Pharmaceutical composition and treatment method for genetic disease associated with splicing abnormalities

Abstract

Provided are a pharmaceutical composition for preventing, ameliorating, suppressing progression of, and/or treating the genetic diseases caused by an aberrant splicing regulation, the pharmaceutical composition containing, as an active ingredient, a compound capable of suppressing an aberrant splicing regulation that contributes to the development or progression of genetic diseases caused by an aberrant splicing regulation, and a method for preventing, ameliorating, suppressing progression of, and/or treating the genetic diseases using a compound capable of suppressing an aberrant splicing regulation that contributes to the development or progression of genetic diseases caused by an aberrant splicing regulation.

1 . A pharmaceutical composition for preventing, ameliorating, suppressing progression of, and/or treating a genetic disease caused by an aberrant splicing regulation, wherein the pharmaceutical composition comprises, as an active ingredient, a compound capable of suppressing a splicing abnormality that contributes to development or progression of the genetic disease. 
     
     
         2 . The pharmaceutical composition according to  claim 1 ,
 wherein the compound is a compound capable of enhancing exon recognition in splicing in which exon recognition is incomplete due to the splicing abnormality, or a compound capable of suppressing exon recognition.   
     
     
         3 . The pharmaceutical composition according to  claim 1 ,
 wherein the disease is selected from the group consisting of Pompe disease, mucopolysaccharidoses, congenital long QT syndrome, Fukuyama congenital muscular dystrophy, progeria syndrome, amyotrophic lateral sclerosis, atypical adenofibrosis, autism, autism spectrum disorder, Charcot-Marie-Tooth disease, CHARGE syndrome, dementia, epilepsy, epileptic encephalopathies, familial dysautonomia, familial isolated growth hormone deficiency type II, Frasier syndrome, frontotemporal dementia, Parkinson's disease, Huntington's disease, Marfan syndrome, mental retardation, Menkes disease, muscular dystrophy, myopathy, myotonic dystrophy type I, myotonic dystrophy type 2, von Recklinghausen NF, peripheral NF, occipital horn syndrome, retinoblastoma, schizophrenia, tuberous sclerosis, Fabry disease, homocystinuria, hereditary breast/ovarian cancer syndrome, ataxia-telangiectasia/Louis-Bar syndrome, Lynch syndrome, neurofibromatosis type 1, tuberous sclerosis, atypical pyridoxine-dependent epilepsy, Leber congenital amaurosis, Alport syndrome, chronic granulomatous disease, 17α-hydroxylase deficiency, X-linked hypophosphatemia, polycystic kidney disease, Bartter syndrome, Becker muscular dystrophy, colon cancer/T-cell acute lymphoblastic leukemia, arrhythmia, cardiomyopathy, Carney complex, ciliary dyskinesia syndrome, Cockayne syndrome, congenital disorders of glycosylation type I, Cornelia de Lange syndrome, cystic fibrosis, hearing impairment, dilated cardiomyopathy, Duchenne muscular dystrophy, familial adenomatous polyposis, hypertrophic cardiomyopathy, fibrochondrogenesis, Finnish congenital nephrotic syndrome, β-galactosidase deficiency, glycogen storage disease type III, hereditary neoplastic syndrome, Hermansky-Pudlak syndrome, hypogonadotropic hypogonadism, I-cell disease, juvenile polyposis syndrome, limb-girdle muscular dystrophy, lissencephaly, meconium ileus, merosin-deficient muscular dystrophy, congenital mirror movement disorder, Miyoshi muscular dystrophy, mucolipidosis type III, myopathy, early-onset-areflexia-respiratory-distress-dysphagia, nemaline myopathy, nonimmunologic hydrops fetalis, neutral lipid storage disease with myopathy, nonketotic hyperglycinemia, Hurler syndrome, maple syrup urine disease, oligodontia-colorectal cancer syndrome, orofaciodigital syndrome, gyrate atrophy, Nance-Sweeney syndrome, palmoplantar keratoderma, phenylketonuria, pituitary hormone deficiency, pyridoxine-dependent epilepsy, severe combined immunodeficiency, severe myoclonic epilepsy of infancy, myotubular myopathy, Sotos syndrome, spinal muscular atrophy, spinocerebellar ataxia, tuberous sclerosis, and familial tumoral calcinosis.   
     
     
         4 . The pharmaceutical composition according to  claim 1 ,
 wherein a gene associated with the splicing abnormality is one or more genes selected from the group consisting of CFTR, GLA, MTRR, BRCA2, ATM, MSH2, NF1, TSC2, CEP290, COL4A3, CYBB, CYP17A1, FBN1, PHEX, PKHD1, COL4A5, CLCNKA, DMD, BRCA1, PALB2, BAX, KCNH2, TNNT2, PRKAR1A, CHD7, ZMYND10, ERCC8, SSR4, NIPBL, RDX, OTOF, SMPX, TTN, APC, MYBPC3, COL11A1, NPHS1, GALC, AGL, CDH1, STK11, HPS5, TACR3, GNPTAB, SMAD4, CAPN3, PAFAH1B1, MLH1, PMS2, GUCY2C, LAMA2, DCC, ANO5, GNPTG, MEGF10, NEB, PNPLA2, GLDC, ID UA, BCKDHA, AXIN2, OFD1, OAT, COL11A2, SERPINB7, LRRK2, PAH, POU1F1, DSP, ALDH7A1, JAK3, SCN1A, MTM1, NSD1, SMN1, ANO10, IKBKAP, and GALNT3.   
     
     
         5 . The pharmaceutical composition according to  claim 1 ,,
 wherein the compound is a compound represented by Formula (II), (II′), (III), (IV), (V), (VI), (VII), or (VIII), a prodrug thereof, or a pharmaceutically acceptable salt thereof,   
       
         
           
           
               
               
           
         
       
       where, in Formulae (II) and (II′),
 R 1a  and R 2a  each independently represent a hydrogen atom, a substituted or unsubstituted C 1-6  alkyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted heteroarylmethyl group, a substituted or unsubstituted heteroarylethyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a substituted or unsubstituted alkoxyamidoalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or alternatively, R 1a  and R 2a  bind to each other to form a ring together with N, and the ring is a substituted or unsubstituted monocyclic heterocyclic ring, or a substituted or unsubstituted bicyclic heterocyclic ring; 
 R 5  represents a hydrogen atom, a halogen atom, a substituted or unsubstituted C 1 -C 6  alkoxy group; 
 X 1  represents N or CH; 
 X 2  represents —N(R 3 )—, S, or O; 
 R 3  represents a hydrogen atom, a C 1-6  alkyl group, a benzyl or heteroarylmethyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or CH 2 OC(O)R 4 —; 
 R 4  represents a C 1 -C 6  alkyl group, a benzyl or heteroarylmethyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; and 
 X represents a hydrogen atom, a halogen atom, an amino group, an R 1a - and R 2a -substituted amino group, an azido group, a cyano group, a nitro group, a hydroxy group, a C 1 -C 6  alkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaryloxy group, a mercapto group, a C 1 -C 6  alkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted heteroarylthio group, a benzyl or heteroarylmethyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; 
 in Formula (III), 
 R 7  and R 8  each independently represent a hydrogen atom, a halogen-substituted or unsubstituted C 1 -C 16  alkyl group, or a C 2 -C 6  alkenyl group; 
 R 9  represents a hydrogen atom, a halogen atom, or a halogen-substituted or unsubstituted C 1 -C 10  alkyl group, —OR 10 , —NHR 10 , or —N(R 10 ) 2 ; 
 R 10  represents a hydrogen atom or a C 1 -C 10  alkyl group; 
 in Formula (IV), 
 R 11  and R 12  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group; 
 R 13  represents 
 
       
         
           
           
               
               
           
         
       
       where Z forms, together with atoms marked with a and b, a ring selected from the group consisting of one benzene ring, one heteroaromatic ring, an aromatic ring fused with one or more benzene rings, a heteroaromatic ring fused with one or more heteroaromatic rings, a mixed fused polycyclic ring in which one or more benzene rings and one or more heteroaromatic rings are fused, and cycloaliphatic compounds, and the ring optionally includes one or more substituents, the substituents being a hydrogen atom, a halogen atom, or a C 1 -C 6  alkyl group;
 R 14  represents a hydrogen atom, a halogen atom, or a C 1 -C 6  alkyl group; 
 in Formula (V), 
 X 3  and X 4  each independently represent S or NH; 
 R 15  represents 
 
       
         
           
           
               
               
           
         
       
       where Z forms, together with atoms marked with a and b, a ring selected from the group consisting of one benzene ring, one heteroaromatic ring, an aromatic ring fused with one or more benzene rings, a heteroaromatic ring fused with one or more heteroaromatic rings, a mixed fused polycyclic ring in which one or more benzene rings and one or more heteroaromatic rings are fused, and cycloaliphatic compounds, and the ring optionally includes one or more substituents, the substituents being a hydrogen atom, a halogen atom, or a C 1 -C 6  alkyl group;
 R 16  represents a hydrogen atom, a halogen atom, or a C 1 -C 6  alkyl group; 
 in Formulae (VI) and (VII), 
 R 17  and R 19  each independently represent a hydrogen atom, a C 1 -C 6  alkyl group, a benzyl or heteroarylmethyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; 
 R 18 represents R 22 , —C□C—R 22 , —CH═CH—R 22 , or —O—(CH 2 ) n R 22 , n is 1 to 6, R 22  represents a hydrogen atom, a hydroxy group, a C 1 -C 8  alkyl group, —Si(R 23 ) 3 , a substituted or unsubstituted phenyl group, a monocyclic heteroaromatic group, or a cycloaliphatic group, or alternatively, R 17  and R 18  bind to each other to form a ring, and —R 17 —R 18 — is substituted by —(CH 2 ) m —CH 2 —, —CH═CH—, —(CH 2 ) m —O—, or a halogen atom, m is 1 to 6, R 23  represents a hydrogen atom, a C 1 -C 6  alkyl group, a trihalo-methyl group, or a hydroxy group, and three R 23  of —Si(R 23 ) 3  are optionally different from each other; 
 R 20  and R 21  represent a hydrogen atom or a C 1 -C 6  alkyl group; 
 in Formula (VIII), 
 X 5  represents 
 
       
         
           
           
               
               
           
         
       
       where R 26 , R 27 , and R 28  each independently represent a hydrogen atom, a halogen atom, a carboxyl group, an amino group, a hydroxy group, a C 1 -C 4  alkyl group, or a halogen-substituted C 1 -C 4  alkyl group;
 X 6  represents —(atomic bonding) or —NH—; 
 R 24  represents 
 
       
         
           
           
               
               
           
         
       
       where R 29 , R 30 , R 31 , and R 32  each independently represent a hydrogen atom, a halogen atom, a carboxyl group, an amino group, a hydroxy group, a C 1 -C 4  alkyl group, or a halogen-substituted C 1 -C 4  alkyl group; and
 R 25  represents a hydrogen atom, a halogen atom, a carboxyl group, an amino group, a hydroxy group, or a halogen-substituted or unsubstituted C 1 -C 4  alkyl group. 
 
     
     
         6 . The pharmaceutical composition according to  claim 5 ,
 wherein the compound represented by Formula (VIII) is selected from the group consisting of the following compounds   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A method for preventing, ameliorating, suppressing progression of, and/or treating a genetic disease caused by an aberrant splicing regulation, the method comprising administering a compound capable of suppressing a splicing abnormality that contributes to development or progression of the genetic diseases to a subject that requires the compound. 
     
     
         8 - 11 . (canceled) 
     
     
         12 . The method according to  claim 7 ,
 wherein the compound is a compound represented by Formula (II), (II′), (III), (IV), (V), (VI), (VII), or (VIII), a prodrug thereof, or a pharmaceutically acceptable salt thereof.   
     
     
         13 . The method according to  claim 7 ,
 wherein the compound is a compound represented by Formula (IX), (IX′), (X), or (X′), a prodrug thereof, or a pharmaceutically acceptable salt thereof,   the disease is Fabry disease.   
     
     
         14 . The method according to  claim 7 ,
 wherein the compound is a compound represented by Formula (III), (VI), (VII), or (VIII), a prodrug thereof, or a pharmaceutically acceptable salt thereof,   the disease is cystic fibrosis.   
     
     
         15 . The pharmaceutical composition according to  claim 1 ,
 wherein the compound is a compound represented by Formula (IX), (IX′), (X), or (X′), a prodrug thereof, or a pharmaceutically acceptable salt thereof,   the disease is Fabry disease.   
     
     
         16 . The pharmaceutical composition according to  claim 1 ,
 wherein the compound is a compound represented by Formula (III), (VI), (VII), or (VIII), a prodrug thereof, or a pharmaceutically acceptable salt thereof,   the disease is cystic fibrosis.