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WO2003090750A1 - Inhibiteurs de tyrosine kinase de recepteur pdgf pour traiter la maladie de vaquez - Google Patents

Inhibiteurs de tyrosine kinase de recepteur pdgf pour traiter la maladie de vaquez Download PDF

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Publication number
WO2003090750A1
WO2003090750A1 PCT/IB2003/001632 IB0301632W WO03090750A1 WO 2003090750 A1 WO2003090750 A1 WO 2003090750A1 IB 0301632 W IB0301632 W IB 0301632W WO 03090750 A1 WO03090750 A1 WO 03090750A1
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WO
WIPO (PCT)
Prior art keywords
methyl
tyrosine kinase
receptor tyrosine
kinase inhibitor
pdgf receptor
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2003/001632
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English (en)
Inventor
Hagop Kantarjian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Texas System
University of Texas at Austin
Original Assignee
University of Texas System
University of Texas at Austin
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
Application filed by University of Texas System, University of Texas at Austin filed Critical University of Texas System
Priority to AU2003219420A priority Critical patent/AU2003219420A1/en
Publication of WO2003090750A1 publication Critical patent/WO2003090750A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • PDGF receptor tyrosine kinase inhibitors for the treatment of Polvcvthema Vera
  • the present invention relates to a method of treating warm-blooded animals, including humans, in which a therapeutically effective dose of a PDGF (platelet-derived growth factor) receptor tyrosine kinase inhibitor, especially of N- ⁇ 5-[4-(4-methyl-piperazino-methyl)- benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine or 4-[(4-methyl-1 - piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide in free form or in pharmaceutically acceptable salt form, said group of compounds hereinafter being referred to collectively as COMPOUNDS OF THE INVENTION, is administered to a warm-blooded animal suffering from polycythema vera (P. vera), and to a new use of a COMPOUND OF THE INVENTION in the manufacture of
  • P. vera is a chronic myeloproliferative disorder. Typically, the disease is characterized by panmyelosis, splenomegaly and a predisposition to venous/arterial thrombosis, myelofi- brosis and acute leukemia.
  • the principal tests used in the diagnosis of P. vera are the following: determination of the red cell volume, the serum erythropoietin level, the arterial blood gas, the leukocyte alkaline phosphatase score or the serum vitamin B 12 level. Further diagnostic means that can be employed are an abdominal computed tomography scan or a chest x-ray. Phlebotomy alone or phlebotomy in combination with the administration of hydroxy- urea constitutes the preferred approach of treating P. vera.
  • the phosphorylation of proteins has long been known as an important step in the differentiation and proliferation of cells.
  • the phosphorylation is catalysed by protein kinases which are divided into serine/threonine kinases and tyrosine kinases.
  • the PDGF receptor tyrosine kinase belongs to the group of tyrosine kinases.
  • STI571 and STI571 B or 4-[(4-methyl- 1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide decrease the activity of the PDGF receptor tyrosine kinase.
  • the present invention relates to a method of treating warm-blooded animals, including humans, in which a therapeutically effective dose of a COMPOUND OF THE INVENTION, is administered to a warm-blooded animal suffering from P. vera. ln particular, the present invention relates to a method of treating warm-blooded animals, including humans, in which a therapeutically effective dose of a is administered to a warm-blooded animal suffering from P. vera.
  • pharmaceutically acceptable salt includes, but is not limited to acid addition salts, for example, salts formed by reaction with an inorganic acid, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with a suitable organic carboxylic or sulfonic acid, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxy- maleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or with an amino acid such as arginine or lysine, an aromatic carboxylic acid, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, an aromatic-aliphatic carboxylic acid, such as mandelic acid or cinnamic acid, a heteroaromatic carb
  • PDGF receptor tyrosine kinase inhibitor includes, but is not limited to the compounds in particular generically and specifically disclosed in the patent applications EP 0564409 A1 and WO 99/03854, especially N- ⁇ 5-[4-(4-methyl-piperazino-methyl)- benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine or 4-[(4-methyl-1 - piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide and the monomesylate salt thereof, the compounds disclosed in WO 98/35958, especially the compound of Example 62, and the compounds disclosed in US 5,093,330, the subject- matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. Comprised are likewise the corresponding polymorphs,
  • treatment as used throughout the specification and in the appended claims is intended to embrace all forms of treatment a person skilled in the pertinent art will consider and includes e.g. preventive, curative and palliative treatment. It can be shown by established test models and especially a clinical study, e.g. as described by Jones, M. C, et al., Am J Med Sci 2003; 325(3): 149-152, that the COMPOUNDS OF THE INVENTION can be used for an effective treatment of P. vera.
  • COMPOUNDS OF THE INVENTION can be used for the manufacture of a medicament for the treatment of P. vera.
  • compositions for the treatment of P. vera comprise an effective amount of the COMPOUNDS OF THE INVENTION together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration, and may be inorganic or organic, solid or liquid.
  • pharmaceutically acceptable carriers suitable for topical, enteral, for example oral or rectal, or parenteral administration, and may be inorganic or organic, solid or liquid.
  • diluents for example lactose, dextrose, sucrose, mannitol, sorbi- tol, cellulose and/or glycerol, and/or lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Tablets may also comprise binders, for example magnesium aluminium silicate, starches, such as com, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavourings and sweeteners.
  • binders for example magnesium aluminium silicate, starches, such as com, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavourings and sweeteners.
  • the COMPOUNDS OF THE INVENTION
  • Such solutions are preferably isotonic aqueous solutions or suspensions, which, for example in the case of lyophilised compositions that comprise at least one COMPOUND OF THE INVENTION alone or together with a carrier, for example mannitol, can be prepared before use.
  • the pharmaceutical compositions may be sterilised and or may comprise excipi- ents, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • the present pharmaceutical compo- sitions are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and comprise approximately from 1 % to 100 %, especially from approximately 1 % to approximately 20 %, active ingredient(s).
  • a commercial package comprising a PDGF receptor tyrosine kinase inhibitor as described hereinbefore and hereinafter, especially N- ⁇ 5-[4-(4-methyl-piperazino-methyl)- benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine or 4-[(4-methyl-1 - piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide or a pharmaceutically acceptable salt thereof, together with instructions for the use thereof alone or in combination with phlebotomy in the treatment of P. vera is also contemplated to be part of the present invention.
  • N- ⁇ 5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2- pyrimidine-amine monomesylate or 4-[(4-methyl-1-piperazinyl)methyI]-N-[4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide monomesylate can, for example, be formulated as disclosed in Examples 4 and 6 of WO 99/03854. In particular, it can be employed in the present invention in the form marketed under the tradename G IVEC® or G EEVEC®.
  • the dosage range of the COMPOUNDS OF THE INVENTION to be employed depends upon factors known to the person skilled in the art including species of the warmblooded animal, body weight and age, the mode of administration, the particular substance to be employed and the disease to be treated. Unless stated otherwise herein, the COMPOUNDS OF THE INVENTION are preferably administered from one to four times per day.
  • the COMPOUNDS OF THE INVENTION are preferably administered to the warm-blooded animal in a dosage in the range of about 1 to 1000 mg/day, more preferably 50 to 500 mg/day and most preferably 25 to 250 mg/day, especially when the warm-blooded animal is a human of about 70 kg body weight.
  • Particularly preferred are dosages of 100, 200, 400 and 600 mg/day, respectively, depending e.g. on the over all condition of the patient to be treated and on the response to initial treatment.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le traitement de la maladie de Vaquez (polycythemia vera) par l'administration de N-{5-[4-(4-méthyl-pipérazino-méthyl)-benzoylamido]-2-méthylphényl}-4-(3-pyridyl)-2-pyrimidine-amine ou de 4-[(4-méthyl-1-pipérazinyl)méthyl]-N-[4-méthyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phényl]-benzamide dans leur forme libre ou sous forme de sel pharmaceutiquement acceptable.
PCT/IB2003/001632 2002-04-24 2003-04-22 Inhibiteurs de tyrosine kinase de recepteur pdgf pour traiter la maladie de vaquez Ceased WO2003090750A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003219420A AU2003219420A1 (en) 2002-04-24 2003-04-22 Pdgf receptor tyrosine kinase inhibitors for the treatment of polycythemia vera

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37514302P 2002-04-24 2002-04-24
US60/375,143 2002-04-24

Publications (1)

Publication Number Publication Date
WO2003090750A1 true WO2003090750A1 (fr) 2003-11-06

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2003/001632 Ceased WO2003090750A1 (fr) 2002-04-24 2003-04-22 Inhibiteurs de tyrosine kinase de recepteur pdgf pour traiter la maladie de vaquez

Country Status (2)

Country Link
AU (1) AU2003219420A1 (fr)
WO (1) WO2003090750A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006040779A3 (fr) * 2004-10-11 2006-08-17 Natco Pharma Ltd Formule à matrice flottante gastrique à libération contrôlée contenant la substance imatinib
US7094785B1 (en) * 2002-12-18 2006-08-22 Cornell Research Foundation, Inc. Method of treating polycythemia vera

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"GLEEVEC (STI-571) FOR CHRONIC MYELOID LEUKEMIA", MEDICAL LETTER ON DRUGS AND THERAPEUTICS, NEW ROCHELLE, NY, US, vol. 43, no. 1106, 11 June 2001 (2001-06-11), pages 49 - 50, XP001036570, ISSN: 0025-732X *
HASSELBALCH HANS CARL: "A possible role for STI571 in the treatment of idiopathic myelofibrosis.", AMERICAN JOURNAL OF HEMATOLOGY, vol. 68, no. 1, September 2001 (2001-09-01), pages 63 - 64, XP009013010, ISSN: 0361-8609 *
JONES C MICHAEL ET AL: "Polycythemia vera responds to imatinib mesylate.", THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES. UNITED STATES MAR 2003, vol. 325, no. 3, March 2003 (2003-03-01), pages 149 - 152, XP009013019, ISSN: 0002-9629 *
MARK H: BEERS AND ROBERT BERKOW (ED.): "The Merck Manual, 17th edition", 1999, MERCK RESEARCH LABORATORIES, WHITEHOUSE STATION, N. J., XP002245694 *
SILVER R T: "Imatinib mesylate (Gleevec(TM)) reduces phlebotomy requirements in polycythemia vera.", LEUKEMIA: OFFICIAL JOURNAL OF THE LEUKEMIA SOCIETY OF AMERICA, LEUKEMIA RESEARCH FUND, U.K. ENGLAND JUN 2003, vol. 17, no. 6, June 2003 (2003-06-01), pages 1186 - 1187, XP009013018, ISSN: 0887-6924 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7094785B1 (en) * 2002-12-18 2006-08-22 Cornell Research Foundation, Inc. Method of treating polycythemia vera
WO2006040779A3 (fr) * 2004-10-11 2006-08-17 Natco Pharma Ltd Formule à matrice flottante gastrique à libération contrôlée contenant la substance imatinib

Also Published As

Publication number Publication date
AU2003219420A1 (en) 2003-11-10

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