Compounds used in the treatment of dystrophinopathy

Abstract

The present invention relates to a compound selected from the group consisting of difenpyramide, veriflavone, amopiroquine, cloricromene, alpelisib, benorilate, xipamide, favomotizole and altizide, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a dystrophinopathy, and combinations thereof; to the use of the above-mentioned compounds for the manufacture of a medicament for the treatment or prevention of a dystrophinopathy; and to a method for the treatment or prevention of a dystrophinopathy in a patient in need thereof by administering the above-mentioned compounds.

Description

[Technical field]

[0001] The present invention relates to compounds for use in the treatment and / or prevention of dystrophinopathy, in particular Duchenne muscular dystrophy. [Background technology]

[0002] Dystrophinopathy is an X-linked, progressive, inherited, degenerative disease of muscle caused by the absence or deficiency of the muscle cell membrane protein dystrophin. Dystrophinopathy encompasses a spectrum of disease severity. The mild end of the spectrum includes muscle spasms with myoglobinuria, while the severe end of the spectrum includes progressive muscle diseases such as Duchenne or Becker muscular dystrophy, when skeletal muscles are primarily affected, or dilated cardiomyopathy, when it is the heart that is primarily affected (Astejada et al., Reference Module in Biomedical Sciences, International Encyclopedia of Public Health, 2nd ed., 2017, Vol. 5, 183-192; Darras et al., September 5, 2000 [Updated April 26, 2018]. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021, PMID: 20301298).

[0003] Duchenne muscular dystrophy (DMD), which affects 1 in 5000 newborn boys, occurs when the gene encoding the dystrophin protein is mutated. It is a progressive neuromuscular disease with clinical symptoms appearing at 2–3 years of age, loss of ambulation in the early teenage years, and death due to either respiratory or cardiac failure in the following decade.

[0004] Becker muscular dystrophy (BMD) is a condition similar to DMD, however, characterized by later onset skeletal muscle weakness, with some patients remaining ambulatory into their 30s. Nevertheless, heart failure remains the most common cause of death in BMD patients. The average age of death is in the mid-40s.

[0005] DMD-associated dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and congestive heart failure, usually without clinical evidence of skeletal muscle disease. Female heterozygosity for DMD pathogenic variants increases the risk of DCM. Heart failure typically appears between the ages of 20 and 40 in men and later in women.

[0006] Dystrophin, the protein affected in these diseases, provides structural integrity to skeletal and cardiac muscles by linking actin filaments of the sarcolemma to basement membrane protein complexes via the dystrophin-associated protein complex (DAPC), resulting in mechanotransduction. In dystrophinopathies, the entire DAPC is lost from the sarcolemma, causing abnormal mechanotransduction in muscle fibers.

[0007] Although the molecular mechanisms underlying dystrophinopathies have been extensively studied, there is still no fully curative treatment available (Soblechero-Martin et al., Neuropathol Appl Neurobiol, 2021;00:1-13). Current standard treatments include corticoids such as prednisone or deflazacort to slow disease progression. Therapies based on dystrophin replacement at the protein or gene level are challenging due to the large size of the gene, the wide distribution of skeletal muscles throughout the body and the potential for immune response activation.

[0008] Upregulation of utrophin protein has recently gained momentum as one of the most promising alternative therapeutic strategies for dystrophinopathy. Utrophin, a dystrophin-associated protein, is an autosomal homolog of dystrophin that can bind to DAPC proteins and functionally recruit dystrophin. Increasing the level of utrophin leads to partial restoration of affected muscle function in dystrophin-deficient myofibers in mdx mice via increasing the level of sarcolemmal-bound utrophin. Furthermore, utrophin overexpression does not induce any immune response in dystrophinopathy patients due to its endogenous expression.

[0009] Recent studies based on high-throughput screening, such as in myoblasts, have made it possible to identify small molecules capable of inducing utrophin upregulation and in this way rescuing muscle function, some of which are currently in clinical trials (Soblechero-Martin et al., Neuropathol Appl Neurobiol, 2021;00:1-13; Verhaart et al., Nature Reviews Neurology 15,373-386(2019)).

[0010] It is an object of the present invention to identify further compounds capable of inducing utrophin upregulation, thereby expanding the range of advantageous therapeutic options for dystrophinopathy. Summary of the Invention

[0011] The present inventors have surprisingly discovered a series of compounds which are capable of inducing utrophin upregulation and which may therefore be useful for preventing and treating dystrophinopathies.

[0012] And in a first aspect, the present invention relates to a compound selected from the group consisting of difenpyramide, veriflavone, amopyroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of dystrophinopathy.

[0013] In a second aspect, the present invention relates to the use of a compound selected from the group consisting of difenpyramide, veriflavone, amopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and / or prevention of a dystrophinopathy.

[0014] In a third aspect, the present invention also relates to a method of treating or preventing a dystrophinopathy in a subject, comprising administering to said subject a therapeutically effective amount of a compound selected from the group consisting of difenpyramide, veriflavone, amopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof.

[0015] In a fourth aspect, the present invention provides a method for treating rheumatoid arthritis comprising administering to a patient a therapeutically effective amount of an anti-rheumatoid arthritis drug, comprising administering to the patient a therapeutically effective amount of an anti-rheumatoid arthritis drug, comprising administering to the patient a therapeutically effective amount of an anti-rheumatoid arthritis drug, comprising administering to the patient a therapeutically effective amount of an anti-rheumatoid arthritis drug, and ... toformin and L-citrulline combination, MA-0211, tamoxifen, dextroepicatechin, exaluren, ARM-210, 2,6-disubstituted pyridazin-3(2H)-ones, N-benzyl-p-toluenesulfonamide, MP-101, MT-002, rimepolide, tetracosactide hexaacetate, elamipretide, KER-050, SRP-5051, TXA- 127, PB-1023, pamrevlumab, eteplirsen, golodirsen, vitolarsen, casimersen, ATL-1102, NS-089, lenadilsen, WVEN-531, fodadystrogen mobaparvovec, GNT-004, AAV1-follistatin viral vector, delandystrogen moxeparvovec, AT-702, AAVrh74-GALGT2, SGT-001, CAP-2003, CAP-1002, wherein at least one of the drugs is selected from the group consisting of difenpyramide, beliflavone, amopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole, and altizide, or a pharmaceutically acceptable salt thereof.

[0016] In a fifth aspect, the present invention relates to a combination according to the fourth aspect of the invention for use in the treatment and / or prevention of a dystrophinopathy.

[0017] In a sixth aspect, the present invention relates to the use of a combination according to the fourth aspect of the invention in the manufacture of a medicament for the treatment and / or prevention of a dystrophinopathy.

[0018] In a seventh aspect, the present invention relates to a method for treating and / or preventing a dystrophinopathy in a subject, comprising administering to said subject a therapeutically effective amount of a combination according to the fourth aspect of the invention. [Brief description of the drawings]

[0019] [Figure 1] Figure 2 shows the maximum twitch contraction force in response to electrical stimulation upon treatment with a compound of the invention. [Diagram 2] 1 shows tetanic contraction force in response to electrical stimulation upon treatment with a compound of the invention. [Diagram 3] 4 shows the tetanic index in response to electrical stimulation upon treatment with compounds of the invention. [Figure 4] FIG. 1 shows increased utrophin expression in human DMD cultures of immortalized DMD patient-derived 3D skeletal muscle upon treatment with compounds of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] As outlined above, the present invention relates to a series of nine compounds that have been found to induce utrophin upregulation. These compounds are presented in detail below.

[0021] Veliflapon (CAS 128253-31-6; https: / / pubchem.ncbi.nlm.nih.gov / compound / Veliflapon), also known as Bay-x-1005, is a compound of the following formula: [ka]

[0022] Preferably, veriflavone refers to the following stereoisomer: [ka]

[0023] Veriflavone is used for the treatment of acute coronary syndrome in patients with a history of unstable angina or myocardial infarction.The compound is commercially available, for example from Sigma Aldrich (Ref. SML0411), or may be synthesized using suitable preparation methods, for example the methods disclosed in US4970215.

[0024] Difenpiramide (CAS 51484-40-3; https: / / pubchem.ncbi.nlm.nih.gov / compound / Difenpiramide) is a compound of the formula: [ka]

[0025] The compound is used for the treatment of degenerative and inflammatory arthropathy, such as osteoarthritis or rheumatoid arthritis. The compound is commercially available, for example, from Smolecule (Ref.: S526059). The compound may also be synthesized by condensation of the carboxy group of biphenyl-4-ylacetic acid (CAS 5728-52-9) with the amino group of 2-aminopyridine (CAS 504-29-0), both of which are also readily available reagents, for example, from Sigma-Aldrich (Ref.: 196487 and 09340, respectively). The compound may also be synthesized by the methods disclosed in US3868380 or Khullar, Asian J.Chem., Vol. 31, No. 3 (2019), 510-514.

[0026] Amopyroquine (CAS 550-81-2; https: / / pubchem.ncbi.nlm.nih.gov / compound / Amopyroquine) is a compound of the formula: [ka]

[0027] This compound is used as an antimalarial drug.The compound is commercially available, for example from Smolecule (Ref.S518739), or may be synthesized using a suitable preparation method, for example the method disclosed in Nobles et al., Journal of Pharmaceutical Sciences, Vol. 52, Vol. 6, June 1963, pp. 600-601.

[0028] Chloricromene (CAS 68206-94-0; https: / / pubchem.ncbi.nlm.nih.gov / compound / Cloricromen) is the compound of the formula: [ka]

[0029] This compound is used as an antithrombotic agent, especially for the treatment of arterial thrombosis.The compound is commercially available, for example from Parchem (Ref.:28592), or may be synthesized using suitable preparation methods, for example the methods disclosed in US4452811A.

[0030] Alpelisib (CAS 1217486-61-7; https: / / pubchem.ncbi.nlm.nih.gov / compound / Alpelisib), also known as BYL-719, is a compound of the following formula: [ka]

[0031] Preferably, alpelisib refers to the following stereoisomer: [ka]

[0032] Alpelisib is used as an anti-neoplastic agent, especially for the treatment of metastatic breast cancer. The compound is commercially available, for example from Abcr GmbH (Ref.:AB337610), or may be synthesized using suitable preparation methods, for example the methods disclosed in US2010105711A1.

[0033] Benorilate (CAS 5003-48-5; https: / / pubchem.ncbi.nlm.nih.gov / compound / Benorilate) is the compound of the formula: [ka]

[0034] This compound is used as an anti-inflammatory, antipyretic and analgesic agent.The compound is commercially available, for example from Sigma-Aldrich (Ref.: PH003407), or may be synthesized using suitable preparation methods, for example the methods disclosed in US3431293.

[0035] Xipamide (CAS 14293-44-8; https: / / pubchem.ncbi.nlm.nih.gov / compound / 26618) is a compound of the following formula: [ka]

[0036] This compound is used as a diuretic for the treatment of edema and hypertension.The compound is commercially available, for example from Parchem (Ref.:13928), or may be synthesized using suitable preparation methods, for example the methods disclosed in US3567777.

[0037] Fabomotizole (CAS 173352-21-1; https: / / pubchem.ncbi.nlm.nih.gov / compound / Fabomotizole), also known as afobazole, is a compound of the following formula: [ka]

[0038] This compound is used as an anxiolytic.The compound is commercially available, for example from Parchem (Ref.:110780), or may be synthesized using suitable preparation methods, for example the methods disclosed in US6376666B1.

[0039] Altizide, also known as Althiazide (CAS 5588-16-9; https: / / pubchem.ncbi.nlm.nih.gov / compound / Althiazide), is a compound of the formula: [ka]

[0040] Preferably, altizide refers to the following stereoisomer: [ka]

[0041] Altizide is used as a diuretic for the treatment of edema, hypertension and hormonal disorders.The compound is commercially available, for example from Sigma-Aldrich (Ref.: Y0000606), or can be synthesized using suitable preparation methods, for example the method disclosed in US3111517, and can be enantioseparated, for example by the method reported in Zhong et al., J.Chromatogr.A 1115 (2006) 19-45.

[0042] The above compounds and their salts as described below can also be purchased from alternative chemical suppliers, such as those found in the PubChem database maintained by the National Center for Biotechnology Information (NCBI), as can be verified, for example, at the different https: / / pubchem.ncbi.nlm.nih.gov web pages provided herein.

[0043] In preferred embodiments, the compound is selected from difenpyramide, veriflavone, cloricromene, alpelisib, favomotisole, or a pharmaceutically acceptable salt thereof.

[0044] In a preferred specific embodiment, the compound is veriflavone or a pharma- ceutically acceptable salt thereof, preferably veriflavone.A preferred veriflavone salt is the sodium salt, which is commercially available, for example, from THE BioTek (Ref. bt-285834), or may be prepared using suitable preparation methods, for example, the methods disclosed in US4970215.

[0045] In a preferred specific embodiment, the compound is difenpyramide or a pharma- ceutically acceptable salt thereof, preferably difenpyramide.Preferred difenpyramide salts are acid addition salts, such as its hydrochloride, sulfate, succinate or maleate salts, which are described in US3868380.

[0046] In certain embodiments, the compound is amopiroquine or a pharmaceutically acceptable salt thereof, preferably amopiroquine.Preferred amopiroquine salt is hydrochloride, more preferably dihydrochloride, which is commercially available, for example, from Smolecule (Ref. S518740), or may be prepared using suitable preparation methods, for example, the method disclosed in Nobles et al., Journal of Pharmaceutical Sciences, Vol. 52, No. 6, June 1963, pp. 600-601.

[0047] In a preferred specific embodiment, the compound is chloricromene or a pharma- ceutically acceptable salt thereof, preferably a pharma- ceutically acceptable salt thereof.A preferred chloricromene salt is the hydrochloride salt, which is commercially available, for example, from Sigma-Aldrich (Ref. C4615), or may be prepared using suitable preparation methods, for example, the methods disclosed in US4452811A.

[0048] In certain preferred embodiments, the compound is alpelisib or a pharma- ceutically acceptable salt thereof, preferably alpelisib.A preferred alpelisib salt is an acid addition salt, such as the hydrochloride salt, which is described in US2010105711A1 or is commercially available, for example, from AdooQ Bioscience (Ref.:A21794).

[0049] In certain embodiments, the compound is benorilate or a pharma- ceutically acceptable salt thereof, preferably benorilate.Benorilate salts, such as its hydrochloride salt, are commercially available, for example, from Consulting & Solutions GmbH (Ref.:AKOS015960742).

[0050] In a particular embodiment, the compound is xipamide or a pharma- ceutically acceptable salt thereof, preferably xipamide.Preferred xipamide salts are the ammonium and alkali metal salts, such as those disclosed in US3567777.

[0051] In a preferred specific embodiment, the compound is favomotisol or its pharmaceutically acceptable salt, preferably its pharmaceutically acceptable salt.Preferred favomotisol salt is hydrochloride (CAS 173352-39-1, 189638-30-0; https: / / pubchem.ncbi.nlm.nih.gov / compound / Afobazol).Another preferred salt is dihydrochloride.These salts are commercially available, for example from Smolecule (Ref.:S517427), or may be prepared using suitable preparation methods, for example the methods disclosed in US6376666B1.

[0052] In certain embodiments, the compound is althiazide or a pharma- ceutically acceptable salt thereof, preferably althiazide.Preferred althiazide salts are base addition salts, such as the potassium salt, which is described in US3111517.

[0053] The term "pharmacologically acceptable" refers to molecular entities and compositions that, when administered to humans, are physiologically tolerated and typically do not produce allergic or similar adverse reactions, such as stomach upset, dizziness, etc.

[0054] Furthermore, the term "pharmaceutically acceptable salt" refers to any salt that can provide (directly or indirectly) the compounds described herein upon administration to a recipient. For example, the pharmaceutically acceptable salts of the compounds provided herein can be acid or base addition salts, which can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of an appropriate base or acid, for example in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include organic salts, for example ammonium salts, or inorganic salts, for example alkali metal salts, for example sodium or potassium salts.

[0055] The combinations of the present invention are combinations of difenpyramide, veriflavone, amopyrroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide with each other or with other compounds known to be useful in the treatment and / or prevention of dystrophinopathy. The present invention provides, for the first time, the motivation to produce said combinations.

[0056] In a preferred embodiment, the combination is selected from the group consisting of difenpyramide, beliflavon, amphopyroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole, altizide, or a pharmaceutically acceptable salt thereof; ataluren, deflazacort, divinostat, pizgranstat, ifetroban, vamorolone, idebenone, prednisone, prednisolone, 20-hydroxyecdysone, a combination of metformin and L-citrulline, MA-0211, tamoxifen, dextroepicatechin, exsallene, ARM-210, 2,6-disubstituted pyridazin-3(2H)-ones, N-benzyl-p-toluenesulfonamide, MP-101, MT-002, rimepolide, tetracosactide hexaacetate, elamipretide, KER-050, SRP-5051, TX A combination comprising two or more agents selected from the group consisting of A-127, PB-1023, pamrevlumab, eteplirsen, gologirsen, viltolarsen, casimersen, ATL-1102, NS-089, lenadilsen, WVEN-531, foldadystrogen mobaparvovec, GNT-004, AAV1-follistatin viral vector, delandystrogen moxeparvovec, AT-702, AAVrh74-GALGT2, SGT-001, CAP-2003, CAP-1002, wherein at least one of the agents is selected from the group consisting of difenpyramide, veriflapone, amopirroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole, and altizide, or a pharmaceutically acceptable salt thereof.

[0057] Ataluren (CAS 775304-57-9; https: / / pubchem.ncbi.nlm.nih.gov / compound / 11219835) is a compound of the formula: [ka]

[0058] This compound allows ribosome read-through of mRNA containing premature termination codons and is commercially available under the trade name Translarna for the treatment of DMD.The compound is commercially available, for example, from MedChemExpress (Ref.:HY-14832), or may be synthesized using suitable preparation methods, for example, the methods disclosed in US20040204461.

[0059] Deflazacort (CAS 14484-47-0; https: / / pubchem.ncbi.nlm.nih.gov / compound / 189821) is a compound of the formula: [ka]

[0060] This compound is a glucocorticoid commercially available under the trade name Emflaza for the treatment of DMD. The compound is commercially available, for example from MedChemExpress (Ref.: HY-13609), or may be synthesized using suitable preparation methods, for example the methods disclosed in WO9721722.

[0061] Givinostat (CAS 497833-27-9; https: / / pubchem.ncbi.nlm.nih.gov / compound / 9804992) is a compound of the formula: [ka]

[0062] This compound is a histone deacetylase inhibitor currently in development for the treatment of DMD. The compound is commercially available, for example from MedChemExpress (Ref.:HY-14842), or may be synthesized using a suitable preparation method, for example the method disclosed in WO2020178776.

[0063] Pizgranstad, also known as TAS-205 (CAS 1244967-98-3; https: / / pubchem.ncbi.nlm.nih.gov / compound / 46911296), is a compound of the following formula: [ka]

[0064] This compound is a selective prostaglandin D2 synthase inhibitor currently being developed for the treatment of DMD. The compound is commercially available, for example from MedChemExpress (Ref.: HY-109134), or may be synthesized using suitable preparation methods, for example the methods disclosed in US8865714.

[0065] Ifetroban (CAS 143443-90-7; https: / / pubchem.ncbi.nlm.nih.gov / compound / 3037233) is a compound of the formula: [ka]

[0066] This compound is a thromboxane A2 / prostaglandin endoperoxide (TP) receptor antagonist currently in development for the treatment of DMD. The compound is commercially available, for example from BOC Sciences (Ref.:143443-90-7), or may be synthesized using suitable preparation methods, for example the methods disclosed in US5332840.

[0067] Bamorolong , also known as VBP-15 (CAS 13209-41-1; https: / / pubchem.ncbi.nlm.nih.gov / compound / 3035000), is a compound of the following formula: [ka]

[0068] This compound is a glucocorticoid analogue currently in development for the treatment of DMD. The compound is commercially available, for example from MedChemExpress (Ref.: HY-109017), or may be synthesized using suitable preparation methods, for example the methods disclosed in US9198921.

[0069] Idebenone (CAS 58186-27-9; https: / / pubchem.ncbi.nlm.nih.gov / compound / 3686) is a compound of the formula: [ka]

[0070] This compound is a coenzyme Q10 analogue and antioxidant analogue that is undergoing clinical trials for the treatment of DMD. The compound is commercially available, for example from MedChemExpress (Ref.: HY-N0303), or may be synthesized using suitable preparation methods, for example the methods disclosed in EP21841.

[0071] Prednisone (CAS53-03-2; https: / / pubchem.ncbi.nlm.nih.gov / compound / 5865) is a compound of the formula: [ka]

[0072] This compound is a glucocorticoid analogue that is used for the treatment of DMD.The compound is commercially available, for example from MedChemExpress (Ref.:HY-B0214), or may be synthesized using a suitable preparation method, for example the method disclosed in GB1063821.

[0073] Prednisolone(CAS 50-24-8; https: / / pubchem.ncbi.nlm.nih.gov / compound / 5755) is a compound of the formula: [ka]

[0074] This compound is a glucocorticoid analogue that has been used for the treatment of DMD. The compound is commercially available, for example from MedChemExpress (Ref.: HY-17463), or may be synthesized using a suitable preparation method, for example the method disclosed in EP127294.

[0075] 20-Hydroxyecdysone , also known as BIO-101 or crustocdysone (CAS 5289-74-7; https: / / pubchem.ncbi.nlm.nih.gov / compound / 5459840), is a compound of the following formula: [ka]

[0076] The compound is an ecdysteroid that is in clinical development for the treatment of DMD. The product is commercially available, for example from MedChemExpress (Ref.:HY-N6979), or may be synthesized using a suitable preparation method, for example the method disclosed in WO2012053994.

[0077] Metformin + L-citrulline metformin (CAS 657-24-9; https: / / pubchem.ncbi.nlm.nih.gov / compound / 4091), a compound with the formula: [ka] and L-citrulline (CAS 372-75-8; https: / / pubchem.ncbi.nlm.nih.gov / compound / 9750), a compound of the formula: [ka] It is a combination of:

[0078] The combination of metformin + L-citrulline is in clinical trials for the treatment of DMD.Metformin is commercially available, for example, from MedChemExpress (Ref.: HY-B0627), or may be synthesized using suitable preparation methods, for example, the methods disclosed in WO2016059507.L-citrulline is commercially available, for example, from MedChemExpress (Ref.: HY-N0391), or may be synthesized using suitable preparation methods, for example, the methods disclosed in GB1176266.

[0079] MA-0211 (ASP-0367; also known as MTB-1; Bosidelpar sulfate) is a compound of the formula [ka]

[0080] This compound is a small molecule that acts as a modulator of PPAR-delta. The product is in clinical development by Mitobridge for the treatment of DMD and mitochondrial diseases and may be synthesized using suitable preparation methods, such as those disclosed in WO2017062468A1.

[0081] Tamoxifen (CAS 10540-29-1; https: / / pubchem.ncbi.nlm.nih.gov / compound / 2733526) is a compound of the formula: [ka]

[0082] The compound is a non-steroidal selective estrogen receptor modulator that is in clinical development for the treatment of DMD.The product is commercially available, for example from MedChemExpress (Ref.:HY-13757A), or may be synthesized using suitable preparation methods, for example the methods disclosed in US4536516.

[0083] Dextroepicatechin , also known as (+)-epicatechin (CAS 35323-91-2; https: / / pubchem.ncbi.nlm.nih.gov / compound / 182232), is the compound of the following formula: [ka]

[0084] The compound is a green tea derived polyphenol that is in clinical development for the treatment of DMD.The compound is commercially available, for example from MedChemExpress (Ref.:HY-N0001A), or may be synthesized using a suitable preparation method, for example the method disclosed in WO2014115174.

[0085] Exallen (CAS 1375073-93-0; https: / / pubchem.ncbi.nlm.nih.gov / compound / 71461382) is a compound of the formula: [ka]

[0086] The compound is an aminoglycoside that is being developed as a sulfate salt for the treatment of DMD and other diseases.The compound is commercially available, for example from MedChemExpress (Ref.:HY-114231), or may be synthesized using suitable preparation methods, for example the methods disclosed in US8895519.

[0087] ARM-210(CAS 1467605-57-7; https: / / pubchem.ncbi.nlm.nih.gov / compound / 71761628) is a compound of the formula: [ka]

[0088] This compound is a ryanodine receptor / calcium release channel stabilizer that is currently in clinical development for the treatment of DMD. The compound is commercially available, for example from Chemieliva (Ref.:CB1384540), or may be synthesized using suitable preparation methods, for example the methods disclosed in US8853198.

[0089] 2,6-Disubstituted pyridazin-3(2H)-ones are suitable for the treatment of DMD, have been reported in the art and are in clinical development for the treatment of DMD. Examples of suitable 2,6-disubstituted pyridazin-3(2H)-ones are those described in WO2021231630. A particularly suitable example is compound 5 of WO2021231630.

[0090] N-benzyl-p-toluenesulfonamide N-Benzyl-p-toluenesulfonamide, also known as BTS (CAS 1576-37-0; https: / / pubchem.ncbi.nlm.nih.gov / compound / N-Benzyl-p-toluenesulfonamide), is a compound of the following formula: [ka]

[0091] This compound is an inhibitor of fast fiber skeletal myosin and has been shown to protect muscles from pathological muscle disorganization in DMD animal models. The compound is commercially available, for example from Sigma-Aldrich (Ref.:203895).

[0092] MP-101(also known as 2,4-dinitrophenol) (CAS 51-28-5; https: / / pubchem.ncbi.nlm.nih.gov / compound / 1493) is the compound of the formula: [ka]

[0093] The compound acts as a mitochondrial modulator and is in clinical development for the treatment of DMD.The compound is commercially available, for example from Sigma-Aldrich (Ref.:07-5190), or can be synthesized using suitable preparation methods, for example the method disclosed in Khabarov et al., Russian Journal of Applied Chemistry, 2012, Vol. 85, No. 10, pp. 1577-1580.

[0094] MT-002 , also known as AZD-9056 or MP-118 (CAS 345304-65-6; https: / / pubchem.ncbi.nlm.nih.gov / compound / 1493), is a compound of the following formula: [ka]

[0095] It is a P2X7 channel antagonist that is in clinical development for the treatment of DMD.The compound is commercially available, for example from Smolecule (Ref.:S520142), or may be synthesized using suitable preparation methods, for example the methods disclosed in US7297818.

[0096] Rimepolid (CAS 187870-78-6; https: / / pubchem.ncbi.nlm.nih.gov / compound / 9799487), also known as EMD-87580, is a compound of the following formula: [ka]

[0097] It is an inhibitor of Na+H+ exchange-1 (NHE-1) channel. This product is in clinical development for the treatment of DMD. The compound is commercially available, for example from MedChemExpress (Ref.:HY-19273), or may be synthesized using suitable preparation methods, for example the methods disclosed in US5744641.

[0098] Tetracosactide hexaacetate (CAS 22633-88-1; https: / / pubchem.ncbi.nlm.nih.gov / compound / Tetracosactide-hexaacetate), also known as cosyntropin depot, synactene depot or MNK-1411, is a synthetic 24 amino acid melanocortin receptor agonist and analog of adrenocorticotropic hormone (ACTH). The product is in clinical development by Mallinckrodt for the treatment of DMD. The product can be obtained by any suitable preparation method, such as the method disclosed in US2015110885.

[0099] Elamipretide (CAS 736992-21-5; https: / / pubchem.ncbi.nlm.nih.gov / compound / 11764719) is a synthetic peptide that targets cardiolipin, which is in clinical development for the treatment of DMD and other diseases. The product is commercially available, for example from Carbosynth (Ref.: LEB99221), or can be obtained by any suitable preparation method, for example the method disclosed in US9988422.

[0100] KER-050is a fusion protein acting as a TGF beta inhibitor that is in clinical development by Keros Therapeutics for the treatment of DMD. This product can be obtained by suitable preparation methods, such as those disclosed in WO2018089706. Indeed, any peptide defined in claim 1 of WO2018089706, which is incorporated herein by reference, can be used as a drug in the combination of the present invention.

[0101] SRP-5051 is a peptide phosphorodiamidate morpholino oligomer compound, comprising eteplirsen conjugated to a cell-penetrating peptide, as an exon skipping therapy targeting exon 51 of dystrophin. This product is in clinical development for the treatment of DMD. This product can be obtained by a suitable preparation method, for example, the method disclosed in WO2019079386. Indeed, any peptide-oligonucleotide conjugate defined in claim 1 of WO2019079386, which is incorporated herein by reference, can be used as a drug in the combination of the present invention.

[0102] TXA-127 is angiotensin II 1-7 (CAS 39386-80-6; https: / / pubchem.ncbi.nlm.nih.gov / compound / 123805). This product is a naturally occurring small peptide in clinical development for the treatment of DMD. This product is commercially available from MedChemExpress (Ref HY-12403).

[0103] PB-1023Glymera (CAS 1417579-81-7), also known as Glymera, is a long-acting glucagon-like peptide 1 (GLP-1) elastin-like peptide (ELP)-120 fusion protein that acts by targeting the glucagon-like peptide 1 receptor (GLP1R). This product is in clinical development for the treatment of DMD. This product can be obtained by suitable preparation methods, such as those disclosed in WO2014113434A1.

[0104] Pamrevlumab , also known as FG-3019 (CAS 946415-13-0), is a recombinant human IgG1 / kappa monoclonal antibody against connective tissue growth factor (CTGF; CCN2). The product is in clinical development for the treatment of DMD and other fibrotic diseases. The product is commercially available, for example, from Creative Biolabs (Ref.:TAB-443CQ).

[0105] Eteplirsen (CAS 1173755-55-9) is an antisense 30-mer phosphorodiamidate morpholino oligonucleotide targeted to skip exon 51 of the dystrophin gene. The product is commercially available under the trade name Exondys 51 for the treatment of DMD patients with mutations suitable for exon 51 skipping. The product may be synthesized using suitable preparation methods, such as those disclosed in WO2017205879.

[0106] Gorojirusen (CAS 1422959-91-8) is an RNA therapeutic based on antisense phosphorodiamidate morpholino oligomers targeted to skip exon 53 of the dystrophin gene. The product is commercially available under the trade name Vyondys 53 for the treatment of DMD patients with mutations suitable for exon 53 skipping. The product may be synthesized using suitable preparation methods, such as those disclosed in WO2021025899.

[0107] Viltralsen(CAS 2055732-84-6) is a morpholino-based antisense oligonucleotide designed to skip exon 53 of the dystrophin gene. The product is commercially available under the trade name Viltepso for the treatment of DMD patients with mutations suitable for exon 53 skipping. The compound is commercially available, for example, from MedChemExpress (Ref.:HY-132586).

[0108] Casimersen (CAS 1422958-19-7) is an antisense RNA therapeutic based on antisense phosphorodiamidate morpholino oligomer targeted to skip exon 45 of the dystrophin gene. The product is commercially available under the trade name Amondys 45 for the treatment of DMD patients with mutations suitable for exon 45 skipping. The product may be synthesized using suitable preparation methods, such as those disclosed in WO2017205879.

[0109] ATL-1102 , also known as TV-1102 or ISIS-107248 (CAS 350263-41-1), is a second generation antisense oligonucleotide that inhibits CD49d (a subunit of VLA-4) mRNA (ITGA4 gene). The product is in clinical development by Antisense Therapeutics for the treatment of DMD. The product is described in Limmroth et al., Neurology. 2014 Nov. 11;83(20):1780-1788 and may be synthesized using suitable preparation methods, such as those disclosed in US6258790.

[0110] NS-089NCNP-02, also known as NCNP-02, is an exon skipping antisense oligonucleotide targeting exon 44 of the dystrophin gene. This product is in clinical development for the treatment of DMD. The product may be synthesized using suitable preparation methods, such as those disclosed in EP3660154. Indeed, any antisense oligomer defined in claim 1 of EP3660154A1, which is incorporated herein by reference, may be used as a drug in the combination of the present invention.

[0111] Rena Jilsen , also known as DS-5141 (CAS 1782108-31-9), is an oligonucleotide therapy that induces exon 45 skipping. This product is in clinical development for the treatment of DMD. The product may be synthesized using a suitable preparation method, such as the method disclosed in Ito et al. 2021 Current issues in molecular biology;43(3):1267-1281 (DOI:10.3390 / cimb43030090).

[0112] WVE-N531 is a phosphorothioate modified nucleic acid that induces exon 53 skipping in the dystrophin gene. This product is in clinical development for the treatment of DMD. The product may be synthesized using a suitable preparation method, such as the method disclosed in WO2019217784. Indeed, any oligonucleotide defined in claims 1-5 of WO2019217784, which is incorporated herein by reference, may be used as a drug in the combination of the present invention.

[0113] Folda dystrogen moba parvovec, also known as PF-06939926 or BMB-D001 (CAS 2248111-37-5), is a gene therapy agent that uses recombinant adeno-associated virus vector serotype 9 (AAV9) to deliver a functional mini-dystrophin gene. The product is in clinical development by Pfizer for the treatment of DMD. The product may be synthesized using suitable preparation methods, such as the methods disclosed in CA2971303.

[0114] GNT-004 is an adeno-associated viral vector 8 (AAV8) gene therapy agent encoding the micro-dystrophin gene. The product is in clinical development by Genethon for the treatment of DMD. The product may be synthesized using suitable preparation methods, such as those disclosed in WO2015197232. Any composition defined in claim 1 of WO2015197232, which is incorporated herein by reference, may be used as a drug in the combination of the present invention.

[0115] AAV1-follistatin viral vector is an adeno-associated virus (AAV) gene therapy agent that delivers muscle-specific transgenes of follistatin, myostatin and TGF-beta ligand inhibitor. The product is in clinical development by Milo Biotechnology for the treatment of DMD. The product may be synthesized using suitable preparation methods, such as those disclosed in WO2008067480. Any composition defined in claim 1 of WO2008067480, which is incorporated herein by reference, may be used as a drug in the combination of the present invention.

[0116] Delan dystrogen moxeparvovec, also known as SRP-9001 or RG-6356 (CAS2305040-16-6), is a gene therapy agent that uses adeno-associated virus serotype rh74 containing human microdystrophin gene. The product is in clinical development by Sarepta Therapeutics for the treatment of DMD. The product may be synthesized using suitable preparation methods, such as the methods disclosed in WO2021108755. Any of the vectors described in the invention of WO2021108755, which is incorporated herein by reference, can be used as a drug in the combination of the present invention.

[0117] AT-702 is a recombinant adeno-associated virus 9 (AAV9) vector containing four antisense sequences that induce exon 2 skipping in the human DMD gene. The product is in clinical development by Astellas for the treatment of DMD. The product may be synthesized using a suitable preparation method, such as the method disclosed in WO2014172669. Any recombinant adeno-associated virus as defined in claim 1 of WO2014172669, which is incorporated herein by reference, may be used as a drug in the combination of the present invention.

[0118] AAVrh74-GALGT2 is a gene therapy agent using recombinant adeno-associated virus serotype rhesus 74 (rh74) expressing human CT GalNac transferase (GALGT2) gene. The product is in clinical development by Sarepta Therapeutics for the treatment of DMD. The product may be synthesized using a suitable preparation method, for example, the method disclosed in WO2017049031. Any recombinant adeno-associated virus as defined in claim 1 of WO2017049031, which is incorporated herein by reference, may be used as a drug in the combination of the present invention.

[0119] SGT-001is an adeno-associated virus serotype 9 (AAV9) vector-based micro-dystrophin gene therapy agent under development for the treatment of DMD. The product is described in Bostick 2008 Human Gene Therapy 19:851-856 (DOI:10.1089 / hum.2008.058) and may be synthesized as disclosed therein.

[0120] CAP-2003 refers to extracellular vesicles containing exosomes (CDC-EVs) derived from cardiosphere-derived cells. These vesicles deliver microRNA and induce cardioprotective and muscle regenerative properties. This product is in clinical development for the treatment of DMD. The product is described in WO2018195210, which is incorporated herein by reference, and may be synthesized as disclosed therein.

[0121] CAP-1002 is a stem cell therapy developed by Capricor Therapeutics Inc for the treatment of DMD. The product may be synthesized using suitable preparation methods, such as those disclosed in WO2013184527. Any cardiosphere-derived cell as defined in claim 1 of WO2013184527, which is incorporated herein by reference, may be used as a drug in the combination of the present invention.

[0122] In certain preferred embodiments, at least one of the agents included in the combination is veriflavone or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0123] In certain preferred embodiments, at least one of the agents included in the combination is difenpyramide or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0124] In certain embodiments, at least one of the agents included in the combination is ampicillin or a pharma- ceutical acceptable salt thereof, as provided in any of the embodiments described above.

[0125] In certain preferred embodiments, at least one of the agents included in the combination is cloricromene or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0126] In certain preferred embodiments, at least one of the agents included in the combination is alpelisib or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0127] In certain embodiments, at least one of the agents included in the combination is benorylate or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0128] In certain embodiments, at least one of the agents included in the combination is xipamide or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0129] In certain preferred embodiments, at least one of the agents included in the combination is favomotisole or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0130] In certain embodiments, at least one of the agents included in the combination is althiazide or a pharma- ceutically acceptable salt thereof, as provided in any of the embodiments described above.

[0131] In one embodiment, the other of the two or more drugs included in the combination is a compound such as ataluren, deflazacort, divinostat, pizgranstat, ifetroban, vamorolone, idebenone, prednisone, prednisolone, 20-hydroxyecdysone, a combination of metformin and L-citrulline, MA-0211, tamoxifen, dextroepicatechin, exsaluren, ARM-210, 2,6-disubstituted pyridazin-3(2H)-ones, N-benzyl-p-toluenesulfonamide, MP-101, MT-002, or rimeporide.

[0132] In another embodiment, the other of the two or more agents included in the combination is a biological agent including a peptide or protein, such as tetracosactide hexaacetate, elamipretide, KER-050, SRP-5051, TXA-127, or PB-1023 (wherein the protein may be, in particular, an antibody, such as pamrevlumab); a nucleic acid, such as eteplirsen, gologirsen, viltolarsen, casimersen, ATL-1102, NS-089, lenadilsen, or WVEN-531 (wherein the nucleic acid may be administered by using a viral vector, such as foldadystrogen mobaparvovec, GNT-004, AAV1-follistatin viral vector, delandystrogen moxeparvovec, AT-702, AAVrh74-GALGT2, or SGT-001); or cells and materials obtained therefrom, such as CAP-2003 or CAP-1002.

[0133] The present invention is directed to the medical use of said compounds and combinations in the treatment and / or prevention of dystrophinopathy.The term "dystrophinopathy" as used in the present invention designates any disease or disorder caused by the absence or deficiency of dystrophin.The non-limiting examples of the disease or disorder caused by the absence or deficiency of dystrophin are DMD, BMD, DMD-related dilated cardiomyopathy, or muscle spasm with myoglobinuria.Preferably, the disease or disorder caused by the absence or deficiency of dystrophin is selected from DMD and BMD, and even more preferably is DMD.

[0134] The terms "treat" and "treatment" as used herein refer to reversing, alleviating, inhibiting the progression of a disease or disorder or one or more symptoms of said disease or disorder, such as muscle weakness, enlarged heart, respiratory restriction, scoliosis, joint contractures, calf muscle hypertrophy, or cognitive impairment, relative to pre-treatment levels.

[0135] The terms "prevent" and "prevention", as used herein, mean avoiding or inhibiting the onset of said disease or disorder, or one or more of said symptoms.

[0136] The compound for use according to the present invention can be administered by any suitable route.Non-limiting examples of administration route are oral, parenteral (such as subcutaneous, intramuscular, intravenous, etc.), topical, sublingual, inhalation, rectal, vaginal or ophthalmic route.In a preferred embodiment, the compound for use according to the present invention is administered by oral or parenteral route, and intravenous and intramuscular route are particularly preferred parenteral routes.

[0137] In particular, the compounds for use according to the invention are administered as pharmaceutical compositions, comprising the corresponding active compound and one or more pharma- ceutically acceptable excipients. The term "pharma-ceutically acceptable excipient" refers to a vehicle, diluent, or adjuvant administered together with an active ingredient. The identity of the pharma-ceutically acceptable excipient will necessarily depend, among other factors, on the chosen route of administration. Said pharmaceutical compositions may be prepared according to conventional methods known to those skilled in the art, for example those described in the Spanish and United States Pharmacopoeias.

[0138] Therefore, the present invention also relates to a pharmaceutical composition comprising a compound selected from the group consisting of difenpyramide, veriflavone, amopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof, or a combination according to the invention; and at least one pharmaceutically acceptable excipient, for use in the treatment or prevention of a dystrophinopathy.

[0139] Similarly, the present invention relates to the use of a pharmaceutical composition comprising a compound selected from the group consisting of difenpyramide, veriflavone, amopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof, or a combination according to the invention, and at least one pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment and / or prevention of a dystrophinopathy.

[0140] Similarly, the present invention also relates to a method for treating and / or preventing a dystrophinopathy in a subject, comprising administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of difenpyramide, veriflavone, amopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof, or a combination according to the present invention; and at least one pharmaceutically acceptable excipient.

[0141] In yet a further aspect, the present invention also relates to a pharmaceutical composition comprising the combination of the present invention and at least one pharma- ceutically acceptable excipient.

[0142] In one embodiment, the pharmaceutical composition is an oral delivery form.The pharmaceutical form suitable for oral administration may be a tablet and a capsule, and may contain conventional excipients known in the art, such as binders, such as syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for preparing tablets, such as magnesium stearate; disintegrants, such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharma-ceutical acceptable wetting agents, such as sodium lauryl sulfate.Solid oral compositions can be prepared by conventional methods such as blending, filling or compressing.Alternatively, the pharmaceutical form suitable for oral administration may be in the form of a solution or suspension, particularly a powder or granules containing the compound or combination of the present invention are dissolved or dispersed in a liquid medium.Oral solutions or suspensions are particularly preferred when administration is to pediatric human subjects.

[0143] In one embodiment, the pharmaceutical composition is in a parenteral delivery form, preferably an intravenous or intramuscular delivery form.

[0144] Pharmaceutical forms suitable for parenteral administration can be sterile solutions or suspensions based on aqueous vehicles, such as water or sodium chloride, Ringer's solution or dextrose solution; water-miscible vehicles, including but not limited to ethyl alcohol, polyethylene glycol and polypropylene glycol; or non-aqueous vehicles, including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate. Suitable excipients, such as fillers, buffers or surfactants, can be used.

[0145] The compounds for use according to the present invention are preferably administered or included in pharmaceutical compositions or combinations in "therapeutically effective amounts", i.e., a sufficient but non-toxic amount of the corresponding compound to provide the desired effect, i.e., treatment and / or prevention of dystrophinopathy. The amount that is "effective" will vary between subjects, depending on the age and general condition of the individual, the specific compound administered, etc. Therefore, it is not always possible to define an exact "therapeutically effective amount". However, the appropriate amount in any individual case can be determined by those skilled in the art using routine knowledge and experimentation.

[0146] The term "subject" preferably refers to a mammal, such as a human. In a preferred embodiment, in any embodiment described herein, the treatment or prevention of dystrophinopathy is in a pediatric human subject. A pediatric human subject is a person under the age of 21, such as a newborn (from birth to 28 days after birth), an infant (29 days to less than 2 years old), a child (2 years to less than 12 years old), or an adolescent (12 years to 21 years old, but up to but not including the 22nd birthday).

[0147] Compounds for use according to the invention will typically be administered one or more times a day, for example 1, 2, 3 or 4 times a day, and the typical total daily dose will depend on a number of factors, such as the particular compound administered, the severity of the disease, or the weight or age of the patient (many patients afflicted with dystrophinopathy are children), all of which are known to the skilled physician, who will then be able to determine the appropriate dose on the basis of their general common knowledge.

[0148] A typical total daily dose of veriflavone or a pharma- ceutically acceptable salt thereof is in the range of 1 to 3000 mg / day (expressed as veriflavone free base), preferably 30 to 1500 mg / day. The compound may be administered by the oral route.

[0149] A typical total daily dose of difenpyramide or a pharma- ceutically acceptable salt thereof is in the range of 1-3000 mg / day (expressed as difenpyramide free base), preferably 10-1500 mg / day. The compound may be administered by the oral route.

[0150] A typical total daily dose of amphotericin or a pharma- ceutical acceptable salt thereof is in the range of 0.1-250 mg / kg / day (expressed as amphotericin free base), preferably 1-25 mg / kg / day. The compound may be administered by parenteral route, preferably intramuscular route.

[0151] A typical total daily oral dose of cloricromene or a pharma- ceutically acceptable salt thereof is in the range of 1-1000 mg / day (expressed as cloricromene free base), preferably 10-300 mg / day. A typical total daily intravenous dose of cloricromene or a pharma-ceutically acceptable salt thereof is in the range of 1-100 mg / day (expressed as cloricromene free base), preferably 10-30 mg / day.

[0152] A typical total daily dose of alpelisib or a pharma- ceutically acceptable salt thereof is in the range of 1-2000 mg / day (expressed as alpelisib free base), preferably 10-500 mg / day. The compound may be administered by the oral route.

[0153] A typical total daily dose of benorilate or a pharma- ceutically acceptable salt thereof is in the range of 0.05 to 50 g / day (expressed as benorilate free base), preferably 0.5 to 20 g / day. The compound may be administered by the oral route.

[0154] A typical total daily dose of xipamide or a pharma- ceutically acceptable salt thereof is in the range of 1-200 mg / day (expressed as xipamide free base), preferably 10-80 mg / day. The compound may be administered by the oral route.

[0155] A typical total daily dose of favomotisole or a pharma- ceutically acceptable salt thereof is in the range of 1-100 mg / day (expressed as favomotisole free base), preferably 10-60 mg / day. The compound may be administered by the oral route.

[0156] A typical total daily dose of altizide or a pharma- ceutically acceptable salt thereof is in the range of 1-1000 mg / day (expressed as altizide free base), preferably 10-100 mg / day. The compound may be administered by the oral route.

[0157] The compound for use according to the present invention can be administered as the sole active ingredient or in combination with other active ingredients as described elsewhere herein.In certain embodiments, the compound is used as the sole active ingredient.In other specific embodiments, the compound is used in combination with other active ingredients as described elsewhere herein.

[0158] The term "combination" refers to a product containing one or more of the defined compounds in a single composition or in multiple compositions (or units), where the corresponding compound is distributed among multiple compositions.

[0159] When the combination is in the form of a single composition, the compounds present in the combination are always administered simultaneously.

[0160] When the combination is in the form of multiple compositions (or units), each containing at least one but not all of the compounds of the combination, the compositions or (units) may be administered simultaneously, sequentially or separately.

[0161] Concomitant administration means that the compounds or compositions (or units) are administered at the same time.

[0162] Sequential administration means that the compounds or compositions (or units) are administered at different times in a chronologically spaced manner.

[0163] Separate administration means that the compounds or compositions (or units) are administered at different times independent of each other.

[0164] The following examples represent specific embodiments of the present invention and are not intended to limit in any way the scope of the invention defined herein. EXAMPLES

[0165] Example 1 mdx 5cv Utrophin upregulation in myotubes material and method Preparation of mdx myotubes Myotube cultures were cultured in mdx mice, a mouse model of DMD created by chemical mutagenesis that does not express dystrophin and has a more severe phenotype than the classical mdx mouse model. 5cv Satellite cell-derived primary myoblasts were prepared from mice (Jackson Laboratory; Beastrom et al. Am J Pathol 2011,179:2464-2474; DOI:10.1016 / j.ajpath.2011.07.009). Isolation of satellite cell-derived primary myoblasts was performed via cell surface antibodies and magnetic separation as previously described and cultured for their expansion (Motohashi et al., J Vis Exp. 2014 Apr 8;(86):50846). Briefly, after collagenase (Worthington, CLS-2) treatment, mdx myoblasts were cultured in 10% PBS. 5cvDissociated cells from mouse hind limb muscle were incubated with phycoerythrin-conjugated anti-CD31 monoclonal antibody (eBioscience, 12-0311), phycoerythrin-conjugated anti-CD45 monoclonal antibody (eBioscience, 30-F11), phycoerythrin-conjugated anti-Sca1 monoclonal antibody (eBioscience, Dec-81) and anti-integrin α7 (MBL International, ABIN487462), followed by anti-PE microbeads (Miltenyi Biotec, 130-048-801), followed by LD column (Miltenyi Biotec, 130-042-901) separation. The negative cell population was incubated with anti-mouse IgG beads (Miltenyi Biotec, 130-048-402) and then subjected to MS column (Miltenyi Biotec, 130-042-201) separation to isolate integrin α7(+) satellite cells. 5cv Myoblasts were maintained in culture on collagen-coated plates in myoblast medium containing 20% ​​FBS and 20 ng / ml bFGF (Invitrogen, PHG0263) in HAM's F10 medium. Cell cultures were maintained in a humidified incubator at 37°C, 5% CO2 and 5% O2. mdx 5cv Myoblasts were induced to differentiate into multinucleated myoblasts following low serum conditions (DMEM supplemented with 5% horse serum).

[0166] Test Compounds Halofuginone was obtained from Selleck. Veriflavone and chloricromene HCl were obtained from Sigma. Favomotisole HCl was obtained from MedChemExpress. Difenpyramide was obtained from Enamine. Amopiroquine and alpelisib were obtained from Carbosynth. Benorilate and xipamide were obtained from Fluorochem. Altizide was obtained from Toronto Research Chemicals. All chemical compounds were dissolved in 100% DMSO to prepare a 10 mM stock solution.

[0167] Processing of myotubes Every day, compounds were added to the mdx mice at different concentrations (0.01–10 μM) by replacing the medium. 5cvThe myotubes were then added with 100% ethanol. After 3 days of compound exposure, cells were harvested for RNA preparation with TRIzol Reagent (15596026, ThermoFisher Scientific). The isolated RNA was used for cDNA synthesis using the Transcriptor First Strand cDNA Synthesis Kit (04379012001, Roche Molecular Diagnostics) using random primers. Dilute DMSO solution was used as a negative control vehicle. qRT-PCR assay for utrophin-A expression was performed using the following primers: Utro-F1 (forward) 5'-CCTGATGATGGGCAGAACGAATTC-3' (SEQ ID NO: 1) and Utro-R1 (reverse) 5'-CTGATGGGTGGTTTCCCACTCTTG-3' (SEQ ID NO: 2). The following primers were used: 18S-F1 (forward) 5'-CGCACGGCCGGTACAGTGAAACTG-3' (SEQ ID NO: 3) and 18S-R1 (reverse) 5'-CACCCGTGGTCACCATGGTAGGCA-3' (SEQ ID NO: 4), with 18S rRNA used as an internal control. qPCR was performed using GoTaq qPCR Master Mix (A6001, Promega). All primers were synthesized as custom DNA oligos from Integrated DNA technologies (IDT). Analysis was performed using the ΔCt method. Statistical analysis was performed on at least three independent experiments with two to four replicates in each experiment.

[0168] result Chemical compounds, mdx 5cv Different concentrations were tested in myotubes for 3 days. Halofuginone was used as a positive control for utrophin upregulation. The molecules repeatedly showed a significant upregulation of utrophin expression (ranging from 5 to 44% depending on the compound and its concentration). Table 1 shows the upregulation of mdx by RT-PCR. 5cv Values ​​for utrophin upregulation in myotubes are shown (values ​​corresponding to fold change of utrophin vs. DMSO expressed as mean±sem values).

[0169] [Table 1]

[0170] Studies in human 3D skeletal muscle cultures material and method Fabrication and processing of human 3D skeletal muscle tissue Human 3D skeletal muscle tissue was produced using a polydimethylsiloxane (PDMS; Sylgard 184 silicone elastomer kit, Dow Corning) casting mold developed and manufactured as described in Fernandez-Costa 2022. Briefly, the casting mold design consists of a square-shaped pool, two vertical flexible PDMS pillars, in which the cell / hydrogel solution is seeded. The PDMS casting molds were prepared for muscle cell culture by first cleaning them by ultrasonication in water with soap, 2-propanol, and Mili-Q water, and sterilizing them with UV light for 15 minutes. This was followed by a 1 hour treatment with 1% Plurionic® F-127 (Sigma-Aldrich) solution in cold PBS (100 μl / well) at 4°C.

[0171] Human 3D skeletal muscle tissue was created using immortalized human muscle satellite cells (iHuMSCs) derived from a DMD patient (DMD2, clone G82) (Massenet et al. 2020). iHuMSCs were cultured in growth medium (skeletal muscle basal medium (PromoCell GmbH), skeletal muscle supplement mix (PromoCell GmbH), 10% fetal bovine serum (FBS) (Gibco™), 100 U / mL penicillin and 100 μg / ml streptomycin (Gibco™)). iHuMSCs were released from the culture flask via gentle trypsinization. Cells were encapsulated at 2.5×107 cells / ml in a cell / hydrogel mixture of 30% v / v Corning® Matrigel® Growth Factor Reduced (GFR) Basement Membrane Matrix (Corning®), 2 units of thrombin from human plasma (Sigma-Aldrich) and 4 mg / mL fibrinogen from human plasma (50% v / v) (Sigma-Aldrich). 35 μl was pipetted into each PDMS casting mold using a cold tip to avoid premature polymerization.

[0172] The cell / hydrogel mixture was polymerized for 30 min at 37° C. and subsequently incubated in growth medium containing 1 mg / mL 6-aminocaproic acid (ACA) (Sigma-Aldrich). ACA acts as an antifibrinolytic drug to avoid fibrin depolymerization. They were kept in growth medium for 2 days and then switched to a different medium (Dulbecco's Modified Eagle Medium, High Glucose, GlutaMAX™ Supplement (Gibco™) containing 1% KnockOut™ Serum Supplement (Gibco™), 1% Insulin-Transferrin-Selenium-Ethanolamine (Gibco™) and 1% Penicillin-Streptomycin-Glutamine (Gibco™)) containing 1 mg / mL ACA for 7 days. Half the volume of the differentiation medium was replaced every 2 days. After 5 days of differentiation, the medium was replaced by differentiation medium with 10 μM of drugs and 0.01% DMSO final concentration. Treatments were held for 48 hours.

[0173] Example 2 Increase in muscle contraction force in response to electrical stimulation Electrical Pulse Stimulation (EPS) and Video Analysis Human 3D skeletal muscle tissue was electrically stimulated after 7 days of differentiation to induce muscle contraction. EPS was performed using a custom-made device consisting of a 12-well plate and two graphite electrodes per well located on the lid. PDMS casting molds were placed in the 12-well plate with fresh differentiation medium. The plate was placed in a Zeiss Axio Observer Z1 / 7 equipped with a XL S1 cell incubator at 37°C and 5% CO2. The device was connected to a pulse generator (Multifunction Generator WF1974, NF Corporation) and the tissue was stimulated with electric square wave pulses of 1V / mm, pulse width of 1ms, and frequencies varying from 1 to 50Hz. Contractility in response to EPS at a frequency of 1Hz was assessed to study twitch kinetics. On the other hand, a frequency of 50Hz was applied to induce tetanus.

[0174] Videos of the movement of the cast mold pillars in response to muscle contraction were obtained using a ZEISS Axio Observer Z1 / 7 microscope. The cross-sectional area and location of the tissue on the axis of the pillar were also recorded during the assay. The videos were analyzed using a custom Python script, and the intrinsic muscle force resulting from the tissue was calculated by applying Euler's displacement theorem together with the calculated displacement of the pillar, as was done in Mestre 2018. The tetanic index was calculated as the ratio between the intrinsic muscle force of maximum tetanus divided by the intrinsic muscle force of maximum twitch.

[0175] Bioengineered 3D skeletal muscle tissue from DMD patients was differentiated and treated with 10 μM veriflavone or difenpyramide for 2 days prior to determination of the force of muscle contraction in response to electrical stimulation. Muscle tissue treated with 0.01% DMSO was used as a negative control.

[0176] Results are shown in Figures 1-3: Improved muscle function in DMD patient-derived 3D skeletal muscle tissue: Immortalized DMD patient-derived 3D skeletal muscle tissue was differentiated for 5 days and treated with 10 μM veriflavone, 10 μM difenpyramide or 0.01% DMSO for 2 days. Muscles were electrically stimulated and the maximal twitch (Figure 1) or tetanus (Figure 2) contractile force in response to electrical stimulation was measured and compared to the force obtained in DMSO-treated muscles. Graphs represent the maximal contractile force normalized by the area of ​​tissue as mean ± sem. Tetanic index (Figure 3) was calculated and expressed as mean ± sem. Statistical significance calculated by analysis of variance and corrected by Dunnett's test, P-value: ** (P ≤ 0.01); *** (P ≤ 0.001); **** (P≦0.0001).

[0177] Treatment with veriflavone and difenpyramide improved muscle function, as indicated by an increase in the force of muscle contraction in response to electrical stimulation, as shown in Figures 1-3. An increase in both twitch (Figure 1) and tetanic (Figure 2) contraction force was observed after treatment with veriflavone and difenpyramide, compared to DMSO-treated cells. Also, a significant increase in the tetanic index (Figure 3) was observed after treatment with the two compounds.

[0178] Example 3. Utrophin Expression Using Immunohistochemistry Freeze sectioning Human 3D skeletal muscle tissues were fixed in 10% formalin solution (approximately 4% formaldehyde) (Sigma-Aldrich) for 30 min at RT and washed three times with PBS for 5 min. The samples were removed from the PDMS platform and placed in a 30% sucrose solution in PBS under stirring at 4°C for 48 h. They were frozen by embedding them in optimal cutting temperature compound (OCT compound) (PolyFreeze, Sigma-Aldrich) in a disposable plastic ryomold® (VWR) using an isopentane bath cooled by liquid nitrogen. The samples were stored at -20°C until sectioning. They were sectioned on a cryostat (Leica CM1900) to obtain 20 μm thick cross sections, which were placed on SuperFrost Plus™ Adhesion slides (Fisher Scientific) and stored at -20°C until staining.

[0179] Immunohistochemistry Slides containing tissue sections were surrounded with a PAP pen (ImmEdge™, Vector laboratories) and they were permeabilized with PBS-T (0.1% Triton-X (Sigma-Aldrich) in PBS) for 10 min, followed by incubation with blocking buffer (0.3% Triton-X, 3% donkey serum (Sigma-Aldrich) in PBS) for 30 min at RT. Samples were then incubated with primary antibody (monoclonal mouse anti-utrophin primary antibody (MANCHO7) in blocking buffer overnight at 4°C. After three PBS-T washes of 5 min, samples were incubated with polyclonal donkey anti-mouse IgG, Alexa Fluor™ 488 conjugated secondary antibody for 45 min at RT. Tissue sections were mounted in Fluoromount-G™ mounting medium with DAPI (Thermo Fisher). Nail polish was used to seal the edges of the coverslip.

[0180] Imaging and image analysis Fluorescence images were acquired using a ZEISS LSM800 confocal laser microscope. Images were analyzed using the Fiji image processing package, a distribution of Image J (Schindelin et al., 2012). For fluorescence quantification, the mean gray value of each image was measured (minimum 4 images per tissue).

[0181] statistics Results are expressed as mean±sem. Statistical significance was determined by one-way analysis of variance and Dunnett's multiple comparison test using GraphPad Prism. p<0.05 was considered statistically significant.

[0182] result Bioengineered 3D skeletal muscle tissue from DMD patients was differentiated and treated with 10 μM beliflavon or difenpyramide for 2 days prior to determination of utrophin expression. Muscle tissue treated with 0.01% DMSO was used as a negative control.

[0183] Results are shown in Figure 4: Increased utrophin expression in human DMD cultures: Immortalized DMD patient-derived 3D skeletal muscle tissue was differentiated for 5 days and treated with 10 μM veriflavone, 10 μM difenpyramide or 0.01% DMSO for 2 days. Utrophin expression in muscle slices was determined by immunohistochemistry and compared to the signal observed in DMSO-treated cells. Graphs represent fluorescence values ​​vs. fold increase in DMSO expression as mean ± sem. Statistical significance calculated by analysis of variance and corrected by Dunnett's test, P values: ** (P ≤ 0.01); **** (P≦0.0001).

[0184] Utrophin expression was increased up to 3-fold following treatment of human DMD 3D muscle tissue with veriflavone and difenpyramide compared to DMSO-treated cells, confirming previous results in mdx myotubes (Table 1).

[0185] Overall, these results indicated that the compounds were useful for increasing utrophin expression and improving muscle function, indicating their potential for the treatment of dystrophinopathy.

Claims

1. A compound selected from the group consisting of difenpyramide, veriflavone, amphopyroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of a dystrophinopathy.

2. 2. The compound for use according to claim 1, wherein the compound is selected from the group consisting of difenpyramide, veriflavone, cloricromene, alpelisib, favomotisole, or a pharmaceutically acceptable salt thereof.

3. 3. The compound for use according to any one of claims 1 and 2, wherein the compound is difenpyramide or a pharma- ceutically acceptable salt thereof.

4. 3. A compound for use according to any one of claims 1 and 2, wherein said compound is veriflavone or a pharma- ceutically acceptable salt thereof.

5. 3. The compound for use according to any one of claims 1 and 2, wherein the compound is chloricromene or a pharma- ceutically acceptable salt thereof.

6. 3. The compound for use according to any one of claims 1 and 2, wherein the compound is alpelisib or a pharma- ceutically acceptable salt thereof.

7. 3. The compound for use according to any one of claims 1 and 2, wherein the compound is favomotisole or a pharma- ceutically acceptable salt thereof.

8. Difenpyramide, beliflavon, amphopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole, altizide, or a pharma- ceutically acceptable salt thereof; ataluren, deflazacort, divinostat, pizgranstat, ifetroban, vamorolone, idebenone, prednisone, prednisolone, 20-hydro- combination of roxyecdysone, metformin and L-citrulline, MA-0211, tamoxifen, dextroepicatechin, exaluren, ARM-210, 2,6-disubstituted pyridazin-3(2H)-ones, N-benzyl-p-toluenesulfonamide, MP-101, MT-002, rimepolide, tetracosactide hexaacetate, elamipretide, KER-050, SRP-50 51, TXA-127, PB-1023, pamrevlumab, eteplirsen, golodirsen, viltolarsen, casimersen, ATL-1102, NS-089, lenadilsen, WVEN-531, foldadystrogen mobaparvovec, GNT-004, AAV1-follistatin viral vector, delandystrogen moxeparvovec, AT-702, AAVrh74-GA A combination comprising two or more drugs selected from the group consisting of LGT2, SGT-001, CAP-2003, CAP-1002, wherein at least one of the drugs is selected from the group consisting of veriflavone, difenpyramide, amopyroquine, chloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof.

9. The combination for use according to claim 8, wherein at least one of the drugs is selected from the group consisting of difenpyramide, veriflavone, cloricromene, alpelisib, favomotisole, or a pharmaceutically acceptable salt thereof.

10. For use in the treatment or prevention of dystrophinopathy, - a compound selected from the group consisting of difenpyramide, veriflavone, amphopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof; or a combination as defined in any one of claims 8 to 9; and at least one pharma- ceutically acceptable excipient; 23. A pharmaceutical composition comprising:

11. The pharmaceutical composition for use according to claim 10, wherein said pharmaceutical composition is administered by oral or parenteral route.

12. The compound for use according to any one of claims 1 to 7, or the combination for use according to any one of claims 8 to 9, or the pharmaceutical composition for use according to any one of claims 10 to 11, wherein the dystrophinopathy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, Duchenne muscular dystrophy associated dilated cardiomyopathy, or muscle spasms with myoglobinuria.

13. The compound for use according to any one of claims 1 to 7, or the combination for use according to any one of claims 8 to 9, or the pharmaceutical composition for use according to any one of claims 10 to 11, wherein the dystrophinopathy is Duchenne muscular dystrophy.

14. The compound for use according to any one of claims 1 to 7 and 12, 13, or the combination for use according to any one of claims 8, 9, 12 and 13, or the pharmaceutical composition for use according to any one of claims 10 to 13, wherein the treatment or prevention of a dystrophinopathy is in a pediatric human subject.

15. Use of a compound selected from the group consisting of difenpyramide, veriflavone, amopirroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a dystrophinopathy.

16. 16. The use according to claim 15, wherein the compound is selected from the group consisting of difenpyramide, veriflavone, cloricromene, alpelisib, favomotisole, or a pharmaceutically acceptable salt thereof.

17. 17. The use according to any one of claims 15 and 16, wherein the compound is difenpyramide or a pharma- ceutically acceptable salt thereof.

18. 17. The use according to any one of claims 15 and 16, wherein the compound is veriflavone or a pharma- ceutically acceptable salt thereof.

19. 17. The use according to any one of claims 15 and 16, wherein the compound is chloricromene or a pharma- ceutically acceptable salt thereof.

20. 17. The use according to any one of claims 15 and 16, wherein the compound is alpelisib or a pharma- ceutically acceptable salt thereof.

21. 17. The use according to any one of claims 15 and 16, wherein the compound is favomotisole or a pharma- ceutically acceptable salt thereof.

22. For the manufacture of a medicament for the treatment or prevention of dystrophinopathy, difenpyramide, veriflavone, amopirroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole, altizide, or a pharma- ceutically acceptable salt thereof; ataluren, deflazacort, divinostat, pizgranstat, ifetroban, vamorolone, idebenone, prednisone, prednisolone , 20-hydroxyecdysone, metformin and L-citrulline combination, MA-0211, tamoxifen, dextroepicatechin, exsallene, ARM-210, 2,6-disubstituted pyridazin-3(2H)-ones, N-benzyl-p-toluenesulfonamide, MP-101, MT-002, rimepolide, tetracosactide hexaacetate, elamipretide, KER-050, SRP-505 1, TXA-127, PB-1023, pamrevlumab, eteplirsen, golodirsen, viltolarsen, casimersen, ATL-1102, NS-089, lenadilsen, WVEN-531, foldadystrogen mobaparvovec, GNT-004, AAV1-follistatin viral vector, delandystrogen moxeparvovec, AT-702, AAVrh74-GALGT2, SGT-003, AT-201 ... 01, CAP-2003, CAP-1002, wherein at least one of the drugs is selected from the group consisting of beliflavon, difenpyramide, amopiroquine, chloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof.

23. 23. The use of the combination according to claim 22, wherein at least one of the drugs is selected from the group consisting of difenpyramide, veriflavone, cloricromene, alpelisib, favomotisole, or a pharmaceutically acceptable salt thereof.

24. For the manufacture of a medicament for the treatment or prevention of dystrophinopathy, - a compound selected from the group consisting of difenpyramide, veriflavone, amphopiroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof; or a combination as defined in any one of claims 22 and 23; and at least one pharma- ceutically acceptable excipient; 20. Use of a pharmaceutical composition comprising:

25. 25. The use of the pharmaceutical composition according to claim 24, wherein said pharmaceutical composition is administered by oral or parenteral route.

26. Use of a compound according to any one of claims 15 to 21, or use of a combination according to any one of claims 22 and 23, or use of a pharmaceutical composition according to any one of claims 24 and 25, wherein the dystrophinopathy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, Duchenne muscular dystrophy associated dilated cardiomyopathy, or muscle spasms with myoglobinuria.

27. The use of a compound according to any one of claims 15 to 21, or the use of a combination according to any one of claims 22 and 23, or the use of a pharmaceutical composition according to any one of claims 24 and 25, wherein the dystrophinopathy is Duchenne muscular dystrophy.

28. The use of a compound according to any one of claims 15 to 21, 26 and 27, or the use of a combination according to any one of claims 22, 23, 26 and 27, or the pharmaceutical composition for use according to any one of claims 24, 25, 26 and 27, wherein the treatment or prevention of a dystrophinopathy is in a pediatric human subject.

29. A method for the treatment or prevention of a dystrophinopathy in a patient in need thereof, comprising administering to the patient a compound selected from the group consisting of difenpyramide, veriflavone, ambroxone, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof.

30. 30. The method of claim 29, wherein the compound is selected from the group consisting of difenpyramide, veriflavone, cloricromene, alpelisib, favomotisole, or a pharmaceutically acceptable salt thereof.

31. 31. The method of any one of claims 29 and 30, wherein the compound is difenpyramide or a pharma- ceutically acceptable salt thereof.

32. 31. The method of any one of claims 29 and 30, wherein the compound is veriflavone or a pharma- ceutically acceptable salt thereof.

33. 31. The method of any one of claims 29 and 30, wherein the compound is chloricromene or a pharma- ceutically acceptable salt thereof.

34. 31. The method of any one of claims 29 and 30, wherein the compound is alpelisib or a pharma- ceutically acceptable salt thereof.

35. 31. The method of any one of claims 29 and 30, wherein the compound is favomotisole or a pharma- ceutically acceptable salt thereof.

36. 20. A method for the treatment or prevention of dystrophinopathy in a patient in need thereof comprising administering to the patient an effective amount of any of the following: difenpyramide, veriflavone, amopirroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole, altizide, or a pharma- ceutically acceptable salt thereof; ataluren, deflazacort, divinostat, pizgranstat, ifetroban, vamorolone, idebenone, prednisone, prednisolone, 20-hydroxyecdysone, a combination of metformin and L-citrulline, MA-0211, tamoxifen, dextroepicatechin, exsallene, ARM-210, 2,6-disubstituted pyridazin-3(2H)-ones, N-benzyl-p-toluenesulfonamide, MP-101, MT-002, rimeporide, tetracosactide hexaacetate, elamipretide, KER-050, SRP-5051, TXA-127, PB-1023, pamrevlumab, eteplirsen, golodirsen, viltolarsen, casimersen, ATL-1102, NS-089, lenadilsen, WVEN-531, foldadystrogen mobaparvovec, GNT-004, AAV1-follistatin viral vector, delandystrogen moxeparvovec, AT-702, AAVrh74-GALGT2, The method comprises administering to said patient a combination comprising two or more drugs selected from the group consisting of: SGT-001, CAP-2003, CAP-1002, wherein at least one of said drugs is selected from the group consisting of: veriflavone, difenpyramide, amopiroquine, chloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof.

37. 37. The method of claim 36, wherein at least one of the agents is selected from the group consisting of difenpyramide, veriflavone, cloricromene, alpelisib, favomotisole, or a pharmaceutically acceptable salt thereof.

38. 1. A method for treating or preventing a dystrophinopathy in a patient in need thereof, comprising: - a compound selected from the group consisting of difenpyramide, veriflavone, amphopyroquine, cloricromene, alpelisib, benorylate, xipamide, favomotisole and altizide, or a pharmaceutically acceptable salt thereof; or a combination as defined in any one of claims 36 and 37; and at least one pharma- ceutically acceptable excipient; The method comprises administering to said patient a pharmaceutical composition comprising:

39. 39. The method of claim 38, wherein the pharmaceutical composition is administered by oral or parenteral route.

40. 40. The method of any one of claims 29 to 39, wherein the dystrophinopathy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, Duchenne muscular dystrophy-associated dilated cardiomyopathy, or muscle spasms associated with myoglobinuria.

41. The method according to any one of claims 29 to 40, wherein the dystrophinopathy is Duchenne muscular dystrophy.

42. The method of any one of claims 29 to 41, wherein the patient is a pediatric human subject.

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