CN100425240C - Use of the quinazoline derivative ZD6474 combined with platinum compounds and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeabi - Google Patents
Use of the quinazoline derivative ZD6474 combined with platinum compounds and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeabi Download PDFInfo
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Abstract
The present invention relates to a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is optionally being treated with ionising radiation, particularly a method for the treatment of a cancer, particularly a cancer involving a solid tumour, which comprises the administration of ZD6474 in combination with a platinum anti-tumour agent; to a pharmaceutical composition comprising ZD6474 and a platinum anti-tumour agent; to a combination product comprising ZD6474 and a platinum anti-tumour agent for use in a method of treatment of a human or animal body by therapy; to a kit comprising ZD6474 and a platinum anti-tumour agent; to the use of ZD6474 and a platinum anti-tumour agent in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is optionally being treated with ionising radiation.
Description
The present invention relates to the homoiothermic animal of ionizing radiation treatment such as the method that philtrum produces angiogenesis inhibitor effect and/or reduction vascular permeability effects selected for use in office, particularly relate to the method for cancer of solid tumor in particular for the treatment cancer, these class methods comprise ZD6474 and platinum antineoplastic medicine administering drug combinations; Relate to the Pharmaceutical composition that contains ZD6474 and platinum antineoplastic medicine; Relate to the combination product that contains ZD6474 and platinum antineoplastic medicine, this product is used for the treatment of in the Therapeutic Method of human or animal's body; Relate to the kit that contains ZD6474 and platinum antineoplastic medicine; Relate to ZD6474 and the platinum antineoplastic medicine purposes in the preparation medicine, drug prepared is used for the homoiothermic animal of ionizing radiation treatment such as the philtrum selected for use in office and produces the angiogenesis inhibitor effect and/or reduce vascular permeability effects.
Normal angiogenesis plays an important role in the various procedures of the several assemblies that comprise fetal development, wound healing and female reproductive function.Do not need or pathologic vessels generates relevant with disease, this class disease comprises diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, sebaceous cyst, kaposi's sarcoma (Kaposi ' s sarcoma) and hemangioma (Fan etc., 1995, TrendsPharmacol Sci.16:57-66; Folkman, 1995, Nature Medicine 1:27-31).Think that vascular permeability changes work (Cullinan-Bove etc., 1993, Endocrinology 133 829-837 in normal and pathophysiological process; Senger etc., 1993, Cancer andMetastasis Reviews, 12303-324).Having determined to have vitro endothelial cell growth promotes active a few peptide species to comprise acid and basic fibroblast growth factor (aFGF﹠amp; BFGF) and VEGF (VEGF).Because the limited expression of its receptor is compared with the FGF growth factor activity, the somatomedin of VEGF has the relative specificity activity to endotheliocyte.Recently evidence shows that VEGF is that normal blood vessels generates and pathologic vessels generates (Jakeman etc., 1993, Endocrinology, 133 848-859, Kolch etc., 1995, Breast CancerResearch and Treatment, 36139-155) and vascular permeability (Connolly etc., 1989, J Biol Chem 26420017-20024) important stimulus thing. can cause suppressing tumor growth (Kim etc., 1993, Nature 362841-844) by VEGF and antibody chelating antagonism VEGF effect.
Receptor tyrosine kinase (RTKs) is very important in the transmittance process of biochemical signals leap cytoplasma membrane.These transmembrane molecules are characterised in that by the extracellular ligand calmodulin binding domain CaM that is connected to intracellular tyrosine kinases zone by the plasma membrane fragment to be formed.Part causes stimulating the tyrosine kinase activity relevant with receptor with receptors bind, thereby causes the tyrosine residue phosphorylation on the molecule in receptor and other cell.These of tyrosine phosphorylation change the priming signal cascade, cause the various kinds of cell response.Up to now, at least 19 kinds of different RTK subclass have been determined by amino acid sequence homology.One of these subclass at present by fms sample tyrosine kinase receptor, Flt-1 (being also referred to as VEGFR-1), contain kinases and insert regional receptor, KDR (being also referred to as VEGFR-2 or Flk-1) and another kind of fms sample tyrosine kinase receptor, Flt-4 and form.These relevant RTK, Flt-1 and KDR two kinds have demonstrated and have combined have high-affinity (De Vries etc., 1992, Science 255.989-991 with VEGF; Terman etc., 1992, Biochem Biophys Res.Comm 1992,187 1579-1586).VEGF is relevant with the calcium variations of flux with the tyrosine phosphorylation situation of these receptors bind expressed in heterogenous cell and cell protein.
VEGF is the critical stimulus thing of blood vessel generation and angiogenesis.This cytokine expresses by inducing endothelial cell propagation, protease and the migration induction of vascular is sprouted phenotype, and vascular tissue forms blood capillary (Keck, P J. subsequently, Hauser, S.D, Krivi, G., Sanzo, K., Warren, T., Feder, J. and Connolly, D T., Science (Washington DC), 246:1309-1312,1989, Lamoreaux, W.J., Fitzgerald, M.E, Reiner, A, Hasty, K.A. and Charles, S T., Microvasc Res., 55:29-42,1998; Pepper, M.S, Montesano, R, Mandroita, S J., Orci, L. and Vassalli, J D, Enzyme Protein, 49.138-162,1996).In addition, VEGF induces main vascular permeability (Dvorak, H.F., Detmar, M, Claffey, K P, Nagy, J.A., van de Water, L and Senger, D.R., (Int Arch Allergy Immunol, 107.233-235,1995, Bates, D.O, Heald, R.I, Curry, F E and Williams, B J.Physiol (Lond.), 533263-272,2001), promote the formation of high infiltration, immaturity vasoganglion, the feature that this generates for pathologic vessels.Shown that independent activation KDR is enough to promote that all the main phenotypes to VEGF respond, and comprises endothelial cell proliferation, migration and survival and vascular permeability induce (Meyer, M., Clauss, M, Lepple-Wienhues, A, Waltenberger, J, Augustin, H G, Ziche, M., Lanz, C, B ü ttner, M, Rziha, H-J and Dehio, C, EMBO J, 18:363-374,1999, Zeng, H, Sanyal, S and Mukhopadhyay, D, J.Biol.Chem, 276:32714-32719,2001, Gille, H, Kowalski, J., Li, B, LeCouter, J., Moffat, B, Zioncheck, T.F., Pelletier, N. and Ferrara, N., J.Biol Chem, 276.3222-3230,2001).
For the quinazoline derivant of vegf receptor tyrosine kinase inhibitor has description in international application published WO 98/13354 and WO 01/32651.Describe among WO 98/13354 and the WO01/32651 have anti-vegf receptor tyrosine kinase (VEGF RTK) active, have some active chemical compounds of anti-epidermal growth factor (EGF) receptor tyrosine kinase (EGF RTK) simultaneously.ZD6474 is 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline:
ZD6474 and carries out illustration in WO 01/32651 in WO 98/13354 general scope of disclosure.ZD6474 is effective inhibitor of VEGF RTK, and also has some activity of anti-EGFRTK.Press oral administration once a day in a series of models, ZD6474 has demonstrated has broad-spectrum anti-tumor activity (Wedge S R, Ogilvie D J., Dukes M etc., Proc Am Assoc Canc.Res.2001,42: make a summary 3126).
The chemical compound that they invent has been described in WO 98/13354 and WO 01/32651: " can treat separately use maybe can except that The compounds of this invention, also comprise one or more other materials and/or the treatment use.This therapeutic alliance can realize by while, each component sequential or that treat respectively." then WO 98/13354 and WO 01/32651 continue to describe the example of these therapeutic alliances, comprise operation, radiotherapy and various types of chemical medicine.
All there are not the ZD6474 that advised and the concrete combination of platinum antineoplastic medicine among WO 98/13354 and the WO 01/32651.
Among WO 98/13354 and the WO 01/32651 all explanation use this to invent arbitrary chemical compound and other treatment can produce unexpected beneficial effect.
Unexpectedly and surprisingly be, we find that selection-platinum antineoplastic medicine specific in the extensive description of listed therapeutic alliance among particular compound ZD6474 and WO 98/13354 and the WO 01/32651 unites use now, than any produces significantly better effect in independent use ZD6474 and the platinum antineoplastic medicine.Specifically, ZD6474 and platinum antineoplastic medicine are united the significantly better effect of any generation in independent ZD6474 of use of use treatment solid tumor ratio and the platinum antineoplastic medicine.
The platinum antineoplastic medicine can be platiniferous any antineoplastic agent.The platinum antineoplastic medicated bag is drawn together cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, husky platinum and AMD473.
The antitumaous effect of Therapeutic Method of the present invention includes but not limited to antitumor action, responsiveness, progression of disease time and survival rate.The antitumor action of Therapeutic Method of the present invention includes but not limited to that tumor growth suppresses, tumor growth is delayed, tumor regression, tumor dwindle, treats the time, the progression of disease that stop the long increase of back tumor regrowth and slow down.Expection has or when the homoiothermic animal of incorporeity tumor cancer such as people's Therapeutic Method of the present invention when needing to treat, and described Therapeutic Method will produce the effects of one or more index tests below for example: the time of the degree of antitumor action, responsiveness, progression of disease and survival rate.Antitumaous effect comprises the treatment of prophylactic treatment and present illness.
According to the present invention, a kind of method that produces angiogenesis inhibitor and/or reduce vascular permeability effects in homoiothermic animal such as people is provided, and this method comprises ZD6474 or its pharmaceutically acceptable salt that gives effective dose before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously.
According to a further aspect of the present invention, provide a kind of method for cancer for the treatment of homoiothermic animal such as people, this method comprises ZD6474 or its pharmaceutically acceptable salt that gives effective dose before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously.
According to a further aspect of the present invention, a kind of method for cancer that relates to solid tumor for the treatment of homoiothermic animal such as people is provided, and this method comprises ZD6474 or its pharmaceutically acceptable salt that gives effective dose before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously.
According to a further aspect of the present invention, a kind of method that produces angiogenesis inhibitor and/or reduce vascular permeability effects in homoiothermic animal such as people is provided, and this method comprises ZD6474 or its pharmaceutically acceptable salt that gives effective dose before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously; Wherein ZD6474 and platinum antineoplastic medicine can be chosen wantonly with pharmaceutically acceptable excipient or carrier separately and give.
According to a further aspect of the present invention, provide a kind of method for cancer for the treatment of homoiothermic animal such as people, this method comprises ZD6474 or its pharmaceutically acceptable salt that gives effective dose before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously; Wherein ZD6474 and platinum antineoplastic medicine can be chosen wantonly with pharmaceutically acceptable excipient or carrier separately and give.
According to a further aspect of the present invention, a kind of method for cancer that relates to solid tumor for the treatment of homoiothermic animal such as people is provided, and this method comprises ZD6474 or its pharmaceutically acceptable salt that gives effective dose before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously; Wherein ZD6474 and platinum antineoplastic medicine can be chosen wantonly with pharmaceutically acceptable excipient or carrier separately and give.
According to a further aspect of the present invention, provide a kind of Pharmaceutical composition, said composition comprises ZD6474 or its pharmaceutically acceptable salt, platinum antineoplastic medicine and pharmaceutically acceptable excipient or carrier.
According to a further aspect of the present invention, provide the combination product of a kind of mankind of being used for the treatment of or animal body Therapeutic Method, this product comprises ZD6474 or its pharmaceutically acceptable salt and platinum antineoplastic medicine.
The kit of a kind of ZD6474 of containing or its pharmaceutically acceptable salt and platinum antineoplastic medicine is provided according to a further aspect of the present invention.
According to a further aspect of the present invention, provide a kind of kit, this kit comprises:
A) ZD6474 of first unit dosage forms or its pharmaceutically acceptable salt;
B) the platinum antineoplastic medicine of second unit dosage forms; With
C) contain the container of described first and second dosage forms.
According to a further aspect of the present invention, provide a kind of kit, this kit comprises:
A) ZD6474 of first unit dosage forms or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient or carrier;
B) the platinum antineoplastic medicine of second unit dosage forms and pharmaceutically acceptable excipient or carrier; With
C) contain the container of described first and second dosage forms.
According to a further aspect of the present invention, provide ZD6474 or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, this medicine is used for producing angiogenesis inhibitor and/or reducing vascular permeability effects at homoiothermic animal such as people.
According to a further aspect of the present invention, provide ZD6474 or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, this medicine is used for producing anticancer effect at homoiothermic animal such as people.
According to a further aspect of the present invention, provide ZD6474 or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, this medicine is used for producing antitumous effect at homoiothermic animal such as people.
According to a further aspect of the present invention, a kind of therapeutic alliance is provided, this treatment comprises homoiothermic animal such as optional ZD6474 or its pharmaceutically acceptable salt that also has the effective dose of pharmaceutically acceptable excipient or carrier of people that needs this treatment, and simultaneously, sequential or give the platinum antineoplastic medicine of effective dose respectively, wherein the platinum antineoplastic medicine can be chosen wantonly with pharmaceutically acceptable excipient or carrier and give.This treatment comprises angiogenesis inhibitor and/or vascular permeability effect, antitumaous effect and antitumor action.
Therapeutic alliance of the present invention defined herein can be by simultaneously, each component sequential or that give described treatment respectively realizes.Therapeutic alliance defined herein therapy is separately used, or can comprise also that except that therapeutic alliance of the present invention operation or radiotherapy or other chemotherapeutics use.
Operation can comprise give before the ZD6474 therapeutic alliance described herein, during or carry out the step of part or all of tumor resection afterwards.
Other chemotherapeutics that therapeutic alliance optional and of the present invention is used comprises the medicine described in the WO 01/32651, and WO 01/32651 is attached to herein by reference.These chemotherapeutics can mainly comprise five class medicines:
(i) other angiogenesis inhibitor medicines comprise the blood-vessels target medicine;
(ii) cytostatic;
(iii) biological response modifier (for example interferon);
(iv) antibody (as edrecolomab); With
(v) cure antiproliferative agents/antineoplastic agent and the combination thereof used in the tumor; And other class medicines:
(vi) antisense therapy;
(vii) gene therapy method; With
(ix) immunotherapy method.
The instantiation of the chemotherapeutics that uses with therapeutic alliance of the present invention is Raltitrexed, etoposide, vinorelbine, paclitaxel, docetaxel, gemcitabine, Irinotecan (CPT-11) and 5-fluorouracil (5-FU); These are united expection and are used in particular for treating pulmonary carcinoma, head and neck cancer, colon cancer, rectal cancer, the esophageal carcinoma, gastric cancer, cervical cancer, ovarian cancer, skin carcinoma, breast carcinoma, bladder cancer and cancer of pancreas.
ZD6474, platinum antineoplastic medicine and ionizing radiation three unite and give to produce than any uses separately the better effect that obtains in ZD6474, platinum antineoplastic medicine and the ionizing radiation, as antitumous effect, than ZD6474 and the platinum antineoplastic medicine associating better effect that obtains, than ZD6474 and the ionizing radiation associating better effect that obtains, than platinum antineoplastic medicine and the ionizing radiation associating better effect that obtains.
According to the present invention, a kind of method that produces angiogenesis inhibitor and/or reduce vascular permeability effects in homoiothermic animal such as people is provided, and this method comprises before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously and give to give before the ionizing radiation of effective dose, afterwards or simultaneously ZD6474 or its pharmaceutically acceptable salt of effective dose.
According to a further aspect of the present invention, a kind of method for the treatment of homoiothermic animal such as human cancer is provided, and this method comprises before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously and give to give before the ionizing radiation of effective dose, afterwards or simultaneously ZD6474 or its pharmaceutically acceptable salt of effective dose.
According to a further aspect of the present invention, provide a kind of method for cancer that homoiothermic animal such as people relate to solid tumor for the treatment of, this method comprises before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously; With before the ionizing radiation that gives effective dose, give ZD6474 or its pharmaceutically acceptable salt of effective dose afterwards or simultaneously.
According to a further aspect of the present invention, provide a kind of method that produces angiogenesis inhibitor and/or reduce vascular permeability effects in homoiothermic animal such as people, this method comprises before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously; With before the ionizing radiation that gives effective dose, give ZD6474 or its pharmaceutically acceptable salt of effective dose afterwards or simultaneously, wherein ZD6474 and platinum antineoplastic medicine can be chosen wantonly with pharmaceutically acceptable excipient or carrier separately and give.
According to a further aspect of the present invention, provide a kind of method for the treatment of homoiothermic animal such as human cancer, this method comprises before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously; With before the ionizing radiation that gives effective dose, give ZD6474 or its pharmaceutically acceptable salt of effective dose afterwards or simultaneously, wherein ZD6474 and platinum antineoplastic medicine can be chosen wantonly with pharmaceutically acceptable excipient or carrier separately and give.
According to a further aspect of the present invention, provide a kind of method for cancer that homoiothermic animal such as people relate to solid tumor for the treatment of, this method comprises before the platinum antineoplastic medicine that gives described animal effective dose, afterwards or simultaneously; With before the ionizing radiation that gives effective dose, give ZD6474 or its pharmaceutically acceptable salt of effective dose afterwards or simultaneously, wherein ZD6474 and platinum antineoplastic medicine can be chosen wantonly with pharmaceutically acceptable excipient or carrier separately and give.
In accordance with a further aspect of the present invention, ZD6474 or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine is provided, and this medicine is used for producing angiogenesis inhibitor and/or reducing vascular permeability effects homoiothermic animal such as people with the ionization radiation therapy.
In accordance with a further aspect of the present invention, provide ZD6474 or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, this medicine is used for producing anticancer effect homoiothermic animal such as people with the ionization radiation therapy.
In accordance with a further aspect of the present invention, provide ZD6474 or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, this medicine is used for producing antitumous effect homoiothermic animal such as people with the ionization radiation therapy.
In accordance with a further aspect of the present invention, a kind of therapeutic alliance is provided, this treatment comprises homoiothermic animal such as optional ZD6474 or its pharmaceutically acceptable salt that also has the effective dose of pharmaceutically acceptable excipient or carrier of people that needs this treatment, choose the platinum antineoplastic medicine of the effective dose that also has pharmaceutically acceptable excipient or carrier wantonly, and give the ionizing radiation of effective dose, wherein ZD6474, platinum antineoplastic medicine and ionizing radiation can any order simultaneously, sequential or give respectively.
Show with the homoiothermic animal of ionization radiation therapy such as people and to give homoiothermic animal such as the people who uses the ionization radiation therapy before the medicine or therapeutic alliance that contains ZD6474 and platinum antineoplastic medicine, afterwards or simultaneously.For example described ionizing radiation can give described homoiothermic animal such as people at the medicine that contains ZD6474 and platinum antineoplastic medicine or before one week of therapeutic alliance to the back time in week.This expression ZD6474, platinum antineoplastic medicine and ionizing radiation can any order respectively or sequential giving, perhaps can give simultaneously.Homoiothermic animal can experience ZD6474, platinum antineoplastic medicine and ionizing radiation effect separately simultaneously.
According to an aspect of the present invention, give ionizing radiation before one of in giving ZD6474 and platinum antineoplastic medicine or after one of giving in ZD6474 and the platinum antineoplastic medicine.
According to an aspect of the present invention, before giving ZD6474 and platinum antineoplastic medicine or giving to give ionizing radiation after ZD6474 and the platinum antineoplastic medicine.
According to an aspect of the present invention, after homoiothermic animal is with the ionization radiation therapy, give this animal ZD6474.
According to another aspect of the present invention, the effect of expection Therapeutic Method of the present invention is equivalent to the independent result of use sum of each component of described treatment at least, be that ZD6474 and platinum antineoplastic prescription solely use effect sum separately, or effect sum is separately used in ZD6474, platinum antineoplastic medicine and ionizing radiation separately.
According to another aspect of the present invention, the effect of expection Therapeutic Method of the present invention is used effect sum separately separately greater than each component of described treatment, promptly solely use effect sum separately, or use effect sum separately separately greater than ZD6474, platinum antineoplastic medicine and ionizing radiation greater than ZD6474 and platinum antineoplastic prescription.
According to another aspect of the present invention, the effect of expection Therapeutic Method of the present invention is a cooperative effect.
According to the present invention, if being better than dosage routinely in treatment, the therapeutic alliance effect gives a kind of of therapeutic alliance component or effect that other reached, then being defined as provides cooperative effect, and therapeutic effect is measured by time or survival period as responsiveness, responsiveness, disease progression.For example, using the effect that is reached separately if the effect of therapeutic alliance is better than ZD6474 or platinum antineoplastic medicine or ionizing radiation in treatment, then is cooperative effect.In addition, if therapeutic alliance obtains advantageous effects in to the independent a group patient who uses ZD6474 or platinum antineoplastic medicine or ionizing radiation not to have response (or response is very weak), then this therapeutic alliance effect is a cooperative effect.In addition, if a kind of component gives with its routine dose, other components give with the dosage that reduces, and being equivalent to each component of therapeutic alliance, therapeutic effect gives the effect that reached with routine dose, then define this therapeutic alliance effect for cooperative effect is provided, therapeutic effect is by measuring as responsiveness, responsiveness, disease progression time or survival period.Particularly, do not damage one or more in responsiveness, responsiveness, disease progression time and the survival data if can reduce the routine dose of ZD6474 or platinum antineoplastic medicine or ionizing radiation, especially do not damage the response duration, but produce produced when using each component routine dose still less and/or littler adverse side effect, then think to have cooperative effect.
The invention described above therapeutic alliance purpose defined herein is their angiogenesis inhibitor and/or vascular permeability effects.Angiogenesis and/or vascular permeability increase are present in the extensive disease, comprise cancer (comprising leukemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, kaposi's sarcoma, hemangioma, acute with chronic nephropathy, sebaceous cyst, arterial restenosis, autoimmune disease, acute inflammation, lymphatic edema, endometriosis, dysfunctional uterine bleeding with comprise the degeneration of macula relevant with the age with the outgrowth disease of eye of retinal vessel.Expect that therapeutic alliance of the present invention is used in particular for preventing and treats disease as cancer and kaposi's sarcoma.Particularly, expect the growth that these therapeutic alliances of the present invention advantageously slow down constitutional solid tumor and recidivity solid tumor, for example colon tumor, Vipoma, bladder tumor, mastadenoma, prostate tumor, lung tumor and skin tumour.More especially, expect that therapeutic alliance of the present invention advantageously slows down growth of tumor in colorectal carcinoma and the pulmonary carcinoma, for example mesothelioma and nonsmall-cell lung cancer (NSCLC).More especially, expect that these therapeutic alliances of the present invention suppress any type of cancer relevant with VEGF, comprise leukemia, multiple myeloma and lymphoma, also suppress as the constitutional solid tumor relevant and the growth of recidivity solid tumor with VEGF, especially their growth and diffusion significantly rely on those tumors of VEGF, comprise as some colon (comprising rectum) tumor, Vipoma, bladder tumor, mastadenoma, prostate tumor, lung tumor, pudendum tumor, skin tumour especially NSCLC.
In the present invention on the other hand, the ZD6474 of expection optionally ionising radiation suppresses those constitutional solid tumors and the growth of recidivity solid tumor, especially their growth relevant with VEGF and spreads those tumors that significantly rely on VEGF with the platinum antineoplastic medicine.
In the present invention on the other hand, those constitutional solid tumors that the ZD6474 of expection optionally ionising radiation is relevant with VEGF and EGF with the inhibition of platinum antineoplastic medicine and growth, especially their growth of recidivity solid tumor and diffusion significantly rely on those tumors of VEGF and EGF.
Compositions described herein can be form such as tablet or the capsule that is applicable to that per os gives, be used for that per nasal gives or give form such as powder or solution through suction, be used for parenteral injection (comprising intravenous injection, subcutaneous injection, intramuscular injection, intravascular injection and infusion) form such as sterile solution agent, suspensoid or Emulsion, be used for topical administration form such as ointment or ointment, be used for rectum and give form such as suppository, or the route of administration that can be direct injection tumor or discharge or discharge through the part through the zone.In other embodiments of the present invention, the ZD6474 of therapeutic alliance can be through endoscope, in trachea, in the damage, discharge in percutaneous, intravenous, subcutaneous, intraperitoneal or the tumor.Preferred ZD6474 per os gives.General compositions described herein can prepare with conventional excipients according to a conventional method.The present composition preferably exists with unit dosage forms.
ZD6474 gives homoiothermic animal with the unit dose of every square metre of animal body surface area 10-500mg usually, and for example the people is about 0 3-15mg/kg.The unit dose of design as 0 3-15mg/kg, preferred 0 5-5mg/kg, and this dosage is generally the treatment effective dose.Unit dosage forms such as tablet or capsule contain the active component as 25-500mg usually.The preferred daily dose scope that adopts is 0 5-5mg/kg.
Can give the platinum antineoplastic medicine according to known route of administration and dosage.
For example can give cisplatin by independent intravenous infusion in 6-8 hour, dosage is every 3-4 week 40-120mg/m
2Perhaps for example can give cisplatin by independent intravenous infusion in 6-8 hour, dosage is every 3-4 15-20mg/m every day in week
2, reach 5 days most continuously.
For example can give carboplatin by independent short-term intravenous infusion in 15-60 minute, dosage is per 4 all 250-400mg/m
2
For example can give oxaliplatin by intravenous infusion in 2-6 hour, dosage is about 85mg/m of per 2 weeks
2Dosage and scheme can change according to disease specific and patient's overall state.If also use one or more other chemotherapeutics except that therapeutic alliance of the present invention, dosage and scheme also can change.Scheme can be by doctor's decision of any concrete patient of treatment.
X-ray therapy can give according to known practice in the clinical radiotherapy.The dosage of ionizing radiation is the known dose of using in the clinical radiotherapy.The radiotherapy that uses will comprise as using gamma-radiation, X-ray and/or from the direct release of radiation of radiosiotope.Other forms that also comprise the DNA damage factor in the present invention are as microwave and UV-irradiation.For example the X-ray daily dose that can give is 18-20Gy, 5 days weeks, 5-6 week.Usually total divided dose will be in the 45-60Gy scope.Single heavy dose gives as the part that 5-10Gy can be used as radiation therapy process.Single dose can give in operation.By in a period of time, regularly giving low dose of X-ray, thereby can use hyperfractionation, for example use 0.1Gy/ hour in many days.Radioisotopic dosage range alters a great deal, and depends on isotopic half-life, radiation emitted intensity and type and cellular uptake.
As mentioned above, the treatment of disease specific or prevent the dosage size of required various treatments to need and change according to the order of severity of the host that treats, route of administration and the disease for the treatment of.Therefore, optimal dose can be by doctor's decision of any concrete patient of treatment.For example may must maybe need to reduce the above-mentioned dosage of each component of therapeutic alliance, so that reduce toxicity.
The present invention relates to platinum antineoplastic medicine and ZD6474 or with the associating of ZD6474 salt.
The ZD6474 salt that is used for Pharmaceutical composition is pharmaceutically acceptable salt, but other salt can be used for preparing ZD6474 and its pharmaceutically acceptable salt.These salt can form with inorganic base or organic base, and this class alkali provides pharmaceutically acceptable cation.Formed these salt of inorganic base or organic base comprise for example alkali metal salt such as sodium salt or potassium salt, alkali salt such as calcium salt or magnesium salt, ammonium salt or as methylamine salt, dimethylamine salt, front three amine salt, piperidinium salt, alkylbenzyldimethylasaltsum saltsum or three-(2-ethoxy) amine salt.
ZD6474 can be synthetic according to any known method of preparation ZD6474.For example ZD6474 can be according to any method preparation described in the WO 01/32651; For example ZD6474 can be according to embodiment 2 (a), 2 (b) and the preparation of the method described in 2 (c) of WO 01/32651.
The platinum antineoplastic medicine can be bought and obtain.
Following test can be used for proving the activity of ZD6474 and the associating of platinum antineoplastic medicine.
Calu 6 lung cancer xenograft model A
End user's pulmonary carcinoma (NSCLC) heteroplastic transplantation model.Athymic nude mice subcutaneous (s.c.) injection Calu 6 human tumor cells.When tumor is set up (gross tumor volume 100-300mm
3, in special test=200mm
3) behind the 7-10 days (in special test 13 days), begin treatment.With animal random packet (n=8/ group in special test, but can be the 10-12/ group), duration of test, animal day is being accepted the independent treatment (4mg/kg is through intraperitoneal (i.p.)) of cisplatin at random, or accepts treatment (the every day 25-75mg/m of ZD6474
2Per os gives (p.o), or every day 625-25mg/kg p.o., be 25mg/kg in special test), or only accept medicine solvent.An other treated animal (n=8 in special test, but can be 10-12) is accepted the associating of cisplatin and ZD6474, uses used same dose and the scheme of single medicine treatment.The sky of animals received ZD6474 and cisplatin gave cisplatin in 2 hours behind the orally give ZD6474.
When the matched group tumor reaches about 2.0cm
3Perhaps, put to death the animal of all groups based on having accepted some therapeutic dose.The tumor size is used the caliper measurements evaluation by test.Determine antitumous effect by growth of tumor in growth of tumor and the vehicle treated group in the comparative drug treatment group.In addition, estimate the effect of therapeutic alliance by relatively accepting growth of tumor in growth of tumor in cisplatin and the ZD6474 animal groups and the animal groups of accepting the single medicine treatment separately.
Use one-sided pair of sample t-test evaluation statistical significance.
The result of use cisplatin (4mg/kg) and ZD6474 (25mg/kg) as shown in Figure 1.
The Combined Ration of ZD6474 (25mg/kg) and two kinds of medicines of cisplatin (4mg/kg) uses cisplatin to suppress growth of tumor more significantly separately.The effect of associating is also greater than the effect of using ZD6474 separately.
Can use the associating of similar experimental observation ZD6474 and platinum antineoplastic medicine and ionizing radiation.
Claims (13)
- (1.4-4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, described medicine is used for producing at homoiothermic animal the effect of angiogenesis inhibitor and/or reduction vascular permeability.
- (2.4-4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, described medicine is used for producing anticancer effect at homoiothermic animal.
- (3.4-4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, described medicine is used for producing the antineoplastic effect at homoiothermic animal.
- (4.4-4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, described medicine is used for producing at the homoiothermic animal with the ionization radiation therapy effect of angiogenesis inhibitor and/or reduction vascular permeability.
- 5.4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, described medicine are used for producing anticancer effect at the homoiothermic animal with the ionization radiation therapy.
- 6.4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and the platinum antineoplastic medicine purposes in the preparation medicine, described medicine are used for producing the antineoplastic effect at the homoiothermic animal with the ionization radiation therapy.
- 7. the purposes of claim 2 or claim 5, wherein said cancer is a nonsmall-cell lung cancer.
- 8. the purposes of claim 3 or claim 6, wherein said tumor is colon tumor, Vipoma, bladder tumor, mastadenoma, prostate tumor, lung tumor, pudendum tumor or skin tumour.
- 9. each purposes among the claim 1-6, wherein said platinum antineoplastic medicine is a cisplatin.
- 10. each purposes among the claim 1-6, wherein said platinum antineoplastic medicine is a carboplatin.
- 11. each purposes among the claim 1-6, wherein said platinum antineoplastic medicine is an oxaliplatin.
- 12. a Pharmaceutical composition, described compositions comprise 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and platinum antineoplastic medicine and pharmaceutically acceptable excipient or carrier.
- 13. a kit, described kit comprise 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline or its pharmaceutically acceptable salt and platinum antineoplastic medicine.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0316176.7 | 2003-07-10 | ||
| GB0316176A GB0316176D0 (en) | 2003-07-10 | 2003-07-10 | Combination therapy |
| GB0406546.2 | 2004-03-24 | ||
| GB0406546A GB0406546D0 (en) | 2004-03-24 | 2004-03-24 | Combination therapy |
| GB0407753.3 | 2004-04-06 | ||
| GB0407753A GB0407753D0 (en) | 2004-04-06 | 2004-04-06 | Combination therapy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1849124A CN1849124A (en) | 2006-10-18 |
| CN100425240C true CN100425240C (en) | 2008-10-15 |
Family
ID=27741942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800257388A Expired - Fee Related CN100425240C (en) | 2003-07-10 | 2004-07-07 | Use of the quinazoline derivative ZD6474 combined with platinum compounds and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeabi |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN100425240C (en) |
| ES (1) | ES2349194T3 (en) |
| GB (1) | GB0316176D0 (en) |
| ZA (1) | ZA200600186B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998013354A1 (en) * | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
| WO2001032651A1 (en) * | 1999-11-05 | 2001-05-10 | Astrazeneca Ab | Quinazoline derivatives as vegf inhibitors |
-
2003
- 2003-07-10 GB GB0316176A patent/GB0316176D0/en not_active Ceased
-
2004
- 2004-07-07 ES ES04743275T patent/ES2349194T3/en active Active
- 2004-07-07 CN CNB2004800257388A patent/CN100425240C/en not_active Expired - Fee Related
-
2006
- 2006-01-09 ZA ZA200600186A patent/ZA200600186B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998013354A1 (en) * | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
| WO2001032651A1 (en) * | 1999-11-05 | 2001-05-10 | Astrazeneca Ab | Quinazoline derivatives as vegf inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200600186B (en) | 2007-04-25 |
| GB0316176D0 (en) | 2003-08-13 |
| CN1849124A (en) | 2006-10-18 |
| ES2349194T3 (en) | 2010-12-28 |
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