Drugs for treating muscular dystrophy

Abstract

Provided is a novel therapeutic agent for MD which is not a drug for exon skipping and which exerts an excellent effect on patients over a broad range.　The therapeutic agent for MD comprises a combination of a prostaglandin synthesis inhibitor with a CRTH2 receptor antagonist.

Description

[Technical field]

[0001] The present invention relates to a new therapeutic agent for muscular dystrophy. [Background technology]

[0002] Muscular dystrophy (MD) is a general term for muscle diseases in which muscle fiber destruction, degeneration (muscle necrosis) and regeneration are repeated, gradually leading to muscle atrophy and muscle weakness. Among these, Duchenne muscular dystrophy (DMD) is caused by a mutation in the dystrophin gene located on the short arm of the X sex chromosome (Xp21), which causes a deficiency of the dystrophin protein. It is the most common type of muscular dystrophy, affecting one in every 3,500 boys regardless of race. Moreover, muscle atrophy progresses most rapidly from around 4 years of age, leading to the need for a wheelchair at around 10 years of age, the need for an artificial ventilator at around 20 years of age, and death from heart failure or other causes at around 40 years of age.

[0003] Although there is an established method for diagnosing DMD, there is no cure. Only symptomatic treatments are available, such as rehabilitation to slow muscle atrophy, the use of wheelchairs to compensate for motor function, the use of artificial respirators, and the use of computers to ensure communication after motor function is lost. A large amount of medical expenses are spent on the lifelong care of patients.

[0004] Currently, exon skipping drugs that skip over DMD mutated exons have been developed for three exons and clinical trials are underway (Non-Patent Document 1). These drugs are specific to the mutated exon and are targeted at about 10% of patients, respectively, and cannot treat patients with different mutated exons. Furthermore, there is a risk that autoantibodies against newly expressed dystrophin will be produced in the patient's body.

[0005] Among the enzymes that catalyze the biosynthesis of PGD2, hematopoietic PDG2 synthase (HPGDS) is known to be induced in the muscles of DMD and polymyositis (Non-Patent Document 2), and it is also known that the urinary metabolic concentration of PGD2 increases with the progression of the disease in DMD patients (Non-Patent Document 3). It has also been reported that administration of the HPGDS inhibitor HQL79 reduces the collective necrotic degeneration area in mdx mice (Non-Patent Document 4), and that the HPGDS inhibitors TFC007, TAS204, and TAS205 have an inhibitory effect on muscle necrosis in DMD model animals (Non-Patent Documents 5 and 6). In addition, clinical trials of TAS205 are being conducted in DMD patients (Non-Patent Document 7). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Clinical Neurology 2014;54:1071-1073 [Non-Patent Document 2] Acta Neuropathol 2002;104:377-384 [Non-Patent Document 3] Clin Chim Acta 2013;423:10-14 [Non-Patent Document 4] Am J Pathol 2009;174:1735-1744 [Non-Patent Document 5] Proceeding of 67th International Astronautical Congress,Guadalajara,Mexico,26-30 September 2016. [Non-Patent Document 6] 15th International Congress on Neuromuscular Diseases,July 6-10 2018,Vienna Austria [Non-Patent Document 7] IAC-16-B.3.3.6 Summary of the Invention [Problem to be solved by the invention]

[0007] However, the therapeutic effect of HPGDS inhibitors on MD remains unclear. Therefore, an object of the present invention is to provide a new MD therapeutic drug that is not an exon skipping drug, but has excellent effects on a wide range of patients. [Means for solving the problem]

[0008] Therefore, the present inventors conducted studies to develop an MD therapeutic agent having a stronger therapeutic effect on MD and discovered that by combining a prostaglandin synthesis inhibitor with a CRTH2 receptor antagonist, the drugs act synergistically to obtain a muscle necrosis inhibitory effect in DMD that is more than 10 times stronger than that of the respective drugs, thereby completing the present invention.

[0009] That is, the present invention provides the following [1] to [6].

[0010] [1] A therapeutic drug for MD comprising a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist. [2] The method for treating MD according to [1], which comprises using a pharmaceutical composition containing a prostaglandin synthesis inhibitor in combination with a pharmaceutical composition containing a CRTH2 receptor antagonist. [3] A composition for treating MD comprising a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist. [4] Use of a combination of a prostaglandin inhibitor and a CRTH2 receptor antagonist for the manufacture of a drug for treating MD. [5] A combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist for treating MD. [6] A method for treating MD, characterized by using a prostaglandin synthesis inhibitor in combination with a CRTH2 receptor antagonist. Effect of the Invention

[0011] By using the MD therapeutic drug of the present invention, a strong muscle necrosis suppression effect more than 10 times stronger than both prostaglandin synthesis inhibitors and CRTH2 receptor antagonists can be obtained, and the progression of muscle weakness in MD patients can be significantly reduced. Therefore, by using the MD therapeutic drug of the present invention, the speed of muscle atrophy in MD patients can be significantly reduced, the period of wheelchair use and artificial respirator use can be significantly extended, and the patient's period of self-sufficiency can be significantly extended. [Brief description of the drawings]

[0012] [Figure 1] The combined use of an HPGDS inhibitor (TFC007) and a CRTH2 receptor antagonist (CAY10471) shows an inhibitory effect on muscle necrosis. [Diagram 2] The combined use of an HPGDS inhibitor (HQL79) and a CRTH2 receptor antagonist (OC000459) shows an inhibitory effect on muscle necrosis. [Diagram 3] The combined use of an HPGDS inhibitor (HQL79) and a CRTH2 receptor antagonist (OC000459) shows an inhibitory effect on muscle necrosis. [Figure 4] The combined use of a nonsteroidal anti-inflammatory drug (indomethacin) and a CRTH2 receptor antagonist (OC000459 or Cay10471) has been shown to inhibit muscle necrosis. [Diagram 5] The combined use of a nonsteroidal anti-inflammatory drug (aspirin) and a CRTH2 receptor antagonist (OC000459, Cay10471, or BAYu3405) has been shown to inhibit muscle necrosis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The therapeutic agent for muscular dystrophy of the present invention contains as active ingredients a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist.

[0014] Prostaglandin synthesis inhibitors include cyclooxygenase inhibitors and prostaglandin D2 (PGD2) synthase inhibitors. As the cyclooxygenase inhibitor, nonsteroidal anti-inflammatory drugs (NSAIDs) are preferred. Nonsteroidal anti-inflammatory drugs include aspirin, mefenamic acid, diclofenac, felbinac, bromfenac, indomethacin, proglumetacin, acemetacin, bendazac, sulindac, etodolac, nebafenac, piroxicam, lornoxicam, meloxicam, ibuprofen, naproxen, ketoprofen, flurbiprofen, loxoprofen, pranoprafen, zaltoprofen, celecoxib, their salts, their esters, etc. Among these, aspirin, diclofenac, indomethacin, ibuprofen, naproxen, ketoprofen, loxoprofen, their salts, their esters are more preferred.

[0015] Among PGD2 synthases, HPGDS is involved in DMD (Non-Patent Document 2), and therefore, as the PGD2 synthase inhibitor used in the present invention, an HPGDS inhibitor is more preferable. Examples of HPGDS inhibitors include the following compounds.

[0016] (1) A benzimidazole compound or a salt thereof represented by the following general formula (1) (Patent No. 4986853)

[0017] [ka]

[0018] [X in the formula 10 represents an oxygen atom or a carbonyl group, R 1 represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents. However, this does not include compounds represented by the general formula (1) in which the substituent is a phosphoric acid group or a phosphoric acid ester group.

[0019] Among the compounds of the general formula (1), the following compounds are more preferred.

[0020] [ka]

[0021] (2) A piperazine compound represented by the following general formula (2) or a salt thereof (Patent No. 5111657):

[0022] [ka]

[0023] [In the formula, R 11 represents an alkyl group having 1 to 6 carbon atoms, and R 12 is a hydroxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, -(C=O)-N(R 13 )(R 14 ) group, or -(C=O)-OR 15 R 13 , R 14 are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent; R 13 and R 14 may form a saturated heterocyclic group together with the nitrogen atom to which they are attached, R 15 represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and n represents 1 or 2.

[0024] Among the compounds of the general formula (2), R 12 is a morpholinocarbonyl group, and the following compound is even more preferred (WO 2017 / 047791).

[0025] [ka]

[0026] (3) A piperazine compound or a salt thereof represented by the following general formula (3) (Patent No. 5677325)

[0027] [ka]

[0028] [wherein X represents CH or an N atom; R 21 represents an alkyl group having 1 to 6 carbon atoms, and R 22 represents an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkenyl group having 2 to 6 carbon atoms which may have a substituent, -(C=O)-N(R 23 )(R 24 ) group, or -(C=O)-OR 25 R 23 , R 24 are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent; R 23 and R 24 may form a saturated heterocyclic group together with the nitrogen atom to which they are attached, R 25 represents a hydrogen atom, or an alkyl or aralkyl group having 1 to 6 carbon atoms which may have a substituent.

[0029] (4) A piperidine compound or a salt thereof represented by the following general formula (4) (Patent No. 5693591):

[0030] [ka]

[0031] [In the formula, X 1 , X 2 , X 3 are the same or different, N or CR 31 m represents 0 or 1; A represents a phenylene group, a divalent saturated heterocyclic group, or a divalent unsaturated heterocyclic group; B is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted phenyl group, an optionally substituted aralkyl group, an optionally substituted heteroaralkyl group, an optionally substituted saturated heterocyclic group, an optionally substituted unsaturated heterocyclic group, NR 32 R 33 group, (C=O)R 34 Group, OR 35 represents one of the groups, R31 represents a hydrogen atom, a halogen atom, or an alkyl group, R 32 , R 33 are the same or different and represent a hydrogen atom, a phenyl group, an alkylcarbonyl group, a (saturated or unsaturated heterocyclic)carbonyl group, a phenylaminocarbonyl group, or an alkoxycarbonyl group, R 34 is a substituted alkyl group, a cycloalkyl group, a trifluoromethyl group, a phenyl group, an unsaturated heterocyclic group, a heteroaralkyl group, a saturated heterocyclic group, or NR 36 R 37 represents a group, R 35 represents a phenyl group, an aralkyl group, or an unsaturated heterocyclic group, R 36 , R 37 are the same or different and represent a hydrogen atom, an alkyl group, a cyclohexyl group, a phenyl group which may have a substituent, an unsaturated heterocyclic group, an aralkyl group, or a heteroaralkyl group, or R 36 and R 37 together with the nitrogen atom to which they are attached represent a pyrrolidyl or piperidyl group.

[0032] (5) A pyrimidine compound or a salt thereof represented by the following general formula (5) (JP 2007-51121 A)

[0033] [ka]

[0034] [During the ceremony, R 41 represents an optionally substituted 5- or 6-membered nitrogen-containing unsaturated heterocyclic group or an optionally substituted phenyl group, R 42 represents an unsaturated heterocyclic group containing, in the ring structure, 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, or a phenyl group, R 42 The unsaturated heterocyclic group represented by the formula (I) is a heterocyclic group represented by the formula (I) 43 -(CH2)m - group, R 42 The phenyl group represented by the formula (I) is represented by the formula (I) in which R 43 -(CH2) m - group, R 42 The unsaturated heterocyclic group or phenyl group represented by two R 43 -(CH2) m - groups, two R 43 -(CH2) m The - groups may be the same or different, Applicable R 43 -(CH2) m In the - group, m is an integer from 0 to 4, R 43 represents a halogen atom, a cyano group, a nitro group, a saturated or unsaturated heterocycle which may have a substituent, -NR 44 R 45 group, -(C=O)-R 46 Group, -OR 47 group, or -SR 48 represents a group, R 44 and R 45 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms, an amino group which may have a substituent, a saturated or unsaturated heterocyclic group which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent, or a carbonyl group which has a substituent, or R 44 and R 45 may form, together with the adjacent nitrogen atom, a saturated or unsaturated cyclic amino group which may have, in addition to the adjacent nitrogen atom, one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure, and the cyclic amino group may have a substituent. R 46 represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, or -NR 49 R 50 represents a group, R 47 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkenyl group having 2 to 6 carbon atoms, or a substituted carbonyl group, R 48 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may have a substituent, R 49 and R 50 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, or an amino group which may have a substituent, or R 49 and R 50 may form, together with the adjacent nitrogen atom, a saturated or unsaturated cyclic amino group which may have, in addition to the adjacent nitrogen atom, one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure, and the cyclic amino group may have a substituent.

[0035] Among the compounds represented by the general formula (5), the compounds represented by the following formula are more preferred.

[0036] [ka]

[0037] (6) A pyrimidine compound represented by the following general formula (6) or a salt thereof (WO 2007 / 041634):

[0038] [ka]

[0039] [During the ceremony, R 51 represents an aryl, heteroaryl, or C5-C6 cycloalkyl group (which may have a substituent); R 52represents a hydrogen atom or a C1-C4 alkyl group; R 53 is -P(=O)(alkoxy)2, -SO2NY 1 Y 2 , a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a saturated heterocycle, or a fused ring group (these groups may have a substituent); L 1 represents a direct bond or a C1-C6 alkylene group.

[0040] (7) A compound represented by the following formula or a salt thereof

[0041] [ka]

[0042] The compound or its salt includes solvates such as hydrates. The salt of the compound includes pharma- ceutically acceptable salts, such as salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases, and amino acids, or salts with inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, paratoluenesulfonic acid, etc.). These salts can be formed by a commonly used method.

[0043] CRTH2 receptor antagonists are antagonists of chemoattractant receptor-homologous molecule on Th2 cells (CRTH2), which is a receptor for PGD2, and have been attracting attention as antiallergic drugs such as drugs for treating bronchial asthma. The effect of this CRTH2 receptor antagonist on muscular dystrophy has not been reported. As the CRTH2 receptor antagonist, the following compounds are preferred.

[0044] (1) A compound represented by the following general formula (7) or a salt thereof (European Patent Application Publication No. 242518):

[0045] [ka]

[0046] (In the formula, R 61 represents a hydrogen atom or a halogen atom)

[0047] (2) A compound represented by the following general formula (8) or a salt thereof (JP Patent Publication No. 2008-500991):

[0048] [ka]

[0049] [In the formula, R 71 represents hydrogen, halogen, phenyl, halogenophenonyl, and nitro groups; R 72 represents a hydrogen atom or a C1-C4 alkyl group; R 73 represents a hydrogen atom or a C1-C4 alkyl group; R 74 represents a hydrogen atom or a C1-C4 alkyl group; R 75 represents a hydrogen atom, a halogen, an alkyl, a halogenoalkyl, an alkoxy, or a phenoxy group; R 76 , R 77 , R 78 , R 79 represents a hydrogen atom, a halogen atom, an alkyl group, or a halogenoalkyl group; X and Y each represent C or N; A represents a carboxyl group or a tetrazolyl group.

[0050] (3) A compound represented by the following general formula (9) or a salt thereof (US2009 / 0105218)

[0051] [ka]

[0052] [In the formula, L1 represents a C1-C3 alkylene or C2-C3 alkenylene group; L3 represents a direct bond, a C1-C3 alkylene group, or a C2-C3 alkenylene group; R a and R b represents a hydrogen atom, halogen, cyano, nitro, alkyl, halogenoalkyl, alkoxyhalogenoalkoxy, alkylSO2-, NH2SO2-, alkylNHSO2-, di(alkyl)NSO2-, aryl, aryloxy, or arylalkoxy group.

[0053] (4) A compound represented by the following general formula (10) or a salt thereof (Patent No. 5291265):

[0054] [ka]

[0055] [During the ceremony, R 81 represents hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, halogen, trifluoromethoxy or trifluoromethyl; R 82 represents hydrogen, a (C1-C4) alkyl, a (C1-C2) alkoxy-(C2-C3) alkyl, a (C1-C4) fluoroalkyl or a (C3-C6) cycloalkyl-(C1-C2) alkyl group; R 83 represents a heteroaryl group that is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, (C1-C4) fluoroalkyl, and phenyl.

[0056] (5) A compound represented by the following general formula (11) or a salt thereof (Patent No. 6484644):

[0057] [ka] [During the ceremony, R 91 and R 92 One of the groups represents hydrogen and the other represents halogen.

[0058] (6) A compound represented by the following general formula (12) or a salt thereof (Patent No. 4313819):

[0059] [ka]

[0060] [In the formula, R c , R e , and R f is hydrogen, R d is a halo, R g and R h each independently represents hydrogen, or C1-C6 alkyl optionally substituted with one or more halo substituents or one or more C3-C7 cycloalkyl groups, or together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R i is hydrogen or C1-C6 alkyl optionally substituted with one or more halo substituents or one or more C3-C7 cycloalkyl groups; R j is a phenyl, naphthalenyl, thiazole, biphenyl, quinolinyl or quinoxalinyl group; C1-C6 alkyl optionally substituted with one or more halo substituents or one or more C3-C7 cycloalkyl groups; —O(C1-C6)alkyl optionally substituted with one or more halo substituents or one or more C3-C7 cycloalkyl groups; —SOR l or may be substituted with an OH group, Each R l is independently hydrogen or C1-C6 alkyl optionally substituted with one or more halo substituents or one or more cycloalkyl groups; However, R j is not unsubstituted phenyl, R kis hydrogen or C1-C6 alkyl optionally substituted with one or more halo substituents or one or more C3-C7 cycloalkyl groups.

[0061] (7) Compounds represented by the following general formulas (A) to (K) or salts thereof (JP Patent Publication No. 2010-132680):

[0062] [ka]

[0063] [In the formula, Z 3 is =N- or =C(-R 7 )-;R 4 , R 5 , R 6 and R 7 each independently represents hydrogen, halogen, haloalkyl, carboxy, alkyloxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl, a group of the formula: -S(O) p R 8 (wherein p is an integer of 0 to 2; and R 8 is alkyl or optionally substituted aryl), a group represented by the formula: -NR 9 R 10 (In the formula, R 9 and R 10 each independently represents hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or acyl; 11 (In the formula, R 11 represents a hydrogen atom, an alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an alkanesulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted aralkylsulfonyl group, a group represented by haloalkyl); R 1 is carboxy, alkyloxycarbonyl, optionally substituted aminocarbonyl or tetrazolyl; Z 4 -N= or -C(-R2 )=; R 2 is hydrogen, alkyl or halogen; R 15 is hydrogen or alkyl; r is an integer of 0 to 2; x is an integer of 0 to 3; m is an integer of 1 to 3; a dashed line represents the presence or absence of a bond; E is a group represented by an optionally substituted aryl, an optionally substituted heteroaryl, an alkyl, an optionally substituted aralkyl, or an optionally substituted arylalkenyl, x is an integer of 0 to 3; m is an integer of 1 to 3; a dashed line represents the presence or absence of a bond; E is a group represented by an optionally substituted aryl, an optionally substituted heteroaryl, an alkyl, an optionally substituted aralkyl, or an optionally substituted arylalkenyl; y is 0 or 1; R 23 and R 24 one of which is alkyl and the other is hydrogen, alkyl or aryl; or R 23 and R 24 are taken together to represent a group represented by the formula: -(CH2)t- (wherein t is an integer of 2 to 5); R 25 and R 26 each independently represents hydrogen or alkyloxyalkyl; R 20 is hydrogen or alkyl; R 21 is a group represented by hydrogen or halogen (excluding 3-(4-chlorophenylsulfonylamino)-9-(2-carboxymethyl)-1,2,3,4-tetrahydrocarbazole, its ethyl ester, 3-(4-chlorophenylsulfonylaminoethyl)indole-1-acetic acid, and 3-(4-chlorophenylsulfonylaminopropyl)indole-1-acetic acid); or R 13 is hydrogen, alkyl, aralkyl, acyl or the formula: -OR 16 (In the formula, R 16 is a group represented by the formula: 14 is hydrogen or alkyl. q is an integer from 0 to 3; R 17is hydrogen or alkyl; Z 1 is -CH2-, -C(=O)-, -C(=NOH)- or -C(=NOMe)-; Z 2 is the formula: -S(=O) s - (wherein s is an integer of 0 to 2), a group represented by the formula: -N(-R 22 )-(wherein, R 22 is hydrogen, alkyl, alkyloxycarbonyl or acyl) or a group represented by the formula: -CR 18 R 19 -(In the formula, R 18 and R 19 are each independently hydrogen, alkyl, or aryl; or R 18 and R 19 are taken together to represent a group represented by the formula: -(CH2)t- (wherein t is an integer of 2 to 5).

[0064] (8) A compound represented by the following general formula (13) or a salt thereof:

[0065] [ka]

[0066] [Wherein, X is -SO2- or -SO2NR 3 - indicates; R 1 represents hydrogen, F, Cl, CN or CF3; R 2 indicates hydrogen, F, Cl; R 3 is hydrogen, C 1-6 Alkyl or C 3-7 Indicates cycloalkyl; Ar 1 represents phenyl or a 5- or 6-membered heteroaryl group (which may be substituted with hydrogen, halogen, CN, alkyl, cycloalkyl, or alkoxy); A 2 represents a 5- or 6-membered heteroaryl group (which may be substituted with hydrogen, halogen, CN, alkyl, cycloalkyl, or alkoxy).

[0067] In the general formula (15), Ar 1 is preferably phenyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; 2 is preferably pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0068] Preferred specific examples of the CRTH2 receptor antagonist include the following compounds:

[0069] [ka]

[0070] [ka]

[0071] The compound or its salt includes solvates such as hydrates. The salt of the compound includes pharma- ceutically acceptable salts, such as salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases, and amino acids, or salts with inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, paratoluenesulfonic acid, etc.). These salts can be formed by a commonly used method.

[0072] As shown in the examples below, the combined use of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist, particularly the combined use of an HPGDS inhibitor and a CRTH2 receptor antagonist, dramatically suppresses muscle necrosis in muscular dystrophy compared to the use of these drugs alone. That is, the combination of these drugs synergistically suppresses muscle necrosis in muscular dystrophy, and is useful as a therapeutic agent for muscular dystrophy, particularly as a therapeutic agent for DMD. More specifically, in muscular dystrophy model mice (mdx mice), muscle necrosis begins around 3 weeks after birth, and the phenomenon common to DMD patients, such as an increase in serum creatine kinase and pyruvate kinase, which are markers of muscle necrosis, occurs, and the pathological findings are similar to those of DMD patients. When these mdx mice were administered a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist, in particular when an HPGDS inhibitor and a CRTH2 receptor antagonist were administered in combination, the increase in serum creatine kinase was suppressed significantly more significantly than when these drugs were administered alone. It is also known that administration of thyroid hormone (T3, triiodothyronine) to mdx mice causes myocardial damage similar to that seen in DMD patients. The combined use of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist can synergistically suppress T3-induced myocardial damage in mdx model mice. Therefore, by using the MD therapeutic drug of the present invention, the rate of muscle atrophy in MD patients can be significantly reduced, the period during which they need to use a wheelchair and be fitted with an artificial respirator can be significantly extended, and the period during which the patients can live independently can be significantly extended.

[0073] The pharmaceutical of the present invention may be a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist, and may be a combination of two compositions containing each drug (combination pharmaceutical), or a pharmaceutical composition containing two types of drugs. The combination drug or pharmaceutical composition of the present invention can be administered in any dosage form, and the formulation can be selected according to the dosage form. Oral dosage forms include, for example, tablets, capsules, granules, powders, syrups, etc. Parenteral dosage forms include injections, suppositories, inhalants, transdermal absorption agents, skin topicals, eye drops, nasal drops, etc. When an injection is selected, the administration route includes subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal injection, and intravenous injection.

[0074] When preparing solid preparations for oral administration, excipients and, if necessary, binders, disintegrants, lubricants, colorants, flavorings, etc. are added, and tablets, granules, powders, capsules, etc. can be produced by conventional methods.

[0075] When preparing liquid preparations for oral administration, flavoring agents, buffering agents, stabilizers, preservatives, etc. can be added in a conventional manner to produce oral liquid preparations, syrups, elixirs, etc.

[0076] When preparing injections, pH adjusters, stabilizers, and isotonicity agents may be added, and subcutaneous, intramuscular, and intravenous injections may be produced by conventional methods.

[0077] In the case of the combination medicine of the present invention, a preparation (composition) containing a prostaglandin synthesis inhibitor and a preparation (composition) containing a CRTH2 receptor antagonist are used in combination.When they are separately formulated in this way, they may be a kit medicine in which the separately formulated medicines are combined with instructions that describe the respective administration methods.In the case of these separately formulated medicines, the dosage forms of the respective preparations may be the same or different, and the administration intervals may be the same or different.

[0078] When the pharmaceutical composition of the present invention contains a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist, it is preferable to contain these two drugs in a single dosage form, for example, a tablet.

[0079] The usage ratio (mass ratio) of the prostaglandin synthesis inhibitor (A) and the CRTH2 receptor antagonist (B) in the pharmaceutical of the present invention varies depending on the types of compounds used, but is preferably (A):(B)=200:1 to 1:10, more preferably 100:1 to 1:5, and even more preferably 50:1 to 1:1.

[0080] The dosage of the pharmaceutical of the present invention varies depending on the compound used, the age, weight, symptoms, etc. of the patient, but the daily dosage of the prostaglandin synthesis inhibitor is preferably 0.01 to 10 mg / kg, more preferably 0.05 to 10 mg / kg, and the daily dosage of the CRTH2 receptor antagonist is preferably 0.01 to 10 mg / kg, more preferably 0.05 to 5 mg / kg. EXAMPLES

[0081] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0082] Example 1 (method) Vehicle (5% DMSO in 5% methylcellulose-containing saline), HPGDS inhibitor TFC007 (30 mg / kg), CRTH2 receptor antagonist CAY10471 (1.0 mg / kg), or a combination of the two drugs (TFC007, 3 mg / kg + CAY10471, 0.1 mg / kg) were administered subcutaneously every day for 4 weeks from 4 weeks of age to muscular dystrophy model mice (mdx mice (C57BL / 6)), and serum creatine kinase activity (a marker of skeletal muscle necrosis) was measured. (result) The results are shown in Figure 1. As shown in Figure 1, when an HPGDS inhibitor and a CRTH2 receptor antagonist were used in combination, the combined dose was 1 / 10 of that when either was administered alone, but the combined dose showed an extremely strong creatine kinase activity reducing effect compared to either administered alone.

[0083] Example 2 (method) Vehicle (5% DMSO in 5% methylcellulose-containing saline), HPGDS inhibitor HQL79 (30 mg / kg), CRTH2 receptor antagonist OC000459 (1.0 mg / kg), or a combination of the two drugs (HQL79, 3 mg / kg + OC000459, 0.1 mg / kg) were subcutaneously administered to muscular dystrophy model mice (mdx mice (C57BL / 10)) every 2-3 days (Monday, Wednesday, and Friday every week) for 2 weeks starting from 4 weeks of age, and serum creatine kinase activity (a marker of skeletal muscle necrosis) was measured. (result) The results are shown in Figure 2. As shown in Figure 2, when an HPGDS inhibitor and a CRTH2 receptor antagonist were used in combination, the combined dose was 1 / 10 of that when each was administered alone, but it showed a stronger effect of reducing creatine kinase activity than when each was administered alone.

[0084] Example 3 (method) Vehicle (5% DMSO in 5% methylcellulose-containing saline), the HPGDS inhibitor HQL79 (30 mg / kg), the CRTH2 receptor antagonist OC000459 (0.5 mg / kg), or a combination of the two drugs (HQL79, 3 mg / kg + OC000459, 0.1 mg / kg) were subcutaneously administered to muscular dystrophy model mice (C57BL / 10-mdx mice) every 2-3 days (Monday, Wednesday, and Friday every week) for 4 weeks starting from 4 weeks of age, and serum creatine kinase activity (a marker of skeletal muscle necrosis) was measured. (result) The results are shown in Figure 3. As shown in Figure 3, when the HPGDS inhibitor HQL79 and the CRTH2 receptor antagonist OC000459 were used in combination, a strong creatine kinase activity reducing effect was observed that was statistically significant (t-test compared to vehicle administration: p<0.05) even though the doses were 1 / 10 and 1 / 5 of those when the drugs were administered alone, whereas no statistically significant changes were observed when the drugs were administered alone.

[0085] Example 4 (method) Vehicle (5% DMSO in 5% methylcellulose-containing saline), the prostaglandin synthesis inhibitor indomethacin (1 mg / kg), or a combination of the prostaglandin synthesis inhibitor indomethacin and a CRTH2 receptor antagonist (indomethacin, 0.1 mg / kg + OC000459, 0.1 mg / kg or indomethacin, 0.1 mg / kg + Cay10471, 0.1 mg / kg) was administered subcutaneously every day for 10 days starting from 16 weeks of age to a muscular dystrophy model mouse (C57BL / 10-mdx mice), and serum creatine kinase activity (a marker of skeletal muscle necrosis) was measured. (result) The results are shown in Figure 4. As shown in FIG. 4, when the prostaglandin synthesis inhibitor indomethacin was used in combination with a CRTH2 receptor antagonist (OC000459 or Cay10471), a strong creatine kinase activity reducing effect was observed that was statistically significant (t-test compared to vehicle administration: p<0.01), although the effect was 1 / 10 of that observed when the drug was administered alone.

[0086] Example 5 (method) Vehicle (5% DMSO in 5% methylcellulose in saline), the prostaglandin synthesis inhibitor aspirin (150 mg / kg), or a combination of the prostaglandin synthesis inhibitor aspirin and a CRTH2 receptor antagonist (aspirin, 150 mg / kg + Cay10471, 0.1 mg / kg; aspirin, 150 mg / kg + OC000459, 0.1 mg / kg; or aspirin, 150 mg / kg + BAYu3405, 10 mg / kg) were administered subcutaneously every day for 4 weeks from the age of 4 weeks to C57BL / 6-mdx mice, and serum creatine kinase activity (a marker of skeletal muscle necrosis) was measured. (result) The results are shown in Figure 5. As shown in FIG. 5, when the prostaglandin synthesis inhibitor aspirin was used in combination with a CRTH2 receptor antagonist (Cay10471, OC000459, or BAYu3405), there was no statistically significant change when it was administered alone, whereas the combination showed a statistically significant (t-test compared to the combination with Cay10471 or OC000459, vehicle administration, and aspirin alone: ​​p<0.05; t-test compared to the combination with BAYu3405, vehicle administration, and aspirin alone: ​​p<0.01) strong creatine kinase activity reducing effect.

Claims

1. A therapeutic agent for MD comprising a combination of a prostaglandin synthesis inhibitor selected from TFC007, HQL79, TAS204, TAS205, indomethacin and aspirin and a CRTH2 receptor antagonist selected from CAY10471, OC000459, BAYu3405 and QAW039. 【Chemistry 1】 【change】 【change】

2. A therapeutic agent for MD as described in claim 1, which is a combination of a pharmaceutical composition containing the prostaglandin synthesis inhibitor and a pharmaceutical composition containing the CRTH2 receptor antagonist.

3. The MD therapeutic drug described in claim 1, which is an MD therapeutic drug composition containing the prostaglandin synthesis inhibitor and the CRTH2 receptor antagonist.

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