US20060030568A1 - Crystal modificaion of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use - Google Patents
Crystal modificaion of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use Download PDFInfo
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- US20060030568A1 US20060030568A1 US11/241,266 US24126605A US2006030568A1 US 20060030568 A1 US20060030568 A1 US 20060030568A1 US 24126605 A US24126605 A US 24126605A US 2006030568 A1 US2006030568 A1 US 2006030568A1
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- KTUFNOKKBVMGRW-UHFFFAOYSA-N [H]N(C(=O)C1=CC=C(CN2CCN(C)CC2)C=C1)C1=CC=C(C)C(N([H])C2=NC(C3=CN=CC=C3)=CC=N2)=C1 Chemical compound [H]N(C(=O)C1=CC=C(CN2CCN(C)CC2)C=C1)C1=CC=C(C)C(N([H])C2=NC(C3=CN=CC=C3)=CC=N2)=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
Definitions
- the invention relates to a particular form of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide, comprising certain crystals, processes for the preparation thereof, pharmaceutical compositions containing this crystal form, and their use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans, or their use for the preparation of pharmaceutical preparations for use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans.
- FIG. 1 / 3 shows the X-ray diffraction diagram of the ⁇ -crystal form of the methanesulfonic acid addition salt of a compound of formula I.
- FIG. 2 / 3 shows the X-ray diffraction diagram of the ⁇ -crystal form of the methanesulfonic acid addition salt of a compound of formula I.
- the angle of refraction 2theta is plotted on the horizontal axis x-axis) and the relative line intensity (background-corrected peak intensity) on the vertical (y-axis).
- a line scanner LS 18, Johansson, Täby, Sweden
- FIG. 2 / 3 there are lines having a relative line intensity of 20 or more at the following angles of refraction 2theta (relative line intensities given in parentheses): 9.7° (40), 13.9° (26), 14.7° (23), 17.5° (57), 18.2° (90), 20.0° (65), 20.6° (76), 21.1° (100), 22.1° (89), 22.7° (38), 23.8° (44), 29.8° (23) and 30.8° (20).
- the fact that in FIG. 2 / 3 the relative line intensity of the line at 30.8° seems to be higher than that of the line at 29.8° is due to a close by further line at 31.0° having a relative line intensity of 13.
- Melting points are determined by means of a DSC thermogram using a Mettler-Toledo TA8000.
- DSC differential scanning calorimetry
- the melting temperature both of the ⁇ -crystal form and of the ⁇ -crystal form can be measured by heating the samples until a thermal, i.e. an endothermic or exothermic, reaction is detected by means of ultrasensitive sensors.
- the melting points indicated in this text are determined using a Mettler-Toledo TA8000 apparatus, about 5.5 to 6.5 mg of each sample being measured in an aluminium crucible with a perforated lid under a quiescent atmosphere of air at a heating rate of 10° C./min (starting at 20° C.).
- the ⁇ -crystal form of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate is characterised by needle-shaped crystals and is hygroscopic.
- the crystals are not particularly well-suited to pharmaceutical formulation as solid dosage forms, because their physical properties, for example their flow characteristics, are unfavourable.
- the ⁇ -crystal form of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate has the advantage that its flow properties are substantially more favourable than those of the ⁇ -crystal form.
- This crystal form has the further advantage of being thermodynamically more stable at temperatures below 140° C.
- the ⁇ -crystal form is less hygroscopic than the ⁇ -crystal form and thus also stores better and is easier to process.
- the invention relates to an acid addition salt of a compound of formula I comprising non-needle-shaped crystals, especially the ⁇ -crystal form of the methanesulfonic acid addition salt of the compound of formula I.
- the invention relates especially to a particular, essentially pure crystal form, preferably that which is referred to hereinafter as the ⁇ -crystal form, of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyrid-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate of formula I,
- methanesulfonic acid salt of a compound of formula I or of 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide is used hereinbefore and hereinafter, this is especially taken to mean the methanesulfonic acid salt of formula II.
- essentially pure is understood in the context of the present invention to mean especially that at least 90, preferably at least 95, and most preferably at least 99 percent by weight of the crystals of an acid addition salt of formula I are present in the crystal form according to the invention, especially the ⁇ -crystal form,
- the term “essentially” means that at least the major lines of the diagram depicted in FIG. 2 / 3 , i.e. those having a relative line intensity of more than 10%, especially more than 20%, as compared to the most intense line in the diagram, have to be present.
- the invention expressly relates also to those forms of the methanesulfonic acid addition salt of a compound of formula I in which crystals of the crystal form according to the invention, especially the ⁇ -crystal form, are present in essentially pure form along with other crystal forms and/or the amorphous form of the 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate.
- the new crystal form especially the ⁇ -crystal form, has the following properties:
- the melting point in the DSC thermogram of the ⁇ -crystal form is 217° C., and that of the ⁇ -crystal form is 226° C. (start of melting).
- FIG. 2 / 3 shows a new additional peak marked (4).
- the new peak marked (5) also appears in FIG. 2 / 3 .
- the X-ray diffraction diagrams also show other marked differences.
- the (preferably essentially pure) ⁇ -crystal form is obtainable by
- the educt, the ⁇ -crystal form of the methanesulfonic acid addition salt of 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide is obtainable for example by precipitating out the salt from a solution in a solvent other than an alcohol, such as methanol, and without adding a seed crystal of the ⁇ -crystal form.
- One of the advantages of the ⁇ -crystal form is especially its more compact crystal form, which results in substantially more beneficial flow properties and thus in better processability of the methanesulfonic acid addition salt of a compound of formula I in the ⁇ -crystal form versus the ⁇ -crystal form, for example in the manufacture of pharmaceutical preparations.
- the ⁇ -crystal form of the methanesulfonic acid addition salt of a compound of formula I is metastable at room temperature.
- the ⁇ -crystal form of the methanesulfonic acid addition salt of a compound of formula I is the thermodynamically stable form at room temperature. Greater stability is thus to be expected.
- the ⁇ -crystal form is less hygroscopic than the ⁇ -crystal form of the methanesulfonic acid addition of a compound of formula I, as can be shown by the following table:
- the ⁇ -crystal form is hygroscopic and rapidly takes up water so that, at 93% relative humidity, the sample is to some extent present in amorphous form, whereas the ⁇ -crystal form remains dry under these conditions. Both crystal forms liquify at 97% relative humidity, but this happens very much more quickly with the ⁇ -crystal form than with the ⁇ -crystal form.
- the lower hygroscopicity is a further advantage for processing and storing the acid addition salt in the ⁇ -crystal form.
- the methanesulfonic acid addition salt of a compound of formula I which is preferably used in the ⁇ -crystal form (hereinafter, the methanesulfonic acid addition salt is always taken to mean the ⁇ -crystal form), as well as 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide in free form, possesses valuable pharmacological properties and may, for example, be used as an anti-tumour agent, as an agent to treat atherosclerosis, as an agent to treat restenosis, for the prevention of transplantation-induced disorders, such as obliterative bronchiolitis, and/or for preventing the invasion of warm-blooded animal cells by certain bacteria, such as Porphyromonas gingivalis.
- the phosphorylation of proteins has long been known as an essential step in the differentiation and division of cells. Phosphorylation is catalysed by protein kinases subdivided into serine/threonine and tyrosine kinases.
- the tyrosine kinases include PDGF (Platelet-derived Growth Factor) receptor tyrosine kinase.
- PDGF Platinum-derived Growth Factor
- PDGF is a very commonly occurring growth factor, which plays an important role both in normal growth and also in pathological cell proliferation, such as is seen in carcinogenesis and in diseases of the smooth-muscle cells of blood vessels, for example in atherosclerosis and thrombosis.
- the inhibition of PDGF-stimulated receptor tyrosine kinase activity in vitro is measured in PDGF receptor immune complexes of BALB/c 3T3 cells, as described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353-5358 (1992).
- a compound of formula I described in more detail hereinbefore such as especially its ⁇ -crystal form, inhibits PDGF-dependent acellular receptor phosphorylation.
- the inhibition of PDGF receptor tyrosine kinase is measured in a microtitre ELISA assay (cf Trinks et al., J. Med. Chem. 37, 1015-27 (1994).
- tumour diseases such as gliomas, sarcomas, prostate tumours, and tumours of the colon, breast, and ovary.
- the methanesulfonic acid addition salt of a compound of formula I also inhibits cellular processes involving the so-called stem-cell factor (SCF, also known as the c-kit ligand or steel factor), such as SCF receptor (kit) autophosphorylation and the SCF-stimulated activation of MAPK kinase (mitogen-activated protein kinase).
- SCF stem-cell factor
- Kit SCF receptor
- MAPK kinase mitogen-activated protein kinase
- MO7e cells are a human promegakaryocytic leukaemia cell line which depends on SCF for proliferation. They are obtained from Grover Bagby, Oregon Health Sciences University, USA. The cells are cultivated in RPMI 1649 medium supplemented with 10 FBS and 2.5 ng/ml GC-CMF. GM-SCF and SCF are commercially available. Serum-deprived MO7e cells are prepared and incubated for 90 min at 37° C.
- the methanesulfonic acid addition salt of a compound of formula I may be used not only as a tumour-inhibiting substance, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma, and fibrosis, as well as for the protection of stem cells, for example to combat the haemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, and in asthma. It may especially be used for the treatment of diseases which respond to an inhibition of the PDGF receptor kinase.
- the methanesulfonic acid addition salt of a compound of formula I prevents the development of multidrug resistance in cancer therapy with other chemotherapeutic agents or abolishes a pre-existing resistance to other chemotherapeutic agents.
- the methanesulfonic acid addition salt of a compound of formula I such as especially the ⁇ -crystal form thereof, may be used to advantage in combination with other antitumor agents.
- abl kinase is inhibited by 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide and its methanesulfonate salt.
- the inhibition of v-abl tyrosine kinase is determined by the methods of N. Lydon et al., Oncogene Research 5, 161-173 (1990) and J. F. Geissler et al., Cancer Research 52, 4492-8 (1992). In those methods [Val 5 ]-angiotensin II and [ ⁇ - 32 P]-ATP are used as substrates.
- 4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide here shows an IC 50 of 38 nM.
- the salt of a compound of formula I also inhibits BCR-abl kinase (see Nature Medicine 2, 561-566 (1996)) and is thus suitable for the treatment of BCR-abl-positive cancer and tumour diseases, such as leukaemias (especially chronic myeloid leukaemia and acute lymphoblastic leukaemia, where especially apoptotic mechanisms of action are found), and also shows effects on the subgroup of leukaemic stem cells as well as potential for the purification of these cells in vitro after removal of said cells (for example, bone marrow removal) and reimplantation of the cells once they have been cleared of cancer cells (for example, reimplantation of purified bone marrow cells).
- BCR-abl kinase see Nature Medicine 2, 561-566 (1996)
- the methanesulfonic acid addition salt of a compound of formula I shows useful effects in the treatment of disorders arising as a result of transplantation, for example, allogenic transplantation, especially tissue rejection, such as especially obliterative bronchiolitis (OB), i.e. a chronic rejection of allogenic lung transplants.
- OB obliterative bronchiolitis
- those with OB often show an elevated PDGF concentration in bronchoalveolar lavage fluids.
- the methanesulfonic acid addition salt of a compound of formula I is also effective in diseases associated with vascular smooth-muscle cell migration and proliferation (where PDGF and PDGF-R often also play a role), such as restenosis and atherosclerosis.
- diseases associated with vascular smooth-muscle cell migration and proliferation where PDGF and PDGF-R often also play a role
- PDGF and PDGF-R often also play a role
- the methanesulfonic acid addition salt of a compound of formula I is used in 0.1N HCl or DMSO at a concentration of 10 mM for in vitro studies.
- the stock solution is further diluted with cell culture medium and used in concentrations of 10 to 0.1 ⁇ M for the experiments.
- the methanesulfonic acid addition salt of a compound of formula I is dissolved for example in DMSO at a concentration of 200 mg/ml and then diluted 1:20 with 1% Tween in 0.9% saline solution. After sonication, a clear solution is obtained.
- the stock solutions are prepared fresh each day before administration.
- the compound of formula I may also be dissolved simply in deionised water for oral administration or in 0.9% saline solution for parenteral administration). Administration is carried out 24 hours before the operation.
- the methanesulfonic acid addition salt of a compound of formula I is administered to rats in one dose of 50 mg/kg i.p. per day for the entire observation period. Control rats are given the same dose of substrate. Oral administration is also possible.
- Subcultures are kept in DMEM (Dulbecco's Modified Eagle's Medium), supplemented with 10% fetal calf serum, 2 mmol/ml glutamine, 100 mmol/ml streptomycin, and 100 IU/ml penicillin.
- DMEM Dulbecco's Modified Eagle's Medium
- the cells are left to grow on glass slide covers and stained on SMC- ⁇ actin (see below).
- the migration of smooth-muscle cells is quantified in vitro using a Transwell cell culture insert (Costar, Cambridge, Mass.) whose upper and lower compartments are separated by a polycarbonate membrane of 8 ⁇ m pore size.
- the cells (100 ⁇ l at a concentration of 1 million cells/ml) are exposed in the upper compartment.
- 60 ng/ml PDGF-BB or PDGF-AA (Upstate Biotechnology Inc., Lake Placid, N.Y.) is added to the lower compartment, supplemented with 0.5% fetal calf serum and 0.1% bovine serum albumin, and the test compound is added in concentrations of 3, 1, 0.3, 0.1, 0.03, 0.01, and 0.003 ⁇ M.
- the Transwell chambers are covered with fibronectin at a concentration of 10 ⁇ g/ml for 24 h at 4° C. (human cellular fibronectin, Upstate Biotechnology Inc.).
- the filters are removed, fixed in methanol, and stained with Mayer's haematoxylin and eosin.
- the migrated cells on the lower side of the filter membrane are determined by counting the specified sectional fields on the filters with the aid of a light microscope with a magnification of 400 ⁇ .
- the inhibition of migration is quantified in terms of the percentage of cells versus with the control.
- the viability of the cells is tested by incorporation of 3H-thymidine in DMEM, supplemented with 10% fetal calf serum. An inhibition of migration induced by PDGF-M and especially by PDGF-BB is observed.
- mice the aorta and carotid artery of male Wistar rats (purchased from the Laboratory Animal Center of the University of Helsinki, Finland) are denuded.
- the rats are anaesthetised with 240 mg/kg chloral hydrate i.p.
- Buprenorphine Temgesic, Reckitt & Coleman, Hull, UK
- All animals are given human care in keeping with the “Principles of Laboratory Animal Care” and the “Guide for the Care and Use of Laboratory Animals” of the NIH (NIH Publication 86-23, revised 1985). Rats weighing 200-300 g were used for the denudation procedure.
- the left common carotid artery is denuded of endothelium through the intraluminal passage of a 2F embolectomy catheter (Baxter Healthcare Corporation, Santa Ana, Calif., 27).
- a 2F embolectomy catheter Baxter Healthcare Corporation, Santa Ana, Calif., 27.
- the catheter is passed through the lumen three times, inflated with 0.2 ml air.
- the external carotid is ligated after removal of the catheter and the wound closed.
- the histological changes are evaluated by reference to sections of mid-carotid 4 days after denudation.
- the thoracic aorta is denuded of endothelium using a 2F Fogarty arterial embolectomy catheter.
- the catheter is inserted into the thoracic aorta via the left iliac artery, inflated with 0.2 ml air, and passed through the lumen five times to remove the endothelium.
- the iliac artery is then ligated. Three times (3, 7 and 14 days) are selected for evaluation of the histological changes.
- the rats were given 3 ⁇ 0.1 ml BrdU-labelling reagent at 8-hour intervals over a period of 72-96 hours after the operation.
- a third group of rats is given a pulsed dose of 0.3 ml BrdU three hours before sacrifice.
- Histological samples are fixed in 3% paraformaldehyde solution for 4 h for embedding in paraffin. Morphological changes are evaluated from paraffin sections stained with Mayer's haematoxylin-eosin. The cell counts of different vessel sections are calculated at a magnification of 400 ⁇ .
- immunohistochemical staining of acetone-fixed samples is carried out using an anti- ⁇ -actin antibody obtained from smooth-muscle cells (Bio-Makor, Rehovot, Israel). Primary smooth-muscle cells are identified on acetone-fixed glass cover slides using the same staining method.
- the sections are incubated with the primary antibody (dilution 1:2000), washed, and incubated consecutively with peroxidase-conjugated rabbit-antimouse-Ig and goat-antirabbit-Ig, followed by treatment with substrate solution with the chromogen 3-amino-9-ethylcarbazol and hydrogen peroxide.
- BrdU stains are prepared from paraffin sections using a primary mouse antibody (Bu20a, Dako, A/S, Denmark) and the Vectastain Elite ABC-Kit (Vector Laboratories, Burliname, Calif.).
- the sections are deparaffinised and treated by microwave at 500 W (2 ⁇ 5 min in 0.1 M citrate buffer, pH 6), followed by treatment with 95% formamide in 0.15M trisodium citrate for 45 min at 70° C.
- Antibody dilutions are prepared according to the manufacturer's specifications.
- the sections are counterstained with Mayer's haematoxylin and eosin, and positive cells are counted separately for the initima, media, and adventitia.
- the methanesulfonic acid addition salt of a compound of formula I can thus inhibit the proliferation, and especially the migration, of vascular smooth-muscle cells.
- the methanesulfonic acid addition salt of a compound of formula I is also capable of inhibiting angiogenesis. This may be demonstrated as follows: a chamber containing agar (0.8%) and heparin (2 U/ml) with or without growth factor (VEGF 3 ⁇ g/ml, PDGF 1 ⁇ g/ml or bFGF 0.3 ⁇ g/ml) is implanted subcutaneously into normal mice (C57 BL/6). The methanesulfonic acid addition salt of a compound of formula I is administered orally in a dose showing good anti-tumour activity in a nude mouse xenotransplant model. Dosing is started one day before implantation of the chambers.
- the chambers are removed after 5 days.
- the angiogenic efficacy is quantified by measuring both the vascularised tissue which has grown around the implant and the blood content of this tissue (external blood).
- the blood is determined by measuring the haemoglobin. Although the vessels do not grow into the agar, the agar becomes intensely red if an antiangiogenic effect is present. If a compound inhibits the increase in blood that is induced by the growth factor, this is seen as an indication that the compound in question is blocking the angiogenic effect of the growth factor concerned. Inhibition of the weight but not the volume of blood suggests an effect on the proliferation of fibroblasts. A suppression of the control response suggests an inhibition of wound healing.
- the compound of formula I inhibits the angiogenic effect of all three growth factors (VEGF, PDFG, bFGF).
- the present invention relates especially to the ⁇ -crystal form of the methanesulfonic acid addition salt of a compound of formula I in the treatment of one of the said diseases or in the preparation of a pharmacological agent for the treatment tereof.
- the invention relates also to a process for the treatment of warm-blooded animals suffering from said diseases, especially a tumour disease, wherein a quantity of the ⁇ -crystal form of the methanesulfonic acid addition salt of a compound of formula I which is effective against the disease concerned, especially a quantity with antiproliferative and especially tumour-inhibiting efficacy, is administered to warm-blooded animals in need of such treatment.
- the invention relates moreover to the use of the ⁇ -crystal form of the methanesulfonic acid addition salt of a compound of formula I for the inhibition of the above-mentioned tyrosine kinases, especially PDGF receptor kinase, v-abl kinase, and/or c-kit receptor kinase, or for the preparation of pharmaceutical compositions for use in treating the human or animal body, especially for the treatment of tumours, such as gliomas, ovarian tumours, prostate tumours, colon tumours, and tumours of the lung, such as especially small cell lung carcinoma, and tumours of the breast or other gynaecological tumours.
- tumours such as gliomas, ovarian tumours, prostate tumours, colon tumours, and tumours of the lung, such as especially small cell lung carcinoma, and tumours of the breast or other gynaecological tumours.
- effective doses for example daily doses of about 1-2500 mg, preferably 1-1000 mg, especially 5-500 mg, are administered to warm-blooded animals of about 70 kg bodyweight.
- the invention relates also to pharmaceutical preparations which contain an effective amount, especially an effective amount for prevention or treatment of one of the said diseases, of the methanesulfonic acid addition salt of a compound of formula I in the ⁇ -crystal form, together with pharmaceutically acceptable carriers which are suitable for topical, enteral, for example oral or rectal, or parenteral administration and may be inorganic or organic and solid or liquid.
- Tablets may likewise contain binders, for example magnesium aluminium silicate, starches, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if so desired, disintegrants, for example starches, agar, alginic acid, or a salt thereof, typically sodium alginate, and/or effervescent mixtures, or adsorbents, colouring agents, flavours, and sweetening agents.
- diluents for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerin, and/or lubricants, for example silica, talc, stearic acid, or salts thereof, typically magnesium or calcium stearate, and/or polyethylene glycol
- Tablets may likewise contain binders, for example magnesium aluminium silicate, starches, typically corn, wheat or rice starch, gelatin, methyl
- the pharmacologically active compounds of the present invention may further be used in the form of preparations for parenteral administration or infusion solutions.
- Such solutions are preferably isotonic aqueous solutions or suspensions, these possibly being prepared before use, for example in the case of lyophilised preparations containing the active substance either alone or together with a carrier, for example mannitol.
- the pharmaceutical substances may be sterilised and/or may contain excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for the regulation of osmotic pressure, and/or buffers.
- the present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances, such as antibiotics, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain from about 1% to 100%, especially from about 1% to about 20%, of the active substance or substances.
- R f -values are determined on TLC plates coated with silica gel (Merck, Darmstadt, Germany). The ratio of the solvents to one another in the solvent systems used is indicated by volume (v/v), and temperatures are given in degrees celsius (° C.).
- 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate is prepared as follows: 98.6 g (0.2 mol) free 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide (for preparation see, for example, EP-A-0 564 409) is added to 1.4 l ethanol. To this beige suspension, 19.2 g (0.2 mol) methanesulfonic acid is added dropwise over a period of 20 minutes.
- Tablets containing 100 mg of the active substance named in the title are usually prepared in the following composition:
- composition Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL 20 mg Aerosil 2 mg Magnesium stearate 5 mg 447 mg
- the active substance is mixed with carrier materials and compressed on a tableting machine (Korsch EKO, punch diameter 10 mm).
- Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).
- PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).
- Aerosil is silicon dioxide (Degussa, Germany).
- Capsules containing 100 mg of the compound named in the title as active substance are usually prepared in the following composition:
- composition Active ingredient 100 mg Avicel 200 mg PVPPXL 15 mg Aerosil 2 mg Magnesium stearate 1.5 mg 318.5 mg
- the capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.
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Abstract
Description
- The invention relates to a particular form of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide, comprising certain crystals, processes for the preparation thereof, pharmaceutical compositions containing this crystal form, and their use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans, or their use for the preparation of pharmaceutical preparations for use in diagnostic methods or preferably for the therapeutic treatment of warm-blooded animals, especially humans.
- The preparation of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide and the use thereof, especially as an anti-tumour agent, are described in Example 21 of EP-A-0 564 409, which was published on 6 Oct. 1993, and in equivalent applications in numerous other countries. This compound is exemplified in these publications only in free form (not as a salt).
- It has now been surprisingly found that a crystal form may under certain conditions be found in the methanesulfonate salt of this compound, which is described hereinafter as β-crystal form, and which has very advantageous properties.
- The invention is described in more detail in the following with the help of drawings and other aids:
-
FIG. 1 /3 shows the X-ray diffraction diagram of the α-crystal form of the methanesulfonic acid addition salt of a compound of formula I. -
FIG. 2 /3 shows the X-ray diffraction diagram of the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I. -
FIG. 3 /3 shows the crystals above of the α-crystal form and below of the β-crystal form of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide methanesulfonate (=Of the methanesulfonic acid addition salt of a compound of formula I). - In both X-ray diagrams, the angle of refraction 2theta is plotted on the horizontal axis x-axis) and the relative line intensity (background-corrected peak intensity) on the vertical (y-axis). The diagrams are obtained as follows: first, the x-ray diffraction diagram is recorded on film using a Guinier camera (Enraf-Nonius FR 552 model) with a Guinier 258-94c film and copper radiation (Kα1 radiation, wavelength λ=1.54060 Angström). The optical density of the lines on the film is proportional to the light intensity. The film is then scanned in using a line scanner (LS 18, Johansson, Täby, Sweden) with SCANPI software.
- In accordance with
FIG. 2 /3 there are lines having a relative line intensity of 20 or more at the following angles of refraction 2theta (relative line intensities given in parentheses): 9.7° (40), 13.9° (26), 14.7° (23), 17.5° (57), 18.2° (90), 20.0° (65), 20.6° (76), 21.1° (100), 22.1° (89), 22.7° (38), 23.8° (44), 29.8° (23) and 30.8° (20). The fact that inFIG. 2 /3 the relative line intensity of the line at 30.8° seems to be higher than that of the line at 29.8° is due to a close by further line at 31.0° having a relative line intensity of 13. - Melting points are determined by means of a DSC thermogram using a Mettler-Toledo TA8000. DSC (“differential scanning calorimetry”) is the technique of dynamic differential calorimetry. Using this technique, the melting temperature both of the α-crystal form and of the β-crystal form can be measured by heating the samples until a thermal, i.e. an endothermic or exothermic, reaction is detected by means of ultrasensitive sensors. The melting points indicated in this text are determined using a Mettler-Toledo TA8000 apparatus, about 5.5 to 6.5 mg of each sample being measured in an aluminium crucible with a perforated lid under a quiescent atmosphere of air at a heating rate of 10° C./min (starting at 20° C.).
- The α-crystal form of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate is characterised by needle-shaped crystals and is hygroscopic. In this form, the crystals are not particularly well-suited to pharmaceutical formulation as solid dosage forms, because their physical properties, for example their flow characteristics, are unfavourable. Under certain conditions, however, it is possible to obtain 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate in a crystal form which is not needle-shaped. This form is described in the present text as β-crystal form.
- The β-crystal form of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate has the advantage that its flow properties are substantially more favourable than those of the α-crystal form. This crystal form has the further advantage of being thermodynamically more stable at temperatures below 140° C. Finally, the β-crystal form is less hygroscopic than the α-crystal form and thus also stores better and is easier to process.
- The invention relates to an acid addition salt of a compound of formula I comprising non-needle-shaped crystals, especially the β-crystal form of the methanesulfonic acid addition salt of the compound of formula I.
- The invention relates especially to a particular, essentially pure crystal form, preferably that which is referred to hereinafter as the β-crystal form, of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyrid-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate of formula I,
-
- The term “essentially pure” is understood in the context of the present invention to mean especially that at least 90, preferably at least 95, and most preferably at least 99 percent by weight of the crystals of an acid addition salt of formula I are present in the crystal form according to the invention, especially the β-crystal form,
- In the context with stating that the acid addition salt of formula II exhibits an X-ray diffraction diagram essentially as in
FIG. 2 /3 the term “essentially” means that at least the major lines of the diagram depicted inFIG. 2 /3, i.e. those having a relative line intensity of more than 10%, especially more than 20%, as compared to the most intense line in the diagram, have to be present. - The invention expressly relates also to those forms of the methanesulfonic acid addition salt of a compound of formula I in which crystals of the crystal form according to the invention, especially the β-crystal form, are present in essentially pure form along with other crystal forms and/or the amorphous form of the 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate. Preferred, however, is the acid addition salt of formula II, which is present in essentially pure form in the β-crystal form.
- The new crystal form, especially the β-crystal form, has the following properties:
- The melting point in the DSC thermogram of the β-crystal form is 217° C., and that of the α-crystal form is 226° C. (start of melting).
- The X-ray diffraction diagram of the β-crystal form does not show the peak of the α-crystal form marked (1) and only to a very minor extent shows that marked (3) (see FIGS. 1/3 and 2/3). By contrast
FIG. 2 /3 shows a new additional peak marked (4). The new peak marked (5) also appears inFIG. 2 /3. - The X-ray diffraction diagrams also show other marked differences.
- In the preferred embodiment, the essentially pure methanesulfonic acid addition salt of a compound of formula I in the β-crystal form shows the X-ray diffraction diagram indicated in
FIG. 2 /3. - (i) Preferred is a crystal form of the methanesulfonic acid addition salt of a compound of formula I which does not show the peak marked (1) in
FIG. 1 /3 on the X-ray diffraction diagram, this crystal form preferably being present in essentially pure form. - (ii) Preferred is also a crystal form of the methanesulfonic acid addition salt of a compound of formula I which remains dry at 93% relative humidity and at a temperature of 25° C., this crystal form preferably being present in essentially pure form.
- (iii) The invention relates preferably to the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which is characterised by the presence of crystals displaying the form shown in
FIG. 3 /3 below; especially the β-crystal form in essentially pure form. - (iv) Stronger preference is for the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which has a melting point of less than 225° C., especially between 217 and 225° C.
- (v) Stronger preference is also for the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which has a melting point of less than 217° C., defined as the start of melting in the DSC thermogram.
- (v) Stronger preference is also for the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which on X-ray diffraction shows the peak marked (4) in
FIG. 213 . - (vii) Stronger preference is also for the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which on X-ray diffraction shows the peak marked (5) in
FIG. 2 /3. - (viii) Still stronger preference is for the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which shows an X-ray diffraction diagram of the type shown in
FIG. 2 /3, especially one in which the relative peak intensities of each peak do not deviate by more than 10% from the relative peak intensities in the diagram shown inFIG. 2 /3, especially an X-ray diffraction diagram identical to that shown inFIG. 2 /3. - (ix) Greatest preference is for the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which has two of the properties named in paragraphs (i) to (viii), greater preference being for three of the properties in the said paragraphs, especially all the said properties, and most especially those properties defined as being preferred.
- Likewise strongly preferred is a crystal form as defined in one of the paragraphs (i) to (ix) in essentially pure form.
- Particularly special preference is for the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I obtainable as described in the Examples.
- In all cases, a form of the methanesulfonic acid addition salt of a compound of formula I comprising the corresponding above-mentioned crystal form is also taken to be meant in a wider aspect of the invention.
- The (preferably essentially pure) β-crystal form is obtainable by
- a) digesting another crystal form, especially the α-crystal form, or an amorphous starting material of the methanesulfonic acid addition salt of a compound of formula I, with a suitable polar solvent, especially an alcohol, most especially methanol, or also a ketone (especially in a mixture with water, for example water/acetone), typically acetone, a N,N-di-lower alkyl-lower alkanecarboxamide, typically N,N-dimethylformamide or -acetamide, or a hydrophilic ether, typically dioxane, preferably in the presence of some water, or mixtures thereof, in suspension at a suitable temperature, preferably a temperature between 20 and 50° C., for example at about 25° C., or
- b) dissolving another crystal form, especially the α-crystal form, or an amorphous starting material of the methanesulfonic acid addition salt of a compound of formula I, with a suitable polar solvent, such as especially an alcohol, typically methanol or ethanol, a ketone (especially in a mixture with water, for example water/acetone) typically acetone, a N,N-di-lower alkyl-lower alkanecarboxamide, typically N,N-dimethylformamide or -acetamide, or a hydrophilic ether, typically dioxane, or mixtures thereof, preferably in the presence of some water, at a suitable temperature, especially after heating the solvent, or while warming during the dissolution process, in both cases preferably to 25° C. up to the reflux temperature of the reaction mixture, and then initiating crystallisation by adding a small amount of the β-crystal form as seed crystal at a suitable temperature, for example between 0 and 70° C., preferably between 20 and 70° C.
- The educt, the α-crystal form of the methanesulfonic acid addition salt of 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide, is obtainable for example by precipitating out the salt from a solution in a solvent other than an alcohol, such as methanol, and without adding a seed crystal of the β-crystal form.
- The above conditions on the selective preparation of the individual crystal forms are not conclusive. In general, for example, it is possible to vary parameters such as the weight ratio of the methanesulfonic acid addition salt of a compound of formula I to the solvent. It is also possible to vary the time needed for the preparation of the β-crystal form, especially when the temperatures are adjusted at the same time.
- One of the advantages of the β-crystal form is especially its more compact crystal form, which results in substantially more beneficial flow properties and thus in better processability of the methanesulfonic acid addition salt of a compound of formula I in the β-crystal form versus the α-crystal form, for example in the manufacture of pharmaceutical preparations.
- It is true to say that the α-crystal form of the methanesulfonic acid addition salt of a compound of formula I is metastable at room temperature. However, the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I is the thermodynamically stable form at room temperature. Greater stability is thus to be expected.
- Finally, the β-crystal form is less hygroscopic than the α-crystal form of the methanesulfonic acid addition of a compound of formula I, as can be shown by the following table:
- On measurement of the crystal forms up to the point where equilibrium is reached (no further adsorption) in a glass climatic chamber at 25° C. and at the humidities shown below, the following content values are found (the % values for the final water content refer to dry weight):
Final water content on adsorption Relative humidity α-crystal form β-crystal form (%) (%) (molar) (%) (molar) 12 0.14 0.05 0.08 0.02 33 0.18 0.06 0.10 0.03 46 0.14 0.05 — — 54 0.13 0.04 0.14 0.05 66 0.07 0.02 0.09 0.03 75 0.49 0.16 — — 85 0.18 0.06 0.16 0.05 93 40 13.1 0.15 0.05 97 63 20.8 23 7.5 100 — — 37 12 - It is shown that, at 25° C., the α-crystal form is hygroscopic and rapidly takes up water so that, at 93% relative humidity, the sample is to some extent present in amorphous form, whereas the β-crystal form remains dry under these conditions. Both crystal forms liquify at 97% relative humidity, but this happens very much more quickly with the α-crystal form than with the β-crystal form.
- The lower hygroscopicity is a further advantage for processing and storing the acid addition salt in the β-crystal form.
- The methanesulfonic acid addition salt of a compound of formula I, which is preferably used in the β-crystal form (hereinafter, the methanesulfonic acid addition salt is always taken to mean the β-crystal form), as well as 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide in free form, possesses valuable pharmacological properties and may, for example, be used as an anti-tumour agent, as an agent to treat atherosclerosis, as an agent to treat restenosis, for the prevention of transplantation-induced disorders, such as obliterative bronchiolitis, and/or for preventing the invasion of warm-blooded animal cells by certain bacteria, such as Porphyromonas gingivalis.
- The phosphorylation of proteins has long been known as an essential step in the differentiation and division of cells. Phosphorylation is catalysed by protein kinases subdivided into serine/threonine and tyrosine kinases. The tyrosine kinases include PDGF (Platelet-derived Growth Factor) receptor tyrosine kinase.
- PDGF (Platelet-derived Growth Factor) is a very commonly occurring growth factor, which plays an important role both in normal growth and also in pathological cell proliferation, such as is seen in carcinogenesis and in diseases of the smooth-muscle cells of blood vessels, for example in atherosclerosis and thrombosis.
- The inhibition of PDGF-stimulated receptor tyrosine kinase activity in vitro is measured in PDGF receptor immune complexes of BALB/c 3T3 cells, as described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353-5358 (1992). A compound of formula I described in more detail hereinbefore, such as especially its β-crystal form, inhibits PDGF-dependent acellular receptor phosphorylation. The inhibition of PDGF receptor tyrosine kinase is measured in a microtitre ELISA assay (cf Trinks et al., J. Med. Chem. 37, 1015-27 (1994). 4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide and the corresponding methanesulfonate salt inhibit the tyrosine kinase activity of the PDGF receptor at an IC50 (concentration at which activity is inhibited by 50% compared with the control) of about 120 nM and about 100 nM, respectively.
- The inhibition of PDGF makes a compound of formula I also suitable for the treatment of tumour diseases, such as gliomas, sarcomas, prostate tumours, and tumours of the colon, breast, and ovary.
- The methanesulfonic acid addition salt of a compound of formula I also inhibits cellular processes involving the so-called stem-cell factor (SCF, also known as the c-kit ligand or steel factor), such as SCF receptor (kit) autophosphorylation and the SCF-stimulated activation of MAPK kinase (mitogen-activated protein kinase).
- The methanesulfonic acid addition salt of a compound of formula I, such as especially the β-crystal form thereof, thus inhibits also the autophosphorylation of SCF receptor (and c-kit, a proto-oncogen). MO7e cells are a human promegakaryocytic leukaemia cell line which depends on SCF for proliferation. They are obtained from Grover Bagby, Oregon Health Sciences University, USA. The cells are cultivated in RPMI 1649 medium supplemented with 10 FBS and 2.5 ng/ml GC-CMF. GM-SCF and SCF are commercially available. Serum-deprived MO7e cells are prepared and incubated for 90 min at 37° C. with the test substance before being stimulated with recombinant SCF for 10 min at 37° C. Identical quantities of cell lysates are analysed by Western blot using antiphosphotyrosine antibodies (Buchdunger et al., Proc. Natl. Acad. Sci (USA) 92, 2558-62 (1995)). The immunodecorated proteins are detected by means of the ECL Western blotting system from Amersham (Amersham, UK). A compound of formula I, especially the crystal form of the methanesulfonate salt of formula II, inhibits the autophosphorylation of SCF-R in the micromolar range.
- On the basis of the described properties, the methanesulfonic acid addition salt of a compound of formula I, such as especially the β-crystal form thereof, may be used not only as a tumour-inhibiting substance, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma, and fibrosis, as well as for the protection of stem cells, for example to combat the haemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, and in asthma. It may especially be used for the treatment of diseases which respond to an inhibition of the PDGF receptor kinase.
- In addition, the methanesulfonic acid addition salt of a compound of formula I, such as especially its β-crystal form C, prevents the development of multidrug resistance in cancer therapy with other chemotherapeutic agents or abolishes a pre-existing resistance to other chemotherapeutic agents. Also regardless of the effect described hereinbefore, the methanesulfonic acid addition salt of a compound of formula I, such as especially the β-crystal form thereof, may be used to advantage in combination with other antitumor agents.
- Also abl kinase, especially v-abl kinase, is inhibited by 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide and its methanesulfonate salt. The inhibition of v-abl tyrosine kinase is determined by the methods of N. Lydon et al.,
Oncogene Research 5, 161-173 (1990) and J. F. Geissler et al., Cancer Research 52, 4492-8 (1992). In those methods [Val5]-angiotensin II and [γ-32P]-ATP are used as substrates. 4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide here shows an IC50 of 38 nM. - By analogy, the salt of a compound of formula I also inhibits BCR-abl kinase (see
Nature Medicine 2, 561-566 (1996)) and is thus suitable for the treatment of BCR-abl-positive cancer and tumour diseases, such as leukaemias (especially chronic myeloid leukaemia and acute lymphoblastic leukaemia, where especially apoptotic mechanisms of action are found), and also shows effects on the subgroup of leukaemic stem cells as well as potential for the purification of these cells in vitro after removal of said cells (for example, bone marrow removal) and reimplantation of the cells once they have been cleared of cancer cells (for example, reimplantation of purified bone marrow cells). - In addition, the methanesulfonic acid addition salt of a compound of formula I shows useful effects in the treatment of disorders arising as a result of transplantation, for example, allogenic transplantation, especially tissue rejection, such as especially obliterative bronchiolitis (OB), i.e. a chronic rejection of allogenic lung transplants. In contrast to patients without OB, those with OB often show an elevated PDGF concentration in bronchoalveolar lavage fluids. If 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate, especially in the β-crystal form, is administered to rats with tracheal allogenic transplants, for example in a dose of 50 mg/kg i.p., it can be shown after removal of 10 transplants per group after 10 and 30 days for morphometric analysis of possible epithelial lesions and occlusion of the airways, and investigation for immunohistochemical pathways of action that, although the methanesulfonic acid addition salt of a compound of formula I has no significant effect on epithelial necrosis or infiltration by inflammatory cells, it does markedly reduce fibroproliferation and occlusion of the lumen compared with controls. Synergistic effects with other immunomodulatory or anti-inflammatory substances are possible, for example when used in combination with ciclosporin, rapamycin, or ascomycin, or immunosuppressant analogues thereof, for example ciclosporin A (CsA), ciclosporin G, FK-506, rapamycin, or comparable compounds; corticosteroids; cyclophosphamide; azathioprine; methotrexate; brequinar; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualin; immunsuppressant antibodies, especially monoclonal antibodies for leucocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands; or other immunomodulatory compounds, such as CTLA4Ig. If CsA (1 mg/kg s.c.), for example, is combined with the acid addition salt of formula I (50 mg/kg), synergism may be observed.
- The methanesulfonic acid addition salt of a compound of formula I is also effective in diseases associated with vascular smooth-muscle cell migration and proliferation (where PDGF and PDGF-R often also play a role), such as restenosis and atherosclerosis. These effects and the consequences thereof for the proliferation or migration of vascular smooth-muscle cells in vitro and in vivo can be demonstrated by administration of the methanesulfonic acid addition salt of a compound of formula I and also by investigating its effect on the thickening of the vascular intima following mechanical injury in vivo.
- The methanesulfonic acid addition salt of a compound of formula I is used in 0.1N HCl or DMSO at a concentration of 10 mM for in vitro studies. The stock solution is further diluted with cell culture medium and used in concentrations of 10 to 0.1 μM for the experiments. For in vivo administration, the methanesulfonic acid addition salt of a compound of formula I is dissolved for example in DMSO at a concentration of 200 mg/ml and then diluted 1:20 with 1% Tween in 0.9% saline solution. After sonication, a clear solution is obtained. The stock solutions are prepared fresh each day before administration. (The compound of formula I may also be dissolved simply in deionised water for oral administration or in 0.9% saline solution for parenteral administration). Administration is carried out 24 hours before the operation. The methanesulfonic acid addition salt of a compound of formula I is administered to rats in one dose of 50 mg/kg i.p. per day for the entire observation period. Control rats are given the same dose of substrate. Oral administration is also possible.
- Primary cultures of smooth-muscle aorta cells are isolated from 9 to 11-day-old DA (AG-B4, RT1a) rat aorta using a modification of the method described by Thyberg et al. (see Differentiation 25, 156-67 (1983)). The aorta is opened by means of a longitudinal incision and the endothelium carefully removed. The adventitia and the tunica media are separated, and the tunica media is digested with 0.1% collagenase and DNAse in phosphate-buffered physiological saline for 30 min at 37° C. The cells are centrifuged, suspended in culture medium, and then allowed to grow on plastic vials. The primary cells are used for the experiments after
passages 2 to 6. Subcultures are kept in DMEM (Dulbecco's Modified Eagle's Medium), supplemented with 10% fetal calf serum, 2 mmol/ml glutamine, 100 mmol/ml streptomycin, and 100 IU/ml penicillin. For identification purposes, the cells are left to grow on glass slide covers and stained on SMC-α actin (see below). - The migration of smooth-muscle cells is quantified in vitro using a Transwell cell culture insert (Costar, Cambridge, Mass.) whose upper and lower compartments are separated by a polycarbonate membrane of 8 μm pore size. The cells (100 μl at a concentration of 1 million cells/ml) are exposed in the upper compartment. After 2 hours, 60 ng/ml PDGF-BB or PDGF-AA (Upstate Biotechnology Inc., Lake Placid, N.Y.) is added to the lower compartment, supplemented with 0.5% fetal calf serum and 0.1% bovine serum albumin, and the test compound is added in concentrations of 3, 1, 0.3, 0.1, 0.03, 0.01, and 0.003 μM. To measure fibronectin-dependent migration, the Transwell chambers are covered with fibronectin at a concentration of 10 μg/ml for 24 h at 4° C. (human cellular fibronectin, Upstate Biotechnology Inc.). After 24 hours' migration, the filters are removed, fixed in methanol, and stained with Mayer's haematoxylin and eosin. The migrated cells on the lower side of the filter membrane are determined by counting the specified sectional fields on the filters with the aid of a light microscope with a magnification of 400×. The inhibition of migration is quantified in terms of the percentage of cells versus with the control. To exclude the possibility of a toxic effect, the viability of the cells is tested by incorporation of 3H-thymidine in DMEM, supplemented with 10% fetal calf serum. An inhibition of migration induced by PDGF-M and especially by PDGF-BB is observed.
- Experimental animals: the aorta and carotid artery of male Wistar rats (purchased from the Laboratory Animal Center of the University of Helsinki, Finland) are denuded. The rats are anaesthetised with 240 mg/kg chloral hydrate i.p. Buprenorphine (Temgesic, Reckitt & Coleman, Hull, UK) is administered for perioperative and postoperative alleviation of pain. All animals are given human care in keeping with the “Principles of Laboratory Animal Care” and the “Guide for the Care and Use of Laboratory Animals” of the NIH (NIH Publication 86-23, revised 1985). Rats weighing 200-300 g were used for the denudation procedure. The left common carotid artery is denuded of endothelium through the intraluminal passage of a 2F embolectomy catheter (Baxter Healthcare Corporation, Santa Ana, Calif., 27). To remove the endothelium, the catheter is passed through the lumen three times, inflated with 0.2 ml air. The external carotid is ligated after removal of the catheter and the wound closed. The histological changes are evaluated by reference to sections of mid-carotid 4 days after denudation. The thoracic aorta is denuded of endothelium using a 2F Fogarty arterial embolectomy catheter. The catheter is inserted into the thoracic aorta via the left iliac artery, inflated with 0.2 ml air, and passed through the lumen five times to remove the endothelium. The iliac artery is then ligated. Three times (3, 7 and 14 days) are selected for evaluation of the histological changes.
- To quantify the proliferating cells, 3 different procedures are used for labelling the cells with bromodeoxyuridine (BrdU) after denudation of the rat carotid. In this model, the media cell proliferation begins 24 h after denudation; cells in the intima first appear after 72-96 hours. To quantify the proliferation of smooth-muscle cells before the appearance of cells in the intima, 0.1 ml BrdU-labelling reagent (ZYMED, San Francisco, Calif.) is administered i.v. during the postoperative period of 0 to 72 h post-denudation (in total 0.1 ml 6 times). To quantify the proliferation during the initial wave of migration, the rats were given 3×0.1 ml BrdU-labelling reagent at 8-hour intervals over a period of 72-96 hours after the operation. To quantity the proliferation at the end of the initial wave of migration, a third group of rats is given a pulsed dose of 0.3 ml BrdU three hours before sacrifice.
- Histological samples are fixed in 3% paraformaldehyde solution for 4 h for embedding in paraffin. Morphological changes are evaluated from paraffin sections stained with Mayer's haematoxylin-eosin. The cell counts of different vessel sections are calculated at a magnification of 400×. To identify cells in culture and cells appearing in the neo-intima within four days of the denudation injury, immunohistochemical staining of acetone-fixed samples is carried out using an anti-α-actin antibody obtained from smooth-muscle cells (Bio-Makor, Rehovot, Israel). Primary smooth-muscle cells are identified on acetone-fixed glass cover slides using the same staining method. The sections are incubated with the primary antibody (dilution 1:2000), washed, and incubated consecutively with peroxidase-conjugated rabbit-antimouse-Ig and goat-antirabbit-Ig, followed by treatment with substrate solution with the chromogen 3-amino-9-ethylcarbazol and hydrogen peroxide. BrdU stains are prepared from paraffin sections using a primary mouse antibody (Bu20a, Dako, A/S, Denmark) and the Vectastain Elite ABC-Kit (Vector Laboratories, Burliname, Calif.). The sections are deparaffinised and treated by microwave at 500 W (2×5 min in 0.1 M citrate buffer, pH 6), followed by treatment with 95% formamide in 0.15M trisodium citrate for 45 min at 70° C. Antibody dilutions are prepared according to the manufacturer's specifications. The sections are counterstained with Mayer's haematoxylin and eosin, and positive cells are counted separately for the initima, media, and adventitia.
- In the carotid of treated animals, a significant decrease is found in the cell count for smooth-muscle cells. The adventitia and the media showed a significant reduction in the cell count. As a result of the methanesulfonic acid addition salt of a compound of formula I, a slight decrease in the absolute number of BrdU-labelled cells is seen in the intima, media, and adventitia during the first two labelling periods (0-72 and 72-96 h), and after 93-96 h a decrease in the number of labelled cells is seen in all compartments. Decreases in the number of smooth-muscle cells are likewise found in the aorta-denuded animals.
- According to these findings, the methanesulfonic acid addition salt of a compound of formula I can thus inhibit the proliferation, and especially the migration, of vascular smooth-muscle cells.
- The methanesulfonic acid addition salt of a compound of formula I, especially the β-crystal form, is also capable of inhibiting angiogenesis. This may be demonstrated as follows: a chamber containing agar (0.8%) and heparin (2 U/ml) with or without growth factor (
VEGF 3 μg/ml,PDGF 1 μg/ml or bFGF 0.3 μg/ml) is implanted subcutaneously into normal mice (C57 BL/6). The methanesulfonic acid addition salt of a compound of formula I is administered orally in a dose showing good anti-tumour activity in a nude mouse xenotransplant model. Dosing is started one day before implantation of the chambers. The chambers are removed after 5 days. The angiogenic efficacy is quantified by measuring both the vascularised tissue which has grown around the implant and the blood content of this tissue (external blood). The blood is determined by measuring the haemoglobin. Although the vessels do not grow into the agar, the agar becomes intensely red if an antiangiogenic effect is present. If a compound inhibits the increase in blood that is induced by the growth factor, this is seen as an indication that the compound in question is blocking the angiogenic effect of the growth factor concerned. Inhibition of the weight but not the volume of blood suggests an effect on the proliferation of fibroblasts. A suppression of the control response suggests an inhibition of wound healing. At an oral dose of 50 mg/kg once daily, the compound of formula I inhibits the angiogenic effect of all three growth factors (VEGF, PDFG, bFGF). - It goes without saying that all the indicated inhibitory and pharmacological effects are also found with the free base, 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide, or other salts thereof. The present invention relates especially to the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I in the treatment of one of the said diseases or in the preparation of a pharmacological agent for the treatment tereof.
- The antiproliferative, especially anti-tumour, activity of the methanesulfonic acid addition salt of a compound of formula I in vivo is, for example, described for the treatment of abl-dependent tumours in Nature Med. 2, 561-6 (1996).
- The invention relates also to a process for the treatment of warm-blooded animals suffering from said diseases, especially a tumour disease, wherein a quantity of the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I which is effective against the disease concerned, especially a quantity with antiproliferative and especially tumour-inhibiting efficacy, is administered to warm-blooded animals in need of such treatment. The invention relates moreover to the use of the β-crystal form of the methanesulfonic acid addition salt of a compound of formula I for the inhibition of the above-mentioned tyrosine kinases, especially PDGF receptor kinase, v-abl kinase, and/or c-kit receptor kinase, or for the preparation of pharmaceutical compositions for use in treating the human or animal body, especially for the treatment of tumours, such as gliomas, ovarian tumours, prostate tumours, colon tumours, and tumours of the lung, such as especially small cell lung carcinoma, and tumours of the breast or other gynaecological tumours. Depending on species, age, individual condition, mode of administration, and the clinical picture in question, effective doses, for example daily doses of about 1-2500 mg, preferably 1-1000 mg, especially 5-500 mg, are administered to warm-blooded animals of about 70 kg bodyweight.
- The invention relates also to pharmaceutical preparations which contain an effective amount, especially an effective amount for prevention or treatment of one of the said diseases, of the methanesulfonic acid addition salt of a compound of formula I in the β-crystal form, together with pharmaceutically acceptable carriers which are suitable for topical, enteral, for example oral or rectal, or parenteral administration and may be inorganic or organic and solid or liquid. Especially tablets or gelatin capsules containing the active substance together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerin, and/or lubricants, for example silica, talc, stearic acid, or salts thereof, typically magnesium or calcium stearate, and/or polyethylene glycol, are used for oral administration, Tablets may likewise contain binders, for example magnesium aluminium silicate, starches, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if so desired, disintegrants, for example starches, agar, alginic acid, or a salt thereof, typically sodium alginate, and/or effervescent mixtures, or adsorbents, colouring agents, flavours, and sweetening agents. The pharmacologically active compounds of the present invention may further be used in the form of preparations for parenteral administration or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these possibly being prepared before use, for example in the case of lyophilised preparations containing the active substance either alone or together with a carrier, for example mannitol. The pharmaceutical substances may be sterilised and/or may contain excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for the regulation of osmotic pressure, and/or buffers. The present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances, such as antibiotics, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain from about 1% to 100%, especially from about 1% to about 20%, of the active substance or substances.
- The following Examples illustrate the invention without limiting the scope thereof. Rf-values are determined on TLC plates coated with silica gel (Merck, Darmstadt, Germany). The ratio of the solvents to one another in the solvent systems used is indicated by volume (v/v), and temperatures are given in degrees celsius (° C.).
- Eluents (Gradients):
- HPLC Gradient:
-
- 0% b) in a) for 20 minutes, then 0%→30% b) in a) for 10 minutes, then 30% b) in a) for 5 minutes.
- Eluent a): Ion pairing reagent and methanol (420 ml+580 ml)
- Eluent b): Ion pairing reagent and methanol (40 ml+960 ml)
- Ion pairing reagent: 7.5 g 1-octanesulfonic acid dissolved in about 800 ml water, pH value adjusted to 2.5 with phosphoric acid, and diluted with water to 1000 ml.
- Column: 150×3.9 mm, packed with Symmetry C18 5μ (Waters), pre-equilibrated with eluent a).
- Flow rate 1.2 ml/min, UV detection at 267 nm.
- An 11% (w/w) suspension of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate in the α-crystal form is digested in methanol for two days at about 25° C. The crystals are isolated by filtration on a glass filter with a G4 frit and dried overnight at room temperature on filter paper. Smp (by DSC): 217° C. (start of melting).
- The starting material, 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide methanesulfonate is prepared as follows: 98.6 g (0.2 mol) free 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide (for preparation see, for example, EP-A-0 564 409) is added to 1.4 l ethanol. To this beige suspension, 19.2 g (0.2 mol) methanesulfonic acid is added dropwise over a period of 20 minutes. The solution is heated under reflux for 20 minutes ard then filtered clear at 65° C. The filtrate is evaporated down to 50% and the residue filtered off at 25° C. (filter material A). The mother liquor is evaporated to dryness. This residue and filter material A are suspended in 2.2 l ethanol and dissolved under reflux with the addition of 30 ml water. Cooling overnight to 25° C., filtration, and drying at 65° C. until constancy of weight is achieved result in 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide as light beige, crystalline mesylate α-crystal form).
- 50.0 g (101 mmol) 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide is suspended in methanol (480 ml). 9.71 g (101 mmol) methanesulfonic acid and methanol (20 ml) is added, heated to 50° C., activated carbon (5.0 g) added, and the mixture boiled under reflux for 30 minutes, filtered, and concentrated by evaporation. The residue is dissolved in methanol-(150 ml) and inoculated with 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate (β-modification, a few mg), leading to crystallisation of the product. Drying at 50 mbar and 60° C. leads to 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate, β-modification; Rf=0.58 (methylene chloride:ethyl acetate:methanol:concentrated aqueous ammonium hydroxide solution=60:10:30:2); HPLC: tret=10.2 min.
- 670 g (1136 mmol) 4-[(4-methyl-1-piperazin-1-yl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl-2-pyrimidinyl]amino]phenyl]benzamide, α-modification, is heated in methanol (1680 ml). The solution is inoculated at 60° C. with 4-[(4-methyl-1-piperazin-1-yl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate (β-modification, 55 mg), whereupon the product starts to crystallise. Drying at 50 mbar and 100° C. leads to 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, β-modification; Rf=0.58 (methylene chloride:ethyl acetate:methanol:concentrated aqueous ammonium hydroxide solution=60:10:30:2); HPLC: tret=10.2 min.
- Tablets containing 100 mg of the active substance named in the title are usually prepared in the following composition:
- Composition
Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL 20 mg Aerosil 2 mg Magnesium stearate 5 mg 447 mg - Preparation: The active substance is mixed with carrier materials and compressed on a tableting machine (Korsch EKO,
punch diameter 10 mm). - Avicel is microcrystalline cellulose (FMC, Philadelphia, USA).
- PVPPXL is polyvinylpolypyrrolidone, cross-linked (BASF, Germany).
- Aerosil is silicon dioxide (Degussa, Germany).
- Capsules containing 100 mg of the compound named in the title as active substance are usually prepared in the following composition:
- Composition
Active ingredient 100 mg Avicel 200 mg PVPPXL 15 mg Aerosil 2 mg Magnesium stearate 1.5 mg 318.5 mg - The capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules,
size 1.
Claims (4)
1-12. (canceled)
14. A process for the preparation of the methansulfonate of a compound of formula I according to claim 1 wherein the free base of formula I is reacted with an equimolar amount of methanesulfonic acid under reflux in ethanol.
15. The use of the methansulfonate salt of a compound of formula I according to claim 1 for the preparation of a β-crystal form of the methansulfonate salt of a compound of formula I.
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US11/241,266 US20060030568A1 (en) | 1997-07-18 | 2005-09-29 | Crystal modificaion of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use |
US11/515,997 US7544799B2 (en) | 1997-07-18 | 2006-09-05 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
US13/238,967 USRE43932E1 (en) | 1997-07-18 | 2011-09-21 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
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CH176497 | 1997-07-18 | ||
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US09/463,097 US6894051B1 (en) | 1997-07-18 | 1998-07-16 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
PCT/EP1998/004427 WO1999003854A1 (en) | 1997-07-18 | 1998-07-16 | Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
US09/991,184 US7151106B2 (en) | 1997-07-18 | 2001-11-16 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
US11/241,266 US20060030568A1 (en) | 1997-07-18 | 2005-09-29 | Crystal modificaion of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use |
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US11/074,399 Continuation US20050192284A1 (en) | 1997-07-18 | 2005-03-07 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use |
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US09/991,184 Expired - Lifetime US7151106B2 (en) | 1997-07-18 | 2001-11-16 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
US11/074,399 Abandoned US20050192284A1 (en) | 1997-07-18 | 2005-03-07 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use |
US11/241,266 Abandoned US20060030568A1 (en) | 1997-07-18 | 2005-09-29 | Crystal modificaion of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use |
US11/515,997 Ceased US7544799B2 (en) | 1997-07-18 | 2006-09-05 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
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US09/991,184 Expired - Lifetime US7151106B2 (en) | 1997-07-18 | 2001-11-16 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
US11/074,399 Abandoned US20050192284A1 (en) | 1997-07-18 | 2005-03-07 | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use |
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CA2483594C (en) | 2002-05-16 | 2011-02-15 | Novartis Ag | Use of edg receptor binding agents in cancer |
US20060052387A1 (en) * | 2002-06-26 | 2006-03-09 | Marsh Clay B | Organic compounds |
JP2005531628A (en) * | 2002-06-28 | 2005-10-20 | ジ アドミニストレイターズ オブ ザ チューレン エデュケイショナル ファンド | 4- (4-Methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl] -benzamide for the treatment of pulmonary fibrosis |
ATE447560T1 (en) | 2002-06-28 | 2009-11-15 | Nippon Shinyaku Co Ltd | AMIDE DERIVATIVE |
AU2003252047A1 (en) * | 2002-07-18 | 2004-02-09 | Medtronic Ave Inc. | Medical devices comprising a protein-tyrosine kinase inhibitor to inhibit restonosis |
AU2003247094A1 (en) * | 2002-07-19 | 2004-02-09 | Ludwig Institute For Cancer Research | Enhancing the effect of radioimmunotherapy in the treatment of tumors |
CN1671389A (en) * | 2002-07-24 | 2005-09-21 | 诺瓦提斯公司 | 4-(4-methylpiperazin-1-ylmethyl)-n-[4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide for treating anaplastic thyroid cancer |
EP1526854A1 (en) * | 2002-07-24 | 2005-05-04 | University Of Cincinnati | 4-4(methylpiperazin-1-ylmethyl)-n- 4-methyl-3-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl -benzamide for treating mutated-ret kinase associated diseases |
DE60313339T2 (en) * | 2002-07-31 | 2008-01-03 | Critical Outcome Technologies, Inc. | PROTEIN TYROSINE KINASE INHIBITORS |
US8450302B2 (en) | 2002-08-02 | 2013-05-28 | Ab Science | 2-(3-aminoaryl) amino-4-aryl-thiazoles and their use as c-kit inhibitors |
DK1525200T3 (en) | 2002-08-02 | 2007-12-03 | Ab Science | 2- (3-aminoaryl) amino-4-aryl-thiazoles for disease treatment |
CA2439440A1 (en) | 2002-09-05 | 2004-03-05 | Emory University | Treatment of tuberous sclerosis associated neoplasms |
DE60318089T2 (en) * | 2002-10-09 | 2008-12-04 | Critical Outcome Technologies, Inc. | PROTEIN TYROSINE KINASE INHIBITORS |
GB0224455D0 (en) * | 2002-10-21 | 2002-11-27 | Novartis Ag | Organic compounds |
AU2003272007A1 (en) * | 2002-10-25 | 2004-05-13 | The Administrators Of The Tulane Educational Fund | Use of n-5-4-(4-methylpiperaziomethyl)-benzoylamido!-2-methylphenyl!-4-(3-pyridyl)2-pyridine-amine for the treatment of pulmonary hypertension |
US7094785B1 (en) | 2002-12-18 | 2006-08-22 | Cornell Research Foundation, Inc. | Method of treating polycythemia vera |
GB2398565A (en) * | 2003-02-18 | 2004-08-25 | Cipla Ltd | Imatinib preparation and salts |
JP2006513791A (en) * | 2003-04-04 | 2006-04-27 | ベイコ テック リミテッド | Vascular stent |
WO2004099186A1 (en) | 2003-05-06 | 2004-11-18 | Il Yang Pharm Co., Ltd. | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
AU2004251146A1 (en) | 2003-05-19 | 2005-01-06 | Irm, Llc | Immunosuppressant compounds and compositions |
MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
GB0312086D0 (en) * | 2003-05-27 | 2003-07-02 | Novartis Ag | Organic compounds |
PL1631291T3 (en) * | 2003-05-27 | 2010-04-30 | Haegerkvist Robert P | Use of tyrosine kinase inhibitors to treat diabetes |
TR200504337T1 (en) | 2003-06-02 | 2006-12-21 | Hetero Drugs Limited | New polymorphs of Imatinib mesylate |
US20060240014A1 (en) * | 2003-06-03 | 2006-10-26 | Beth Israel Deaconess Medical Center | Methods and compounds for the treatment of vascular stenosis |
US20080096864A1 (en) * | 2003-09-19 | 2008-04-24 | Sasa Dimitrijevic | Treatment Of Gastrointestinal Stromal Tumors With Imatinib And Midostaurin |
CA2542909C (en) | 2003-10-23 | 2012-07-10 | Ab Science | 2-aminoaryloxazole compounds as tyrosine kinase inhibitors |
CN1882344A (en) | 2003-11-18 | 2006-12-20 | 诺瓦提斯公司 | Inhibitors of the mutant form of KIT |
WO2005063720A1 (en) * | 2003-12-25 | 2005-07-14 | Nippon Shinyaku Co., Ltd. | Amide derivative and medicine |
AR047530A1 (en) | 2004-02-04 | 2006-01-25 | Novartis Ag | FORMS OF SALT OF 4- (4-METHYLIPIPERAZIN-1-ILMETIL) -N- (4-METHYL-3- (4-PIRIDIN-3-IL) PIRIMIDIN-2-ILAMINO) PHENYL) -BENZAMIDA |
PT1720853E (en) * | 2004-02-11 | 2016-03-04 | Natco Pharma Ltd | Novel polymorphic form of imatinib mesylate and a process for its preparation |
CN1309719C (en) * | 2004-02-18 | 2007-04-11 | 陈国庆 | Derivative of phenylamide pyrimidine and application thereof |
UA84462C2 (en) | 2004-04-02 | 2008-10-27 | Институт Фармацевтични | Crystalline polymorphs of methanesulfonic acid addition salts of imatinib |
ME02125B (en) | 2004-04-07 | 2013-04-30 | Novartis Ag | Inhibitors of iap |
GB0512324D0 (en) | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
MXPA06015148A (en) * | 2004-07-01 | 2007-08-21 | Netherlands Cancer Inst | Combination comprising a bcrp inhibitor and 4-(4-methylpiperazin- 1-ylmethyl)-n-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino) phenyl]-benzamide. |
WO2006024863A1 (en) * | 2004-09-02 | 2006-03-09 | Cipla Limited | Stable crystal form of imatinib mesylate and process for the preparation thereof |
SI1786799T1 (en) | 2004-09-09 | 2012-12-31 | Natco Pharma Limited | Novel phenylaminopyrimidine derivatives as inhibitors of bcr-abl kinase |
US8735415B2 (en) | 2004-09-09 | 2014-05-27 | Natco Pharma Limited | Acid addition salts of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3yl-pyrimidin-2ylamino)-phenyl]-benzamide |
WO2006048890A1 (en) * | 2004-11-04 | 2006-05-11 | Sun Pharmaceutical Industries Limited | Imatinib mesylate crystal form and process for preparation thereof |
WO2006054314A1 (en) * | 2004-11-17 | 2006-05-26 | Natco Pharma Limited | Polymorphic forms of imatinib mesylate |
US20070078121A1 (en) | 2004-12-23 | 2007-04-05 | Flynn Daniel L | Enzyme modulators and treatments |
KR20080019578A (en) | 2005-04-04 | 2008-03-04 | 에이비 사이언스 | Substituted oxazole derivatives and their use as tyrosine kinase inhibitors |
WO2006119154A1 (en) | 2005-05-02 | 2006-11-09 | Novartis Ag | Use of pyrimidylamimobenzamide derivatives for the treatment of systematic mastocytosis |
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
ES2339593T3 (en) | 2005-06-03 | 2010-05-21 | Novartis Ag | COMBINATION OF PIRIMIDILAMINOBENZAMIDA AND IMATINIB COMPOUNDS TO TREAT OR PREVENT PROLIFERATIVE DISEASES. |
GT200600316A (en) * | 2005-07-20 | 2007-04-02 | SALTS OF 4-METHYL-N- (3- (4-METHYL-IMIDAZOL-1-ILO) -5-TRIFLUOROMETILO-PHENYL) -3- (4-PIRIDINA-3-ILO-PIRIMIDINA-2-ILOAMINO) - BENZAMIDA. | |
KR100674813B1 (en) | 2005-08-05 | 2007-01-29 | 일양약품주식회사 | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
ES2334933T3 (en) * | 2005-08-15 | 2010-03-17 | Siegfried Generics International Ag | COVERED OR GRANULATED TABLET CONTAINING A PYRIDYL PIRIMIDINE. |
JP2009506014A (en) * | 2005-08-26 | 2009-02-12 | ノバルティス アクチエンゲゼルシャフト | Delta and epsilon crystal forms of imatinib mesylate |
AU2006314444C1 (en) | 2005-11-21 | 2018-01-04 | Novartis Ag | Neuroendocrine tumor treatment using mTOR inhibitors |
KR20080078804A (en) * | 2005-11-25 | 2008-08-28 | 노파르티스 아게 | F, g, h, i and k crystal forms of imatinib mesylate |
GB0605120D0 (en) | 2006-03-14 | 2006-04-26 | Novartis Ag | Organic Compounds |
MX2008012715A (en) | 2006-04-05 | 2008-10-14 | Novartis Ag | Combinations of therapeutic agents for treating cancer. |
KR20140020367A (en) | 2006-04-05 | 2014-02-18 | 노파르티스 아게 | Combinations comprising bcr-abl/c-kit/pdgf-r tk inhibitors for treating cancer |
US20060223816A1 (en) * | 2006-05-08 | 2006-10-05 | Chemagis Ltd. | Imatinib mesylate alpha form and production process therefor |
MX2008014292A (en) | 2006-05-09 | 2008-11-18 | Novartis Ag | Combination comprising an iron chelator and an anti-neoplastic agent and use thereof. |
US20060223817A1 (en) * | 2006-05-15 | 2006-10-05 | Chemagis Ltd. | Crystalline imatinib base and production process therefor |
WO2008004944A1 (en) * | 2006-07-04 | 2008-01-10 | Astrazeneca Ab | Novel crystalline form ii |
WO2008004945A1 (en) * | 2006-07-04 | 2008-01-10 | Astrazeneca Ab | Novel crystalline forms i and ii |
US8246966B2 (en) | 2006-08-07 | 2012-08-21 | University Of Georgia Research Foundation, Inc. | Trypanosome microsome system and uses thereof |
CA2662977A1 (en) | 2006-09-22 | 2008-03-27 | Novartis Ag | Method of optimizing the treatment of philadelphia-positive leukemia with abl tyrosine kinase inhibitors |
US20090286779A1 (en) | 2006-09-29 | 2009-11-19 | Novartis Ag | Pyrazolopyrimidines as lipid kinase inhibitors |
US8466154B2 (en) | 2006-10-27 | 2013-06-18 | The Board Of Regents Of The University Of Texas System | Methods and compositions related to wrapping of dehydrons |
EP2089003A1 (en) * | 2006-11-09 | 2009-08-19 | Abbott GmbH & Co. KG | Pharmaceutical dosage form for oral administration of tyrosine kinase inhibitor |
EP1920767A1 (en) * | 2006-11-09 | 2008-05-14 | Abbott GmbH & Co. KG | Melt-processed imatinib dosage form |
US8338433B2 (en) | 2006-11-22 | 2012-12-25 | University Of Georgia Research Foundation, Inc. | Tyrosine kinase inhibitors as anti-kinetoplastid agents |
CA2673683C (en) | 2007-01-11 | 2014-07-29 | Critical Outcome Technologies, Inc. | Compounds and method for treatment of cancer |
WO2008093246A2 (en) | 2007-02-02 | 2008-08-07 | Vegenics Limited | Vegf receptor antagonist for treating organ transplant alloimmunity and arteriosclerosis |
KR100799821B1 (en) * | 2007-02-05 | 2008-01-31 | 동화약품공업주식회사 | Novel imatinib camsylate and method for preparing thereof |
NZ578944A (en) * | 2007-02-13 | 2011-03-31 | Ab Science | PROCESS FOR THE SYNTHESIS OF 2-AMINOTHIAZOLE COMPOUNDS SUCH AS 4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide AS KINASE INHIBITORS |
RU2009134223A (en) | 2007-02-15 | 2011-03-20 | Новартис АГ (CH) | COMBINATION OF LBH589 WITH OTHER THERAPEUTIC MEDICINES FOR THE TREATMENT OF CANCER |
CN101265274B (en) * | 2007-02-16 | 2013-09-04 | 中国医学科学院药物研究所 | Pyrimidinthiazolamine derivatives, and preparation method, medicament composition and use thereof |
US20080234286A1 (en) * | 2007-03-20 | 2008-09-25 | Chemagis Ltd. | Stable amorphous imatinib mesylate and production process therefor |
US7550591B2 (en) * | 2007-05-02 | 2009-06-23 | Chemagis Ltd. | Imatinib production process |
WO2008136010A1 (en) * | 2007-05-07 | 2008-11-13 | Natco Pharma Limited | A process for the preparation of highly pure imatinib base |
EP2305263B1 (en) | 2007-06-07 | 2012-09-19 | Novartis AG | Stabilized amorphous forms of imatinib mesylate |
US20090082361A1 (en) * | 2007-09-26 | 2009-03-26 | Protia, Llc | Deuterium-enriched imatinib |
WO2009048947A1 (en) * | 2007-10-09 | 2009-04-16 | Board Of Regents, The University Of Texas System | Methods of treatment of opioid tolerance, physical dependence, pain, and addiction with inhibitors of certain growth factor receptors |
US8466151B2 (en) * | 2007-12-26 | 2013-06-18 | Critical Outcome Technologies, Inc. | Compounds and method for treatment of cancer |
WO2009118292A1 (en) | 2008-03-24 | 2009-10-01 | Novartis Ag | Arylsulfonamide-based matrix metalloprotease inhibitors |
EA019033B1 (en) | 2008-03-26 | 2013-12-30 | Новартис Аг | Hydroxamate-based inhibitors of deacetylases b |
US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
LT2300013T (en) | 2008-05-21 | 2017-12-27 | Ariad Pharmaceuticals, Inc. | Phosphorous derivatives as kinase inhibitors |
CN101584696A (en) | 2008-05-21 | 2009-11-25 | 上海艾力斯医药科技有限公司 | Composition containing quinazoline derivatives, preparation method and use |
NZ590076A (en) | 2008-06-27 | 2012-11-30 | Univ Indiana Res & Tech Corp | Treating plexiform neurofibroma and related tumors |
DE102008031037A1 (en) | 2008-06-30 | 2009-12-31 | Dömling, Alexander, Priv.-Doz. Dr. | Use of 2-aminopyrimidine derivatives as receptor tyrosine kinase inhibitor for accompanying treatment of organ transplantations |
EP2318406B1 (en) | 2008-07-17 | 2016-01-27 | Critical Outcome Technologies, Inc. | Thiosemicarbazone inhibitor compounds and cancer treatment methods |
WO2010019557A1 (en) * | 2008-08-12 | 2010-02-18 | Concert Pharmaceuticals Inc. | N-phenyl-2-pyrimidineamine derivatives |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
EP2344161B1 (en) | 2008-10-16 | 2018-12-19 | Celator Pharmaceuticals, Inc. | Combinations of a liposomal water-soluble camptothecin with cetuximab or bevacizumab |
EP2186514B1 (en) | 2008-11-14 | 2016-06-29 | Kinki University | Treatment of Malignant Peripheral Nerve Sheath Tumors |
WO2010065433A1 (en) | 2008-12-01 | 2010-06-10 | Novartis Ag | Method of optimizing the treatment of philadelphia-positive leukemia with imatinib mesylate |
CN103204794A (en) | 2008-12-18 | 2013-07-17 | 诺瓦提斯公司 | New Salts |
US8173634B2 (en) | 2008-12-18 | 2012-05-08 | Novartis Ag | Polymorphic form of 1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl}-2-ethyl-benzyl)-azetidine-3-carboxylic |
RS53041B (en) | 2008-12-18 | 2014-04-30 | Novartis Ag | Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid |
WO2010083617A1 (en) | 2009-01-21 | 2010-07-29 | Oncalis Ag | Pyrazolopyrimidines as protein kinase inhibitors |
US20110281917A1 (en) | 2009-01-29 | 2011-11-17 | Darrin Stuart | Substituted Benzimidazoles for the Treatment of Astrocytomas |
UA103918C2 (en) | 2009-03-02 | 2013-12-10 | Айерем Элелси | N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators |
WO2010120386A1 (en) | 2009-04-17 | 2010-10-21 | Nektar Therapeutics | Oligomer-protein tyrosine kinase inhibitor conjugates |
ES2753874T3 (en) | 2009-04-28 | 2020-04-14 | Daiichi Sankyo Co Ltd | Novel Solvate Crystals |
US20100330130A1 (en) | 2009-05-22 | 2010-12-30 | Actavis Group Ptc Ehf | Substantially pure imatinib or a pharmaceutically acceptable salt thereof |
TW201102068A (en) * | 2009-06-02 | 2011-01-16 | Novartis Ag | Treatment of ophthalmologic disorders mediated by alpha-carbonic anhydrase isoforms |
CA2765983C (en) | 2009-06-26 | 2017-11-14 | Novartis Ag | 1,3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17 |
US8389526B2 (en) | 2009-08-07 | 2013-03-05 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives |
EA201200260A1 (en) | 2009-08-12 | 2012-09-28 | Новартис Аг | HETEROCYCLIC HYDRAZONES AND THEIR APPLICATION FOR THE TREATMENT OF CANCER AND INFLAMMATION |
GEP201706639B (en) | 2009-08-17 | 2017-03-27 | Intellikine Llc | Heterocyclic compounds and uses thereof |
IN2012DN01453A (en) | 2009-08-20 | 2015-06-05 | Novartis Ag | |
WO2011023677A1 (en) | 2009-08-26 | 2011-03-03 | Novartis Ag | Tetra-substituted heteroaryl compounds and their use as mdm2 and/or mdm4 modulators |
CZ2009570A3 (en) | 2009-08-26 | 2011-03-09 | Zentiva, K. S. | Preparation, stabilization and use of imatinib mesylate polymorphs for development of medicinal forms |
MX2012002997A (en) | 2009-09-10 | 2012-08-01 | Novartis Ag | Ether derivatives of bicyclic heteroaryls. |
WO2011039782A1 (en) * | 2009-09-29 | 2011-04-07 | Ind-Swift Laboratories Limited | Processes for preparing imatinib and pharmaceutically acceptable salts thereof |
PL389357A1 (en) | 2009-10-22 | 2011-04-26 | Tomasz Koźluk | Tartaric acids derivatives imatinib salts and process for the preparation thereof |
EA201200651A1 (en) | 2009-11-04 | 2012-12-28 | Новартис Аг | HETEROCYCLIC SULPHONAMIDE DERIVATIVES APPLICABLE AS MEK INHIBITORS |
CN102781237A (en) | 2009-11-23 | 2012-11-14 | 天蓝制药公司 | Cyclodextrin-based polymers for therapeutic delivery |
US20120289501A1 (en) | 2009-11-25 | 2012-11-15 | Novartis Ag | Benzene-fused 6-membered oxygen-containing heterocyclic derivatives of bicyclic heteroaryls |
WO2011070030A1 (en) | 2009-12-08 | 2011-06-16 | Novartis Ag | Heterocyclic sulfonamide derivatives |
AU2012265844A1 (en) | 2009-12-08 | 2013-05-02 | Novartis Ag | Heterocyclic sulfonamide derivatives |
US8440693B2 (en) | 2009-12-22 | 2013-05-14 | Novartis Ag | Substituted isoquinolinones and quinazolinones |
CU24130B1 (en) | 2009-12-22 | 2015-09-29 | Novartis Ag | ISOQUINOLINONES AND REPLACED QUINAZOLINONES |
WO2011090940A1 (en) | 2010-01-19 | 2011-07-28 | Cerulean Pharma Inc. | Cyclodextrin-based polymers for therapeutic delivery |
WO2011095835A1 (en) | 2010-02-02 | 2011-08-11 | Actavis Group Ptc Ehf | Highly pure imatinib or a pharmaceutically acceptable salt thereof |
JP2013519665A (en) | 2010-02-15 | 2013-05-30 | リライアンス ライフ サイエンシズ ピーヴィーティー リミティッド | Process for producing α form of imatinib mesylate |
PL390611A1 (en) | 2010-03-04 | 2011-09-12 | Tomasz Koźluk | Process for the preparation of polymorphic alpha form and new polymorphic form of imatinib mesylate |
CA2792472A1 (en) | 2010-03-15 | 2011-09-22 | Natco Pharma Limited | Process for the preparation of highly pure crystalline imatinib base |
US20110237686A1 (en) | 2010-03-26 | 2011-09-29 | Cerulean Pharma Inc | Formulations and methods of use |
WO2011120153A1 (en) | 2010-04-01 | 2011-10-06 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
WO2011130918A1 (en) | 2010-04-23 | 2011-10-27 | 上海百灵医药科技有限公司 | Process for synthesizing imatinib |
EP2382976A1 (en) | 2010-04-30 | 2011-11-02 | Hiroshima University | Use of pdgf-r inhibitors for the treatment of lymph node metastasis of gastric cancer |
WO2011158255A1 (en) * | 2010-06-16 | 2011-12-22 | Aptuit Laurus Private Limited | Process for preparation of stable imatintb mesylate alpha form |
CN102947274A (en) | 2010-06-17 | 2013-02-27 | 诺瓦提斯公司 | Biphenyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives |
CN102947275A (en) | 2010-06-17 | 2013-02-27 | 诺瓦提斯公司 | Piperidinyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives |
SI2582689T1 (en) | 2010-06-18 | 2017-05-31 | Krka, D.D., Novo Mesto | New polymorphic form of imatinib base and preparation of salts thereof |
UA112517C2 (en) | 2010-07-06 | 2016-09-26 | Новартіс Аг | TETRAHYDROPYRIDOPYRIMIDINE DERIVATIVES |
RU2013110058A (en) | 2010-08-11 | 2014-09-20 | Синтон Б.В. | PHARMACEUTICAL GRANULATE CONTAINING IMATINIB MESILATE |
TR201007005A2 (en) | 2010-08-23 | 2011-09-21 | Mustafa Nevzat İlaç Sanayi̇i̇ A.Ş. | Imatinib base production method |
WO2012027716A1 (en) | 2010-08-27 | 2012-03-01 | Collabrx, Inc. | Method to treat melanoma in braf inhibitor-resistant subjects |
RU2456280C2 (en) * | 2010-08-27 | 2012-07-20 | Общество с ограниченной ответственностью "Химфармресурс" | Crystalline (-modification of 4-[(4-methyl-1-piperazinyl)methyl]-n-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl] benzamide methanesulphonate, method for preparing it and based pharmaceutical composition |
JP2013537210A (en) | 2010-09-16 | 2013-09-30 | ノバルティス アーゲー | 17α-hydroxylase / C17,20-lyase inhibitor |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
CN102477031B (en) | 2010-11-30 | 2015-07-15 | 浙江九洲药业股份有限公司 | Method for preparing imatinib mesylate alfa crystal form |
TR201010618A2 (en) * | 2010-12-20 | 2012-07-23 | Bi̇lgi̇ç Mahmut | An oral dosage form comprising imatinib and the manufacture of an oral dosage form |
CN103270026A (en) | 2010-12-21 | 2013-08-28 | 诺瓦提斯公司 | Bi-heteroaryl compounds as vps34 inhibitors |
WO2012090221A1 (en) | 2010-12-29 | 2012-07-05 | Cadila Healthcare Limited | Novel salts of imatinib |
EP2673277A1 (en) | 2011-02-10 | 2013-12-18 | Novartis AG | [1, 2, 4]triazolo [4, 3 -b]pyridazine compounds as inhibitors of the c-met tyrosine kinase |
CN102649785B (en) * | 2011-02-23 | 2015-08-19 | 江苏先声药物研究有限公司 | Her agate a kind of replaces the preparation method of Buddhist nun's methane sulfonates beta crystal |
WO2012116237A2 (en) | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
CN102146073A (en) * | 2011-02-23 | 2011-08-10 | 江苏先声药物研究有限公司 | New preparation method of alpha crystal form of imatinib mesylate |
WO2012122058A2 (en) | 2011-03-04 | 2012-09-13 | Newgen Therapeutics, Inc. | Alkyne substituted quinazoline compound and methods of use |
CN103492390A (en) | 2011-03-08 | 2014-01-01 | 诺瓦提斯公司 | Fluorophenyl bicyclic heteroaryl compounds |
PL394169A1 (en) | 2011-03-09 | 2012-09-10 | Adamed Spółka Z Ograniczoną Odpowiedzialnością | The pharmaceutical composition of imatinib mesylate for filling unit dosage forms and the method for its preparation |
JP2014509642A (en) | 2011-03-31 | 2014-04-21 | アイエヌディー−スイフト ラボラトリーズ リミテッド | An improved method for the formation of imatinib and its mesylate |
CN103649073B (en) | 2011-04-28 | 2016-04-13 | 诺瓦提斯公司 | 17 α-hydroxylase/C 17,20-lyase inhibitor |
CN103501612B (en) | 2011-05-04 | 2017-03-29 | 阿里亚德医药股份有限公司 | The compound that cell is bred in cancer caused by suppression EGF-R ELISA |
WO2012155339A1 (en) | 2011-05-17 | 2012-11-22 | 江苏康缘药业股份有限公司 | 4-phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, preparative method and use thereof |
ES2841809T3 (en) | 2011-06-03 | 2021-07-09 | Eisai R&D Man Co Ltd | Biomarkers to predict and evaluate the degree of response of subjects with thyroid and kidney cancer to lenvatinib compounds |
US8859586B2 (en) | 2011-06-20 | 2014-10-14 | Novartis Ag | Cyclohexyl isoquinolinone compounds |
EP2721008B1 (en) | 2011-06-20 | 2015-04-29 | Novartis AG | Hydroxy substituted isoquinolinone derivatives as p53 (mdm2 or mdm4) inhibitors |
US9750700B2 (en) | 2011-06-22 | 2017-09-05 | Natco Pharma Limited | Imatinib mesylate oral pharmaceutical composition and process for preparation thereof |
EA201490164A1 (en) | 2011-06-27 | 2014-04-30 | Новартис Аг | SOLID FORMS AND SALTS DERIVATIVES OF TETRAHYDROPYRIDOPYRIMIDINE |
ITMI20111309A1 (en) | 2011-07-14 | 2013-01-15 | Italiana Sint Spa | PREPARATION PROCEDURE OF IMATINIB MESILATO |
CN102321070B (en) * | 2011-07-27 | 2013-05-22 | 江苏先声药物研究有限公司 | Method for preparing imatinib methylolsulfonate alpha crystal through inverse solvent recrystallization method |
WO2013038362A1 (en) | 2011-09-15 | 2013-03-21 | Novartis Ag | 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase |
WO2013063000A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
WO2013063003A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
CA2853961C (en) | 2011-11-01 | 2016-09-20 | Modgene, Llc | Compositions and methods for reduction of amyloid-beta load |
JP5992054B2 (en) | 2011-11-29 | 2016-09-14 | ノバルティス アーゲー | Pyrazolopyrrolidine compound |
US9408885B2 (en) | 2011-12-01 | 2016-08-09 | Vib Vzw | Combinations of therapeutic agents for treating melanoma |
EP2604596A1 (en) | 2011-12-16 | 2013-06-19 | Deva Holding Anonim Sirketi | Polymorphs of imatinib |
US20150148377A1 (en) | 2011-12-22 | 2015-05-28 | Novartis Ag | Quinoline Derivatives |
CR20200286A (en) | 2011-12-22 | 2020-09-23 | Novartis Ag | Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives |
CA2859862A1 (en) | 2011-12-23 | 2013-06-27 | Novartis Ag | Compounds for inhibiting the interaction of bcl2 with binding partners |
EA201491259A1 (en) | 2011-12-23 | 2014-11-28 | Новартис Аг | COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE INTERACTION OF BCL2 WITH BOND PARTNERS |
AU2012355624A1 (en) | 2011-12-23 | 2014-07-17 | Novartis Ag | Compounds for inhibiting the interaction of BCL2 with binding partners |
EA201491264A1 (en) | 2011-12-23 | 2014-11-28 | Новартис Аг | COMPOUNDS FOR INHIBITING THE INTERACTION OF BCL-2 WITH PARTNERS ON BINDING |
KR20140107575A (en) | 2011-12-23 | 2014-09-04 | 노파르티스 아게 | Compounds for inhibiting the interaction of bcl2 with binding partners |
US20130178520A1 (en) | 2011-12-23 | 2013-07-11 | Duke University | Methods of treatment using arylcyclopropylamine compounds |
PL226174B1 (en) | 2011-12-30 | 2017-06-30 | Inst Farm | Combination therapy of non-small-cell lung carcinoma |
UY34591A (en) | 2012-01-26 | 2013-09-02 | Novartis Ag | IMIDAZOPIRROLIDINONA COMPOUNDS |
EP2817030A1 (en) | 2012-02-21 | 2014-12-31 | Ranbaxy Laboratories Limited | Stable dosage forms of imatinib mesylate |
CN102617549A (en) * | 2012-03-02 | 2012-08-01 | 瑞阳制药有限公司 | Method for preparing imatinib mesylate beta crystalline form |
IN2012DE00728A (en) | 2012-03-13 | 2015-08-21 | Fresenius Kabi Oncology Ltd | |
GB201204810D0 (en) | 2012-03-20 | 2012-05-02 | Pharos Pharmaceutical Oriented Services Ltd | Pharmaceutical compositions |
ES2894830T3 (en) | 2012-04-03 | 2022-02-16 | Novartis Ag | Combination products with tyrosine kinase inhibitors and their use |
CN102617552A (en) * | 2012-04-06 | 2012-08-01 | 江南大学 | Crystallizing method for preparing alpha crystal form methanesulfonic acid imatinib |
CN102633775B (en) * | 2012-04-06 | 2013-07-17 | 江南大学 | Method for preparing alpha-crystal-form imatinib mesylate |
JP2013216644A (en) * | 2012-04-11 | 2013-10-24 | Takada Seiyaku Kk | Imatinib mesilate oral administration preparation |
WO2013169401A1 (en) | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
CN104321325B (en) | 2012-05-24 | 2016-11-16 | 诺华股份有限公司 | Pyrrolopyrrole alkanone compound |
BR112014031421A2 (en) | 2012-06-15 | 2017-06-27 | Brigham & Womens Hospital Inc | cancer treatment compositions and methods for producing them |
KR101242955B1 (en) * | 2012-06-25 | 2013-03-12 | 제일약품주식회사 | A METHOD OF PREPARING IMATINIB MESYLATE α |
IN2014DN10801A (en) | 2012-07-11 | 2015-09-04 | Novartis Ag | |
WO2014016848A2 (en) | 2012-07-24 | 2014-01-30 | Laurus Labs Private Limited | Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof |
MX2015001194A (en) | 2012-07-27 | 2015-11-23 | Izumi Technology Llc | Effluz inhibitor compositions and methods of treatment using the same. |
CN103570677B (en) * | 2012-08-02 | 2017-03-01 | 广东东阳光药业有限公司 | A kind of preparation method of alpha-crystal form imatinib mesylate |
US9738643B2 (en) | 2012-08-06 | 2017-08-22 | Duke University | Substituted indazoles for targeting Hsp90 |
WO2014041551A1 (en) | 2012-09-14 | 2014-03-20 | Natco Pharma Limited | Formulation comprising imatinib as oral solution |
WO2014048377A1 (en) | 2012-09-28 | 2014-04-03 | 杭州本生药业有限公司 | Drug composition for treating tumors and application thereof |
US9439903B2 (en) | 2012-10-25 | 2016-09-13 | Cadila Healthcare Limited | Process for the preparation of amorphous imatinib mesylate |
JP6374392B2 (en) | 2012-11-05 | 2018-08-15 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | XBP1, CD138 and CS1 peptides, pharmaceutical compositions containing the peptides, and methods of using such peptides and compositions |
TW201422625A (en) | 2012-11-26 | 2014-06-16 | Novartis Ag | Solid form of dihydro-pyrido-oxazine derivative |
EP2749269A1 (en) | 2012-12-31 | 2014-07-02 | Deva Holding Anonim Sirketi | Process for the preparation of adsorbates of imatinib |
EP2749557A1 (en) | 2012-12-31 | 2014-07-02 | Deva Holding Anonim Sirketi | Process for preparation of alpha polymorph of imatinib mesylate from IPA and THF solvate forms of imatinib mesylate |
EP2749271A1 (en) | 2012-12-31 | 2014-07-02 | Deva Holding Anonim Sirketi | Optimized manufacturing method and pharmaceutical formulation of imatinib |
WO2014115080A1 (en) | 2013-01-22 | 2014-07-31 | Novartis Ag | Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction |
WO2014115077A1 (en) | 2013-01-22 | 2014-07-31 | Novartis Ag | Substituted purinone compounds |
EP3626741A1 (en) | 2013-02-20 | 2020-03-25 | The Trustees Of The University Of Pennsylvania | Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor |
WO2014128612A1 (en) | 2013-02-20 | 2014-08-28 | Novartis Ag | Quinazolin-4-one derivatives |
WO2014151147A1 (en) | 2013-03-15 | 2014-09-25 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
GB201304699D0 (en) | 2013-03-15 | 2013-05-01 | Remedica Ltd | Pharmaceutical compositions |
WO2014155268A2 (en) | 2013-03-25 | 2014-10-02 | Novartis Ag | Fgf-r tyrosine kinase activity inhibitors - use in diseases associated with lack of or reduced snf5 activity |
US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
ES2683361T3 (en) | 2013-05-14 | 2018-09-26 | Hetero Research Foundation | Imatinib compositions |
US20150018376A1 (en) | 2013-05-17 | 2015-01-15 | Novartis Ag | Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof |
UY35675A (en) | 2013-07-24 | 2015-02-27 | Novartis Ag | SUBSTITUTED DERIVATIVES OF QUINAZOLIN-4-ONA |
AU2014296032A1 (en) | 2013-07-31 | 2016-03-17 | Windward Pharma, Inc. | Aerosol tyrosine kinase inhibitor compounds and uses thereof |
WO2015022664A1 (en) | 2013-08-14 | 2015-02-19 | Novartis Ag | Compounds and compositions as inhibitors of mek |
US9227969B2 (en) | 2013-08-14 | 2016-01-05 | Novartis Ag | Compounds and compositions as inhibitors of MEK |
WO2015022663A1 (en) | 2013-08-14 | 2015-02-19 | Novartis Ag | Compounds and compositions as inhibitors of mek |
SG11201600028YA (en) | 2013-09-22 | 2016-02-26 | Calitor Sciences Llc | Substituted aminopyrimidine compounds and methods of use |
AU2014336016B2 (en) | 2013-10-17 | 2019-12-19 | Sartar Therapeutics Ltd | Compositions comprising phosphodiesterase inhibitors for use in the treatment of a solid tumor in a human patient |
US9636340B2 (en) | 2013-11-12 | 2017-05-02 | Ayyappan K. Rajasekaran | Kinase inhibitors |
WO2015084804A1 (en) | 2013-12-03 | 2015-06-11 | Novartis Ag | Combination of mdm2 inhibitor and braf inhibitor and their use |
WO2015110949A1 (en) | 2014-01-22 | 2015-07-30 | Novartis Ag | Imatinib as cholesterol decreasing agent |
JOP20200094A1 (en) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | Antibody molecules to pd-1 and uses thereof |
JOP20200096A1 (en) | 2014-01-31 | 2017-06-16 | Children’S Medical Center Corp | Antibody molecules to tim-3 and uses thereof |
CN103800671B (en) * | 2014-02-11 | 2016-02-10 | 王思成 | A kind of Chinese medicine preparation for the treatment of aphtha |
EP3116909B1 (en) | 2014-03-14 | 2019-11-13 | Novartis Ag | Antibody molecules to lag-3 and uses thereof |
WO2015148714A1 (en) | 2014-03-25 | 2015-10-01 | Duke University | Heat shock protein 70 (hsp-70) receptor ligands |
WO2015145388A2 (en) | 2014-03-27 | 2015-10-01 | Novartis Ag | Methods of treating colorectal cancers harboring upstream wnt pathway mutations |
US9394281B2 (en) | 2014-03-28 | 2016-07-19 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
KR20160132496A (en) | 2014-04-03 | 2016-11-18 | 인빅터스 온콜로지 피비티. 엘티디. | Supramolecular combinatorial therapeutics |
US9630944B2 (en) | 2014-04-04 | 2017-04-25 | F.I.S.—Fabbrica Italiana Sintetici S.p.A. | Process for preparing Imatinib and salts thereof, free of genotoxic impurity F |
CN104974133B (en) * | 2014-04-09 | 2018-04-27 | 石药集团中奇制药技术(石家庄)有限公司 | A kind of Crystal form of imatinib mesylate and preparation method thereof |
CN104055745A (en) * | 2014-06-11 | 2014-09-24 | 连云港杰瑞药业有限公司 | Method for preparing imatinib mesylate tablets |
WO2016011658A1 (en) | 2014-07-25 | 2016-01-28 | Novartis Ag | Combination therapy |
ES2831416T3 (en) | 2014-07-31 | 2021-06-08 | Novartis Ag | Combination therapy of a MET inhibitor and an EGFR inhibitor |
ES2926687T3 (en) | 2014-08-28 | 2022-10-27 | Eisai R&D Man Co Ltd | Highly pure quinoline derivative and method for its production |
MA41044A (en) | 2014-10-08 | 2017-08-15 | Novartis Ag | COMPOSITIONS AND METHODS OF USE FOR INCREASED IMMUNE RESPONSE AND CANCER TREATMENT |
EP4245376A3 (en) | 2014-10-14 | 2023-12-13 | Novartis AG | Antibody molecules to pd-l1 and uses thereof |
CN111888368B (en) | 2014-10-21 | 2024-02-02 | 武田药品工业株式会社 | Crystalline forms of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine |
EP3233918A1 (en) | 2014-12-19 | 2017-10-25 | Novartis AG | Combination therapies |
HUE064614T2 (en) | 2015-02-25 | 2024-04-28 | Eisai R&D Man Co Ltd | Method for suppressing bitterness of quinoline derivative |
KR102662228B1 (en) | 2015-03-04 | 2024-05-02 | 머크 샤프 앤드 돔 코포레이션 | Combination of PD-1 antagonists and VEGFR/FGFR/RET tyrosine kinase inhibitors to treat cancer |
JO3746B1 (en) | 2015-03-10 | 2021-01-31 | Aduro Biotech Inc | Compositions and methods for activating “stimulator of interferon gene”-dependent signalling |
CN106518844A (en) * | 2015-04-14 | 2017-03-22 | 江苏豪森药业集团有限公司 | An imatinib mesylate crystal form suitable for officinal uses and a preparing method thereof |
AU2016279474B2 (en) | 2015-06-16 | 2021-09-09 | Eisai R&D Management Co., Ltd. | Anticancer agent |
LT3317301T (en) | 2015-07-29 | 2021-07-26 | Novartis Ag | Combination therapies comprising antibody molecules to lag-3 |
EP3328418A1 (en) | 2015-07-29 | 2018-06-06 | Novartis AG | Combination therapies comprising antibody molecules to pd-1 |
US20180207273A1 (en) | 2015-07-29 | 2018-07-26 | Novartis Ag | Combination therapies comprising antibody molecules to tim-3 |
EP3347097B1 (en) | 2015-09-11 | 2021-02-24 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine derivatives as modulators of the kinases jak, flt3 and aurora |
MA43186B1 (en) | 2015-11-03 | 2022-03-31 | Janssen Biotech Inc | Antibodies specifically binding to pd-1 and uses thereof |
CN105503825B (en) * | 2015-12-16 | 2019-01-11 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of imatinib mesylate beta crystal |
MX2018007423A (en) | 2015-12-17 | 2018-11-09 | Novartis Ag | Antibody molecules to pd-1 and uses thereof. |
EP3407874B1 (en) | 2016-01-25 | 2024-05-22 | KRKA, d.d., Novo mesto | Fast dispersible pharmaceutical composition comprising tyrosine-kinase inhibitor |
CN108883108B (en) | 2016-03-25 | 2021-08-06 | Ab科学有限公司 | Use of masitinib for treating a subpopulation of patients with amyotrophic lateral sclerosis |
US11261187B2 (en) | 2016-04-22 | 2022-03-01 | Duke University | Compounds and methods for targeting HSP90 |
EP3257499A1 (en) | 2016-06-17 | 2017-12-20 | Vipharm S.A. | Process for preparation of imatinib methanesulfonate capsules |
EP3507367A4 (en) | 2016-07-05 | 2020-03-25 | Aduro BioTech, Inc. | Locked nucleic acid cyclic dinucleotide compounds and uses thereof |
WO2018039203A1 (en) | 2016-08-23 | 2018-03-01 | Oncopep, Inc. | Peptide vaccines and durvalumab for treating multiple myeloma |
US20190209669A1 (en) | 2016-08-23 | 2019-07-11 | Oncopep, Inc. | Peptide vaccines and durvalumab for treating breast cancer |
EP4089116A1 (en) | 2016-09-27 | 2022-11-16 | Cero Therapeutics, Inc. | Chimeric engulfment receptor molecules |
US10207998B2 (en) | 2016-09-29 | 2019-02-19 | Duke University | Substituted benzimidazole and substituted benzothiazole inhibitors of transforming growth factor-β kinase and methods of use thereof |
US10927083B2 (en) | 2016-09-29 | 2021-02-23 | Duke University | Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase |
KR102199253B1 (en) | 2016-10-17 | 2021-01-06 | 데루타-후라이 화마 가부시키가이샤 | Pharmaceutical composition for the treatment or remission of chronic myeloid leukemia |
US10777331B2 (en) | 2016-11-11 | 2020-09-15 | Curium Us Llc | Processes for generating germanium-68 with reduced volatiles |
UY37695A (en) | 2017-04-28 | 2018-11-30 | Novartis Ag | BIS 2’-5’-RR- (3’F-A) (3’F-A) CYCLE DINUCLEOTIDE COMPOUND AND USES OF THE SAME |
EP3642240A1 (en) | 2017-06-22 | 2020-04-29 | Novartis AG | Antibody molecules to cd73 and uses thereof |
CA3073421A1 (en) | 2017-09-26 | 2019-04-04 | Daniel Mark COREY | Chimeric engulfment receptor molecules and methods of use |
AU2018353984A1 (en) | 2017-10-24 | 2020-05-07 | Oncopep, Inc. | Peptide vaccines and pembrolizumab for treating breast cancer |
WO2019083960A1 (en) | 2017-10-24 | 2019-05-02 | Oncopep, Inc. | Peptide vaccines and hdac inhibitors for treating multiple myeloma |
WO2019099311A1 (en) | 2017-11-19 | 2019-05-23 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use |
EP3730483B1 (en) | 2017-12-21 | 2023-08-30 | Hefei Institutes of Physical Science, Chinese Academy of Sciences | Class of pyrimidine derivative kinase inhibitors |
JP7450541B2 (en) | 2018-01-20 | 2024-03-15 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | Substituted aminopyrimidine compounds and methods of use |
KR20210024441A (en) | 2018-03-28 | 2021-03-05 | 세로 테라퓨틱스, 인코포레이티드 | Expression vectors for chimeric phagocytic receptors, genetically modified host cells, and uses thereof |
US20210087251A1 (en) | 2018-03-28 | 2021-03-25 | Cero Therapeutics, Inc. | Chimeric tim4 receptors and uses thereof |
EP3774865A1 (en) | 2018-03-28 | 2021-02-17 | Cero Therapeutics, Inc. | Cellular immunotherapy compositions and uses thereof |
TW202015726A (en) | 2018-05-30 | 2020-05-01 | 瑞士商諾華公司 | Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies |
EP3826988A4 (en) | 2018-07-24 | 2023-03-22 | Hygia Pharmaceuticals, LLC | Compounds, derivatives, and analogs for cancer |
US20220040324A1 (en) | 2018-12-21 | 2022-02-10 | Daiichi Sankyo Company, Limited | Combination of antibody-drug conjugate and kinase inhibitor |
CN114502590A (en) | 2019-09-18 | 2022-05-13 | 诺华股份有限公司 | ENTPD2 antibodies, combination therapies, and methods of using these antibodies and combination therapies |
US20240058446A1 (en) | 2019-10-03 | 2024-02-22 | Cero Therapeutics, Inc. | Chimeric tim4 receptors and uses thereof |
EP4058465A1 (en) | 2019-11-14 | 2022-09-21 | Cohbar Inc. | Cxcr4 antagonist peptides |
WO2021233534A1 (en) | 2020-05-20 | 2021-11-25 | Pvac Medical Technologies Ltd | Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof |
WO2021185844A1 (en) | 2020-03-16 | 2021-09-23 | Pvac Medical Technologies Ltd | Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof |
US20230285576A1 (en) | 2020-08-05 | 2023-09-14 | Ellipses Pharma Ltd | Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor |
WO2022036287A1 (en) | 2020-08-14 | 2022-02-17 | Cero Therapeutics, Inc. | Anti-cd72 chimeric receptors and uses thereof |
WO2022036285A1 (en) | 2020-08-14 | 2022-02-17 | Cero Therapeutics, Inc. | Compositions and methods for treating cancer with chimeric tim receptors in combination with inhibitors of poly (adp-ribose) polymerase |
WO2022036265A1 (en) | 2020-08-14 | 2022-02-17 | Cero Therapeutics, Inc. | Chimeric tim receptors and uses thereof |
US11999964B2 (en) | 2020-08-28 | 2024-06-04 | California Institute Of Technology | Synthetic mammalian signaling circuits for robust cell population control |
TW202237638A (en) | 2020-12-09 | 2022-10-01 | 日商武田藥品工業股份有限公司 | Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof |
EP4298114A1 (en) | 2021-02-26 | 2024-01-03 | Kelonia Therapeutics, Inc. | Lymphocyte targeted lentiviral vectors |
WO2023010097A1 (en) | 2021-07-28 | 2023-02-02 | Cero Therapeutics, Inc. | Chimeric tim4 receptors and uses thereof |
CN114957206B (en) * | 2022-04-11 | 2024-02-27 | 中国药科大学 | Imatinib eutectic crystal and preparation method thereof |
WO2024030441A1 (en) | 2022-08-02 | 2024-02-08 | National University Corporation Hokkaido University | Methods of improving cellular therapy with organelle complexes |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4351832A (en) * | 1980-04-18 | 1982-09-28 | American Home Products Corporation | 2-(Piperazinyl)-4-pyrimidinamines |
US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
US5985893A (en) * | 1994-11-18 | 1999-11-16 | Pharmacia & Upjohn Company | Physically stable solid form of a fluoroquinolone |
US6048866A (en) * | 1997-03-14 | 2000-04-11 | Celltech Therapeutics, Limited | Substituted 2-anilinopryimidines useful as protein kinase inhibitors |
US6894051B1 (en) * | 1997-07-18 | 2005-05-17 | Novartis Ag | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3887551A (en) | 1964-11-04 | 1975-06-03 | Glaxo Lab Ltd | Crystalline forms of cephaloridine |
GB1413516A (en) * | 1972-10-06 | 1975-11-12 | Leo Pharm Prod Ltd | Crystalline pivaloyloxymethal d - -alpha- aminobenzylpenicillinate |
US3905959A (en) | 1973-05-07 | 1975-09-16 | Pfizer | Process for the manufacture of crystalline anhydrous ampicillin |
US4061853A (en) | 1975-12-09 | 1977-12-06 | Ciba-Geigy Corporation | Virtually solvent-free crystal form of the sodium salt of Cephacetril |
US4512993A (en) | 1983-07-25 | 1985-04-23 | Sterling Drug Inc. | 4(Or 5)-(pyridinyl)-2-pyrimidinamines and cardiotonic use thereof |
TW225528B (en) * | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
EP0672041B1 (en) * | 1993-10-01 | 2001-11-14 | Novartis AG | Pharmacologically active pyridine derivatives and processes for the preparation thereof |
-
1998
- 1998-07-09 CO CO98038983A patent/CO4940418A1/en unknown
- 1998-07-14 TW TW087111408A patent/TW491845B/en not_active IP Right Cessation
- 1998-07-16 PT PT98941342T patent/PT998473E/en unknown
- 1998-07-16 US US09/463,097 patent/US6894051B1/en not_active Expired - Lifetime
- 1998-07-16 JP JP2000503078A patent/JP3276359B2/en not_active Expired - Lifetime
- 1998-07-16 EP EP98941342A patent/EP0998473B1/en not_active Expired - Lifetime
- 1998-07-16 AU AU89759/98A patent/AU740713B2/en not_active Expired
- 1998-07-16 PE PE1998000632A patent/PE97899A1/en not_active IP Right Cessation
- 1998-07-16 CN CNB98807303XA patent/CN1134430C/en not_active Ceased
- 1998-07-16 ES ES98941342T patent/ES2209194T3/en not_active Expired - Lifetime
- 1998-07-16 DE DE69818674T patent/DE69818674T2/en not_active Expired - Lifetime
- 1998-07-16 AR ARP980103483A patent/AR016351A1/en active IP Right Grant
- 1998-07-16 DK DK98941342T patent/DK0998473T3/en active
- 1998-07-16 BR BR9810920-0A patent/BR9810920A/en not_active Application Discontinuation
- 1998-07-16 TR TR2000/00060T patent/TR200000060T2/en unknown
- 1998-07-16 PL PL98338129A patent/PL188348B1/en unknown
- 1998-07-16 HU HU0003230A patent/HU230185B1/en unknown
- 1998-07-16 SK SK5044-2005A patent/SK287276B6/en not_active IP Right Cessation
- 1998-07-16 AT AT98941342T patent/ATE251152T1/en active
- 1998-07-16 SK SK43-2000A patent/SK286551B6/en not_active IP Right Cessation
- 1998-07-16 NZ NZ502295A patent/NZ502295A/en not_active IP Right Cessation
- 1998-07-16 IL IL13390698A patent/IL133906A0/en active IP Right Grant
- 1998-07-16 KR KR10-2000-7000515A patent/KR100450356B1/en not_active IP Right Cessation
- 1998-07-16 WO PCT/EP1998/004427 patent/WO1999003854A1/en active IP Right Grant
- 1998-07-16 CA CA002296604A patent/CA2296604C/en not_active Expired - Lifetime
- 1998-07-16 RU RU2000102914/04A patent/RU2208012C2/en active
- 1998-07-16 ID IDW20000051A patent/ID24093A/en unknown
- 1998-07-16 CZ CZ20000149A patent/CZ298531B6/en not_active IP Right Cessation
- 1998-07-17 MY MYPI20043263A patent/MY128664A/en unknown
- 1998-07-17 ZA ZA986362A patent/ZA986362B/en unknown
- 1998-07-17 MY MYPI98003282A patent/MY129772A/en unknown
-
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- 2000-01-17 NO NO20000227A patent/NO319486B1/en not_active IP Right Cessation
- 2000-11-09 HK HK00107150A patent/HK1028599A1/en not_active IP Right Cessation
-
2001
- 2001-11-16 US US09/991,184 patent/US7151106B2/en not_active Expired - Lifetime
-
2004
- 2004-08-12 AR ARP040102891A patent/AR043266A2/en not_active Application Discontinuation
-
2005
- 2005-03-07 US US11/074,399 patent/US20050192284A1/en not_active Abandoned
- 2005-06-02 IL IL168972A patent/IL168972A/en not_active IP Right Cessation
- 2005-06-07 NO NO20052755A patent/NO331016B1/en not_active IP Right Cessation
- 2005-09-29 US US11/241,266 patent/US20060030568A1/en not_active Abandoned
-
2006
- 2006-03-02 IL IL174082A patent/IL174082A/en active IP Right Review Request
- 2006-04-03 IL IL174732A patent/IL174732A0/en unknown
- 2006-09-05 US US11/515,997 patent/US7544799B2/en not_active Ceased
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4351832A (en) * | 1980-04-18 | 1982-09-28 | American Home Products Corporation | 2-(Piperazinyl)-4-pyrimidinamines |
US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
US5985893A (en) * | 1994-11-18 | 1999-11-16 | Pharmacia & Upjohn Company | Physically stable solid form of a fluoroquinolone |
US6048866A (en) * | 1997-03-14 | 2000-04-11 | Celltech Therapeutics, Limited | Substituted 2-anilinopryimidines useful as protein kinase inhibitors |
US6894051B1 (en) * | 1997-07-18 | 2005-05-17 | Novartis Ag | Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
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EP2829538A1 (en) | 2006-04-27 | 2015-01-28 | Sicor, Inc. | Polymorphic form of imatinib mesylate and process for its preparation |
US8067421B2 (en) | 2006-04-27 | 2011-11-29 | Sicor Inc. | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form α |
US7977348B2 (en) | 2006-04-27 | 2011-07-12 | Sicor Inc. | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form α |
EP2311821A1 (en) | 2006-04-27 | 2011-04-20 | Sicor, Inc. | Polymorphic form of Imatinib mesylate and processes for its preparation |
US20080090833A1 (en) * | 2006-04-27 | 2008-04-17 | Alexandr Jegorov | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha |
US20090324718A1 (en) * | 2006-09-01 | 2009-12-31 | Ilan Zalit | Imatinib compositions |
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US20090012296A1 (en) * | 2007-05-29 | 2009-01-08 | Alexandr Jegorov | Processes for the preparation of crystalline form beta of imatinib mesylate |
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US10836745B2 (en) | 2015-12-24 | 2020-11-17 | Takeda Pharmaceutical Company Limited | Cocrystal, production method thereof, and medicament containing cocrystal |
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