CN101036652A - Use of 4-pyridylmethylphthalazines for cancer treatment - Google Patents

Abstract

Patients suffering from renal carcinoma are treated with a 4-pyridylmethyl-phthalazine anti-angiogenesis agents. Patients having different tumor types, e.g. renal cancer, are treated with a 4-pyridylmethyl-phthalazine anti-angiogenesis agent while undergoing chemotherapy.

Description

The application of 4-pyridylmethyl phthalazines in the treatment cancer

The application is that JIUYUE in 2002 11 days is that submit to, denomination of invention is divided an application for the PCT application PCT/EP02/10194's of " application of 4-pyridylmethyl phthalazines in the treatment cancer ", it is on March 12nd, 2004 that described PCT application enters the date in China national stage, and application number is 02817883.1.

Technical field

The present invention relates to the application of 4-pyridylmethyl phthalazine derivatives in the treatment renal carcinoma.In addition, the invention still further relates to 4-pyridylmethyl phthalazines anti-angiogenic agent by simultaneously, the respectively or successively application in administration and the amic therapy method associating, particularly treat proliferative disease, especially solid tumor disease, as the application in the renal carcinoma.The present invention also relates to this in addition and unites in preparation and be used for the treatment of purposes in the medicine of proliferative disease; Comprise and be used for simultaneously, respectively or the commercial packing or the product of the operation instructions of the described associating of the combination formulations form of using successively and this associating; To homoiothermic animal, particularly people's Therapeutic Method, and the dosage regimen of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines that improves.

Background technology

The method that optionally suppresses 4-pyridylmethyl phthalazine derivatives and preparation, the drug prescription of vegf receptor tyrosine kinase and prepare these chemical compounds has description in WO00/59509, EP02/04892 and WO01/10859, especially at U.S. Patent number 6,258, description is arranged in 812, and these patents are hereby incorporated by.This chemical compound can reduce microvasculature, the growth of primary tumor and metastatic tumor in the inhibition animal model, and can effectively treat and angiogenesis imbalance diseases associated, tumor disease (solid tumor) particularly, as mastocarcinoma, colon cancer, pulmonary carcinoma, especially small cell lung cancer and carcinoma of prostate.

Summary of the invention

Find that unexpectedly 4-pyridylmethyl phthalazine derivatives can be treated renal carcinoma effectively, particularly can effectively suppress the transitivity growth of renal carcinoma.Therefore, the present invention relates to treat the method for patient's renal carcinoma, this method comprises the 4-pyridylmethyl phthalazine derivatives that gives patient's medicine effective quantity.Specifically, the present invention relates to suppress the method for the transitivity growth of patients with renal cell carcinoma, this method comprises the 4-pyridylmethyl phthalazine derivatives that gives patient's medicine effective quantity.

In the present invention in full, 4-pyridylmethyl phthalazine derivatives specifically refers to 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt.To studies show that the people carries out, the toleration of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines is fine, and can reduce the vascular permeability of tumor.Be understandable that mentioned 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines also is intended to comprise its officinal salt.

The invention still further relates to the purposes of pharmaceutical preparation that 4-pyridylmethyl phthalazine derivatives is used for the treatment of the pharmaceutical preparation of renal carcinoma, especially transitivity renal carcinoma and is used for suppressing the transitivity growth of patients with renal cell carcinoma in preparation.

The amic therapy method that is used for the treatment of proliferative disease is known in this area.

Unexpectedly find, as herein defined the antitumor of associating render a service, particularly treatment proliferative disease, especially solid tumor disease such as renal carcinoma and particularly with other antitumor in known transitivity renal carcinoma invalid as the chemotherapeutics of antineoplastic agent render a service and be higher than the effectiveness that independent use amic therapy method or 4-pyridylmethyl phthalazine derivatives are treated.

In a preferred embodiment of the invention, amic therapy method comprises platinum compounds and/or anti-tumor metabolic drug, and comprises formyl tetrahydrofolic acid alternatively.In specific embodiments of the present invention, amic therapy method comprises platinum compounds, 5-fluorouracil and formyl tetrahydrofolic acid.In another specific embodiments of the present invention, amic therapy method comprises platinum compounds, capecitabine and formyl tetrahydrofolic acid.

In a preferred embodiment of the invention, amic therapy method comprises topoisomerase I inhibitor and/or anti-tumor metabolic drug, and comprises formyl tetrahydrofolic acid alternatively.In specific embodiments of the present invention, amic therapy method comprises topoisomerase I inhibitor, 5-fluorouracil or capecitabine and formyl tetrahydrofolic acid.

Term " anti-tumor metabolic drug " comprises ZD 1694 (RALTITREXED in addition including, but not limited to the salt of 5-fluorouracil, tegafur, capecitabine, cladribine, cytosine arabinoside, fludarabine phosphate, 5-floxuridine, gemcitabine, Ismipur, hydroxyurea, methotrexate, edatrexate and these chemical compounds ^TM), LY231514 (ALIMTA ^TM), LY264618 (LOMOTREXOL ^TM) and OGT719.

5-fluorouracil can be for example according to US 2,802, the content preparation of describing in 005.It can be EFUDEX with commercial form such as trade mark ^TM, FLURACIL ^TMOr FLUROBLASTIN ^TMForm be used for the present invention.Tegafur can be especially with as US 5,116,600 and US 5,525,603 in disclosed composition forms use.In addition, tegafur can for example be FTORAFUR with the trade mark ^TM, LAMAR ^TMOr NEBEREK ^TMThe commercial form administration.Capecitabine can be for example with US 5,472, disclosed form or be XELODA with the trade mark in 949 ^TMThe commercial form administration.Cladribine can be for example according to US4, disclosed content preparation in 760,135.It can be LEUSTATIN with the trade mark ^TMOr LEUSTAT ^TMThe commercial form administration.Cytosine arabinoside can be for example according to US 3,116, in 282 or Hessler at J.Org.Chem. 41Disclosed content preparation in (1970) 1828.It can be ARA-C with for example trade mark ^TM, CYTOSAR ^TMOr UDICIL ^TMThe commercial form administration.The suitable salt of this chemical compound be can be according to US 4,812, the cytarabine octadecyl phosphate (STARASID that the content of describing in 560 prepares ^TM).Fludarabine phosphate can be according to US 4,357, the content preparation of describing in 324.It can be FLUDARA with the trade mark ^TMCommercial form use.Gemcitabine can be for example according to US 5,464, and disclosed content administration in 826 is GEMZAR with for example trade mark perhaps ^TMThe commercial form administration.Ismipur (6-mercaptopurine) can be for example according to US 2,933, disclosed content preparation in 498.It can be LEUKERIN with for example trade mark ^TMOr PURINETHOL ^TMCommercial form use.Hydroxyurea can be for example according to US 2,705, disclosed content preparation in 727.Methotrexate can be FOLEX with for example trade mark ^TMOr MTX ^TMCommercial form use.Edatrexate can be for example according to US4, disclosed content preparation in 369,319.

Term " formyl tetrahydrofolic acid " refer to " N-[4-[[(2-amino-5-formoxyl-1,4,5,6,7,8-six hydrogen-4-oxo-6-pteridyl) methyl] amino] benzoyl-L-glutamic acid, it is with for example trade mark LEUCOVORIN ^TMSell.

Term used herein " platinum compounds " refers to carboplatin, cisplatin or oxaliplatin.Preferred platinum compounds is an oxaliplatin.

Term used herein " carboplatin " refers to antineoplastic agent cis diamidogen (1, the 1-cyclobutane dicarboxylic acid) platinum (II), and it is for example at US 4,140,707 or people such as R.C.Harrison at Inorg.Chim.Acta 46, open among the L15 (1980).This medicine can for example be CARBOPLAT with the trade mark ^TMOr PARAPLATIN ^TMThe commercial form administration.

Term used herein " oxaliplatin " refers to be also referred to as the antineoplastic agent of oxalatoplatinum, and it is for example disclosing among the US 5,716,988.This medicine can be for example is ELOXANTINE with the form of describing in the United States Patent (USP) of being quoted or with for example trade mark ^TMOr 1-OHP ^TMThe commercial form administration.

Term used herein " cisplatin " refers to be also referred to as the antineoplastic agent along diamidogen two chloro platinum, this chemical compound and as the application examples of antineoplastic agent as at DE 2,318, open in 020.

Term used herein " topoisomerase I inhibitor " is including, but not limited to hycamtin, irinotecan, 9-nitrocamptothecin and macromole camptothecine conjugates PNU-166148 (compd A 1 among the WO99/17804).Irinotecan can be CAMPTOSAR with commercial form such as trade mark for example ^TMForm administration.Hycamtin can be HYCAMTIN with commercial form such as trade mark for example ^TMForm administration.

In broad scope of the present invention, term " amic therapy method " is showed to give and is selected from but is not limited to the antineoplastic agent of aromatase inhibitor, estrogen antagonist, topoisomerase II inhibitor, microtubule activator, inhibitors of protein kinase C, gonadorelin agonist, androgen antagonist, bisphosphonate, histone deacetylase inhibitor, Ado-Met decarboxylase inhibitor and trastuzumab.

In a preferred embodiment of the invention, antineoplastic agent is selected from aromatase inhibitor, estrogen antagonist, topoisomerase II inhibitor, microtubule activator, particularly discodermolide (discodermolide), inhibitors of protein kinase C, particularly staurosporine derivatives, gonadorelin agonist, androgen antagonist, bisphosphonate, particularly pamidronic acid or zoledronic acid and trastuzumab.Another preferred embodiment of the present invention relates to the associating of 4-pyridylmethyl phthalazines anti-angiogenic agent, particularly 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines and discodermolide.

Term used herein " aromatase inhibitor " relates to and can suppress estrogen and generate, be about to the chemical compound that ANDROSTENEDIONE and testosterone substrate are separately converted to estrone and estradiol.This term is including, but not limited to the steroid class, especially exemestane and formestane and be non-steroid class, especially aminoglutethimide, vorozole, fadrozole, Anastrozole and particularly letrozole especially.Exemestane for example commercial form such as trade mark is AROMASIN ^TMForm administration.Formestane for example commercial form such as trade mark is LENTARON ^TMForm administration.Fadrozole for example commercial form such as trade mark is AFEMA ^TMForm administration.Anastrozole for example commercial form such as trade mark is ARIMIDEX ^TMForm administration.Letrozole for example commercial form such as trade mark is FEMARA ^TMOr FEMAR ^TMForm administration.Aminoglutethimide for example commercial form such as trade mark is ORIMETEN ^TMForm administration.

The administering drug combinations that contains the aromatase inhibitor antineoplastic agent among the present invention is effective especially to treatment hormone receptor positive mastoncus.

Term used herein " antiestrogen " refers to can be at the chemical compound of the horizontal antagonism estrogen effect of estrogen receptor.This term is including, but not limited to tamoxifen, fulvestrant, raloxifene and RALOXIFENE HCL.Tamoxifen for example commercial form such as trade mark is NOLVADEX ^TMForm administration.RALOXIFENE HCL for example commercial form such as trade mark is EVISTA ^TMForm administration.Fulvestrant can be by US 4,659, and disclosed method makes or is FASLODEX with for example commercial form such as trade mark in 516 ^TMForm administration.

Term used herein " topoisomerase II inhibitor " (comprises the liposome dosage form, for example CAELYX including, but not limited to the anthracyclines amycin ^TM), epirubicin, idarubicin and Nemorubicin, anthraquinone class mitoxantrone and losoxantrone and podophyllotoxin etoposide and teniposide.Etoposide for example commercial form such as trade mark is ETOPOPHOS ^TMForm administration.Teniposide for example commercial form such as trade mark is VM 26-BRISTOL ^TMForm administration.Amycin is ADRIBLASTIN with for example commercial form such as trade mark ^TMForm administration.Epirubicin is FARMORUBICIN with for example commercial form such as trade mark ^TMForm administration.Idarubicin is ZAVEDOS with for example commercial form such as trade mark ^TMForm administration.Mitoxantrone is NOVANTRON with for example commercial form such as trade mark ^TMForm administration.

Term " microtubule activator " relates to microtubule stabilizer and microtubule destabilizer, described microtubule stabilizer and microtubule destabilizer are selected from paclitaxel, docetaxel, slender acanthopanax glycosides element (eleutherobin), Changchun alkaloid such as vincaleucoblastine, particularly Vinblastine Sulfate, vincristine, particularly vincristine sulfate, vinorelbine and discodermolide.Vinblastine Sulfate is VINBLASTIN R.P. with for example commercial form such as trade mark ^TMForm administration.Vincristine sulfate is FARMISTIN with for example commercial form such as trade mark ^TMForm administration.Discodermolide can be as the US 4 of Harbor BranchOceanographic Intitute, 939,168 and US 5, disclosed content obtains or by for example GB 2280677, WO 98/24429 and U.S. Patent number 5,789 in 618,487,605 and 6, the chemical synthesis process of describing in 031,133 obtains, and these documents are hereby incorporated by.

Term " inhibitors of protein kinase C " specifically refers to staurosporine derivatives, preferred US5, disclosed staurosporine derivatives in 093,330.Described chemical compound can be with as disclosed form administration among the WO 99/48896.

Term used herein " anti-angiogenic compounds " refers to Thalidomide (THALOMID ^TM) and SU5416.

Term used herein " gonadorelin agonist " is including, but not limited to 1: PN: WO02056903 PAGE: 25 claimed protein, goserelin and goserelin acetate.Goserelin is at US 4,100, and is open in 274, can be ZOLADEX as commercial form such as trade mark ^TMForm administration.1: PN: WO02056903 PAGE: 25 claimed protein can be according to US 5,843, disclosed content preparation in 901.

Term used herein " antiandrogen " is including, but not limited to bicalutamide (CASODEX ^TM), it can be according to US 4,636, disclosed content preparation in 505.

Term used herein " bisphosphonate " is including, but not limited to etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic Acid, ibandronic acid, risedronic acid and zoledronic acid." etidronic acid " can be DIDRONEL with for example commercial form such as trade mark ^TMForm administration." clodronic acid " can be BONEFOS with for example commercial form such as trade mark ^TMForm administration." tiludronic acid " can be SKELID with for example commercial form such as trade mark ^TMForm administration." pamidronic acid " is AREDIA with for example commercial form such as trade mark ^TMForm administration." alendronic Acid " can be FOSAMAX with for example commercial form such as trade mark ^TMForm administration." ibandronic acid " can be BONDRANAT with for example commercial form such as trade mark ^TMForm administration." risedronic acid " can be ACTONEL with for example commercial form such as trade mark ^TMForm administration." zoledronic acid " can be ZOMETA with for example commercial form such as trade mark ^TMForm administration.

Term used herein " histone deacetylase inhibitor " disclosed chemical compound, particularly NVP-LAQ824 or its lactate in MS-275, SAHA, FK228 (being referred to as FR901228 in the past), Trichostatin A and the WO 02/22577.

Term used herein " Ado-Met decarboxylase inhibitor " is including, but not limited to US5, disclosed chemical compound in 461,076.

Term used herein " trastuzumab " for example commercial form such as trade mark is HERCEPTIN ^TMForm administration.

Structure with the active medicine of Code Number, common name or trade name representative can or obtain from data base such as international monopoly (as the IMS international publication) from the general general introduction of " Merck index " current edition.Content corresponding is incorporated herein for referencial use herein.

The invention still further relates to and contain (a) 4-pyridylmethyl-phthalazines anti-angiogenic agent, particularly 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines and (b) " combination formulations " of one or more chemotherapeutic, particularly oxaliplatin, formyl tetrahydrofolic acid and 5-fluorouracil.Term used herein " combination formulations " especially refer to coupling component as defined above (a) wherein and (b) respectively administration or by use contain not commensurability coupling component (a) and different fixing combination medicine-feeding (b), promptly simultaneously or at " medicine box " of different time points administration.The each several part of medicine box is while or staggered in chronological order administration for example, promptly can be at different time points with identical or different interval administration for any part of medicine box.Therefore, the present invention also comprises the commercial packing that contains 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of being suitable for the oral administration form or its officinal salt and the patient who accepts amic therapy method treatment solid tumor disease is given the teachings of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt.

The invention still further relates to of the present invention the associating in treatment proliferative disease and the purposes for preparing in the medicine that is used for the treatment of proliferative disease.

Conjoint therapy of the present invention is effective especially to the treatment solid tumor disease.Term " solid tumor " especially refers to renal carcinoma, mastocarcinoma, ovarian cancer, colon cancer such as advanced colorectal cancer and gastrointestinal cancer such as gastric cancer, cervical cancer, pulmonary carcinoma, particularly small cell lung cancer and nonsmall-cell lung cancer, head and neck cancer, bladder cancer, carcinoma of prostate, Kaposi sarcoma, carcinoid tumor and carcinoid syndrome.This conjoint therapy can suppress the growth of solid tumor and liquid tumor, and is suitable for preventing the transitivity growth of these tumors.

Term used herein " carcinoid tumor " refers to the neuroendocrine tumor that caused by the enterochromaffin cell, and this enterochromaffin cell mainly intersperses among in intestinal and the main bronchus.Comprise 5-hydroxy tryptamine and 5-hydroxyryptophan by the synthetic phthalein of carcinoid tumor.

Term used herein " carcinoid syndrome " refers to that its symptom comprises the clinical manifestation of the disease, particularly terminal illness of erubescence, diarrhoea and obvious abdomen piece or hepatomegaly.In described disease, the concentration of 5-hydroxyindoleacetic acid (5-HIAA) is typically directly related with gross tumor volume in the urine, and is associated with chance of surviving.When 5-HIAA＞8mg/24 hour level, have 75% can detect in all carcinoid syndrome cases.Another index of syndrome is that the 5-hydroxy tryptamine level increases in the blood plasma, and particularly the 5-hydroxy tryptamine level is higher than about 250ng/ml, especially 350ng/ml in the blood plasma.

Term used herein " transitivity growth " comprises the generation and the development of micrometastasis kitchen range on other organ of the transitivity diffusion of tumor and cancer patient.

Be understandable that mentioned coupling component (a) and (b) also be intended to comprise the officinal salt of described chemical compound.

Below will contain known antineoplastic agent in (a) at least a amic therapy method and (b) 4-pyridylmethyl-phthalazine derivatives, wherein said active component exist and can choose wantonly to contain with the form of free or its officinal salt and uniting of at least a pharmaceutically suitable carrier be referred to as associating of the present invention.

The character of proliferative disease is multifactorial.Under specific circumstances, can unite the medicine that use has the different mechanisms of action.Yet, just will have without the medicine of binding mode arbitrarily with regard to the associating, this associating might not produce favourable effectiveness.

All more surprisingly, experiment is found, give associating of the present invention in the body and not only produced beneficial effect, especially synergistic therapeutic effect (for example delay, stop or the formation of reversing tumor or prolong response phase of tumor), but also produced other surprising beneficial effect, for example with only use associating of the present invention in the independent therapy of one of employed active constituents of medicine compare, side effect reduces, quality of life raising and mortality rate and sickness rate reduce.

The effective dose of each coupling component of using in the associating of the present invention changes with the order of severity of the specific compound that uses or pharmaceutical composition, mode of administration, the state of an illness of being treated, the state of an illness for the treatment of.Therefore, select the dosage of combination of the present invention according to multiple factor, the hepatic and renal function that comprises route of administration and patient.Attending doctor, clinicist or veterinary with common skill can easily determine and specify prevention, prevention or disease controlling to develop the effective dose of needed single active component.The dynamic (dynamical) dosage regimen that the concentration of active component is reached to produce optimum efficiency and do not have in the toxic scope to be utilized by target site based on active component.

For determine 4-pyridylmethyl-phthalazines anti-angiogenic agent in therapy or conjoint therapy separately, be used for patient's active dose, especially for the active dose of individual patient, can adopt two kinds of Biological indicators---DCE-MRI and level of plasma VEGF, and contact amount (exposure), safety and tumor response data.For this purpose, the patient for example accepts every day dosage continuously and is for example 50,150,300,500,750,1000,1500 or 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of 2000mg.Before administration, gathered pharmacokinetics (PK) sample on the the 1st, 15 and 28 day.In ground state, carried out reflecting in the tumor DEC-MRI that perfusion and vascularity change in the 2nd day and the 28th day.For all valuable MRI scanning, the contrast of whole tumor strengthens and can estimate by calculating two-way transfer constant (Ki), and the evaluation during for the 2nd and 28 day is then recently expressed with the percentage that accounts for ground state Ki.Plasma VEGF (the short angiogenesis factor that is produced by tumor cell) can reflect the anaerobic condition of tumor, in ground state, sampling the 1st, 8,15,22 and 28 day the time.Dosage at the percentage ratio that accounts for ground state Ki and 4-pyridylmethyl-phthalazines anti-angiogenic agent increases, significant relation is arranged between the amount of contact and the plasma concentration, as measuring by Spearman Rank Correlation.There is significant relation between the variation of the hepatopathy size that can survey the variation of hepatic injury (two-dimentional product) summation with all during in addition, at Ki decline percent and second loop ends and measure.The patient's of stable disease average Ki value descends obviously bigger.Ki decline 50-60% is relevant with stable disease.

Usually, in order to treat renal carcinoma, can give 4-pyridylmethyl-phthalazine derivatives continuously, for example administration every day.Can adopt oral dose every day of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines is 300mg to 4000mg, for example 300mg/ days to 2000mg/ days or 300mg/ days to 1000mg/ days, particularly 300,500,750,1000,1500 or 2000mg/ days as medicine effective dose.Yet other dosage regimen also may be effectively, and comprises within the scope of the invention.When giving the officinal salt of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines, then give the amount suitable (promptly with above-mentioned amount equivalent) with free alkali.

In associating of the present invention, 4-pyridylmethyl-phthalazine derivatives, particularly 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt can be during amic therapy methods or successive administration, for example administration every day afterwards.Adoptable every day, dosage was 500mg to 4000mg, for example 500mg/ days to 2000mg/ days, and particularly 1000,1500 or 2000mg/ days.Yet other dosage regimen is also included within the scope of the present invention.When the 4-pyridylmethyl-phthalazine derivatives, the particularly 1-that give salt form (4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines, tackle above-mentioned every day oral dose and adjust so that give the free alkali of equivalent.

If not otherwise specified, when the used coupling component of associating of the present invention was used with the form of commercially available single medicine, the information that its dosage and mode of administration are provided on can the packing box according to each marketed drugs was carried out, to produce advantageous effects described herein.

Amic therapy method is generally according to set relieve pain.Described dosage regimen, the deGramont dosage regimen of for example treating colorectal carcinoma are known in the art.In specific embodiments, amic therapy method comprises according to set dosage regimen scheme as known in the art and gives oxaliplatin, formyl tetrahydrofolic acid and 5-fluorouracil.Wherein gave 85mg/m at the 1st day ²Oxaliplatin, at the 1st and the 2nd day infusion 200mg/m in 2 hours ²Formyl tetrahydrofolic acid, the 1st with the 2nd day 22 hours continuous mutually 400mg/m that gives at interval ²And 600mg/m ²5-fluorouracil inject (bolus), the specific chemotherapy regimen that gave once in per 14 days is effective especially.

5-fluorouracil is about 50 to 1000mg/m to the dosage range of people's administration ²My god, as 500mg/m ²My god.

Capecitabine is about 10 to 1000mg/m to the dosage range of people's administration ²My god.

Gemcitabine hydrochloride is about 10 to about 1000mg/ weeks to the dosage range of people's administration.

Methotrexate is about 5 to 500mg/m to the dosage range of people's administration ²My god.

ZD 1694 (RALTITREXED ^TM) be about 2.0 to 4.0mg/m to the dosage range of people's administration ², 3.5mg/m for example ², per 3 weeks once, infusion in 15 minutes.

Carboplatin to the dosage range of people's intravenous administration for per approximately four to six week about 100 to 400mg/m ²Body surface area, for example 200mg/m ²Body surface area.

Oxaliplatin to the dosage range of people's intravenous administration for per approximately two to three week about 25 to 135mg/m ²Body surface area, for example 45 or 85mg/m ²Body surface area.

Cisplatin to the dosage range of people's administration for per approximately three week about 25 to 100mg/m ²

Hycamtin is about 1 to 5mg/m to the dosage range of people's administration ²My god.

Irinotecan is about 50 to 350mg/m to the dosage range of people's administration ²My god.

Fadrozole is about 0.5 to about 10mg/ day for people's oral dose scope, preferred about 1 to about 2.5mg/ day.

Exemestane is about 5 to 200mg/ days for people's oral dose scope, and preferred about 10 to about 25mg/ days, perhaps the dosage range of parenteral administration was about 50 to 500mg/ days, preferred about 100 to about 250mg/ days.If medicine is with independent pharmaceutical composition administration, can be according to GB 2,177, disclosed mode administration in 700.

Formestane is about 100 to 500mg/ days for people's parenteral administration dosage range, preferred about 250 to about 300mg/ days.

Anastrozole is about 0.25 to 20mg/ day for people's oral dose scope, preferred about 0.5 to about 2.5mg/ day.

Aminoglutethimide is about 200 to 500mg/ days to the dosage range of people's administration.

The citric acid tamoxifen is about 10 to 40mg/ days to the dosage range of people's administration.

Vincaleucoblastine is about 1.5 to 10mg/m to the dosage range of people's administration ²My god.

Vincristine sulfate is about 0.025 to 0.05mg/kg body weight * jede Woche to the dosage range of people's parenteral administration.

Vinorelbine is about 10 to 50mg/m to the dosage range of people's administration ²My god.

The phosphoric acid etoposide is about 25 to 115mg/m to the dosage range of people's administration ²My god, as 56.8 or 113.6mg/m ²My god.

Teniposide to the dosage range of people's administration for per approximately fortnight about 75 to 150mg.

Amycin is about 10 to 100mg/m to the dosage range of people's administration ²My god, as 25 or 50mg/m ²My god.

Epirubicin is about 10 to 200mg/m to the dosage range of people's administration ²My god.

Idarubicin is about 0.5 to 50mg/m to the dosage range of people's administration ²My god.

Mitoxantrone is about 2.5 to 25mg/m to the dosage range of people's administration ²My god.

Paclitaxel is about 50 to 300mg/m to the dosage range of people's administration ²My god.

Alendronic Acid is about 5 to 10mg/ days to the dosage range of people's administration.

Clodronic acid is about 750 to 1500mg/ days to the dosage range of people's administration.

Etidronic acid is about 200 to 400mg/ days to the dosage range of people's administration.

Ibandronic acid is per three to four stars phase 1-4mg to the dosage range of people's administration.

Risedronic acid is about 20 to 30mg/ days to the dosage range of people's administration.

Pamidronic acid is that per three to four week about 15 is to 90mg to the dosage range of people's administration.

Tiludronic acid is about 200 to 400mg/ days to the dosage range of people's administration.

Trastuzumab is about 1 to 4mg/m to the dosage range of people's administration ²Week.

Bicalutamide is about 25 to 50mg/m to the dosage range of people's administration ²My god.

One of purpose of the present invention provides a kind of pharmaceutical composition that contains the associating of the present invention of therapeutic alliance proliferative disease effective dose.In said composition, coupling component (a) and (b) can independently unit dosage form is simultaneously, successively or administration respectively with the unit dosage form of an associating or two.Unit dosage form also can be fixed combination.

According to the present invention, be used for coupling component (a) and (b) administration and being used for respectively with fixed combination, the pharmaceutical composition that promptly contains at least two kinds of coupling components (a) and single galenical administration (b) can be with known method preparation itself, and be that those are suitable for enteral such as oral or rectum and parenteral route to mammal (homoiothermic animal), the compositions that comprises people's administration, it contains the coupling component of at least a pharmacological activity for the treatment of effective dose, or contain one or more pharmaceutically suitable carrier simultaneously, particularly be suitable for the carrier that intestinal or parenteral route use.

New pharmaceutical composition contains, and for example about 10% to about active component of 100%, preferred about 20% to about 60%.Being used for by the pharmaceutical preparation that enteral or parenteral administration carry out therapeutic alliance is the preparation of unit dosage form for example, as sugar coated tablet, tablet, capsule or suppository, or ampoule.If not explanation in addition, these preparations are with known method preparation itself, for example conventional mixing, granulation, sweet tablet, dissolving or freeze-drying.Be understandable that, since can reach required effective dose by giving a plurality of dosage units, the not pattern of wants of unit content itself effective dose of contained coupling component in the single dosage of each dosage form.

The present invention relates to the dosage regimen of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of improvement or its officinal salt and suffers from solid tumor disease in treatment, comprises the purposes among the patient of renal carcinoma for example on the other hand.According to one of the solution of the present invention, 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines is administered twice with the amount of lacking than known dosage regimen once a day or repeatedly every day, for example twice or three times of every day.Perhaps, the present invention includes the therapeutic scheme that 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines wherein is administered once with 1000mg/ days to 1400mg/ days, particularly 1200mg/ days to 1300mg/ days, especially 1250mg/ days dosage every day.Dosage of the present invention has reduced the toxic action of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines, and has improved therapeutic efficiency by making concentration medicine (for example being higher than about 1 micromole) keep the long period.

Therefore, the present invention relates to the patient is given the method for 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines, this method comprise to the patient according to every day twice scheme give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt of medicine effective quantity.

Alternatively, the present invention relates to the patient is given the method for 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines, this method comprise to the patient according to once a day scheme, with 1000mg/ days to 1400mg/ days, particularly 1200mg/ days to 1300mg/ days, give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt as 1250mg/ days dosage.

The invention still further relates to the method for solid tumor disease among the treatment patient, this method comprise to the patient according to every day twice scheme or scheme once a day give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt of medicine effective quantity.

1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines is effective especially to suppressing the cancer metastasis growth.Therefore, the invention still further relates to the method that suppresses transitivity growth among cancer patient, particularly the solid tumor cancer patient, this method comprise to the patient according to every day twice scheme give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt of medicine effective quantity.Alternatively, the invention still further relates to the method for the transitivity growth that suppresses among cancer patient, particularly the solid tumor cancer patient, this method comprises the patient according to once a day scheme, with 1000mg/ days to 1400mg/ days, particularly 1200mg/ days to 1300mg/ days, give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt as 1250mg/ days dosage.

According to an aspect of the present invention, 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) but twice of phthalazines every day individually dosed continuously, perhaps during other treatment is as amic therapy method and administration afterwards.In every day twice scheme, adopt be divided into two dosage, for 300mg to 4000mg, for example for 300mg/ days to 2000mg/ days or 300mg/ days to 1000mg/ days, particularly 300,500,750,1000,1500 or 2000mg/ days every day oral administration dosage as medicine effective quantity.1000mg/ days dosage can be with dosage, the administration in 6 to 12 hours at interval of two 500mg, and for example the interval is about 8 hours, and 2000mg/ days dosage can be with dosage, the administration in 6 to 8 hours at interval of two 1000mg, and for example the interval is about 12 hours.

In alternative dosage regimen once a day, 1000mg/ days to 1400mg/ days, particularly 1200mg/ days to 1300mg/ days, can give once in per 24 hours as 1250mg/ days dosage.

When 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines gives with the form of officinal salt, should give the amount suitable (that is, with above-mentioned amount equivalent) with free alkali.In this application, mentioned 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines is intended to comprise its officinal salt.

But different aspect combination in any of the present invention.For example, can once a day or give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines for twice to patients with renal cell carcinoma or the patient that suffers from other tumor types treats.1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines dosage regimen of improving can be used in independent therapy or the conjoint therapy, and in other words, 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines can give separately or unite use with other therapeutic agent.In conjoint therapy, its according to describe herein once a day or twice scheme give, any other therapeutic agent can be according to its set relieve pain.

The specific embodiment

Embodiment 1

With 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines and treat uniting of chemotherapy regimen, wherein 7 patients once accepted the adjuvant chemotherapy method to 15 patients that suffer from the metastatic colorectal cancer that the histology makes a definite diagnosis.Chemotherapy regimen is to give 85mg/m on the 1st day ²Oxaliplatin, the 1st and the 2nd day infusion 200mg/m in 2 hours ²Formyl tetrahydrofolic acid, the 1st with the 2nd day 22 hours continuous mutually 400mg/m that gives at interval ²And 600mg/m ²5-fluorouracil inject.Chemotherapy regimen gave once in per 14 days.1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines gives continuously with single every day of the dosage of 500mg/ days, 1000mg/ days or 2000mg/ days.This treatment can tolerate well.The pharmacokinetics of oxaliplatin does not change because of giving 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines simultaneously.Through observing, 2 conditions of patients are stable, and 3 patients have less response, and 8 patients have partial response.

Embodiment 2

To 10 patients that suffer from metastatic renal cell cancer 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of orally give 300,750 or 1000mg/ days once a day, wherein 6 were once carried out treatment biology.7 disease of patient can be stablized average 3 months among 10 patients.

Embodiment 3

To suffering from the advanced solid tumor that the histology makes a definite diagnosis and can measuring twice orally give 1-patient's every day (4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of disease, up to PD or the toxicity that can not tolerate occurs.Continuously patient group's (3 of each dose evaluations) with every day accumulated dose 300mg, 500mg, 1000mg and 2000mg handle, it is individually dosed that described accumulated dose is divided into 8 hours two of being separated by.Strengthen nuclear magnetic resonance (DCE-MRI) monitoring patient by tumor being carried out dynamic contrast, the measured value of the two-dimentional transfer constant (Ki) after, the 2nd day and the circulation in per 28 days preceding to obtain medical treatment.In addition, obtained complete pharmacokinetic curve at the 1st day and the 28th day by nuclear magnetic resonance mensuration gross tumor volume in per 28 days.Treatment can well tolerate, and does not have the SAE relevant with medicine.Following toxicity appears in the patient who gives 300mg, 500mg and 1000mg dosage every day: 3 grades of risings of of short duration liver transaminase (2 patients), 1 grade drowsiness (1 patient), 2 grades have a dizzy spell (4 patients).Following minimizing is compared in the DCE-MRI demonstration, and (the 2nd and 28 day average % minimizing is respectively 300mg-68.3,500mg-72.98) with ground state.Pharmacodynamic study shows, average C _Minimum(ng/ml) and area under curve (AUC) (h.ng.ml) be respectively 300mg-7.7,82,500mg-4.3,46,1000mg-27,370.Tables of data in the research is understood and is being reduced tumor perfusion/vascular permeability and delaying biological effect aspect the tumor growth.

Embodiment 4

To the patient that suffers from the advanced solid tumor that the histology makes a definite diagnosis and can measure disease orally give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines once a day, up to PD or the toxicity that can not tolerate occurs.Continuously patient group's (3 of each dose evaluations) with every day accumulated dose 50mg, 150mg, 300mg, 500mg, 750mg, 1000mg, 1200mg, 1500mg and 2000mg treat as single dosage every day.Before administration, carried out comprehensive pharmacokinetics (PK) sampling on the the 1st, 15 and 28 day.In ground state, carried out reflecting the DCE-MRI that tumor perfusion and vascular permeability change on the the 2nd and 28 day.For all appreciable MRI scanning, estimate the contrast enhancing of whole tumor by calculating two-way transfer constant (Ki).By tumor cell produce short angiogenesis factor---plasma VEGF can reflect the anaerobic condition of tumor, in ground state, measured this value on the the 1st, 8,15,22 and 28 day.In 76 patients altogether that carry out that two I phases study, 22 patients that suffer from colorectal carcinoma and metastatic liver cancer can use the DCE-MRI assay, and 63 patients that suffer from advanced carcinoma can carry out plasma VEGF and PK analyzes.Use the SWOG response criteria, Fa Zhan disease is not defined as stablizing 〉=2 months disease.

The absorption of 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines is (T rapidly _MaximumIt is 1 to 2.5 hour).After reaching stable state in 15 days, whole body contact amount (AUC) was compared with the 1st day and is reduced about 30%.Just observing exposure dose in the time of 1000mg/ days increases pro rata.The final half-life is 3 to 6 hours.Do not observe the toxicity of dose limitation up to 2000mg/ days yet.

Increase (the 2nd day: p=0.01 at the 2nd and 28 day percentage ratio that accounts for ground state Ki and dosage; The 28th day: p=0.0003), contact amount (AUC; The 2nd day: p＜0.0001; The 28th day: p=0.003) and plasma concentration (C _MinimumThe 2nd day: p=0.0003; The 28th day: have dependency relation p＜0.0001), as measuring by Spearman Rank Correlation.In addition, can survey the variation of hepatic injury (product of two dimension) summation in the decline of the 2nd and 28 day the percentage ratio that accounts for ground state Ki and when finishing in the 56th day with all and have relation between the variation of the hepatic metastases tumor size measured.The decline of the average Ki value of the patient of stable disease obviously big (the 2nd day: p=0.004; The 28th day: p=0.006).Ki decline 50-60% is relevant with stable disease.Contact amount based on the contact response model approaches 114hr. μ M.Calculate the PK variability, have the dosage of low restriction (95%CI) to should be optimal dose to the contact amount of 114hr. μ M, therefore recommending dosage every day of 1250mg is biological effective dose.Support the level of plasma VEGF that selected biologic activity dosage is the stable disease patient to be increasing sharply of dose dependent.In preceding 28 days of treatment, the respondent's of acceptance＞1000mg/ days dosage level of plasma VEGF has increased by 5 times.

Claims (27)

1. joint product, described joint product contains (a) 4-pyridylmethyl-phthalazines anti-angiogenic agent and (b) platinum compounds and/or anti-tumor metabolic drug and dispensable formyl tetrahydrofolic acid, wherein said active component exists with the form of free form or officinal salt, and can not contain or contain at least a pharmaceutically suitable carrier, be used for simultaneously, use respectively or successively.

2. joint product according to claim 1, described joint product contain (a) 4-pyridylmethyl-phthalazines anti-angiogenic agent and (b) platinum compounds, 5-fluorouracil and formyl tetrahydrofolic acid.

3. joint product according to claim 1, described joint product contain (a) 4-pyridylmethyl-phthalazines anti-angiogenic agent and (b) platinum compounds, capecitabine and formyl tetrahydrofolic acid.

4. joint product, described joint product contains (a) 4-pyridylmethyl-phthalazines anti-angiogenic agent and (b) topoisomerase I inhibitor and/or anti-tumor metabolic drug and dispensable formyl tetrahydrofolic acid, wherein said active component exists with the form of free form or officinal salt, and can not contain or contain at least a pharmaceutically suitable carrier, be used for simultaneously, use respectively or successively.

5. joint product according to claim 4, described joint product contain (a) 4-pyridylmethyl-phthalazines anti-angiogenic agent and (b) topoisomerase I inhibitor, 5-fluorouracil or capecitabine and formyl tetrahydrofolic acid.

6. joint product, described joint product contain (a) 4-pyridylmethyl-phthalazines anti-angiogenic agent and (b) are selected from the antitumor agent of estrogen antagonist, topoisomerase II inhibitor, microtubule activator, gonadorelin agonist, androgen antagonist, bisphosphonate and trastuzumab.

7. joint product according to claim 6, wherein antitumor agent is a discodermolide.

8. pharmaceutical composition, this pharmaceutical composition contain therapeutic alliance proliferative disease effective dose according to each described joint product and at least a pharmaceutically suitable carrier in the claim 1 to 7.

9. the purposes that is used for the treatment of proliferative disease according to each described joint product in the claim 1 to 7.

10. be used for the treatment of purposes in the medicine of proliferative disease according to each described joint product in the claim 1 to 7 in preparation.

11. a method for the treatment of patient's proliferative disease, described method comprise 4-pyridylmethyl-phthalazines anti-angiogenic agent of giving patient's angiogenesis inhibitor effective dose and in conjunction with amic therapy method.

12. method according to claim 11, wherein 4-pyridylmethyl-phthalazines anti-angiogenic agent is 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt.

13. method according to claim 12, dosage wherein are to give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of 500mg/ days to 4000mg/ days every day, or its salt of equivalent.

14. method according to claim 13, dosage range wherein are 500mg/ days to 2000mg/ days.

15. method according to claim 14 wherein gives 500,1000,1500 or 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of 2000mg/ days, or its salt of equivalent.

16. method according to claim 11, amic therapy method wherein comprise according to set relieve pain oxaliplatin, formyl tetrahydrofolic acid and 5-fluorouracil.

17. method according to claim 16, wherein said 4-pyridylmethyl-phthalazines anti-angiogenic agent are 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt.

18. method according to claim 17, wherein said dosage are to give 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines of 500mg/ days to 4000mg/ days every day, or its salt of equivalent.

19. according to each described method in the claim 11 to 18, proliferative disease wherein is a solid tumor disease.

20. method according to claim 19, solid tumor disease wherein are colorectal carcinoma.

21. a commercial packing product, this packaging product contain 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt that is suitable for the oral administration form and the teachings that the patient who accepts amic therapy method treatment solid tumor disease is given 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt.

22. 4-pyridylmethyl-phthalazine derivatives is used for the treatment of purposes in the pharmaceutical preparation of renal carcinoma in production.

23. 4-pyridylmethyl-phthalazine derivatives is used for suppressing purposes in the pharmaceutical preparation of patients with renal cell carcinoma transitivity growth in production.

24. a method for the treatment of patient's renal carcinoma, described method comprise the 4-pyridylmethyl-phthalazine derivatives that the patient is given medicine effective quantity.

25. according to the described purposes or the described method of claim 24 of claim 22 or 23, wherein 4-pyridylmethyl-phthalazine derivatives is 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its officinal salt.

26. according to claim 22 or 23 described purposes or the described method of claim 24, wherein medicine effective quantity is to give 300mg to 2000mg every day.

27. according to claim 22 or 23 described purposes or the described method of claim 24, wherein said renal carcinoma is the transitivity renal carcinoma.