WO2005070432A1 - Utilisation d'inhibiteurs de pdgf-r tk pour le traitement de la myocardite et de ses complications - Google Patents

Utilisation d'inhibiteurs de pdgf-r tk pour le traitement de la myocardite et de ses complications Download PDF

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WO2005070432A1
WO2005070432A1 PCT/EP2005/000749 EP2005000749W WO2005070432A1 WO 2005070432 A1 WO2005070432 A1 WO 2005070432A1 EP 2005000749 W EP2005000749 W EP 2005000749W WO 2005070432 A1 WO2005070432 A1 WO 2005070432A1
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pdgf
myocarditis
compound
pharmaceutically acceptable
treatment
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PCT/EP2005/000749
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English (en)
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Carola Leipner
Frank-Dietmar Boehmer
Katja Gruen
Suraj Shivappa Shetty
Giorgio Massimini
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Novartis Ag
Novartis Pharma Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of a PDGF-R TK inhibitor, e.g. 4-(4-methylpiperazin-l-ylmethyl)-N-[4-methyl-3- (4-pyridin-3-yl)pyrirmdin-2-ylainino)phenyl]-benzamide, hereinafter referred to as "Compound I”, or a pharmaceutically acceptable salt thereof for the manufacture of pharmaceutical compositions for the treatment of myocarditis, to the use of a PDGF-R TK inhibitor, e.g.
  • Compound I or a pharmaceutically acceptable salt thereof in the treatment of myocarditis to a method of treating warm-blooded animals including mammals, especially humans, suffering from myocarditis by administering to a said animal in need of such treatment a dose effective against said disease of Compound I or a pharmaceutically acceptable salt thereof.
  • Myocarditis is an inflammation of the heart muscle.
  • Myocarditis is an uncommon disorder and can be caused by a variety of conditions such as virus, e.g. coxsackie virus, adenovirus and echovirus, sarcoidosis and immune diseases, e.g. systemic lupus, etc ., pregnancy and others, e.g. various viral, bacterial or parasitic infections, e.g. rubella, influenza.
  • the condition may be caused by exposure to chemicals or allergic reactions to c ertain medications and it can be associated with auto-immune diseases.
  • the most common cause of myocarditis is infection of the heart muscle by a virus. It is believed that the virus causes the initial muscle inflammation. After viral infection subsides, the body's immune system continues to inflict inflammatory damage on the heart muscles, prolonging the myocarditis, a process called auto-immunity.
  • DCM dilated cardiomyopathy
  • DCM may at least partially develop as a consequence of myocarditis.
  • Human pathogenic coxsackie virus B3 (CVB3) is considered the most frequent viral cause of myocarditis.
  • Acute myocarditis as a consequence of CVB3 infection is either followed by complete healing or by transition to progressive illness with an increase of connective tissue in the heart muscle, i.e. fibrosis.
  • This process of fibrosis is characteristic for the chronic stage of viral myocarditis and also an important aspect of DCM.
  • the mechanism of fibrosis development in chronic myocarditis and DCM is currently not well understood.
  • the prognosis for long term damage is not predictable.
  • the complications of myocarditis include cardiac remodelling and hypertrophy, left ventricular dysfunction, QT prolongation, dyspnea, angina, pericarditis, dilated cardiomyopathy and heart failure.
  • the QT interval represents the time for electrical activation and inactivation of the ventricles, the lower chambers of the heart.
  • a doctor can measure the time it takes for the QT interval to occur , e.g. in fractions of a second, and can tell if it occurs in a normal amount of time. If it takes longer than normal, it's called a QT prolongation.
  • platelet-derived growth factor receptor tyrosi e kinase inhibitors herein after abbreviated as PDGF-R TK inhibitors, are particularly useful for the treatment of myocarditis.
  • a PDGF-R TK inhibitor is meant a drug which interferes with the enzymatic activity of the tyrosine kinase of the receptor of the platetet-derived growth factor, e.g. by blocking the ATP binding site, by blocking the access of the substrate to the substrate binding site.
  • the PDGF-R TK inhibitors are not limited to the following compounds: 4-(4-methylpiperazin-l-ylmefhyl)-N-[4- me yl-3-(4-pyrid -3-yl) ⁇ yrin ⁇ idm-2-ylamino)phenyl]-benzamide, herein after referred as Compound I, an inhibitor of PDGF-receptor isoforms, Bcr-Abl, and c-Kit, which stands out by high potency, and oral availability; Bis(l -2-indolyl)-l-methanones another class of tyrosine kinase inhibitors which have been characterized as PDGF-R TK inhibitors as described in Mahboobi S et al, J.
  • CT52923 (4-(6,7-dimethoxy-4- quinazol yl)-N-(3,4-mefhylenedioxybenzyl)-l- ⁇ iperazinethiocarboxamide); RP-1776; GFB-111; pyrrolo[3,4-c]- beta-carboline-diones, SU 102 (developed by SUGEN); AG1296 having the CAS Number 146535-11-7; RPR101511 A developed by Aventis Pharma; CDP 860 and Zvegf3 developed by ZymoGenetics; CP 673451 and PD 170262 from Pfizer; KI 6783, having the CAS number 190726-45-5, an inhibitor of PDGF-R developed by Kirin Brewery, Japan; KN 1022 developed by Kyowa Hakko in Japan and Millenium Pharmaceuticals in US; AG 13736 developed by Pfizer; CHIR 258 developed
  • CT52923 has been described by Matsuno K, et al., "Synthesis and structure activity relationships of PDGF receptor phosphorylation inhibitor-1.” in 18th Symposium on Medicinal Chemistry; 1998 Nov 25-27; Kyoto, Japan, the Pharmaceutical Society of Japan, Division of Medicinal Chemistry, Tokyo, Japan : Abstract 2-P-05.
  • RP-1776 a cyclic peptide, was isolated from the culture broth of Streptomyces sp. KYI 1784. It is described, e.g. by Toki S, Agatsuma T, et al, J. Antibiot. (Tokyo) 2001 May;54(5):405-14.
  • GFB-111 is described, e.g. in Blaskovich MA et al, Nat. Biotechnol. 2000 Oct;18(10):1065-70 and in Delarue F. et al, 91 st Annual meeting of the American Association for Cancer research, 41:458, 2000.
  • CDP 860 is a pegylated antibody fragment derived from the human anti-platelet derived growth factor beta receptor antibody.
  • CP 673451 targets the PDGF receptor.
  • PD 170262 or 2-[4-(2-dietWaminoelhoxy)phenylamino]-8-methyl-6-(3-thienyl)pyrido[2,3-d] pyrimidin-7(8H)- one is a potent inhibitor of tyrosine kinase with selectivity for the platelet -derived growth factor tyrosine kinase.
  • Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8H-pyrido[2,3-d] pyrimidines is described, e.g. in Klutchko S. et al., 213 th American Chemical Society National meeting: abst. MEDI 201 (poster), 1997, USA.
  • AG 013736 or N-methyl-2-[3-[2-(2-pyridyl)vinyl]-lH-indazole-6-ylsulfanyl]-benzamide is disclosed, e.g. in Heller et al., Pharmacological activities of AG 013736, a small molecule inhibitor of V ⁇ GF/PDGFR tyrosine kinases, 93 rd Annual meeting f the American association for Cancer research 43:1082, 2002, USA.
  • CHER.258 is an orally active amino-benzimidazole quinoline growth factor kinase inhibitor which demonstrated a spectrum of inhibitory activity against receptor tyrosine kinases, e.g. from the PDGFR family.
  • CHIR 258 is disclosed, e.g. in Steigerwalt R et al. and Lee SH et al. in 94 th Annual Meeting of the American Association for Cancer Research 753(plus poster) abstr. 3783 and 934 (plus poster) abstr. R4702, respectively, 2003, USA.
  • SU11248 or 5-[3-fluoro-2-oxo-l ,2-dihydxoindol-(3Z)-ylidenemethyl]-2,4-dimethyl-lH-pyrrole-3-carboxylic acid(2-die ylaminoethyl)amine is multiple targeted kinase inhibitor with selectivity for, e.g. PDGFR.
  • SU11248 is disclosed, e.g. in Xin L. et al., 93 rd Annual Meeting of the American Association for Cancer Research 43:1081 (plus poster), 2002, USA.
  • SU6668 or (Z)-3- [2,4-Dimethyl-5-(2-oxo-2,3-dihydro- -indol-3-yUdenemethyl)-l-i : - ⁇ yrrol-3-yl] propionic acid is an anti-angiogenic and cytostatic agent developed by SUGEN (Pfizer) for the potential treatment of cancer. It targets, inter alia, the platelet derived growth factor (PDGF) receptor. It is described in e.g. Thurnher A, Liang C, Shawver LK, Laird AD, et al. Cancer Research. 60: 4152-4160, 1 Aug 2000. USA.
  • PDGF platelet derived growth factor
  • MLN 518 is a piperazinyl derivative of quinazoline of formula 4 ⁇ [4-(N-para-iso-propoxyphenylcarbamoyl)-l- piperazinyl]-6-methoxy-7-( ⁇ iperidinopropyloxy)-quinazoline that inhibits, e.g. PDGF R phosphorylation in binding assays, it is described, e.g. by Stone RM et al., Blood 102:65-66, 2003, Kelly LM et al., Cancer Cell 1: 421-23, 2002.
  • Compound I is 4-(4-memylpiperazm-l-ylmefl ⁇ yl)-N-[4-memyl-3-(4-pyridm-3-yl)pyrimimh-2-ylammo)phenyl ⁇ benzamide having the following formula
  • Compound I free base is disclosed in the European granted patent 0564409, hereby incorporated by reference.
  • Compound I free base corresponds to the active moiety.
  • Compound I is an inhibitor of platelet-derived growth factor receptors alpha and beta (PDGFRs ⁇ and ⁇ ), Bcr- Abl and c-kit tyrosine kinases.
  • Salt I The monomethanesulfonic acid addition s alt of Compound I , hereinafter referred to as "Salt I", crystal forms thereof, e.g. the alpha crystal form and the beta crystal form, e.g. a preferred crystal form thereof, e.g. the beta crystal form, are described in PCT patent application WO99/03854 published on January 28, 1999, hereby incorporated by reference.
  • the invention relates to the use of a PDGF-R TK inhibitor, e.g. Compound I, or a pharmaceutically acceptable salt thereof, as a drug against myocarditis.
  • a PDGF-R TK inhibitor e.g. Compound I
  • the invention relates in the use a PDGF-R TK inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of myocarditis.
  • the present invention pertains to the use of a PDGF-R TK inhibitor or a pharmaceutically acceptable salt thereof for the prevention or treatment of complications of myocarditis.
  • the present invention pertains to the use of a PDGF-R TK inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of complications of myocarditis.
  • the present invention relates to the use of a PCGF-R TK inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of myocarditis and/or prevention or treatment of complications of myocarditis that are not induced or attributed to an activated renin-angiotensin system.
  • the present invention pertains to the use of a PDGF-R TK inhibitor selected from the group comprising Compound 1, Bis(l#-2-indolyl)-l-methanones , AG1295, AG1296, CT52923, RP-1776, GFB-111, pyrrolo[3,4- c]-beta-carboline-diones, SU 102, RPR101511A, CDP 860, Zvegf3, CP 67345, PD 170262, KI 6783, KN 1022, AG 13736, CHIR 258, MLN 518, SU6668 and SU 11248, or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of myocarditis and/or of its complications.
  • a PDGF-R TK inhibitor selected from the group comprising Compound 1, Bis(l#-2-indolyl)-l-methanones , AG1295, AG1296, CT52923, RP-1776, G
  • the present invention pertains to the use of a PDGF-R TIC inhibitor for the preparation of a medicament for the treatment of pericarditis.
  • the PDGFR-TK inhibitor is Compound I or a pharmaceutically acceptable salt thereof, e.g. the monomethane sulfonate salt thereof.
  • the monomethane sulfonate salt of Compound I is in the beta crystal form.
  • compositions according to the present invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to warm-blooded animals, including man, comprising a therapeutically effective amount of at least one pharmacologically active ingredient, alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.
  • enteral such as oral or rectal
  • parenteral administration to warm-blooded animals, including man
  • the preferred route of administration of the dosage forms of the present invention is orally.
  • the invention relates to a method of treating a warm-blooded animal having myocarditis comprising administering to said animal in need for such a treatment a PDGF-R TK inhibitor, e.g. a PDGF-R TK inhibitor selected from the group comprising Compound 1, Bis(l -2-indolyl)-l-methanones , AG1295, AG1296, CT52923, RP-1776, GFB-111, pyrrolo[3,4-c]-beta-carboline-diones, SU 102, RPR101511A, CDP 860, Zveg ⁇ , CP 67345, PD 170262, KI 6783, KN 1022, AG 13736, CHIR 258, MLN 5 18, SU6668 and SU 1 1248 or a pharmaceutically acceptable salt thereof, in a quantity which is therapeutically effective against myocarditis.
  • a PDGF-R TK inhibitor selected from the group comprising Compound 1,
  • the invention relates to a method of treating a warm-blooded animal having myocarditis comprising administering to s aid animal in need for such a treatment, C ompound I or a pharmaceutically acceptable salt thereof, in a quantity which is therapeutically effective against myocarditis.
  • the invention relates to a method of treating the complications of myocarditis or preventing the complications of myocarditis, e.g. cardiac remodelling and hypertrophy, left ventricular dysfunction, QT prolongation, myocellular necrosis, dyspnea, angina, pericarditis, anhythmia, stroke, cardiomyopathy including dilated cardiomyopathy and heart failure, of a warm-blooded animal comprising administering to said animal in need for such a treatment Compound I or a pharmaceutically acceptable salt thereof, in a quantity which is therapeutically effective against said complications.
  • cardiac remodelling and hypertrophy left ventricular dysfunction
  • QT prolongation myocellular necrosis
  • dyspnea dyspnea
  • angina pericarditis
  • anhythmia anhythmia
  • stroke cardiomyopathy including dilated cardiomyopathy and heart failure
  • the present invention also pertains to the use of a PDGF-R TK inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament for tihe treatment and/or prevention of heart fibrosis.
  • a PDGF-R TK inhibitor or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for the treatment and/or prevention of heart muscle fibrosis.
  • myocarditis inflammation of the heart muscle, e.g. viral-caused myocarditis, e.g. adenovirus, echovirus, coxackie-virus, e.g. CVB3-caused myocarditis.
  • viral-caused myocarditis e.g. adenovirus, echovirus, coxackie-virus, e.g. CVB3-caused myocarditis.
  • myocarditis by complications of myocarditis is meant the diseases deriving from myocarditis, e.g. cardiac remodelling and hypertrophy, left ventricular dysfunction, QT prolongation, myocellular necrosis, dyspnea, angina, pericarditis, arrhythmia, stroke, cardiomyopathy including dilated cardiomyopathy and heart failure.
  • myocarditis e.g. cardiac remodelling and hypertrophy, left ventricular dysfunction, QT prolongation, myocellular necrosis, dyspnea, angina, pericarditis, arrhythmia, stroke, cardiomyopathy including dilated cardiomyopathy and heart failure.
  • the invention relates to a method for administering to a human subject suffering from myocarditis an acid addition salt of 4-(4-memylpiperazin-l-ylmethyl)-N-[4-memyl-3-(4- ⁇ yridin-3-yl)pyrin ⁇ din-2-ylamino)phenyl]- benzamide and preferably Salt I, the monomethanesulfonate salt of Compound I.
  • the person skilled in the pertinent art is fully enabled to select relevant test models to prove the beneficial effects mentioned herein on myocarditis.
  • the pharmacological activity of such a compound may, for example, be demonstrated by means of the Examples described below, by in vitro tests and in vivo tests or in suitable clinical studies. Suitable clinical studies are, for example, open label non-randomized, dose escalation studies in patients with myocarditis. The efficacy of the treatment is determined in these studies, e.g. by evaluation of the disease every 4 weeks.
  • the present invention relates in one embodiment to the use of a PDGP-R TK inhibitor, e.g. a PDGF-R TK inhibitor selected from the group comprising Compound 1, Bis(l -2-mdolyl)-l-methanones , AG1295, AG1296, CT52923, RP-1776, GFB-111, pyrrolo[3,4-c]-beta-carboline-diones, SU 102, RPR101511A, CDP 860, Zveg ⁇ , CP 67345, PD 170262, KI 6783, KN 1022, AG 13736, CHIR 258, M LN 5 18, SU6668 and SU 1 1248 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of myocarditis or myocartis complications, that are not attributed or linked or due to an activated renin-angiotensin system.
  • a PDGP-R TK inhibitor selected from the group
  • the effective dosage of Compound I may vary depending on the particular compound or pharmaceutical composition employed, on the mode of administration, the type of the myocarditis being treated or its severity.
  • the dosage regimen is selected in accordance with a variety of further factors including the renal and hepatic function of the patient. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of compounds required to prevent, counter or arrest the progress of the condition.
  • effective doses for example daily doses of Compound I or a pharmaceutically acceptable salt thereof corresponding to 100 to 1000 mg of the free base as active moiety, e.g. 400 to 800 mg, e.g. 4O0 mg, 600 mg, 800 mg, especially 600 mg, are administered to warm-blooded animals of about 70 kg body weight.
  • the warm-blooded animal is a human.
  • dose escalation can be safely considered and patients may be treated as long as they benefit from treatment and in the absence of limiting toxicities.
  • the present invention relates to use of Compound I for the preparation of a medicament for the treatment or prevention of myocarditis and or its complications, wherein Compound I is administered at a daily dose corresponding to 100 mg to 1000 mg of Compound I free base.
  • the invention relates also to a method for administeriiig to a human subject suffering from myocarditis, Compound I or a pharmaceutically acceptable salt thereof, which comprises administering a pharmaceutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to the human subject once daily for a period exceeding 3 months.
  • the invention relates especially to such method wherein a daily dose of 100 to 1000 mg, e.g. 400 to 800 mg, e.g. 400 mg, 600 mg, 800 mg, preferably 800 mg, of Compound I is administered to an adult.
  • Example I The PDGF receptor as a candidate target in chronic myocarditis
  • Elevated expression of different isoforms of the platelet-derived growth factor (PDGF) including PDGF-C correlate with the chronic inflammatory process according to data obtained in previous experiments.
  • Transgenic expression of PDGF-C in the myocard results in massive cardiac fibrosis.
  • Activation of PDGF receptors may be causally related to myocardial fibrosis development.
  • a mouse model of CVB3-induced chronic myocarditis is used to test selective PDGF receptor kinase inhibitors as a potential novel treatment modality for the prevention and attenuation of fibrosis.
  • CVB3-induced myocarditis depends on the immune status of appropriate mouse recipient models, as well as on the virus variant used for infection. Further modifying factors are modulators of the immune response, such as lipopolysacchari.de, IL-1, or TNF- ⁇ . These molecules have also themselves the potential of inducing chronic myocarditis. Overexpression of TNF- ⁇ in heart of transgenic mice leads to severe myocarditis and cardiomegaly.
  • CVB3-induced myocarditis is regarded by many as an autoimmune process, it is still a matter of controversy whether virus persistency or cross reactivity of T-cells (molecular mimicry) without virus persistence is the basis for the disease process.
  • the expression of a cDNA coding for restrained CVB3 in the myocard of transgene mice is sufficient for triggering myocardial fibrosis.
  • Fibrosis of the myocardium as a consequence of chronic inflammation. Fibrosis in general is characterised by substantial proliferation of resident fibroblasts with subsequent deposition of extracellular matrix c omponents, like collagen, fibronectin as well as tenascin. Both processes, proliferation as well as matrix protein synthesis by fibroblasts, are stimulated by a set of cytokines, including TGF- ⁇ , TNF- ⁇ , IL-1 and PDGF. Substantial sources of these growth factors are immune cells invading the tissue upon inflammation. Isoforms of the PDGF family are potent mitogens for fibroblasts and other mesenchymal cells.
  • PDGF Different forms of PDGF are synthesised in inflammatory cells, including macrophages.
  • the PDGF family comprises several disulfide-linked dimeric growth factors including PDGF-AA, -BB, -AB and the more recently discovered molecules PDGF-C and PDGF-D.
  • There activity is exerted by activation of PDGF receptor (R) - ⁇ or PDGF receptor (R) - ⁇ , two structurally related receptor tyrosine kinases (RTKs).
  • R PDGF receptor
  • R PDGF receptor
  • R two structurally related receptor tyrosine kinases
  • Investigations in different tissues have suggested an important role for the PDGF-system in fibrotic processes including fibrosis of lung and kidney.
  • Application of PDGF-RTK blockers in an experimental model of interstitial kidney fibrosis in rats has been shown to reduce fibrosis.
  • MHC class II knockout mice are infected with the CVB3 virus variant M ⁇ /J (Nancy strain) and compared them with immunocompetent C57BL/6 mice (identical genetic background).
  • CVB3-M ⁇ /J induces acute myocarditis with pronounced cell-infiltration, healing completely in immunocompetent C57BL/6 mice within three weeks after infection.
  • the MHC class II knockout mice develop a chronic myocarditis with pronounced areas of infiltrating inflammatory cells and a severe fibrosis of the heart muscle.
  • Virus load is identical in the myocardium of both mouse strains on day 7 after infection.
  • C57BL/6 mice completely eliminate the virus from the heart until day 14 p .
  • the virus persists in the hearts of MHC class II deficient mice up to day 56 p.i.
  • MHC class II knockout mice succeed, however, in eliminating replicating viruses from pancreas, spleen and serum.
  • This mouse model is suitable for examining mechanisms of the CVB3-related fibrosis.
  • the expression of selected growth factors and cytokines in the myocard is analysed using s emi quantitative RT-PCR. S everal cytokines, including TNF- ⁇ , IL-l ⁇ and IFN- ⁇ exhibit an elevated expression at day 7 after CVB3 infection.
  • the expression levels of the three examined PDGF-isoforms correlate positively with the inflammation.
  • the expression of PDGF-C is further analysed by in-situ-hybridisation and is localized to the infiltrates of inflammatory cells. Similar data are obtained in other immunodeficient mouse strains (data not shown).
  • a key condition for efficacy of Compound I in treating myocarditis is to reach a sufficient inhibitor concentration in the cardiac tissue.
  • Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I is applied under a range of conditions: at two different doses (50 and 200 mg/kg, respectively or 50 and 150 mg/kg, respectively), for periods of 1, 2 and 3 days, once or twice daily. These treatments are done both with uninfected and CVB3 infected mice during the acute phase.
  • Compound I is extracted from the cardiac tissue under conditions established at Novartis. The Compound I amount in the tissue is determined by bioassay, using titration of the extracted material in an in vitro assay of PDGFR phosphorylation in murine fibroblasts (see below, method a). Alternatively, samples, e.g.
  • mice are treated under conditions established above as suitable to reach a sufficient cardiac Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I, concentration for up to 3 weeks to monitor for a possible toxicity. The weight of the mice is followed up and the mice are subjected to a gross pathological inspection upon termination of treatment. Expression of PDGF-isoforms is elevated upon inflammation of the cardiac tissue.
  • the biological activity of the PDGF/PDGFR system is studied by the following approaches: a) To monitor the activity of the PDGFR in the tissue, PDGFR-immunoprecipitates, e.g. using antibodies to PDGFR, are obtained and the PDGFR phosphorylation level is analysed by immunoblotting, e.g. using anti-pTyr antibodies.
  • mice for type a) experiments are taken from day 7, i.e. corresponding to the acute phase, and 21, i.e. corresponding to the chronic phase, after CVB3 infection since previous experiments show an elevated PDGF level during this period of myocarditis.
  • b) In addition, the possibility to detect PDGFR activity by stimulating PDGFRs in cardiac tissue extracts using exogenous PDGF is explored. While this assay does not allow detecting the in situ activation status directly, it permits to momtor efficacy of Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I, treatment. If sufficient concentrations are reached in the heart, activation should no be longer possible. Mice from the toxicity experiment and corresponding controls are subjected to this type of analysis.
  • fibrosis in cardiac tissue has been reliably detected by Sirius red staining. Fibrosis in cardiac tissue is also explored using earlier fibrosis markers.
  • a suitable marker e.g. a marker different from those which are associated with granulation, since the latter process will always take place in the myocards of CVB3 infected hearts in the context of healing.
  • Real Time-PCR protocol is established to detect fibrosis marker mRNA expression. This protocol allows to monitor the effect of Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I, treatment on the development of fibrosis. Phase II. Test of a principal efficacy of Compound I against cardiac fibrosis
  • Compound I has efficacy against fibrosis development in a standard protocol. This includes: • application of Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I, from day 1 p.L, the earliest possible time-point • use of the maximal tolerable dose defined in Phase I versus solvent control • evaluation of cardiac tissue at day 21 for fibrosis, or with at least one suitable earlier reliable marker of fibrosis could be defined.
  • a pharmaceutically acceptable salt thereof e.g. Salt I
  • Four treatment groups comprise: 1) non-infected control, solvent 2) non-infected control, compound, 3) infected animals, solvent, 4) infected animals, compound
  • mice In the clinical setting, patient treatment is not normally possible before a chronic stage of myocarditis is already established. Therefore, this situation shall be approximated in the animal experiments.
  • the treatment of mice is performed at two different time intervals: from day 7 - 21, and from day 21 - 56 after infection. The latter period has to be included since earlier studies have confirmed that the development of fibrosis is still progressive at late stages of infection. Moreover, it is not known, to what extent the fibrosis at late time-points may be reversible.
  • the used dose-range depends on the limits established in pb ase I.
  • the treatment schedule is as described in phase
  • This phase includes work on the mechanism of both fibrosis induction and Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I.
  • Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I.
  • expression analysis of inflammatory cytokines is performed. Different types of c ross-talk b etween PDGFR and cytokines have b een reported.
  • a method to eliminate virus by injection of neutralizing IgG has been developed recently and is applied to study whether the fibrosis at late time points is still maintained by the virus burden or has become an autonomous process.
  • Compound I or a pharmaceutically acceptable salt thereof, e.g. Salt I, is useful for the treatment of myocarditis and its complications and for treatment of myocardial fibrosis,
  • Example 2 Capsules with 4-[f4-methvI-l-piperazin-l- ⁇ l ⁇ ethyl)-N-r4-methyl-3-f[4-(3-pyridinvI)-2- pyrin ⁇ dinyllaminolnhenyllbenzamide methanesulfonate. beta crystal form
  • Capsules containing 119.5 mg of Salt I corresponding to 100 mg of Compound I (free base) as active moiety are prepared in the following composition:
  • composition Salt I 119.5 mg Avicel 200 mg PVPPXL 15 mg Aerosil 2 mg Magnesium stearate 1.5 mg
  • the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1 -

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  • Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un inhibiteur de PDGF-R TK, par ex. de 4-(4-méthylpipérazine-1-ylméthyl)-N-[4-méthyl-3(4-pyridine-3-yl)pyrimidine-2-ylamino)phényl]-benzamide ou d'un de ses sels pharmaceutiquement acceptables, pour la fabrication de compositions pharmaceutiques destinées au traitement de la myocardite et de ses complications.
PCT/EP2005/000749 2004-01-27 2005-01-26 Utilisation d'inhibiteurs de pdgf-r tk pour le traitement de la myocardite et de ses complications WO2005070432A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0401761.2 2004-01-27
GBGB0401761.2A GB0401761D0 (en) 2004-01-27 2004-01-27 Organic compounds

Publications (1)

Publication Number Publication Date
WO2005070432A1 true WO2005070432A1 (fr) 2005-08-04

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PCT/EP2005/000749 WO2005070432A1 (fr) 2004-01-27 2005-01-26 Utilisation d'inhibiteurs de pdgf-r tk pour le traitement de la myocardite et de ses complications

Country Status (2)

Country Link
GB (1) GB0401761D0 (fr)
WO (1) WO2005070432A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003077892A2 (fr) * 2002-03-15 2003-09-25 Novartis Ag 4-(4-methylpiperazin-1-ylmethyl)-n-[4-methyl-3(4-pyridin-3-yl)pyrimidin-2-yl-amino)phenyl]-benzamide pour le traitement de maladies induites par l'angiotensine ii

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003077892A2 (fr) * 2002-03-15 2003-09-25 Novartis Ag 4-(4-methylpiperazin-1-ylmethyl)-n-[4-methyl-3(4-pyridin-3-yl)pyrimidin-2-yl-amino)phenyl]-benzamide pour le traitement de maladies induites par l'angiotensine ii

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ASCIONE L ET AL: "Reversal of cardiac abnormalities in a young man with idiopathic hypereosinophilic syndrome using a tyrosine kinase inhibitor", EUROPEAN JOURNAL OF ECHOCARDIOGRAPHY, HARCOURT PUBLISHERS, EDINBURGH, GB, vol. 5, no. 5, October 2004 (2004-10-01), pages 386 - 390, XP004541182, ISSN: 1525-2167 *
KAZAMA RYU ET AL: "Therapeutic role of pericardiocentesis for acute necrotizing eosinophilic myocarditis with cardiac tamponade.", MAYO CLINIC PROCEEDINGS. JUL 2003, vol. 78, no. 7, July 2003 (2003-07-01), pages 901 - 907, XP009046300, ISSN: 0025-6196 *
ROTOLI BRUNO ET AL: "Rapid reversion of Loeffler's endocarditis by imatinib in early stage clonal hypereosinophilic syndrome.", LEUKEMIA & LYMPHOMA. DEC 2004, vol. 45, no. 12, December 2004 (2004-12-01), pages 2503 - 2507, XP009046316, ISSN: 1042-8194 *

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