HK1236004A - A compound for use in the treatment of muscular dystrophy - Google Patents

Description

Compounds for the treatment of muscular dystrophy

This application is a divisional application of the chinese patent application having application number 201280067188.0, application date 2012, 2/3, entitled "diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride for the treatment of muscular dystrophy".

Technical Field

The present invention relates to a method of treating muscular dystrophy comprising administering diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride or a pharmaceutically acceptable salt and/or solvate thereof to a patient in need of such treatment.

The invention further relates to a method of treating muscular dystrophy comprising administering diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride or a pharmaceutically acceptable salt and/or solvate thereof in combination with one or more other anti-inflammatory active agents to a patient in need of such treatment.

Background

Muscle wasting (MD) comprises a heterogeneous group of genetic diseases that invariably lead to muscle degeneration and impaired function. Approximately 30 genetic mutations cause various forms of Muscular dystrophy, which varies in age, severity and muscle groups of injury (Dalkilic I, Kunkel LM. (2003) muscle strains: genes topathiones. curr. Opin. Genet. Dev.13: 231-.

The most common MD is Duchenne Muscular Dystrophy (DMD), a severe recessive X-linked disease that affects 3500 males and is characterized by rapid progression of muscle degeneration, ultimately leading to loss of walking and death in the second decade of life.

Attempts to replace or correct mutated genes with the aid of gene or cell therapy may lead to a final solution for muscular dystrophy, which is however not easy to achieve. Alternative strategies to prevent or delay muscle degeneration, reduce inflammation, or promote muscle metabolism or regeneration may benefit all patients and synergize in the future with gene or cell therapies. Steroids that reduce inflammation are the only therapeutic tools currently used in most DMD patients (Cossu G, Sampaolesi M. (2007) New therapeutics for Duchenne molecular dynamics: gallens, proctects and clinical trials. trends mol. med.13: 520-526).

Diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride, described in WO 97/43251 (anhydrous form) and WO 2004/065355 (monohydrate crystalline form), both incorporated herein by reference, is an anti-inflammatory agent that can inhibit the synthesis of a large proportion of pro-inflammatory cytokines while sparing anti-inflammatory factors.

Diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride is also known as ITF 2357.

The monohydrate crystalline form of diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride is known as gevistat (Givinostat).

Gevistat is being evaluated in several clinical studies, including studies for the treatment of myeloproliferative diseases, polycythemia, periodic fever syndrome, crohn's disease, and systemic juvenile idiopathic arthritis. For the treatment of juvenile idiopathic arthritis of all-body type and for the treatment of polycythemia, rare drug qualification (Orphandrug designation) is specified in the european union.

It has recently been found that gevistasol also acts as a histone deacetylase inhibitor (WO 2011/048514).

Histone Deacetylases (HDACs) are a family of enzymes capable of removing acetyl groups bound to lysine residues in the N-terminal portion of histones and in other proteins.

HDACs can be divided into four classes based on structural homology. Class I HDACs (HDAC1, 2, 3 and 8) are similar to RPD3 yeast proteins and are located in the nucleus. Class II HDACs (HDACs 4, 5, 6, 7, 9 and 10) are similar to HDA1 yeast protein and are located in the nucleus and cytoplasm. Class III HDACs are structurally distinct forms of NAD-dependent enzymes associated with SIR2 yeast proteins. Class IV (HDAC 11) is composed of a single enzyme with specific structural features at present. HDACs of classes I, II and IV are zinc enzymes and can be inhibited by various classes of molecules: hydroxamic acid derivatives, cyclic tetrapeptides, short chain fatty acids, aminobenzamides, derivatives of electrophilic ketones, and the like. Class III HDACs are not inhibited by hydroxamic acids and their inhibitors have structural features that differ from those of the other classes.

The expression "histone deacetylase inhibitor" in the context of the present invention is intended to mean any molecule of natural, recombinant or synthetic origin capable of inhibiting the activity of at least one enzyme of a histone deacetylase classified as class I, class II or class IV.

Although HDAC inhibitors, as a class, are considered potentially useful as anti-tumor agents, it is noteworthy that only two, Vorinostat and Romidepsin, have been approved as drugs for the treatment of single neoplasia (cutaneous T cell lymphoma) until now.

It is clear that the pharmaceutical properties of each HDAC inhibitor may be different and depend on the specific status of the inhibitory potency against the various isozymes, as well as on the specific pharmacokinetic profile and tissue distribution.

Some HDAC Inhibitors have been protected as potential therapeutic combinations with other agents for the treatment of DMD (WO 2003/033678, WO 2004/050076, Consalvi S. et al. Histone Deacetylase Inhibitors in the treatment of the Diseases of the bacterial dynamics: epigenic Drugs for Genetic Diseases (2011) mol. Med.17: 457-phase).

However, the potential therapeutic use of HDAC inhibitors for DMD may be limited by the potentially deleterious effects of these relatively toxic agents, particularly when used for long-term therapy in pediatric patients.

Gevistat, as an anti-inflammatory agent, has been used in phase II studies of systemic juvenile idiopathic arthritis in children; gevigstat was administered at 1.5 mg/kg/day for twelve weeks to achieve an improvement in the American pediatric rheumatology Association (ACR Pedi)30, 50 and 70 response criteria (Vojinovic J, Nemanja D. (2011) HDAC inhibition in Rheumatoidal arthritis and Juvenele Idiopathic arthritis. mol. Med 17: 397-.

To date more than 500 patients (including 29 children) have received treatment with gevista.

Repeated dose toxicity studies were performed in dogs, rats and monkeys. The oral daily dose of drug was administered for nine consecutive months. The drug tolerates well at high doses without significant toxicity. The "no adverse effect level" (NOAEL) ranges from 10 to 25 mg/kg/day, depending on the animal species and duration of treatment.

In young animals, 60 mg/kg/day of gevistasol did not affect the behavior and physical development and reproductive ability of the young animal.

No genotoxic effects were observed in the in vitro mouse lymphoma test and chromosome aberration test and in the in vivo micronucleus test and UDS test.

Disclosure of Invention

We have now found that administration of diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride can prevent or delay muscle degeneration, reduce inflammation and promote muscle metabolism or regeneration.

Accordingly, an object of the present invention is a method for the treatment of muscular dystrophy comprising administering diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride, preferably in the form of the monohydrate, more preferably in the form of the monohydrate crystals, or a pharmaceutically acceptable salt and/or solvate thereof, to a patient in need of such treatment.

The muscular dystrophy is preferably duchenne muscular dystrophy.

The diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride according to the invention, preferably in the form of the monohydrate, more preferably in the form of the monohydrate crystals, or the pharmaceutically acceptable salts and/or solvates thereof, is administered in an amount ranging from 0.5 to 15 mg/kg/day, preferably from 1 to 10 mg/kg/day. More preferably, it is administered daily.

For the purposes of the present invention, diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride (or the pharmaceutically acceptable salts and/or solvates thereof) is administered in the form of a pharmaceutical composition comprising it and at least one physiologically acceptable excipient. The pharmaceutical composition is preferably administered to the patient by an enteral and/or parenteral route, preferably by an oral, sublingual, rectal, intravascular, intravenous, subcutaneous route, more preferably by an oral route.

The pharmaceutical composition may be formulated in solid or liquid form. Preferably, the solid form is selected from tablets, granules, aggregates, compressed or coated pills, hard or gelatin capsules and the liquid form is selected from suspensions or syrups.

The pharmaceutical composition of the present invention preferably comprises 7.5 to 200mg of diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or a pharmaceutically acceptable salt and/or solvate thereof per unit dosage form, more preferably 25 to 150 mg.

For the purposes of the present invention, diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof may be administered effectively alone or in combination with at least one other anti-inflammatory active agent.

According to a preferred embodiment of the invention, the "at least one other anti-inflammatory active agent" is a steroid.

The steroid is preferably a glucocorticoid corticosteroid, more preferably it is selected from the group consisting of prednisolone (prednisone), prednisone (prednisone), deflazacort (deflazacort), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisolone), dexamethasone (dexamethasone), betamethasone (betamethasone), triamcinolone (triamcinone), beclomethasone (beclometasone), fludrocortisone acetate (fluorocortisone acetate), deoxycorticosterone acetate (deoxyorterosterone acetate), even more effectively it is selected from the group consisting of prednisolone and deflazacort.

The combination therapy according to the invention comprises the administration of a single pharmaceutical dosage form comprising diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof and at least one further anti-inflammatory active agent, and the administration of diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof and at least one further anti-inflammatory active agent, each in its own separate pharmaceutical dosage form.

When a single dosage form is used, it may comprise 7.5 to 200mg of diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or a pharmaceutically acceptable salt and/or solvate thereof, preferably 25 to 150mg, and 0.25 to 2.5mg/kg of said at least one anti-inflammatory active agent, preferably 0.5 to 1 mg/kg.

When separate dosage forms are used, diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof and at least one other active agent may be administered at substantially the same time, i.e. simultaneously; or separately staggered time administration, i.e. sequential administration. It is to be understood that the combination therapy according to the invention encompasses all such regimens.

According to one embodiment of the invention, the recipient of the claimed method is a child.

In more detail, diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof, alone or in combination with at least one further active agent or pharmaceutical compositions thereof, is administered to children, preferably daily, in an amount ranging from 0.5 to 15 mg/kg/day, preferably from 1.0 to 10 mg/kg/day.

Drawings

Figure 1 shows that gevistasol enhances fatigue resistance in mdx mice after 90 days of treatment (plate test).

Figure 2A shows that gevista treatment increased muscle size (whole naked body) in mdx mice; figure 2B shows that gevista treatment increased muscle size in mdx mice (hind leg detached from mdx).

Figure 3 shows that gevistasol reduces the area of fibrosis (masson trichrome staining) in treated mdx mice.

Detailed Description

The following examples are intended to illustrate the invention without limiting its scope.

Brief introduction to the drawings

The animal model chosen for the experiment was C57BL/10 ScSn-Dmdmdmx/J mouse (hereinafter "mdx"). mdx mice (X chromosome-linked myopathy mutations) are the most amenable and closest disease model for preclinical studies of human duchenne muscular dystrophy. mdx mice have a single base substitution within the exon that causes premature termination of the polypeptide chain. The mutation is X chromosome-linked and results in a viable homozygous animal that lacks the muscle protein dystrophin (dystrophin), has high serum levels of myozyme, and possesses histological lesions similar to human muscular dystrophy. The histological features, connections and mapping of mdx make these mice a valuable animal model of duchenne muscular dystrophy. mdx mice have progressive muscle degeneration starting at approximately three weeks of age. At eight weeks, mdx forelimb strength diminished, while hindlimb showed normal strength. These findings reflect the progression of the acute phase of muscle necrosis in young mdx mice (groups et al, 2008). Muscle atrophy, inflammation and fibrosis were present in mdx mice at eight weeks of age (Conssalvi S. et al. Histone deacylase antibodies in the Treatment of Muscular dyeabilities: Epigentic Drugs for genetic Diseases, 2011) mol. Med.17: 457-.

Description of the experiments:

2-month-old mdx mice were randomly divided into three groups of 10 animals each.

Control group (CTR) was treated once daily with methylcellulose solution (0.5%, gavage) for 90 days.

Test group (ITF) was treated once daily with a solution of diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) -naphthalen-2-yl-methyl ] -ammonium chloride (ITF2357) (10mg/Kg, gavage) for 90 days.

Trichostatin group a (TSA) was treated once daily with TSA solution (0.6mg/Kg, i.p.) for 90 days.

Example 1

Geviginostat enhances fatigue resistance in mdx mice after 90 days of treatment (plate test)

The effect of in vivo treatment on kinetic energy was observed by a plate test according to the following protocol:

running: 8 cm/sec for 5 minutes

After 5 minutes-increasing by 2 cm/min

Numbness: 0.2mA (Stable)

If the board stops for more than 5-10 seconds, the run stops.

As shown in fig. 1, the ITF-treated group had a longer physical exhaustion time than the CTR group.

Example 2

Givista treatment increased muscle size in mdx mice (visual evaluation)

At the end of the experiment as described above, mice were sacrificed for skeletal muscle analysis by visual assessment.

As shown in fig. 2A) (whole naked body) and B) (hind limb leg detached from mdx), the ITF treated group had increased muscle size compared to the CTR group.

Example 3

Givisstat reduced the area of fibrosis in treated mdx mice (masson trichrome stain)

At the end of the treatment period, the "tibialis anterior" (TA) cross-sectional area was analyzed by masson trichrome staining, indicating that the ITF treated group strongly reduced the area of fibrosis (blue) as shown in fig. 3.

Claims (27)

1. Use of diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof for the preparation of a medicament for the treatment of muscular dystrophy.

2. Use according to claim 1, characterized in that the muscular dystrophy is duchenne muscular dystrophy.

3. Use according to any one of the preceding claims, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof is administered to the patient daily.

4. Use according to any of the preceding claims, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof is administered to a patient in an amount ranging from 0.5 to 15 mg/kg/day, preferably from 1 to 10 mg/kg/day.

5. Use according to any one of the preceding claims, characterized in that the patient is a child.

6. Use according to claim 5, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof is administered to said child in an amount ranging from 0.5 to 15 mg/kg/day, preferably from 1 to 10 mg/kg/day.

7. Use according to any one of the preceding claims, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof is administered to the patient in the form of a pharmaceutical composition comprising it together with at least one physiologically acceptable excipient.

8. Use according to claim 7, characterized in that the pharmaceutical composition is administered by the oral, sublingual, rectal, intravascular, intravenous, subcutaneous route, preferably the oral route.

9. Use according to claim 7, characterized in that the pharmaceutical composition is in solid or liquid form.

10. Use according to claim 9, characterized in that the solid form is selected from powders, tablets, granules, aggregates, pressed or coated pills, hard or gelatin capsules.

11. Use according to claim 9, characterized in that the liquid form is a suspension or a syrup.

12. Use according to any one of the preceding claims, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof is administered to the patient together with at least one anti-inflammatory active agent.

13. Use according to claim 12, characterized in that the at least one anti-inflammatory active agent is a steroid, preferably a glucocorticoid corticosteroid.

14. Use according to claim 13, characterized in that said at least one steroid is selected from prednisolone, prednisone, deflazacort, hydrocortisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate.

15. Use according to claim 12, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof is administered simultaneously, separately or sequentially in combination with at least one anti-inflammatory active agent.

16. Use according to any one of the preceding claims, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride is in the form of the monohydrate.

17. Use according to any one of the preceding claims, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride is in crystalline form.

18. A combination comprising diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or the pharmaceutically acceptable salts and/or solvates thereof, and at least one anti-inflammatory active agent.

19. Combination according to claim 18, characterized in that the at least one anti-inflammatory active agent is a steroid, preferably a glucocorticoid corticosteroid.

20. A combination according to claim 19, characterized in that said at least one steroid is selected from prednisolone, prednisone, deflazacort, hydrocortisone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate.

21. A pharmaceutical composition comprising a combination according to any one of claims 18 to 20 and at least one physiologically acceptable excipient.

22. The pharmaceutical composition of claim 21, which is in solid or liquid form.

23. The pharmaceutical composition of claim 22, wherein the solid form is selected from the group consisting of a powder, a tablet, a granule, an aggregate, a compressed or coated pill, a hard capsule, or a gelatin capsule.

24. The pharmaceutical composition of claim 22, wherein the liquid form is a suspension or a syrup.

25. Pharmaceutical composition according to any one of claims 21 to 24, characterized in that it comprises from 7.5 to 250mg of diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride or of the pharmaceutically acceptable salts and/or solvates thereof, preferably from 25 to 150 mg; and 0.25 to 2.5mg/kg of the at least one anti-inflammatory active agent, preferably 0.5 to 1 mg/kg.

26. Pharmaceutical composition according to any one of claims 21 to 25, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride is in the form of the monohydrate.

27. Pharmaceutical composition according to any one of claims 21 to 25, characterized in that diethyl- [6- (4-hydroxycarbamoyl-phenylcarbamoyloxymethyl) -naphthalen-2-yl-methyl ] -ammonium chloride is in crystalline form.