Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • 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 products or combinations comprising an abl-, PDGF-Receptor- and/or Kit receptor-tyrosine kinase inhibitor with an organic compound capable of binding to oti-acidic glycoprotein, either in fixed combination or for chronologically staggered or simultaneous administration, and the combined use of both classes of compounds, either in fixed combination or for chronologically staggered or simultaneous administration, for the treatment of proliferative diseases, especially tumor diseases, especially those that can be treated by inhibition of abl-, PDGF-Receptor- and/or Kit receptor- tyrosine kinase activity.
• the resistance against a tyrosine kinase inhibitor may be due to AGP binding and thus lower free concentration of the active drug in blood plasma forms a basis for the search for a solution, be it by way of stopping a regulatory molecule, e.g.
• the definitions of the substituents given above have the meanings, especially the preferred meanings, described in International Patent Application WO 97/02266.
• Most preferred of these compounds is the compound of the formula VII having the name (R)-6-(4-hydroxy-phenyl)-4-[(1-phenylethyl)-amino]-7H-pyrrolo[2,3- djpyrimidine; or most preferred
• X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino
• Y is oxygen or the group NH
• n is 0 or 1 and
• R 10 is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic- aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, and the remaining radicals R , R 5 , R 6 , R and R 8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy, or a salt of such compounds having at least one salt-forming group.
• the definitions of the substituents given above have the meanings, especially the preferred meanings, described in European Patent Application EP 0 564409. Most preferred of these compounds is the compound of the formula III
• the parts of the kit of parts can then be administered simultaneously or in a chronologically staggered manner, that is at different time points and with equal or different time intervals for any part of the kit of parts, with the condition that the time intervals are chosen such that the effect on the proliferative disease in the combined use of the parts is larger than the effect which would be obtained by use of only component (a), that is, stronger inhibition of proliferation or, preferably, stronger regression or even cure of the proliferative disease is found than when the same dose of only component (a) is administered alone.
• Salts are especially the pharmaceutically acceptable, e.g. substantially non-toxic, salts.
• a combination preparation comprising (a) at least one abl-, PDGF-R- and/or Kit receptor- tyrosine kinase inhibitor and (b) at least one organic compound capable of binding to ⁇ -r acidic glycoprotein (AGP); or pharmaceutically acceptable salts of any component (a), (b) or
• a pharmaceutical composition or combination that is suitable for administration to a warm-blooded animal, especially a human, suffering from any disease mentioned herein; preferably any disease is meant that responds to an abl-, PDGF-R- and/or Kit receptor-tyrosine kinase inhibitor; especially, a proliferative disease selected from a cancer disease, especially a tumor disease or leukemia, or a non-malignant proliferative disease, e.g.
• compositions are prepared in a manner known perse, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
• pharmaceutical compositions for oral administration can be obtained by combining component (a) and/or (b) with one or more solid or liquid carriers, where necessary granulating a resulting mixture and processing the mixture or the granules, if desired or appropriate with the addition of further excipients, to form tablets or drag ⁇ e cores or solutions, respectively.
• Suitable carriers are especially fillers, such as sugars, e.g. lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starches, e.g. corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, and also carboxymethyl starch, crosslinked polyvinylpyrrolidone or alginic acid or a salt thereof, such as sodium alginate.
• fillers such as sugars, e.g. lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate
• STI571 (formerly known as CGP57148) represents an active and relatively specific inhibitor of bcr/abl kinase activity. STI571 blocks proliferation and induces apoptosis in BCR/ABL+ cells in vitro; it inhibits the growth of clonogenic bone marrow cells obtained from CML patients, and can eradicate leukemic cell growth in vivo. The activity of STI571 in vivo is conditioned to the achievement of stable and continuous bcr/abl inhibition, which requires multiple daily administrations in the murine model which was studied (le Coutre et al., J. Natl. Cancer Inst. 91, 163-168 (1999)).
• Cell lysates corresponding to 90,000 -150,000 cells, are boiled at 95 °C for 10 minutes, sonicated for 1 minute and analysed by SDS Gel Electrophoresis on 7.5% polyacrylamide gels.
• Endogenous bcr/abl, tyrosinephosphorylated bcr/abl and the endogenous actin are detected with the corresponding mouse monoclonal antibody or rabbit antiserum and then visualised by enhanced chemiluminescence detection (ECL, Amersham Corp.) using horseradish peroxidase-linked goat anti-mouse or anti-rabbit immunoglobulin G as the secondary antibody (Amersham Corp.).
• ECL enhanced chemiluminescence detection
• the monoclonal anti-abl antibody (Clone Ab-3) is purchased from Calbiochem.
• Plasma or purified human AGP (Sigma) or Albumin (diluted in PBS) are incubated with various STI571 concentrations at room temperature for 30 min.
• STI571 concentrations are determined by HPLC, with a lower limit of detection of 0.1 ⁇ M.
• Free STI571 is determined by ultrafiltration with a cut off at 30 KD. Modified Scatchard plots are constructed.
• the Association Constant (Ka) is calculated as previously described (Fuse E, Tanii H, Kurata N et al., Cancer Res., 58, 3248-53, 1998).
• Fig. 1 A shows the results of a representative experiment. While all animals in group I are reproducibly cured, mice in group II develop between 33% and 40% relapses; no cure is ever observed in group III. Relapses usually develop 1 to 3 weeks after treatment discontinuation.
• Fig. 1 B presents the combined results from 3 different experiments. A clear relationship between the amount of tumor present at the beginning of treatment and the outcome of the therapy is evident. A possible explanation for these results could reside in the insufficient length of STI571 administration in group II and III. To test this hypothesis mice in group II are treated for 11 or 18 days. The result of one representative experiment is shown in Fig. 1C and indicates that increasing the duration of treatment does not ameliorate the cure rate.
• Example 5 Relationship among AGP serum levels, tumor load and STI571 treatment
• AGP an inducible plasma protein
• the plasma levels of AGP are determined in nude mice at various stages of disease by immunodiffusion, to assess whether those values can be associated to the in vivo sensitivity of KU812 leukemic cells to STI571 treatment.
• Fig. 8A presents the AGP values in mice in various stages of disease. Basal AGP values in mice are very low (96 ⁇ 21 ⁇ g/ml). AGP concentrations rise proportionally to the tumor load present.
• Aerosil 200 pure silica gel (surface area according to BET 200 ⁇ 25 m 2 /g. mean grain size 12 nm).

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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Hematology (AREA)
• Dermatology (AREA)
• Oncology (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Diabetes (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Saccharide Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Cited By (29)

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• 1999
  • 1999-12-27 IT IT1999MI002711A patent/ITMI992711A1/it unknown
• 2000
  • 2000-12-08 TW TW089126229A patent/TWI246917B/zh active
  • 2000-12-22 EP EP00985244A patent/EP1250140B1/en not_active Expired - Lifetime
  • 2000-12-22 AU AU21719/01A patent/AU2171901A/en not_active Abandoned
  • 2000-12-22 WO PCT/EP2000/013161 patent/WO2001047507A2/en not_active Ceased
  • 2000-12-22 HK HK03101801.4A patent/HK1050993A1/zh unknown
  • 2000-12-22 AT AT00985244T patent/ATE432069T1/de active
  • 2000-12-22 US US10/169,035 patent/US20030125343A1/en not_active Abandoned
  • 2000-12-22 PE PE2000001393A patent/PE20010991A1/es not_active Application Discontinuation
  • 2000-12-22 DE DE60042283T patent/DE60042283D1/de not_active Expired - Lifetime
  • 2000-12-22 CA CA002394944A patent/CA2394944A1/en not_active Abandoned
  • 2000-12-22 PT PT00985244T patent/PT1250140E/pt unknown
  • 2000-12-22 BR BR0016817-3A patent/BR0016817A/pt not_active Application Discontinuation
  • 2000-12-22 CN CNB008178976A patent/CN1304005C/zh not_active Expired - Fee Related
  • 2000-12-22 AR ARP000106887A patent/AR030179A1/es not_active Application Discontinuation
  • 2000-12-22 CO CO00097404A patent/CO5271710A1/es not_active Application Discontinuation
  • 2000-12-22 ES ES00985244T patent/ES2326307T3/es not_active Expired - Lifetime
  • 2000-12-22 JP JP2001548102A patent/JP2003523325A/ja active Pending
• 2009
  • 2009-03-04 US US12/397,374 patent/US20090221519A1/en not_active Abandoned

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