WO2021066136A1

WO2021066136A1 - Therapeutic agent for muscular dystrophy

Info

Publication number: WO2021066136A1
Application number: PCT/JP2020/037520
Authority: WO
Inventors: 裏出　良博
Original assignee: 国立大学法人東京大学
Priority date: 2019-10-03
Filing date: 2020-10-02
Publication date: 2021-04-08
Also published as: JPWO2021066136A1

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

Muscular dystrophy remedy

The present invention relates to a new therapeutic agent for muscular dystrophy.

Muscular dystrophy (MD) is a general term for muscle diseases in which muscle atrophy and weakness gradually progress while repeating destruction / degeneration (muscle necrotizing) and regeneration of muscle fibers. Of these, Duchenne muscular dystrophy (Duchene MD: DMD) develops due to a dystrophin protein deficiency due to a mutation in the dystrophin gene on the short arm of the X sex chromosome (Xp21). It is the most common type of muscular dystrophy and affects 1 in 3,500 boys of all races. Moreover, the progression of muscular atrophy is the fastest, and muscular atrophy progresses rapidly from around 4 years old, requiring a wheelchair around 10 years old, wearing a respirator around 20 years old, and dying from heart failure etc. around 40 years old. ..

The diagnostic method for DMD has been established, but there is no cure. Only coping therapy is performed, such as rehabilitation to delay muscular atrophy, use of wheelchairs that complement motor function, wearing a respirator, and ensuring communication by using a personal computer after loss of motor function. Large amounts of medical expenses are spent on the lifelong care of patients.

Currently, a drug for exon skipping that skips DMD mutant exons has been developed for three exons and clinical trials are being conducted (Non-Patent Document 1). These drugs are specific to mutant exons, targeting about 10% of patients, and cannot treat patients with different mutant exons. In addition, there is a risk of developing autoantibodies to newly expressed dystrophin in the patient's body.

Of the enzyme that catalyzes the biosynthesis reaction of PGD _2, hematopoietic PGD ₂ synthase (hematopoietic PDG ₂ synthase, HPGDS) is, DMD or the muscles polymyositis disease is known to be induced (Non _{It is also known that the urinary metabolic concentration of PGD 2} increases as the medical condition of DMD patients progresses (Patent Document 2) (Non-Patent Document 3). It has also been reported that administration of the HPGDS inhibitor HQL79 reduces the collective necrotic degeneration region of mdx mice (Non-Patent Document 4), and that the HPGDS inhibitors TFC007, TAS204, and TAS205 show a myonecrotic inhibitory effect on DMD model animals. (Non-Patent Documents 5 and 6). A clinical trial of TAS205 in DMD patients has also been conducted (Non-Patent Document 7).

However, the therapeutic effect of MD with HPGDS inhibitors is still unclear.
Therefore, an object of the present invention is to provide a new therapeutic agent for MD that exerts an excellent effect on a wide range of patients, not a drug for exon skipping.

Therefore, the present inventor investigated to develop an MD therapeutic agent having a stronger MD therapeutic effect, and found that the prostaglandin synthesis inhibitor and the CRTH2 receptor antagonist were used in combination to synergize these agents. The present invention has been completed by finding that a myonecrosis inhibitory effect in DMD, which is more than 10 times stronger than those of these drugs, can be obtained.

That is, the following [1] to [6] of the present invention are provided.

[1] An MD therapeutic agent comprising a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist.
[2] The MD therapeutic agent according to [1], wherein a pharmaceutical composition containing a prostaglandin synthesis inhibitor and a pharmaceutical composition containing a CRTH2 receptor antagonist are used in combination.
[3] An MD therapeutic agent composition containing 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 production of MD therapeutic agents.
[5] A combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist for treating MD.
[6] An MD treatment method characterized by using a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist in combination.

When the MD therapeutic agent of the present invention is used, a strong muscle necrotizing inhibitory effect more than 10 times that of both the prostaglandin synthesis inhibitor and the CRTH2 receptor antagonist can be obtained, and the progression of muscle weakness in MD patients is significantly reduced. Will be done. Therefore, by using the MD therapeutic agent of the present invention, the rate of muscle atrophy of MD patients can be greatly reduced, the period of wheelchair use and mechanical ventilation can be greatly extended, and the patient's self-sustaining period can be significantly extended. it can.

The combined use of the HPGDS inhibitor (TFC007) and the CRTH2 receptor antagonist (CAY10471) exhibits an inhibitory effect on myonecrotizing fasciitis. The combined use of an HPGDS inhibitor (HQL79) and a CRTH2 receptor antagonist (OC000459) exhibits an inhibitory effect on muscle necrotizing. The combined use of an HPGDS inhibitor (HQL79) and a CRTH2 receptor antagonist (OC000459) exhibits an inhibitory effect on muscle necrotizing. The combined use of a non-steroidal anti-inflammatory drug (indomethacin) and a CRTH2 receptor antagonist (OC000459 or Cay10471) exhibits an inhibitory effect on myonecrosis. The combined use of a non-steroidal anti-inflammatory drug (aspirin) and a CRTH2 receptor antagonist (OC000459, Cay10471 or BAYu3405) exhibits an inhibitory effect on myonecrosis.

The therapeutic agent for muscular dystrophy of the present invention contains a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist as an active ingredient.

Examples of prostaglandin synthesis inhibitors include cyclooxygenase inhibitors and prostaglandin D ₂ (PGD ₂ ) synthase inhibitors.
As the cyclooxygenase inhibitor, non-steroidal anti-inflammatory drugs (NSAIDs) are preferable. Non-steroidal anti-inflammatory agents include aspirin, mephenamic acid, diclofenac, fervinac, bromfenac, indomethacin, proglumetacin, acemetacin, bendazac, sulindac, etdrac, nevafenac, pyroxicum, lornoxicum, meloxicam, ibuprofen, naproxen. Examples include biprofen, loxoprofen, planoprphen, zartprofen, selecoxib, salts thereof, esters thereof and the like. Of these, aspirin, diclofenac, indomethacin, ibuprofen, naproxen, ketoprofen, loxoprofen, salts thereof, and esters thereof are more preferable.

Of the PGD ₂ synthases, HPGDS is involved in DMD (Non-Patent Document 2), so the HPGDS inhibitor is more preferable as the _{PGD 2 synthase inhibitor used in the present invention.} Examples of the HPGDS inhibitor include the following compounds.

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

[In the formula, X ¹⁰ represents an oxygen atom or a carbonyl group, and R ¹ represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents.
However, the compound represented by the general formula (1) in which the substituent is a phosphoric acid group or a phosphoric acid ester group is excluded. ]

Of the compounds of the general formula (1), the following compounds are more preferable.

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

[In the formula, R ¹¹ represents an alkyl group having 1 to 6 carbon atoms, R ¹² is a hydroxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, and-(C = O) -N (R ^13). ) (R ¹⁴ ) group or-(C = O) -OR ¹⁵ group, and R ¹³ and R ¹⁴ are the same or different, and may have a hydrogen atom or a substituent. ^{R 13} and R ¹⁴ may form a saturated heterocyclic group together with the nitrogen atom to which they are attached, indicating the number 1 to 6 alkyl group ^{, and R 15} has a hydrogen atom or a substituent. It represents an alkyl group having 1 to 6 carbon atoms which may be present, and n represents 1 or 2. ]

Among the compounds of the general formula (2), a compound in which R ¹² is a morpholinocarbonyl group is more preferable, and the following compound is further preferable (International Publication No. 2017/047791).

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

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

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

[In the formula, X ¹ , X ² , X ³ are the same or different, ^{indicating N or CR 31} , m indicates 0 or 1, A is a phenylene group, a divalent saturated heterocyclic group, or Shows a divalent unsaturated heterocyclic group,
B has a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a phenyl group which may have a substituent, and a substituent. May have an aralkyl group, a heteroaralkyl group which may have a substituent, a saturated heterocyclic group which may have a substituent, an unsaturated heterocyclic group which may have a substituent, NR ^32. Indicates any of ³³ R, (C = O) R ³⁴ , and OR ^35.
R ³¹ represents a hydrogen atom, a halogen atom, or an alkyl group.
R ³² and 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, and an alkoxycarbonyl group.
R ³⁴ represents a substituted alkyl group, a cycloalkyl group, a trifluoromethyl group, a phenyl group, an unsaturated heterocyclic group, a heteroaralkyl group, a saturated heterocyclic group, and an NR ³⁶ R ³⁷ group.
R ³⁵ represents a phenyl group, an aralkyl group, an unsaturated heterocyclic group,
Do R ³⁶ and R ³⁷ represent the same or different hydrogen atom, alkyl group, cyclohexyl group, phenyl group which may have a substituent, unsaturated heterocyclic group, aralkyl group, heteroaralkyl group? , Or R ³⁶ and R ³⁷ together with the nitrogen atom to which they are attached represent a pyrrolidyl or piperidyl group. ]

(5) A pyrimidine compound represented by the following general formula (5) or a salt thereof (Japanese Patent Laid-Open No. 2007-51121)

[In the formula,
R ⁴¹ represents a 5- or 6-membered nitrogen-containing unsaturated heterocyclic group which may have a substituent, or a phenyl group which may have a substituent.
R ⁴² represents an unsaturated heterocyclic group or a phenyl group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in the ring structure.
The unsaturated heterocyclic group represented by ^{R 42} ^{has 0 to 2 R 43-} (CH ₂ ) _m- groups.
The phenyl group represented by R ⁴² ^{has an R 43-} (CH ₂ ) _m -group at either or both of its 3-position and 4-position.
When the unsaturated heterocyclic group or phenyl group represented by ^{R 42} ^{has two R 43-} (CH ₂ ) _m -groups, two R ^43- (CH ₂ ) _m -groups. May be the same or different,
In the R ^43- (CH ₂ ) _m- group,
m indicates 0 to 4,
R ⁴³ is a saturated or unsaturated heterocycle which may have a halogen atom, a cyano group, a nitro group, a substituent, -NR ⁴⁴ R ⁴⁵ groups,-(C = O) -R ⁴⁶ groups, -O-. Shows R ⁴⁷ or -SR ⁴⁸ ,
R ⁴⁴ and R ⁴⁵ each have 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, and a substituent, respectively. Indicates an amino group which may be present, a saturated or unsaturated heterocyclic group which may have a substituent, an aryl group which may have a substituent and has 6 to 14 carbon atoms, or a carbonyl group which has a substituent. Or, or
R ⁴⁴ and R ⁴⁵ , together with adjacent nitrogen atoms, are one or two selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the adjacent nitrogen atoms in the ring structure, respectively. It may form a saturated or unsaturated cyclic amino group which may have a number of complex atoms, and the cyclic amino group may have a substituent.
R ⁴⁶ represents an alkoxy group having 1 to 6 carbon atoms or −NR ⁴⁹ R ⁵⁰ groups which may have a hydrogen atom, a hydroxyl group and a substituent.
R ⁴⁷ is a hydrogen atom, 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, or a carbonyl group having a substituent. Indicates,
R ⁴⁸ represents an alkyl group having 1 to 6 carbon atoms which may have a hydrogen atom or a substituent.
R ⁴⁹ and R ⁵⁰ are the same or different from each other, and have a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, and 1 to 6 carbon atoms which may have a substituent, respectively. Indicates an amino group that may have an alkoxy group or a substituent, or
R ⁴⁹ and R ⁵⁰ , together with adjacent nitrogen atoms, are one or two selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the adjacent nitrogen atoms in the ring structure, respectively. It may form a saturated or unsaturated cyclic amino group which may have a number of complex atoms, and the cyclic amino group may have a substituent. ]

Among the compounds represented by the general formula (5), the compound represented by the following formula is more preferable.

(6) A pyrimidine compound represented by the following general formula (6) or a salt thereof (International Publication No. 2007/041634)

[In the formula,
R ⁵¹ is aryl, heteroaryl or C ₅ -C ₆ cycloalkyl group (these groups may have a substituent group); the
R ⁵² represents a hydrogen atom or a C ₁ -C ₄ alkyl group;
R ⁵³ is -P (= O) (alkoxy) ₂ , -SO ₂ NY ¹ Y ² , cycloalkyl, cycloalkenyl, aryl, heteroaryl, saturated heterocycle, or fused cyclic group (these groups are substituted). May have a group);
L ¹ represents a direct bond or C ₁ -C ₆ alkylene group]

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

The compound or a salt thereof contains a solvate such as a hydrate. Examples of the salt of the compound include pharmaceutically acceptable salts, for example, salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases, and amino acids. Alternatively, 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.) can be mentioned. These salts can be formed by conventional methods.

The CRTH2 receptor antagonist is _{a chemoattractant receptor-homologous molecule on Th2 cells (CRTH2) antagonist that is a PGD 2} receptor, and is attracting attention as an antiallergic agent such as a therapeutic agent for 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 preferable.

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

(In the formula, R ⁶¹ indicates a hydrogen atom or a halogen atom)

(2) A compound represented by the following general formula (8) or a salt thereof (Japanese Patent Publication No. 2008-500991)

[In the formula, R ⁷¹ represents hydrogen, halogen, phenyl, halogenofenonyl, nitro group;
R ⁷² represents a hydrogen atom or a C ₁ -C ₄ alkyl group;
R ⁷³ represents a hydrogen atom or a C ₁ -C ₄ alkyl group;
R ⁷⁴ represents a hydrogen atom or a C ₁ -C ₄ alkyl group;
R ⁷⁵ represents a hydrogen atom, halogen, alkyl, halogenoalkyl, alkoxy, phenoxy group;
R ⁷⁶ , R ⁷⁷ , R ⁷⁸ , R ⁷⁹ indicate hydrogen atom, halogen atom, alkyl, halogenoalkyl group;
X, Y indicate C or N;
A indicates a carboxy group or a tetrazolyl group]

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

Wherein, L ₁ is or a _C 1 -C ₃ represents alkylene or C ₂ -C ₃ alkenylene group;
L ₃ represents a direct _bond, C 1 -C ₃ alkylene or C ₂ -C ₃ alkenylene group;
R ^a and R ^b are hydrogen atom, halogen, cyano, nitro, alkyl, halogenoalkyl _{, alkoxyhalogenoalkoxy, alkyl SO 2-} , NH ₂ SO _2- , alkyl NHSO _2- , di (alkyl) NSO _2- , aryl. , Aryloxy, shows arylalkoxy groups]

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

[In the formula,
R ⁸¹ represents hydrogen, (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ alkoxy, halogen, trifluoromethoxy or trifluoromethyl;
R ⁸² is hydrogen, (C ₁ -C ₄₎ alkyl, (C ₁ -C ₂₎ alkoxy - (C ₂ -C ₃₎ alkyl, (C ₁ -C ₄₎ fluoroalkyl, or (C ₃ -C ₆₎ It represents (C ₁ -C ₂₎ alkyl group - cycloalkyl;
R ⁸³ represents a heteroaryl group substituted by or is 1, 2 or 3 substituents unsubstituted, the substituents are halogen, (C ₁ -C ₄₎ alkyl, (C ₃ -C ₆₎ cycloalkyl, (C ₁ -C ₄₎ alkoxy, are independently selected from the group consisting of (C ₁ -C ₄₎ fluoroalkyl and phenyl. ]

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

[In the formula,
One of R ⁹¹ and R ⁹² shows hydrogen and the other shows halogen. ]

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

[In the equation, R ^c , R ^e , and R ^f are hydrogen,
R ^d is halo,
R ^g and R ^h are each independently substituted with hydrogen, or one or more halo substituents or one or more C _3- C ₇ cycloalkyl groups, or C _1- C ₆ alkyl or they are attached. Forming a _{C 3-} C ₇ cycloalkyl group with a carbon atom,
^Ri _{is a C 1-} C ₆ alkyl optionally substituted with hydrogen or one or more halo substituents or one or more C _3- C ₇ cycloalkyl groups.
R ^j is a phenyl, naphthalenyl, thiazole, biphenyl, quinolinyl or quinoxalinyl group and may be substituted with one or more halos, one or more halo substituents or one or more C _3- C ₇ cycloalkyl groups. C _1- C ₆ alkyl, optionally substituted with one or more halo substituents or one or more C ₃ -C ₇ cycloalkyl groups-O (C _1- C ₆ ) alkyl, -SO ₂ R ^l or May be substituted with an OH group
Each R ^l _{is a C 1-} C ₆ alkyl that may be independently substituted with hydrogen or one or more halo substituents or one or more cycloalkyl groups.
However, R ^j is not an unsubstituted phenyl,
R ^k _{is hydrogen or a C 1-} C ₆ alkyl optionally substituted with one or more halo substituents or one or more C _3- C ₇ cycloalkyl groups. ]

(7) Compounds represented by the following general formulas (A) to (K) or salts thereof (Japanese Patent Laid-Open No. 2010-132680)

[In the formula, Z ³ is = N- or = C (-R ⁷ )-; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently substituted with hydrogen, halogen, haloalkyl, carboxy, alkyloxycarbonyl, respectively. Alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted or aralkyl which may be substituted, formula: -S (O) _p R ⁸ ( In the formula, p is an integer of 0 to 2; and R ⁸ is an alkyl or optionally substituted aryl group, formula: -NR ⁹ R ¹⁰ (in the formula, R ⁹ and R ¹⁰ are independent of each other). Hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or acyl), formula: -OR ¹¹ ( ^{wherein R 11} is hydrogen, alkyl, optionally substituted). Aryl, optionally substituted aralkyl, alkanesulfonyl, optionally substituted arylsulfonyl, optionally substituted aralkylsulfonyl, group indicated by haloalkyl)).
R ¹ is carboxy, alkyloxycarbonyl, optionally substituted aminocarbonyl or tetrazolyl;
Z ⁴ is -N = or -C (-R ² ) =;
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; dashed lines indicate the presence or absence of a bond; E may be substituted aryl, optionally substituted A group represented by a good heteroaryl, alkyl, optionally substituted aralkyl or optionally substituted arylalkenyl),
x is an integer from 0 to 3; m is an integer from 1 to 3; dashed lines represent the presence or absence of bonds; E is optionally substituted aryl, optionally substituted heteroaryl, alkyl, substituted A group represented by an aralkyl which may be present or an arylalkenyl which may be substituted),
y is 0 or 1; one of R ²³ and R ²⁴ is alkyl, the other is hydrogen, alkyl or aryl; or R ²³ and R ²⁴ are together in the formula:-(CH ₂ ) t- (in the formula, t is Groups represented by (integer 2-5); R ²⁵ and R ²⁶ are independent groups represented by hydrogen or alkyloxyalkyl), respectively.
R ²⁰ is hydrogen or alkyl; R ²¹ is a group represented by hydrogen or halogen. (However, 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-excluding acetic acid);
Alternatively, R ¹³ is a group represented by hydrogen, alkyl, aralkyl, acyl or the formula: −OR ¹⁶ (where R ¹⁶ is hydrogen or alkyl), and R ¹⁴ is hydrogen or alkyl.
q is an integer from 0 to 3; R ¹⁷ is hydrogen or alkyl; Z ¹ is -CH _2- , -C (= O)-, -C (= NOH)-or -C (= NOMe)-; Z ² is Formula: -S (= O) _s- (in the formula, s is an integer of 0 to 2), formula: -N (-R ²² )-(in the formula, R ²² is hydrogen, alkyl, alkyloxy group or the formula represented by carbonyl or acyl): -CR ¹⁸ R ¹⁹ - (wherein, R ¹⁸ and R ¹⁹ are each independently hydrogen, alkyl or aryl; or R ¹⁸ and R ¹⁹ taken together wherein: -(CH ₂ ) t- (in the equation, t is the group represented by an integer of 2 to 5))

(8) A compound represented by the following general formula (13) or a salt thereof.

[In the formula, X indicates -SO ₂ -or -SO ₂ NR ^3- ;
R ¹ indicates hydrogen, F, Cl, CN or CF ₃ ;
R ² indicates hydrogen, F, Cl;
R ³ indicates hydrogen, C _1-6 alkyl or C _3-7 cycloalkyl;
Ar ¹ represents a phenyl or 5- or 6-membered heteroaryl group (hydrogen, halogen, CN, alkyl, cycloalkyl, alkoxy may be substituted);
A ² indicates a 5- or 6-membered heteroaryl group (hydrogen, halogen, CN, alkyl, cycloalkyl, alkoxy may be substituted)]

In the general formula (15), Ar ¹ is preferably phenyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isooxazolyl, isothiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, and Ar ² is pyrrolyl, furanyl, thienyl, oxazolyl, Thiazolyl, imidazolyl, pyrazolyl, isooxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl are preferred.

Preferred specific examples of the CRTH2 receptor antagonist include the following compounds.

As shown in Examples below, these drugs were used alone when a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist were used in combination, especially when an HPGDS inhibitor and a CRTH2 receptor antagonist were used in combination. It dramatically suppresses muscle necrotizing in muscular dystrophy compared to the case. That is, these drugs synergistically suppress muscle necrotizing in muscular dystrophy by their combination, and are 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 a phenomenon common to DMD patients such as elevation of serum creatine kinase and pyruvate kinase, which are markers of muscle necrosis, occurs. , Pathological findings are similar to those of DMD patients. When a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist are administered in combination to these mdx mice, in particular, when an HPGDS inhibitor and a CRTH2 receptor antagonist are administered in combination, these agents are administered alone. The increase in serum creatine kinase was remarkably suppressed as compared with the case of administration.
It is also known that administration of thyroid hormone (T3, triiodothyronine) to mdx mice causes similar myocardial damage to DMD patients. The T3-induced myocardial injury in this mdx model mouse can also be synergistically suppressed by the combined use of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist.
Therefore, by using the MD therapeutic agent of the present invention, the rate of muscle atrophy of MD patients can be greatly reduced, the period of wheelchair use and mechanical ventilation can be greatly extended, and the patient's self-sustaining period can be significantly extended. it can.

The drug of the present invention may be a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist, and two compositions containing each drug may be used in combination (combination drug). It may be a pharmaceutical composition containing.
The concomitant drug or pharmaceutical composition of the present invention can be administered in any administration form, and the preparation can be selected according to the administration form. Examples of the orally administered preparation include tablets, capsules, granules, powders, syrups and the like. Examples of parenteral preparations include injections, suppositories, inhalants, transdermal absorbents, external preparations for skin, eye drops, nasal drops and the like. When an injection is selected, the route of administration includes subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal injection and intravenous injection.

When preparing an oral solid preparation, after adding excipients, binders, disintegrants, lubricants, colorants, flavoring agents, etc. as necessary, tablets, granules, powders, etc. Capsules and the like can be manufactured.

When preparing an oral liquid preparation, an oral liquid preparation, a syrup preparation, an elixir preparation, etc. can be produced by adding a flavoring agent, a buffering agent, a stabilizer, a preservative, etc. by a conventional method.

When preparing an injection, a pH adjuster, a stabilizer, an isotonic agent can be added, and a subcutaneous, muscular, or intravenous injection can be produced by a conventional method.

Among the drugs of the present invention, in the case of a concomitant drug, a preparation (composition) containing a prostaglandin synthesis inhibitor and a preparation (composition) containing a CRTH2 receptor antagonist are used in combination. When they are formulated separately in this way, they may be kit drugs in which the separately formulated drugs are combined with the instructions describing the respective administration methods. In the case of these separately formulated drugs, the dosage forms of the respective formulations may be the same or different, and the dosing intervals may be the same or different.

Among the drugs of the present invention, in the case of a pharmaceutical composition containing a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist, one dosage form, for example, a tablet contains these two drugs. preferable.

The usage ratio (mass ratio) of the prostaglandin synthesis inhibitor (A) and the CRTH2 receptor antagonist (B) in the medicament of the present invention differs depending on the type of the compound used, but (A): (B). = 200: 1 to 1:10 is preferable, 100: 1 to 1: 5 is more preferable, and 50: 1 to 1: 1 is even more preferable.

The dose of the medicament of the present invention varies depending on the compound used, the age, body weight, symptoms, etc. of the patient, but the daily dose of the prostaglandin synthesis inhibitor is preferably 0.01 to 10 mg / kg. More preferably, 05 to 10 mg / kg. The daily dose of the CRTH2 receptor antagonist is preferably 0.01 to 10 mg / kg, more preferably 0.05 to 5 mg / kg.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1
(Method)
Solvent (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 two agents (TFC007, 3 mg / kg + CAY10471, 0.1 mg / kg) was subcutaneously administered daily to muscular dystrophy model mice (mdx mice (C57BL / 6)) for 4 to 4 weeks after birth to measure serum creatine kinase activity (marker of skeletal muscle necrosis). ..
(result)
The results are shown in FIG.
From FIG. 1, when the HPGDS inhibitor and the CRTH2 receptor antagonist were used in combination, the doses thereof were 1/10 of those when each was administered alone, but the doses were extremely higher than those when each was administered alone. It showed a strong creatine kinase activity lowering effect.

Example 2
(Method)
Solvent (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 two agents (HQL79, 3 mg / kg + OC000459, Serum creatine after subcutaneous administration of 0.1 mg / kg) to muscular dystrophy model mice (mdx mice (C57BL / 10)) every 2-3 days (weekly, Monday, Wednesday, Friday) for 4 to 2 weeks after birth. Kinase activity (marker of skeletal muscular necrosis) was measured.
(result)
The results are shown in FIG.
From FIG. 2, when the HPGDS inhibitor and the CRTH2 receptor antagonist are used in combination, the doses thereof are 1/10 of those of the single dose, but stronger than those of the single dose. It showed a creatine kinase activity lowering effect.

Example 3
(Method)
Solvent (5% DMSO in 5% methylcellulose-containing saline), HPGDS inhibitor HQL79 (30 mg / kg), CRTH2 receptor antagonist OC000459 (0.5 mg / kg), or a combination of two agents (HQL79, 3 mg / kg) (Kg + OC000459, 0.1 mg / kg) was subcutaneously administered to muscular dystrophy model mice (C57BL / 10-mdx mice) every 2-3 days (weekly, Monday, Wednesday, Friday) for 4 to 4 weeks after birth. Later serum creatinine kinase activity (marker of skeletal muscular necrosis) was measured.
(result)
The results are shown in FIG.
From FIG. 3, when the HPGDS inhibitor HQL79 and the CRTH2 receptor antagonist OC000459 were used in combination, there was no statistically significant change when each was administered alone, whereas these doses were each alone. Despite being 1/10 and 1/5 of the dose, it showed a strong creatinine kinase activity-lowering effect statistically significantly (t-test compared to solvent administration: p <0.05). ..

Example 4
(Method)
Solvent (5% DMSO in 5% methylcellulose-containing physiological saline), prostaglandin synthesis inhibitor indomethacin (1 mg / kg), or a combination of prostaglandin synthesis inhibitor indomethacin and 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 subcutaneously administered to muscle dystrophy model mice (C57BL / 10-mdx mice) daily from 16 weeks to 10 days after birth. Later serum creatinine kinase activity (marker of skeletal muscle necrosis) was measured.
(result)
The results are shown in FIG.
From FIG. 4, when the prostaglandin synthesis inhibitor indomethacin was used in combination with a CRTH2 receptor antagonist (OC000459 or Cay10471), it showed no statistically significant change when administered alone, whereas it alone showed no significant change. Despite being 1/10 of the administration, it showed a strong creatinine kinase activity-lowering effect statistically significantly (t-test compared with solvent administration: p <0.01).

Example 5
(Method)
Solvent (5% DMSO in 5% methylcellulose-containing physiological saline), prostaglandin synthesis inhibitor aspirin (150 mg / kg), or a combination of prostaglandin synthesis inhibitor aspirin and CRTH2 receptor antagonist (aspirin, 150 mg / kg) kg + Cay10471, 0.1 mg / kg; aspirin, 150 mg / kg + OC000459, 0.1 mg / kg; or aspirin, 150 mg / kg + BAYu3405, 10 mg / kg) in muscle dystrophy model mice (C57BL / 6-mdx mice), 4 weeks old Serum creatinine kinase activity (marker of skeletal muscle necrosis) was measured after subcutaneous administration every day for 4 weeks.
(result)
The results are shown in FIG.
From FIG. 5, when the prostaglandin synthesis inhibitor aspirin was used in combination with a CRTH2 receptor antagonist (Cay10471, OC000459, or BAYu3405), no statistically significant change was shown when administered alone. T-test compared to statistically significant (Cay10471 or OC000459 combination, solvent administration and aspirin alone administration: p <0.05; compared to BAYu3405 combination, solvent administration and aspirin alone administration The t-test: p <0.01) showed a strong creatinine kinase activity-lowering effect.

Claims

MD therapeutic agent consisting of a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist.
The MD therapeutic agent according to claim 1, wherein a pharmaceutical composition containing a prostaglandin synthesis inhibitor and a pharmaceutical composition containing a CRTH2 receptor antagonist are used in combination.
MD therapeutic agent composition containing a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist.
Use of a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist for the manufacture of MD therapeutic agents.
A combination of a prostaglandin inhibitor and a CRTH2 receptor antagonist for the treatment of MD.
An MD treatment method comprising a combination of a prostaglandin synthesis inhibitor and a CRTH2 receptor antagonist.