WO2009013477A1 - Composés pour traiter la dystrophie musculaire de duchenne - Google Patents

Composés pour traiter la dystrophie musculaire de duchenne Download PDF

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Publication number
WO2009013477A1
WO2009013477A1 PCT/GB2008/002495 GB2008002495W WO2009013477A1 WO 2009013477 A1 WO2009013477 A1 WO 2009013477A1 GB 2008002495 W GB2008002495 W GB 2008002495W WO 2009013477 A1 WO2009013477 A1 WO 2009013477A1
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WO
WIPO (PCT)
Prior art keywords
thiazole
imidazo
alkyl
methylimidazo
compound
Prior art date
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PCT/GB2008/002495
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English (en)
Inventor
Graham Michael Wynne
Stephen Paul Wren
Paul Damien Price
Original Assignee
Summit Corporation Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0714303A external-priority patent/GB0714303D0/en
Priority claimed from GB0803906A external-priority patent/GB0803906D0/en
Application filed by Summit Corporation Plc filed Critical Summit Corporation Plc
Priority to EP08776016A priority Critical patent/EP2167508A1/fr
Priority to CA002685599A priority patent/CA2685599A1/fr
Priority to JP2010517478A priority patent/JP2010534231A/ja
Priority to AU2008278824A priority patent/AU2008278824A1/en
Publication of WO2009013477A1 publication Critical patent/WO2009013477A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a method of treatment of Duchenne muscular dystrophy.
  • DMD Duchenne muscular dystrophy
  • DMD has been characterized as an X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene.
  • the gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons.
  • Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements.
  • Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein.
  • the high incidence of DMD (1 in 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable.
  • the max mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulfield, G., Siller, W. G., Wight, P. A. & Moore, K. J. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Natl Acad. Sci. USA 81, 1189-1192 (1984)).
  • Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein.
  • the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment.
  • These strategies offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies.
  • investigations with corticosteroids and sodium cromoglycate, to reduce inflammation, dantrolene to maintain calcium homeostasis and clenbuterol to increase muscle strength have produced promising results none of these potential therapies has yet been shown to be effective in treating DMD.
  • Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein.
  • Upregulation of utrophin an autosomal paralogue of dystrophin has been proposed as a potential therapy for DMD (Perkins & Davies, Neuromuscul Disord, Sl: S78-S89 (2002), Khurana & Davies, Nat Rev Drug Discov 2:379-390 (2003)).
  • DAPC dystrophin-associated protein complex
  • X 1 , X 2 and X 3 are each independently a linker selected from a bond, -NR 4" , -O-, -S-, -NR 4 C(O)-, -NR 4 C(S)-, -NR 4 C(O)O-, -NR 4 SO 2 -, -NR 4 C(O)NR 4 -, -NR 4 C(S)NR 4 -, -NR 4 C(NH)NR 4 -, -NR 4 C(NH)-, -C(O)-, -C(S)-, -C(O)NR 4 -, -C(S)NR 4 -, -SO-, -SO 2 -, -OC(O)O-, -SO 2 NR 4 -, -OC(O)NR 4 - or -P(O)OR 4 -; each R 4 is independently H or C 1 - 6 alkyl optionally substituted by halo;
  • R 1 , R 2 and R 3 are each independently hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, Ci -C 10 alkyl, C 2 -Ci O alkenyl or C 2 -Ci 0 alkynyl, any of which may optionally be substituted with halo or a group X 4 -R 6 , or when X 1 , X 2 or X 3 is a bond, R 1 , R 2 or R 3 may also be halo, NO 2 or CN; or alternatively
  • R 2 and R 3 together with the atoms to which they are attached may form a 5 to 12 membered monocyclic or bicyclic aromatic or non aromatic ring system optionally containing one or more heteroatoms selected from O, S or N, optionally substituted by one or more substitutents X 4 R 6 ; where: X 4 is selected from a bond, -NR 4" , -0-, -S-,
  • R 6 is H or Ci -C O alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be substituted with halo or -0(C I -C O alkyl) and wherein cycloalkyl, heterocyclyl, aryl and heteroaryl groups may also be subsituted with C 1 -C6 alkyl; or, when X 4 is a bond, R 6 may also be halo; NO 2 or CN;
  • Y is O, S or NR 7 ;
  • R 7 is hydrogen or Ci-C ⁇ alkyl; Z is N or CR 8 ;
  • R 8 is hydrogen or Ci-C ⁇ alkyl; provided that when R 1 is phenyl substituted with X 4 R 6 and X 4 is -NR 4 C(O)-, R 6 is not phenyl; or tautomer, enantiomer or pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
  • the invention also relates to a method for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia, the method comprising administering to a patient in need of such treatment an effective amount of a compound of general formula (I) as defined above.
  • Ci-C ⁇ alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl.
  • C 1 -C 4 alkyl and “Ci-Cio alkyl” have similar meanings except that they contain respectively from one to four and from one to ten carbon atoms.
  • C 2 -Ce alkenyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond. Examples include ethenyl, 2-propenyl, and 3-hexenyl.
  • C 2 -Cn alkynyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon triple bond. Examples include ethynyl, 2-propynyl, and 3-hexynyl.
  • C 2 -CiO alkenyl and “C 2 -Ci 0 alkynyl” have similar meanings except that they contain from one to ten carbon atoms.
  • C 2 -C 6 haloalkyl refers to a Ci_6 alkyl group as defined above substituted by one or more halogen atoms.
  • cyclic groups refers to cycloalkyl, heterocyclyl, aryl or heteroaryl groups.
  • cycloalkyl refers to a saturated 3 to 14 membered carbocyclic ring including fused bicyclic or tricyclic systems. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and also bridged systems such as norbornyl and adamantyl.
  • heterocyclyl refers to a saturated 3 to 14 membered ring system similar to cycloalkyl but in which at least one of the carbon atoms has been replaced by N, O or S.
  • heterocyclyl refers to a saturated 3 to 14 membered ring system similar to cycloalkyl but in which at least one of the carbon atoms has been replaced by N, O or S. Examples include piperidine, piperazine, morpholine, tetrahydrofuran and pyrrolidine,
  • aryl and aromatic moiety in the context of the present specification refer to an aromatic ring system having from 5 to 14 ring carbon atoms and containing up to three rings. Examples of aromatic moieties are benzene and naphthalene.
  • heteroaryl and “heteroaromatic moiety” refer to an aromatic ring system, which may be partially saturated and which has from 5 to 14 ring carbon atoms and containing up to three rings and at least one heteroatom selected from N, O and S.
  • heteroatom selected from N, O and S. Examples include pyridine, pyrimidine, furan, thiophene, indole, iso indole, benzofuran, benzimidazole, benzimidazoline quinoline, isoquinoline, tetrahydroisoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole, indazole and imidazole ring systems.
  • halo refers to fluoro, chloro, bromo or iodo.
  • Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulae (Ia) and (Ib) include basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine and other well known basic addition salts.
  • pharmaceutically or veterinarily acceptable salts may also include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalate,
  • Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to general formula (I) in vivo.
  • a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • X 1 , X 2 and X 3 are bonds;
  • R 1 is a cycloalkyl, heterocyclyl, aryl or heteroaryl, any of which may optionally be substituted with one or more substituents selected from halo, OH, 0(C I -C O alkyl) or
  • NHC(O)R 6 wherein R 6 is Ci-C 6 alkyl, optionally substituted with halo or 0(Ci-C 6 alkyl);
  • R 2 and R 3 are hydrogen, Ci-C 6 alkyl or halo or R 2 and R 3 together with the atoms to which they are attached form an aromatic ring;
  • Y is O or S
  • Z is CR 8 where R is as defined above.
  • X 1 , X 2 and X 3 are bonds
  • R 1 is a cycloalkyl, aryl or heteroaryl group optionally substituted with one or more substituents selected from halo, OH, O(C,-C 4 alkyl) or NHC(O)R 6 , wherein R 6 is C,-
  • R 2 and R 3 are hydrogen, C 1 -C 4 alkyl or halo or R 2 and R 3 together with the atoms to which they are attached form a phenyl ring;
  • Y is O or S; and Z is CR 8 where R 8 is hydrogen, methyl or ethyl.
  • X 1 , X 2 and X 3 are bonds;
  • R 1 is a phenyl, naphthyl, thienyl, cyclohexyl or 3-chromene-2-onyl any or which is optionally substituted with one or more substituents selected from halo, OH, methoxy, ethoxy or NHC(O)R 6 , wherein R 6 is Ci-C 4 alkyl;
  • R 2 and R 3 are hydrogen, methyl or chloro or R 2 and R 3 together with the atoms to which they are attached form a phenyl ring; Y is O or S; and Z is CH.
  • Particularly preferred compounds of general formula (I) include:
  • a compound of general formula (I) as defined above in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
  • Many of the compounds of general formula (I) are commercially available and others can be synthesised from commercially available starting materials using the following method.
  • a compound of general formula (I) in which Z is CR 8 may be prepared from a compound of general formula (II):
  • the starting material is cooled to a temperature of about -15 to O 0 C before addition of the Lewis acid.
  • the reaction mixture is then allowed to warm to room temperature and heated under reflux for 1 to 5 hours before the product is isolated.
  • An intermediate compound of general formula (II) may be prepared from a compound of general formula (III):
  • the reaction may be carried out by mixing a compound of general formula (III) in a polar organic solvent such as acetonitrile and a compound of general formula (IV) in an organic solvent such as tetrahydrofuran.
  • a polar organic solvent such as acetonitrile
  • a compound of general formula (IV) in an organic solvent such as tetrahydrofuran.
  • the reaction is most suitable carried out under anhydrous conditions and under an inert atmosphere such as nitrogen or argon.
  • the reaction temperature is suitably from about 15 to 25 0 C.
  • compounds of general formula (IV) in which Q is bromo can be prepared by reacting the appropriate compound of general formula (V) with bromine in polar organic solvent, especially an alcoholic solvent such as methanol.
  • the reaction is typically carried out under basic conditions.
  • a compound of general formula (VI) can be prepared from a compound of general formula (II) as defined above by reaction with carbon disulphide followed by a compound of general formula (VIII):
  • Compounds of general formula (I) can be converted to other compounds of general formula (I).
  • compounds of general formula (I) in which X 1 R 1 , X 2 R 2 or X 3 R 3 is C(0)0(Ci-Cio) alkyl can be converted to the equivalent compound of general formula (I) in which X 1 R 1 , X 2 R 2 or X 3 R 3 is C(O)OH by hydrolysis, for example base hydrolysis using sodium hydroxide in a polar organic solvent such as tetrahydrofuran.
  • X 1 R 1 , X 2 R 2 or X 3 R 3 is C(O)OH
  • compounds in which X 1 R 1 , X 2 R 2 or X 3 R 3 is OH can in turn be converted to compounds in which X 1 R 1 , X 2 R 2 or X 3 R 3 is OH by standard reduction methods, for example using NMM in tetrahydrofuran at O 0 C, followed by reaction with aqueous sodium borohydride.
  • the alcohols can, in turn, be converted to numerous other functional groups, for example carbamates, phosphinates, ethers or amines, using standard methods well known to those of skill in the art.
  • X 1 R 1 , X 2 R 2 or X 3 R 3 is C(O)OH may in addition be converted to a range of further compounds, including amine derivatives (by a Curtius reaction), acyl derivatives and carbonyl derivatives. The methods used for these conversions are all well known and would be familiar to a skilled chemist.
  • protecting groups In the syntheses described above, it may sometimes be necessary to use protecting groups. The necessity for using such protecting groups would be apparent to a skilled chemist who would also be capable of choosing appropriate protecting groups. Information concerning protecting groups is available in in "Protecting Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc.
  • the compounds of general formula (I) for use in the treatment of DMD will generally be administered in the form of a pharmaceutical composition and some of these pharmaceutical compositions form a further aspect of the invention.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from:
  • the pharmaceutical composition may include less than 80% w/w, more preferably less than 50% w/w, e.g. 0.1 to 20%, of a compound of general formula (I), or a pharmaceutically acceptable salt thereof, as defined above, in admixture with a pharmaceutically acceptable diluent or carrier.
  • Examples of pharmaceutical formulations which may be used, and suitable diluents or carriers, are as follows: for intravenous injection or infusion - purified water or saline solution; for inhalation compositions - coarse lactose; for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes.
  • chelating or sequestering agents antioxidants, tonicity adjusting agents, pH- modifying agents and buffering agents.
  • Solutions containing a compound of general formula (I) may, if desired, be evaporated, e.g. by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use.
  • the compound of general formula (I) preferably is in a form having a mass median diameter of from 0.01 to lO ⁇ m.
  • the compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, e.g. a water- soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol, sweetening and colouring agents and flavourings. Where appropriate, the compositions may be formulated in sustained release form.
  • the content of compound general formula (I) in a pharmaceutical composition is generally about 0.01 -about 99.9wt%, preferably about 0.1 -about 50wt%, relative to the entire preparation.
  • the dose of the compound of general formula (I) is determined in consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment then, and other factors.
  • While the dose varies depending on the target disease, condition, subject of administration, administration method and the like, for oral administration as a therapeutic agent for the treatment of Duchenne muscular dystrophy in a patient suffering from such a disease is from 0.01 mg - 1O g, preferably 0.1 - 100 mg, is preferably administered in a single dose or in 2 or 3 portions per day.
  • FIGURE 1 shows an example of TA muscle sections stained with antibody specific for mouse utrophin.
  • CPD-A 5-amino-2-(5,6- dimethylbenzo[d]oxazol-2-yl)phenol
  • FIGURE 2 Shows a Western blot of excised and processed muscles from the above treated mice stained with specific antibodies (see Figure 2). Muscle dosed with
  • CPD-A shows a significant increase in the overall levels of utrophin present in both the TA leg muscle and the diaphragm. Both mice exposed to CPD-A (V2 and V3) showed increased levels of utrophin expression compared to the negative control.
  • HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionisation mode.
  • the HPLC column used is a Phenomenex Gemini Cl 8 150x4.6mm.
  • Preparative HPLC was performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector.
  • the preparative HPLC column used is a Phenomenex Gemini Cl 8 150x 10mm and the mobile phase is acetonitrile/water.
  • DMSO dimethylsulfoxide
  • HATU O-(7- azabenzotriazol- IyI)-N ,N,N',N'-tetramethyluronium hexafluorophosphate
  • HCl hydrochloric acid
  • MgSO 4 magnesium sulfate
  • NaOH sodium hydroxide
  • Na 2 C ⁇ 3 sodium carbonate
  • NaHCU 3 sodium bicarbonate
  • STAB sodium triacetoxyborohydride
  • THF tetrahydrofuran
  • the cell line used for the screen is an immortalized mdx mouse H2K cell line that has been stably transfected with a plasmid containing ⁇ 5kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene.
  • the cells Under conditions of low temperature and interferon containing media, the cells remain as myoblasts. These are plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase is then determined by cell lysis and reading of the light output from the expressed luciferase gene utilising a plate luminometer.
  • ADMET data obtained from the ADMET data is prioritised and the compounds with the best in vitro luciferase activity and reasonable ADMET data are tested in the mdx proof of concept study where the outcome identified is the ability to increase the levels of utrophin protein in dystrophin deficient muscle when compared to vehicle only dosed negative control animals.
  • Figure 1 shows an example of TA muscle sections stained with antibody specific for mouse utrophin.
  • CPD-A 5-amino-2-(5,6- dimethylbenzo[d]oxazol-2-yl)phenol
  • Muscles from the above treated mice were also excised and processed for Western blotting and stained with specific antibodies (see Figure 2). Again using muscle dosed with CPD-A shows a significant increase in the overall levels of utrophin present in both the TA leg muscle and the diaphragm. Both mice exposed to CPD-A (V2 and V3) showed increased levels of utrophin expression compared to the negative control. Positive upregulation data from the first 28 day study are then repeated in a further two mouse 28 day study. Such data will demonstrate the ability of the test compounds to significantly increase levels of utrophin in the mdx muscle when delivered ip. Since all the published data to date demonstrate that any increase of utrophin levels over three fold has significant functional effects on dystrophin deficient muscle, such an assay is likely to be an excellent predictor of clinical efficacy.
  • the H2K/mdx/Utro A reporter cell line maintenance The H2K/mdx/Utro A reporter cell line was passaged twice a week until ⁇ 30% confluent. The cells were grown at 33 0 C in the presence of 10% CO 2
  • the H2K/mdx/Utro A reporter cell line cells were plated out into 96 well plates (Falcon 353296, white opaque) at a density of approximately 5000 cells/well in 190 ⁇ l normal growth medium. The plates were then incubated at 33 0 C in the presence of 10% CO 2 for 24 hrs.
  • mice from a breeding colony were selected for testing. Mice were injected daily with either vehicle or 10mg/kg of compound using the intraperitoneal route (ip). Mice were weighed and compounds diluted in 5% DMSO, 0.1% TweenTM in PBS. Mice were sacrificed by cervical dislocation at desired time points, and muscles excised for analysis
  • sections were blocked in 5% foetal calf serum in PBS for 30 mins.
  • the primary antibodies were diluted in blocking reagent and incubated on sections for 1.5 hrs in a humid chamber then washed three times for 5mins in PBS.

Abstract

L'invention porte sur des composés représentés par la formule générale (I) dans laquelle X1, X2, X3, R1, R2, R3, Y et Z sont tels que définis dans le descriptif. Lesdits composés s'utilisent pour le traitement et la prévention de la dystrophie musculaire de Duchenne, de la dystrophie musculaire de Becker et de la cachexie.
PCT/GB2008/002495 2007-07-23 2008-07-21 Composés pour traiter la dystrophie musculaire de duchenne WO2009013477A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP08776016A EP2167508A1 (fr) 2007-07-23 2008-07-21 Composés pour traiter la dystrophie musculaire de duchenne
CA002685599A CA2685599A1 (fr) 2007-07-23 2008-07-21 Composes pour traiter la dystrophie musculaire de duchenne
JP2010517478A JP2010534231A (ja) 2007-07-23 2008-07-21 デュシェンヌ型筋ジストロフィーを治療するための化合物
AU2008278824A AU2008278824A1 (en) 2007-07-23 2008-07-21 Compounds for treating Duchenne muscular dystrophy

Applications Claiming Priority (4)

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GB0714303.5 2007-07-23
GB0714303A GB0714303D0 (en) 2007-07-23 2007-07-23 Use of compounds for preparing anti-tuberculosis agents
GB0803906A GB0803906D0 (en) 2008-03-03 2008-03-03 Compounds for treating duchenne muscular dystrophy
GB0803906.7 2008-03-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001682A1 (fr) 2014-07-04 2016-01-07 Summit Therapeutics Plc Traitement de l'hypertransaminasémie

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040204461A1 (en) * 2003-04-11 2004-10-14 Karp Gary Mitchell 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2007019344A1 (fr) * 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Dérivés d’imidazo [2,1-b] thiayole en tant que modulateurs de sirtuine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040204461A1 (en) * 2003-04-11 2004-10-14 Karp Gary Mitchell 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2007019344A1 (fr) * 2005-08-04 2007-02-15 Sirtris Pharmaceuticals, Inc. Dérivés d’imidazo [2,1-b] thiayole en tant que modulateurs de sirtuine

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANDREANI A ET AL: "Synthesis and antitubercular activity of imidazo[2,1-b]thiazoles", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 36, no. 9, 1 September 2001 (2001-09-01), pages 743 - 746, XP004372885, ISSN: 0223-5234 *
BILLI R ET AL: "Ring-ring Interconversions. Part 2. Effect of the Substituent on the Rearrangement of 6-Aryl-3-methyl-5-nitrosoimidazo[2,1-b][1,3]thiazoles into 8-Aryl-8-hydroxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazo l-3-ones. A Novel Class of Potential Antitumor Agents", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 55, no. 17, 23 April 1999 (1999-04-23), pages 5433 - 5440, XP004223053, ISSN: 0040-4020 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1 July 2007 (2007-07-01), XP002502521, retrieved from STN Database accession no. 940584-48-5 *
MEKONNEN B ET AL: "A New and Facile Synthesis of Imidazo[2,1-b]oxazoles", JOURNAL OF HETEROCYCLIC CHEMISTRY, HETEROCORPORATION. PROVO, US, vol. 34, 1 January 1996 (1996-01-01), pages 589 - 599, XP002305535, ISSN: 0022-152X *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001682A1 (fr) 2014-07-04 2016-01-07 Summit Therapeutics Plc Traitement de l'hypertransaminasémie

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