or solvates and of a potassium channel blocker, such as for example fampridine (4-amino pyridine). In a further aspect, the present invention relates to a method of treating diseases resulting in demyelination which comprises administering to a subject in need of an effective amount of an EP 0 462 264 compound or a salt thereof or pharmaceutically acceptable solvates.

According to another aspect, the subject of the present invention is a method of treating diseases causing demyelination which comprises administering to a subject in need of an effective amount of a combination comprising a compound of EP 0 462 264 or a its pharmaceutically acceptable salts or solvates and at least one compound chosen from immunosuppressive agents, such as interferon β-1 b; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; interleukin-1 inhibitors.

EXAMPLE

Induction of experimental allergic encephalitis (EAE).

8-9 week old female Lewis rats were used. EAE was induced by the administration of 100 μg of fragment 68-82 of the basic protein of myelin (MBP ₆₈ - ₈₂ ) (Sigma) prepared in a suspension containing 50 μl of a sodium chloride solution at 0 , 9% and 50 μl of incomplete Freund's adjuvant with 1 mg of Mycobacterium tuberculosis H37RA (ACF) (Difco Laboratories Inc., Detroit, Ml). A total volume of 100 μl of this suspension was injected subcutaneously into the plantar pads of the 2 hind legs, under isoflurane anesthesia. The control animals (vehicle group + ACF) simply received the incomplete Freund's adjuvant containing Mycobacterium tuberculosis. Treatment and clinical monitoring of EAE.

The groups treated with foropafant (n = 10) received doses of 10 or 2 mg / kg orally daily, from day 0 of induction of EAE until the end of the experiment. The control animals (n = 10) received the vehicle from the foropafant (5% of

DMSO, 5% Tween 80 and 90% water for injections). The pathology was followed daily according to a conventional scale of severity as indicated below: no neurological sign = grade 0, loss of tone in the tail = grade 1, 5, flickering gait or weakness of the rear axle = grade 2, paralysis one leg = grade 2.5, placed on the back, the animal cannot return to its normal position = grade 3, paralysis of the rear end or nasal bleeding or incontinence = grade 4, dying = grade 5, death = grade 6. In addition, the animals were weighed daily. These two criteria, clinical signs and weight loss, have made it possible to highlight the severity of this pathology. The results obtained were as follows: Experiment 1 carried out at 10 mg / kg, orally (FIGURE 1).

Animals immunized with MBP ₆₈ -82 and treated with vehicle foropafant (MBP + vehicle group), showed the classic signs of EAE (weight loss and clinical signs) from 15 ^ee day after the immunization. The pathology reached its maximum on day 18, with a maximum weight loss of 10g. After that, the animals recovered, the disease regressed and disappeared on day 29 of the experiment. Thus, on these criteria, the acute attack of EAE lasted 14 days (between days 15 and 29 of the experiment).

Animals immunized with MBP ₆₈ -82 and treated with foropafant showed significant weight loss from day 18 until day 24 of the experiment. Thus, the acute attack of EAE lasted only 6 days in this group.

In addition, the analysis of clinical signs by studying the areas under the clinical severity curves revealed that over the duration of the experiment, the animals immunized with MBP ₆₈ . ₈ 2 and treated with foropafant at a dose of 10 mg / kg did not overall present clinical signs superior to those of animals in the control group (ACF + vehicle), unlike animals immunized with MBP ₆₈ . ₈₂ and processed by the vehicle (MBP group + vehicle).

Treatment with foropafant at a dose of 10 mg / kg has shown that the attack of EAE begins later, the attack of EAE disappears earlier, the attack of EAE is less severe. Experiment 2 carried out with 2 mg / kg, orally (FIGURE 2).

Foropafant was administered orally at a dose of 2 mg / kg and the same trend (exemplified here by the analysis of weight loss following the onset of the disease) was obtained.

Claims

1. Use of the foropafant or one of its pharmaceutically acceptable salts and solvates, for the preparation of pharmaceutical compositions intended for combating diseases causing demyelination. 2. Use according to claim 1, characterized in that the foropafant salt is fumarate. 3. Use according to one of claims 1 or 2 for the preparation of medicaments intended for the treatment of multiple sclerosis. 4. Pharmaceutical composition containing foropafant fumarate in combination with a pharmaceutical excipient intended to combat diseases causing demyelination. 5. Pharmaceutical composition according to claim 4 for combating multiple sclerosis.