RU2320344C2 - Use of 4-pyridylmethylphthalazines in cancer treatment - Google Patents

Abstract

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to drugs and concerns a combination used in treatment of proliferative disease. The combination comprises 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salt, oxaliplatin and 5-fluorouracil wherein active components present in free form or in form of pharmaceutically acceptable salt in therapeutically effective doses in each case and optionally at least one pharmaceutically acceptable carrier, and this combination is used for separate or successive using. Also, invention discloses a pharmaceutical composition, method for treatment of proliferative disease and package for sale comprising 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salt, oxaliplatin and 5-fluorouracil.

EFFECT: improved method of treatment, valuable medicinal properties of agent.

7 cl, 4 ex

Description

The present invention relates to the use of 4-pyridylmethyl-phthalazine derivatives for the treatment of kidney cancer. In addition, the invention relates to the use of a 4-pyridylmethylphthalazine derivative having anti-angiogenic properties in combination therapy by administering agents simultaneously, separately or sequentially, especially for treating a proliferative disease, especially a solid tumor, for example, kidney cancer. The present invention further relates to the use of such a combination in the manufacture of a medicament for the treatment of a proliferative disease; to the product packaging sold, including such a combination, as a combined preparation for simultaneous, separate or sequential use along with instructions for using such a combination, to a method for treating warm-blooded mammals, especially humans, and to improved modes of administration of 1- (4-chloroanilino) -4 - (4-pyridylmethyl) phthalazine.

Derivatives of 4-pyridylmethylphthalazine are selective inhibitors of vascular epithelial growth factor receptor tyrosine kinase receptor (VEGF), and their pretreatment, pharmaceutical compositions and methods for preparing such compounds are described in WO 00/59509, EP 02/04892 and in particular in US Pat. No. 6,258,812, which Included in the application by citation. Such compounds reduce the microcirculatory part of the vascular bed, inhibit the post primary tumors and metastases in animal models and are used to treat diseases associated with uncontrolled angiogenesis, especially with tumor diseases (solid tumors), such as breast cancer, colon cancer, lung cancer , especially small cell lung cancer, and prostate cancer.

Surprisingly, 4-pyridylmethylphthalazine derivatives have been found to be useful in the treatment of kidney carcinoma, especially to inhibit the growth of kidney carcinoma metastases. Therefore, the present invention relates to a method for treating kidney carcinoma in a patient, which comprises administering to the patient a pharmaceutically effective amount of a 4-pyridylmethylphthalazine derivative. In particular, the present invention relates to a method for suppressing the growth of metastases in a patient with kidney carcinoma, which comprises administering to the patient a pharmaceutically effective amount of a 4-pyridylmethylphthalazine derivative.

Throughout the present invention, the 4-pyridylmethyl-phthalazine derivative is, in particular, 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof. Human studies have shown that 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine is well tolerated and reduces the permeability of the tumor vascular system. It is understood that the following references to 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine imply the inclusion of pharmaceutically acceptable salts thereof.

The present invention also relates to the use of a 4-pyridylmethylphthalazine derivative in the manufacture of a pharmaceutical preparation for the treatment of kidney carcinoma, in particular metastatic kidney carcinoma, and a pharmaceutical preparation for suppressing the growth of metastases in patients with renal carcinoma.

The possibilities of chemotherapy in the treatment of proliferative diseases are known to those skilled in the art.

It was unexpectedly found that the antitumor effect of a combination defined in the context, in particular in the treatment of a proliferative disease, especially a solid tumor, such as kidney cancer, and in particular metastatic kidney cancer, which is resistant to other chemotherapeutic agents known as antitumor agents, is higher than the effect treatment using chemotherapy or only a derivative of 4-pyridylmethylphthalazine.

In a preferred embodiment of the present invention, chemotherapy includes a platinum compound and / or an antitumor antimetabolite and optionally folinic acid. In a particular embodiment of the present invention, chemotherapy comprises a platinum compound, 5-fluorouracil and folinic acid. In a further specific embodiment of the present invention, chemotherapy comprises a platinum compound, capecitabine and folinic acid.

In a preferred embodiment of the present invention, chemotherapy comprises a topoisomerase I inhibitor and / or an antitumor antimetabolite and optionally folinic acid. In a specific embodiment of the invention, chemotherapy includes a topoisomerase I inhibitor, 5-fluorouracil or capecitabine and folinic acid.

The term “antitumor antimetabolite” includes, but is not limited to, 5-fluorouracil, tegafur, capecitabine, sladribine, cytarabine, fludarabine phosphate, fluoruridine, gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and the salts of such D, and (raltitrexed ^TM ), LY231514 (alimta ^TM ), LY264618 (lomotrexol ^TM ) and OGT719.

5-Fluorouracil can be prepared, for example, as described in US Pat. No. 280,2005. It can be used in the present invention as sold, for example, under the trade name Efudex ^TM , Fluracil ^TM or Fluoroblastin ^TM . Tegafur can be used especially in the form of a composition, as disclosed in US Pat. Nos. 5,116,600 and 5,525,603. In addition, tegafur can be introduced, for example, in a form sold under the trademarks of fluoroafur ^TM , Lamar ^TM or Non-Berek ^TM . Capecitabine may be administered, for example, in the form disclosed in US Pat. No. 5,472,949, or in a form sold, for example, under the trademark Xeloda ^™ . Cladribine can be obtained, for example, as disclosed in US patent 4760135. It can be introduced, for example, in the form sold under the trademarks Leistatin ^TM or Leistat ^TM . Cytarabine can be prepared, for example, as disclosed in US Pat. No. 3,116,282 or in Hessler's publication by J. Org. Chem., 41 (1970) 1828. It can be introduced, for example, in the form sold under the trademarks ara-C ^TM , cytosar ^TM or unicyl ^TM . A suitable salt of such a compound is cytarabine ophosphate (stucidide ^TM ), which can be prepared as described in US Pat. No. 4,812,560. Fludarabine phosphate can be prepared as described in US Pat. No. 4,357,324. It can be used as sold under the trade name Fludara ^TM . Gemcitabine may be administered, for example, in accordance with the disclosure of US Pat. No. 5,464,826 or in a form sold, for example, under the brand name Gemzar ^™ . 6-Mercaptopurine (6-purintiol) can be obtained, e.g., as disclosed in US 2933498. It can be applied as marketed, e.g., under the trademark leykerin Purinethol ^TM or ^TM. Hydroxyurea can be obtained, for example, as disclosed in US Pat. No. 2,757,727. Methotrexate can be used as marketed, for example, under the trade name Folex ^TM or MTX ^TM . Edatrexate can be obtained, for example, as disclosed in US patent 4369319.

The term “folinic acid” refers to N- [4 - [[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl) methyl] amino] benzoyl -L-glutamic acid, which is sold, for example, under the brand name leucovorin ^TM .

The term “platinum compound” as used herein means carboplatin, cisplatin or oxaliplatin. Preferably, the platinum compound is oxaliplatin.

The term "carboplatin", as used in context, refers to the antitumor agent cis-diamine- (1,1-cyclobutanedicarboxylato) platinum (II), which is disclosed in US patent 4140707 or in the publication RCHarrison and others, Inorg. Chim. Acta 46, L15 (1980). This preparation can be administered, for example, in a form sold, for example, under the trademark carboplate ^TM or paraplatin ^TM .

The term “oxaliplatin,” as used herein, refers to an antitumor agent, also known as oxalatoplatin, which is disclosed, for example, in US Pat. No. 5,716,988. This preparation may be administered, for example, in the form described in the cited US patent or in the form in which it is sold, for example, under the brand name Eloxanthin ^TM or 1-OHP ^TM .

The term “cisplatin”, as used herein, refers to an antitumor agent, also known as cis-diamindichloroplatin, which compound and its use as an antitumor agent are disclosed, for example, in DE 2318020.

The term “topoisomerase I inhibitors”, as used herein, includes, but is not limited to, topotecan, irinotecan, 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO 99/17804). Irinotecan can be introduced, for example, in the form in which it is sold, for example, under the brand name camptosar ^TM . Topotecan can be introduced, for example, in the form in which it is sold, for example, under the brand name hicamtin ^TM .

In a broader sense according to the invention, the term "chemotherapy" refers to the administration of a chemotherapeutic agent selected from the group which includes, but is not limited to, aromatase inhibitors, antiestrogens, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, gonadorelin agonists, antiandrogens, bisphosphonates, histone deacetylase inhibitors, S-adenosylmethionine decarboxylase inhibitors and trastuzumab.

In one preferred embodiment, the antitumor agent is selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase II inhibitors, microtubule active agents, in particular discodermolide, protein kinase C inhibitors, in particular, staurosporin derivatives, gonadorelin agonists, bisosphanophan phosphates and antiandrogen in particular pamidronic or zoledronic acid, and trastuzumab. Another preferred embodiment of the present invention relates to a combination of a 4-pyridylmethylphthalazine antiangiogenic agent, in particular 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine, and discodermolide.

The term aromatase inhibitors, as used herein, refers to compounds that suppress estrogen production, i.e. the conversion of substrates of androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially exemestane and formestane, and in particular non-steroidal compounds, especially aminoglutethimide, Vorozol, fadrozole, anastrozole, and mainly letrozole. Exemestane can be introduced, for example, in the form in which it is sold, for example, under the brand name aromatazine ^TM . Formestane can be introduced, for example, in the form in which it is sold, for example, under the brand name lentarone ^TM . Fadrozole may be administered, for example, in the form in which it is sold, for example, under the trademark Apema ^TM . Anastrozole may be administered, for example, in the form in which it is sold, for example, under the brand name arimidex ^TM . Letrozole may be administered, for example, in the form in which it is sold, for example, under the trademark Femara ^TM or Femar ^TM . Aminoglutethimide can be introduced, for example, in the form in which it is sold, for example, under the brand name Orienten ^TM .

The combination of the invention, comprising an antitumor agent that is an aromatase inhibitor, is particularly useful for treating breast tumors with positive hormone receptors.

The term “antiestrogens,” as used herein, refers to compounds that counteract the effect of estrogens at the level of estrogen receptors. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, raloxifene hydrochloride. Tamoxifen can be introduced, for example, in the form in which it is sold, for example, under the brand name Nolvadex ^™ . Raloxifene hydrochloride may be introduced, for example, in the form in which it is sold, for example, under the brand name of Evista ™. The fulvestrant may be in the dosage form that is disclosed in US Pat. No. 4,659,516, or may be administered, for example, in the form in which it is sold, for example, under the trademark Faslodex ^™ .

The term “topoisomerase II inhibitors”, as used herein, includes, but is not limited to, anthracyclines — doxorubicin (including a liposomal dosage form, for example, Celix ^TM ), epirubicin, idarubicin and nemorubicin, anthraquinones — mitoxantrone and isoxantrone and podophyllotoxins — etoposide and etoposide . Etoposide can be administered, for example, in the form in which it is sold, for example, under the brand name etofos ^TM . Teniposide can be administered, for example, in the form in which it is sold, for example, under the brand name VM 26-Bristol ^TM . Doxorubicin may be administered, for example, in the form in which it is sold, for example, under the trade name Adriblastin ^TM . Epirubicin can be introduced, for example, in the form in which it is sold, for example, under the brand name pharmorubicin ^TM . Idarubicin can be introduced, for example, in the form in which it is sold, for example, under the brand name zavoz ^TM . Mitoxantrone can be introduced, for example, in the form in which it is sold, for example, under the brand name novantron ^TM .

The term “microtubule active agents” refers to microtubule stabilizing agents and microtubule destabilizing agents selected from the group consisting of paclitaxel, docetaxel, eleutherobin, winc alkaloids, for example vinblastine, especially vinblastine sulfate, vincristine sulfate, especially and vinorelbine and discodermolide. Vinblastine sulfate can be introduced, for example, in the form in which it is sold, for example, under the trademark Vinblastine RP ^TM . Vincristine sulfate can be introduced, for example, in the form in which it is sold, for example, under the brand name Pharmistin ^TM .

Discodermolide can be obtained, for example, as disclosed in US Pat. No. 4,939,168 and 5,618,448 issued by Harbor Branch Oceanographic Institute, or chemical synthesis, as described, for example, in GB 2280677, WO 98/24429 and US Pat. Nos. 5,789,605 and 6,031,133, which are incorporated in invention by citation.

The term "protein kinase C inhibitors" refers, in particular, to staurosporin derivatives, and preferably to those disclosed in US Pat. No. 5,093,330. Such compounds may be administered in the form disclosed in WO 99/48896.

The term “antiangiogenic compounds”, as used herein, refers to thalidomide (thalomide ^TM ) and SU5416.

The term “gonadorelin agonist,” as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in US Pat. No. 4,100,274 and may be introduced, for example, in the form in which it is sold, for example, under the trademark zoladex ^TM . Abarelix may be in a dosage form, for example, as disclosed in US Pat. No. 5,843,901.

The term "antiestrogens" as used in context includes, but is not limited to, bicalutamide (casodex ^TM ), which may be in a dosage form, for example, as disclosed in US Pat. No. 4,636,505.

The term “bisphosphonates” as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid can be introduced, for example, in the form in which it is sold, for example, under the brand name didronel ^TM . Clodronic acid can be introduced, for example, in the form in which it is sold, for example, under the trademark Bonefos ^TM . Tiludronic acid can be introduced, for example, in the form in which it is sold, for example, under the trademark Skelid ^TM . Pamidronic acid can be introduced, for example, in the form in which it is sold, for example, under the brand name Aredia ^TM . Alendronic acid can be introduced, for example, in the form in which it is sold, for example, under the brand name fosamax ^TM . Ibandronic acid can be introduced, for example, in the form in which it is sold, for example, under the brand name bondranate ^TM . Risedronic acid can be introduced, for example, in the form in which it is sold, for example, under the brand name Actonel ^™ . Zoledronic acid can be introduced, for example, in the form in which it is sold, for example, under the trademark Zometa ^TM .

The term "histone deacetylase inhibitors" as used in the context includes, but is not limited to, MS275, SAHA, FK228 (formerly FR901228), trichostatin A and the compounds disclosed in WO 02/22577, in particular NVP-LAQ824 or its lactate salt.

The term “S-adenosylmethionine decarboxylase inhibitors”, as used herein, includes, but is not limited to, the compounds disclosed in US Pat. No. 5,461,076.

Trastuzumab may be administered, for example, in the form in which it is sold, for example, under the brand name Herceptin ^TM .

The structure of active agents identified by code numbers, generic or trade names can be taken from the modern edition of the standard guide "The Merck Index" or from a database, for example, Patents International (for example, IMS World Publications). Their corresponding content is included in the invention by citation.

The present invention further relates to “combination preparations” comprising (a) a 4-pyridylmethylphthalazine derivative with antiangiogenic properties, in particular 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine, and (b) one or more antitumor agents, in particular oxaliplatin, folinic acid and 5-fluorouracil. The term “combination preparation”, as used in the context, particularly defines a “set of parts” in the sense that components (a) and (b) of the combination, as defined above, can be dispensed independently or using various predetermined combinations with different amounts of components (a) and (b) combinations, i.e. simultaneously or at different times. Parts of the kit can then be entered, for example, simultaneously or chronologically differentially, that is, at different times and with equal or different gaps for each part of the kit. Thus, the present invention further includes a commercial package comprising 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof in an oral dosage form and instructions for administering 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or its pharmaceutically acceptable salt, when the patient is undergoing chemotherapy aimed at the disease of a solid tumor.

The present invention also relates to the use of a combination of the invention in the treatment of a proliferative disease and in the manufacture of a medicament for the treatment of a proliferative disease.

The combination therapy of the invention is especially useful for treating diseases with solid tumors. The term “solid tumor diseases” refers mainly to kidney cancer, breast cancer, ovarian cancer, colon cancer, for example progressive colorectal cancer, and especially gastrointestinal cancer, such as stomach cancer, cervical cancer, lung cancer, in particular small cell lung cancer and non-small cell lung cancer, head and neck cancer, bladder cancer, prostate cancer, Kaposi’s sarcoma, carcinoid tumors and carcinoid syndrome. The present combination inhibits the growth of solid tumors and non-solid tumors and is also suitable for preventing the metastatic growth of these tumors.

The term "carcinoid tumor," as used in context, refers to a neuroendocrine tumor arising from enterochromaffin cells, which cells spread mainly through the intestines and major bronchi. Peptides synthesized in carcinoid cells contain 5-hydroxytryptamine and 5-hydroxytryptophan.

The term “carcinoid syndrome,” as used herein, refers to a disease, in particular the detection of a progressive disease, the syndromes of which include sudden redness of the skin of the face and neck, diarrhea and palpable mass in the abdominal cavity or enlargement of the liver. With the aforementioned disease, the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in the urine is usually directly related to the tumor volume and correlates with the possibility of survival. A 5-HIAA level> 8 mg / 24 h is a sensitive control in 75% of all cases of carcinoid syndrome. Another indicator of the syndrome is elevated plasma serotonin levels, in particular, plasma serotonin levels are higher than about 250, especially 350 ng / ml.

The term "metastatic growth", as used in the context, includes metastatic spread and the growth and development of micrometastases in other organs in cancer patients.

It will be understood that references to components (a) and (b) of the combination also mean that pharmaceutically acceptable salts of the compounds are included.

A combination that includes (a) at least one antitumor agent known in chemotherapy, and (b) a 4-pyridylmethylphthalazine derivative in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier will be referred to hereinafter as a combination of the invention.

The nature of proliferative diseases is multifactorial. In some circumstances, drugs with a different mechanism of action may be combined. However, just under the circumstances, any combination of drugs with a different type of action does not necessarily lead to beneficial effects.

Even more unexpected is the experimental discovery of the fact that the introduction of an in vivo combination according to the invention leads not only to a beneficial effect, especially to a synergistic therapeutic effect, for example, in relation to slowing, stopping or reversing the development of a neoplasm, but also to further unexpected beneficial effects, for example, fewer side effects, improved quality of life and reduced mortality and morbidity compared to monotherapy, which uses only one and pharmaceutically active ingredients used in the COMBINATION OF THE INVENTION.

The effective dose of each of the components of the combination used in the combination of the invention may vary depending on the particular compound or pharmaceutical composition used, the route of administration, the condition undergoing therapy and its severity. Thus, the dosage regimen of the combination according to the invention is selected in accordance with a variety of factors, including the route of administration and the state of the patient's kidney and liver functions. A general practitioner, clinician or veterinarian can easily determine and prescribe the effective amount of one active ingredient necessary to prevent, counteract or stop the progression of the condition. Optimum accuracy in achieving a concentration of active ingredients within a range that provides efficacy without toxicity requires a regimen based on the kinetics of accessibility of the active ingredients to the intended sites.

To determine the active dose of an antiangiogenic agent - 4-pyridylmethyl-phthalazine - applicable to patients and, in particular, applicable to an individual patient, two biomarkers, dynamic contrast enhancement of magnetic resonance image (DCE-MRI) and plasma vascular epithelial growth factor (VEGF) level along with exposure duration, safety and tumor response data. For this purpose, the patient receives, for example, a long daily dose, for example, 50, 150, 300, 500, 750, 1000, 1500 or 2000 mg of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine. Samples for pharmacokinetics (PK) are taken before dosing and on days 1, 15 and 28. The DCE-MRI study, which reflects a change in tumor perfusion and the presence of blood vessels, is performed relative to the baseline on day 2 and day 28. For all scans being evaluated The MRI contrast enhancement for the entire tumor can be determined by calculating the bidirectional transfer constant (Ki) and expressed as a percentage of the baseline Ki for scores on days 2 and 28. The level of VEGF, a pro-angiogenic factor, in the plasma produced by the tumor cells reflects hypoxic the tumor status, and samples are taken relative to the baseline and on days 1, 8, 15, 22 and 28. There is a significant relationship between the percentage Ki of the baseline and the increase in the dose of antiangiogenic 4-pyridylmethylphthalazine, its duration of action and its concentration in plasma, as determined Spearman rank correlation. Moreover, a significant relationship exists between the percentage reduction in Ki and the volume change in liver disease at the end of cycle 2, which is determined by the change in the sum of all measured liver lesions (two-dimensional product). Patients with non-progressive disease have a significantly larger decrease in Ki. A non-progressive disease is associated with a 50-60% decrease in Ki.

Typically, in the treatment of renal carcinoma, the 4-pyridylmethyl-phthalazine derivative can be given on a continuous basis, for example, daily. For 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine, a daily oral dose in the range of 300-4000 mg, for example, in the range of 300 mg / day to 2000 mg / day or 300 mg / day to 1000 mg / day, in particular 300, 500, 750, 1000, 1500 or 2000 mg / day is considered as a pharmaceutically effective dose. However, other regimens are obviously also effective and are included in the scope of the present invention. When 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine is administered as a pharmaceutically acceptable salt, an equivalent amount of the free base (i.e., one equivalent to the amounts given above) is administered.

In the combination of the invention, a 4-pyridylmethylphthalazine derivative, in particular 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof, may be given on a continuous basis, for example, daily during and after chemotherapy. A daily oral dose in the range of 500 mg to 4000 mg, for example in the range of 500 mg / day to 2000 mg / day, in particular 1000, 1500 or 2000 mg / day, is contemplated. However, other administration schemes are also included in the scope of the present invention. When a 4-pyridylmethyl-phthalazine derivative, in particular 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine, is administered in salt form, the daily oral dosage ranges described above are adjusted so that an equivalent amount of free base is administered.

When the combination components used in the combination according to the invention are used in the form in which they are sold as the only drugs, their dosage and type of administration may occur in accordance with the information provided on the package insert of the respective drug sold in order to have a beneficial effect, described in context, unless otherwise indicated.

Chemotherapy, as a rule, is carried out in accordance with the established regimen of administration. Such administration regimens, for example, the regimen proposed by deGramont for colorectal cancer, are known in the art. In a particular embodiment, chemotherapy comprises administering oxaliplatin, folinic acid and 5-fluorouracil according to a prescribed administration regimen, such as those known to those skilled in the art. Particularly useful is a specific chemotherapeutic regimen in which 85 mg / m ^{2 of} oxaliplatin is administered on day 1, 200 mg / m ^{2 of} folinic acid is administered as a two-hour infusion on days 1 and 2, 5-fluorouracil is administered bolus at a dose of 400 mg / m ² , then 600 mg / m ² after 22 hours on the first and second days every 14 days.

5-fluorouracil can be administered to humans in a dosage range ranging from about 50 to 1000 mg / m ² day, for example, 500 mg / m ² day.

Capecitabine can be administered to humans in a dose range ranging from about 10 to 1000 mg / m ² day.

Gemcitabine hydrochloride can be administered to humans in a dosage range ranging from 10 to about 1000 mg / week.

Methotrexate can be administered to humans in a dose range ranging from about 5 to 500 mg / m ² day.

ZD 1694 (raltitrexed ^TM ) can be administered to humans in a dosage range ranging from about 2.0 to 4.0 mg / m ² , for example 3.5 mg / m ² , every 3 weeks as a 15-minute infusion.

Carboplatin can be administered intravenously to humans in a dose range that varies from about 100 to 400 mg / m ² , for example, 200 mg / m ^{2 of} the body surface, approximately every 4-6 weeks.

Oxaliplatin can be administered intravenously to humans in a dose range ranging from about 25 to 135 mg / m ² , for example, 45 or 85 mg / m ^{2 of} the body surface, approximately every 2-3 weeks.

Cisplatin can be administered to humans in a dose range ranging from about 25 to 100 mg / m ² about every 3 weeks.

Topotecan can be administered to humans in a dose range that varies from about 1 to 5 mg / m ² day.

Irinotecan can be administered to humans in a dose range ranging from about 50 to 350 mg / m ² day.

Fadrozole may be administered orally to humans in a dosage range ranging from about 0.5 to about 10 mg / day, preferably from about 1 to about 2.5 mg / day.

Exemestane can be administered orally to humans in a dose range ranging from about 5 to about 200 mg / day, preferably from about 10 to about 25 mg / day, or parenterally from about 50 to 500 mg / day, preferably from about 100 to about 250 mg / day. If the drug will be administered in a separate pharmaceutical composition, it can be entered in the form disclosed in patent GB 2177700.

Formestane can be administered parenterally to a person in a dosage range ranging from about 100 to 500 mg / day, preferably from about 250 to about 300 mg / day.

Anastrozole can be administered orally to humans in a dosage range ranging from about 0.25 to about 20 mg / day, preferably from about 0.5 to about 2.5 mg / day.

Aminoglutethimide can be administered to humans in a dosage range ranging from about 200 to 500 mg / day.

Tamoxifen can be administered to humans in a dose range ranging from about 10 to 40 mg / day.

Vinblastine can be administered to humans in a dosage range ranging from about 1.5 to 10 mg / day, preferably from about 1 to about 2.5 mg / m ² day.

Vincristine sulfate can be administered parenterally to humans in a dosage range ranging from about 0.0255 to 0.05 mg / kg per week.

Vinorelbine can be administered to humans in a dose range varying from about 10 to 50 mg / m ² day.

Etoposide phosphate can be administered to humans in a dosage range ranging from about 25 to 115 mg / m ² day, for example, 56.8 or 113.6 mg / m ² day.

Teniposide can be administered to humans in a dosage range ranging from about 75 to 150 mg, about every two weeks.

Doxorubicin can be administered to humans in a dose range ranging from about 10 to 100 mg / m ² day, for example, 25 or 50 mg / m ² day.

Epirubicin can be administered to humans in a dosage range ranging from about 10 to 200 mg / m ² day.

Idarubicin can be administered to humans in a dose range ranging from about 0.5 to 50 mg / m ² day.

Mitoxantrone can be administered to humans in a dose range ranging from about 2.5 to 25 mg / m ² day.

Paclitaxel can be administered to humans in a dose range ranging from about 50 to 300 mg / m ² day.

Alendronic acid can be administered to humans in a dose range ranging from about 5 to 10 mg / day.

Clodronic acid can be administered to humans in a dose range ranging from about 750 to 1500 mg / day.

Ethidronic acid can be administered to humans in a dose range ranging from about 200 to 400 mg / day.

Ibandronic acid can be administered to humans in a dose range varying from about 1 to 4 mg every 3-4 weeks.

Risedronic acid can be administered to humans in a dosage range ranging from about 20 to 30 mg / day.

Pamidronic acid can be administered to humans in a dose range ranging from about 15 to 90 mg every 3-4 weeks.

Tiludronic acid can be administered to humans in a dose range ranging from about 200 to 400 mg / day.

Trastuzumab can be administered to humans in a dose range that varies from about 1 to 4 mg / m ² per week.

Bicalutamide can be administered to humans in a dosage range ranging from about 25 to 50 mg / m ² day.

One object of this invention is to provide a pharmaceutical composition comprising an amount, including a combination of the invention, which together is therapeutically effective against a proliferative disease. In this composition, the components (a) and (b) of the combination can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. A unit dosage form may also be a specific combination.

Pharmaceutical compositions for the separate administration of components (a) and (b) of the combination and for administration in a specific combination, i.e. single galenic compositions comprising at least two components (a) and (b) combinations in accordance with the invention can be prepared in a manner known per se and suitable for enteral administration such as oral or rectal and parenteral administration to mammals (warm-blooded mammals), including humans, containing a therapeutically effective amount of at least one pharmacologically active component of the combination alone or in combination with one or more pharmaceutically acceptable n carriers, especially suitable for enteral or parenteral use.

The new pharmaceutical composition contains, for example, from about 10% to about 100%, preferably from about 20% to about 60% of the active ingredients. Pharmaceutical preparations for combination therapy for enteral or parenteral administration are, for example, preparations in unit dosage forms, such as sugar coated tablets, tablets, capsules or suppositories, and also ampoules. Unless otherwise indicated, they are prepared in a manner known per se, for example, using conventional mixing, granulation, sugar coating, dissolving or lyophilization techniques. It will be recognized that the standard content of the combination component in a single dose of each dosage form is not necessarily an effective amount per se, since the required effective amount can be achieved by administering a plurality of unit doses.

A further aspect of the present invention relates to the use of improved modes of administration of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof in the treatment of patients suffering from solid tumors, including, for example, kidney cancer. In accordance with one regimen of the invention, 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof is administered daily twice a day or more, for example, two or three times a day, in reduced amounts compared with the already known daily administration regimens. Alternatively, the present invention encompasses a therapeutic regimen in which 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine is administered daily once a day at a dose in the range of 1000 mg / day to 1400 mg / day, specifically dose of 1200 mg / day to 1300 mg / day, in particular 1250 mg / day. Dosage regimens of the invention reduce the toxic effects of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine and improve the effectiveness of the treatment by maintaining an effective level of the drug, for example, above about 1 μM, over a longer period of time.

Thus, the present invention relates to a method for administering 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine to a patient, which comprises administering a pharmaceutically effective amount of 1- (4-chloroanilino) -4- (4-pyridylmethyl) -phthalazine or a pharmaceutically acceptable salt thereof to a patient according to the scheme daily twice daily.

Alternatively, the present invention relates to a method for administering 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine to a patient, which method comprises administering 1- (4-chloranilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof to a patient according to the scheme daily once a day at a dose in the range from 1000 mg / day to 1400 mg / day, specifically at a dose of 1200 mg / day to 1300 mg / day such as 1250 mg / day.

The invention further relates to a method for treating a solid tumor in a patient, comprising administering a pharmaceutically effective amount of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof to a patient according to a twice daily regimen daily or alternatively according to one once a day daily.

1- (4-Chloranilino) -4- (4-pyridylmethyl) phthalazine is especially useful for inhibiting the growth of cancer metastases. Therefore, the present invention further relates to a method for inhibiting the growth of metastases in a patient with a malignant tumor, especially a solid malignant tumor, which comprises administering a pharmaceutically effective amount of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof the patient according to the scheme twice a day daily. Alternatively, the present invention further relates to a method for inhibiting the growth of metastases in a patient with a malignant tumor, especially a solid malignant tumor, which comprises administering a pharmaceutically effective amount of an effective amount of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or its pharmaceutically acceptable salt to the patient according to the scheme once a day daily at a dose in the range from 1000 mg / day to 1400 mg / day, specifically at a dose of 1200 mg / day to 1300 mg / day such as 1250 mg / day.

In accordance with one aspect of the present invention, 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine is given once daily twice daily for an extended period of time or during and after other treatments, for example chemotherapy. Daily oral administration of an amount in the range of 300 mg to 4000 mg, for example in the range of 300 mg / day to 2000 mg / day or 300 mg / day to 1000 mg / day, in particular 300, 500, 750, 1000, 1500 or 2000 mg / day, divided into two doses, is considered as a pharmaceutically effective amount on a twice daily basis. A dose of 1000 mg / day is given as two doses of 500 mg with a difference of 6-12 hours, for example, with a difference of about 8 hours, and a dose of 2000 mg / day is administered as two doses of 1000 mg with a difference of 6-8 hours, for example, a difference of about 12 hours

Alternatively, once a day, a dose in the range of 1000 mg / day to 1400 mg / day, especially a dose of 1200 mg / day to 1300 mg / day such as 1250 mg / day, is administered once for a time period of about 24 h

When 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine is administered as a (pharmaceutically acceptable salt, then an equivalent amount of the free base (i.e., one equivalent to the amounts described above) is administered. that reference to 1- (4-chloroanilino) -4- (4-pyridylmethyl) -phthalazine includes a pharmaceutically acceptable salt thereof.

Various aspects of the present invention can be freely combined with one another. For example, a patient with a malignant tumor of the kidney or a patient with a different type of tumor can be treated by administering 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine on a daily basis or twice daily. Improved administration regimens of 1- (4-chloranilino) -4- (4-pyridylmethyl) -phthalazine can be used in monotherapy or in combination therapy, in other words, 1- (4-chloranilino) -4- (4-pyridylmethyl) phthalazine is administered alone or in combination with other therapeutic agents. As a combination therapy, it is administered on a daily basis once or twice a day, and any other therapeutic agent or therapeutic agents are administered in accordance with the administration regimen established for them.

Example 1

Fifteen patients with histologically confirmed metastatic colorectal cancer, of which seven had previously received adjuvant chemotherapy, were treated with a combination of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine with a chemotherapeutic regimen. The chemotherapeutic regimen consisted of 85 mg / m ^{2 of} oxaliplatin per day 1, 200 mg / m ^{2 of} folinic acid, administered as a two-hour infusion on days 1 and 2, and 5-fluorouracil, administered as a bolus at a dose of 400 mg / m ² , then 600 mg / m ² after 22 hours on days 1 and 2. A chemotherapeutic regimen is prescribed every 14 days. 1- (4-Chloroanilino) -4- (4-pyridylmethyl) phthalazine is administered continuously as a single daily dose of 500 mg / day, 1000 mg / day or 2000 mg / day. The treatment is well tolerated. The pharmacokinetics of oxaliplatin is not altered by co-administration with 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine. Stable diseases were observed in 2 patients, mild reactions in 3 patients and partial reactions in 8 patients.

Example 2

Ten patients with metastatic renal cell carcinoma, of which six had previously received biotherapy, were exposed to 300 mg, 750 mg or 1000 mg / day of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine orally administered once a day. Seven out of ten patients had a stable disease with a median for 3 months.

Example 3

Patients with histologically confirmed measurable solid tumors were orally administered 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine daily twice a day until disease progression or unacceptable toxicity was observed. Subsequent patients (3 evaluated at each dose) were treated with total daily doses of 300 mg, 500 mg, 1000 mg and 2000 mg, which were divided into two separate doses administered at intervals of 8 hours. The patients were monitored using dynamic contrast enhancement magnetically resonance imaging (DCE-MRI) of tumors to allow measurement of the bidirectional transfer constant (Ki) before treatment, on day 2 and after each 28-day cycle. In addition, tumor volume was measured using magnetic resonance imaging every 28 days, and complete pharmacokinetic profiles were obtained on days 1 and 28. The treatment was well tolerated without undesirable side effects (SAEs) associated with the drug. The following types of toxicity were found among patients who were given daily doses of 300 mg, 500 mg and 1000 mg: temporary elevations of grade 3 liver transaminases (2 patients), drowsiness of grade 1 (1 patient), dizziness of grade 2 (4 patients). Using DCE-MRI, the following tumor decreases were found when compared with the baseline (median reduction on days 2-28), respectively, for 300 mg - 68.3%, for 500 mg - 72.98%. A pharmacokinetic study gave the average value of the minimum concentration C _min (ng / ml) and the area under the AUC curve (time, h - concentration, ng / ml) for 300 mg, respectively, 7.7, 82; for 500 mg - 4.3, 46; for 1000 mg - 27, 370. These studies indicate the biological effect of reducing tumor perfusion / vascular permeability and slowing tumor growth.

Example 4

Patients with histologically confirmed developed solid tumors, measurable, were administered orally 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine once daily, until disease progression or unacceptable toxicity was observed. Subsequent patient populations (3 evaluated at each dose) were treated with total daily doses of 50 mg, 150 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1200 mg, 1500 mg and 2000 mg, which were administered as a single daily dose. A complete pharmacokinetic (PK) sampling was performed before dosing and on days 1, 15 and 28. The DCE-MRI study, which reflects the change in tumor perfusion and blood vessel permeability, was performed relative to the baseline on day 2 and day 28. For all assessed MRI scans contrast enhancement for the entire tumor was determined by calculating the bidirectional transfer constant (Ki). Plasma levels of VEGF, a pro-angiogenic factor produced by tumor cells and reflecting the hypoxic status of the tumor, were determined relative to the baseline and on days 1, 8, 15, 22 and 28. Of the total of 76 patients from two studies conducted in phase I, 22 a patient with colorectal cancer and liver metastases was evaluated by DCE-MRI analysis, and 63 patients with advanced malignant tumors were evaluated by plasma VEGF analysis and pharmacokinetic analysis. Using the response criteria of the Southwestern Cancer Group (SWOG), a non-progressive disease was characterized as a stable disease for 2 months or more.

1- (4-Chloranilino) -4- (4-pyridylmethyl) phthalazine is rapidly absorbed (T _max 1-2.5 h). With homeostasis, which was achieved on day 15, the systemic effect (reflected AUC) was reduced by 30% compared to day 1. A proportional dose increase in exposure was observed up to a dose of 1000 mg / day. The final half-life was 3-6 hours. No dose-limiting toxicity was observed up to 2000 mg / day. There is a correlation between the percentage value of the Ki baseline on days 2 and 28, dose increase (day 2: p = 0.01; day 28: p = 0,0003), exposure (AUC; day 2: p <0.0001; day 28: p = 0.003) and plasma concentration (C _min ; day 2: p = 0.0003; day 28: p <0.0001), as determined by Spearman rank correlation. In addition, there is a relationship between the percentage reduction in Ki on days 2 and 28 and the change in liver metastases (day 2: p = 0.004; day 28: p = 0.0001) at the end of day 56, as determined by the change in the sum of all measured lesions liver (two-dimensional product). Patients with a non-progressive disease had a significantly greater decrease in Ki value (day 2: p = 0.004; day 28: p = 0.006). A 50-60% reduction in Ki is associated with a non-progressive disease. Exposure based on the impact-response model was approximately 114 ppm. Given the variability of the pharmacokinetics, the dose at the lower limit (95% confidence interval) of exposure to 114 h / μM should be the optimal dose, and therefore, a daily dose of 1250 mg is recommended as a biologically active dose. Supporting the selected biologically active dose is a sharp increase in plasma VEGF levels in patients with non-progressive disease. In patients responding to treatment who received doses greater than 1000 mg / day, the increase in plasma VEGF levels reached five-fold levels during the first 28 days of treatment.

Claims (7)

1. The combination for the treatment of proliferative diseases, which includes 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or its pharmaceutically acceptable salt, oxaliplatin and 5-fluorouracil, where the active ingredients are present in each case in free form or in a pharmaceutically acceptable salt form in therapeutically effective amounts, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use. 2. A pharmaceutical composition for treating a proliferative disease, comprising 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof, oxaliplatin and 5-fluorouracil in therapeutically effective amounts, and at least one pharmaceutically acceptable carrier . 3. A method of treating a proliferative disease in a patient, which comprises administering to it a therapeutically effective amount of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof in combination with oxaliplatin and 5-fluorouracil, the patient being administered daily 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine in a dose of 500 mg / day to 2000 mg / day or an equivalent amount of its salt. 4. The method according to claim 3, where 500, 1000, 1500 or 2000 mg / day of 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or an equivalent amount of its salt is administered. 5. The method according to claim 4, where the proliferative disease is a solid tumor disease. 6. The method according to claim 5, where the disease of the solid tumor is colorectal cancer. 7. Packaging for sale, including 1- (4-chloroanilino) -4- (4-pyridylmethyl) -phthalazine or a pharmaceutically acceptable salt thereof in a form suitable for oral administration, oxaliplatin and 5-fluorouracil, and instructions for their administration.