RU2379032C9 - Combinations including epothilones and their pharmaceutical application - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention includes description of novel pharmaceutical combination, pharmaceutical composition, which includes said combination, application of said combination for obtaining medication and commercial packing. Combination includes (a) at least one anti-inflammatory agent, selected from group, which includes inhibitors of topoisomerase I and inhibitors of topoisomerase II, and (b) epothilone B derivative of formula (I), and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or successive application.

EFFECT: obtaining of effective combination for treatment of proliferative disease, namely disease connected with considerable tumor and resistant to other medications.

12 cl

Description

The invention relates to a pharmaceutical combination, which includes (a) an HER-1 or HER-2 antibody or (b) at least one antitumor agent selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, agents, microtubule-active, protein kinase C inhibitors, anti-angiogenic compounds, gonadorelin agonists, anti-androgens, histone deacetylase inhibitors and S-adenosylmethionine decarboxylase inhibitors and c) an epothilone derivative and optionally at least at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use, primarily for the treatment of a proliferative disease, preferably a disease associated with a solid tumor, to a pharmaceutical composition comprising such a combination, to the use of such a combination for the manufacture of a medicament for the treatment of a proliferative disease , to a commercial package or product comprising such a combination as a combination preparation for simultaneous use alternating, separate or sequential use, and a method of treating a warm-blooded animal, especially a human.

Despite the widespread use of Taxol® and Taxotere® in the treatment of many different types of tumors, there is a slight effect of taxanes on the patient's lifespan and the vast majority of metastatic solid tumors remain incurable. Taxane treatment is accompanied by a number of side effects, and the effectiveness of taxanes is extremely limited due to the rapid development of drug resistance mechanisms. Due to these limitations, as well as side effects that are usually observed with standard combination treatment, there is a need to develop new cytotoxic antitumor agents with a broad profile of action, including a spectrum of antitumor activity, efficacy against multiresistant tumors, safety and tolerability.

The stabilizing effect of epothilones against microtubules was first described by Bollag et al. Cancer Research, 55, 2325-2333 (1995). A suitable treatment regimen for various types of tumors, especially tumors that are resistant to treatment with other drugs, especially Taxol ™, using epothilone, especially epothilone A or B, is described in WO 99/43320.

It was found that the antitumor effect of the combination specified in the application description is more effective than the action of any of the two components of the combination, i.e. more effective than monotherapy with one of the two components (a) and (c) of the combinations indicated in the description of the application.

It was found that the antitumor effect of the combination indicated in the description is preferable in the treatment of a proliferative disease, especially a disease associated with a solid tumor and resistant to other drugs known as antitumor agents, is more effective than the action of any of the two components of the combination, t .e. more effective than monotherapy with one of the two components (a) and (c) of the combination indicated in the description of the application.

Therefore, the present invention relates to a combination, such as a combination drug or pharmaceutical composition, which comprises (a) an HER-1 or HER-2 antibody or (b) at least one antitumor agent selected from the group consisting of aromatase inhibitors, antiestrogens , topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, histone deacetylase inhibitors and inhibitors Orae S-adenosylmethionine decarboxylase, and c) an epothilone derivative of formula I

where A is O or NR _N , where R _N is hydrogen or lower alkyl, R is hydrogen or lower alkyl, R` is methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, a Z is O or a chemical bond in which the active ingredients (a) and (b) 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 for simultaneous, separate or sequential use.

In addition, the present invention relates to a method for treating a warm-blooded animal with a proliferative disease, the method comprising administering to the animal a combination that comprises (a) an HER-1 or HER-2 antibody or (b) at least one antitumor agent selected from the group including aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, inhibitors histone deacetylases and S-adenosylmethionine decarboxylase inhibitors, and c) an epothilone derivative of formula I, where A is O or NR _N , where R _N is hydrogen or (lower) alkyl, R is hydrogen or (lower) alkyl, R 'means methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, Z is O or a chemical bond, the composition being administered in an amount that is therapeutically effective against a proliferative disease in total, and the compounds may be present in the composition also in the form of a pharmacist nical acceptable salts.

Unless otherwise specified, in the description of the application, organic radicals and compounds with the prefix (ness.) Contain not more than 7, preferably not more than 4, carbon atoms.

A compound of formula I where A is O, R is hydrogen, and Z is O, is known as epothilone A, a compound of formula I where A is O, R is methyl, and Z is O, is known as epothilone B, a compound of formula I, where A is O, R is hydrogen, and Z is a chemical bond, known as epothilone C; a compound of formula I, where A is O, R is methyl, and Z is a chemical bond, known as epothilone D.

Unless otherwise indicated, the compounds used in the claimed combination of components (a), (b) and (c) can be prepared and administered as described in the cited documents, respectively.

Epothilone derivatives of formula I, wherein A is O or NR _N , where R _N is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a chemical bond, and methods for preparing such epothilone derivatives are preferably in general terms and specifically claimed in patents and patent applications WO 93/10121, US 6194181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247, in each case, in particular paragraphs relating to the compound, and the final products described in the examples, the object of the invention in the form of final products, pharmaceutical preparations and paragraphs form s of the invention are incorporated in the application by reference to the above publication. Similarly, the present invention includes the corresponding stereoisomers, as well as corresponding crystalline modifications, for example, solvates and polymorphic formations.

The conversion of epothilone B to the corresponding lactam is shown in Scheme 21 (p. 31, 32) and described in Example 3 of WO 99/02514 (p. 48-50). The conversion of a compound of formula I, which differs from epothilone B, into the corresponding lactam is carried out in a similar manner. The corresponding epothilone derivative of formula I, where R _N is lower alkyl, can be prepared by known methods, such as reductive alkylation of an epothilone derivative, where R _N is hydrogen.

Derivatives of an epothilone of formula I, where A is O or NR _N , where R _N is hydrogen or (ness.) Alkyl, R is hydrogen or (ness.) Alkyl, R` is methoxy, ethoxy, amino, dimethylamino, aminomethyl or methylthio, a Z is O or a chemical bond, and methods for preparing and administering such epothilone derivatives are preferably generically and specifically claimed in patent application WO 99/67252, which is hereby incorporated by reference. Similarly, the present invention includes the corresponding stereoisomers, as well as corresponding crystalline modifications, for example, solvates and polymorphic formations.

The compound of formula I, where A is O, R is methyl, R 'is aminomethyl, and Z is O, can be obtained, as described in examples 13-16 of application WO 01/72721, from a compound of formula I, where A is O, R and R 'both mean methyl, and Z means O.

The term “combination drug” used in the description of the application primarily means “a set of components” in the sense that the combination of components (a), (b) and (c) above can be entered independently or in the form of various fixed combinations containing known amounts of each of the components (a), (b) and (c), i.e. simultaneously or at different times. In this case, the components of set (a), (b) and (c) can be entered, for example, simultaneously or in chronological order, i.e. at different times and at the same or different intervals for any part of the set. The most preferred intervals are selected so that the effect of the combination of the constituent parts on the disease being treated is more effective than the action of any of the components of the combination (a), (b) and (c) separately, or so that the action of the component (c) increased due to the presence of component (a). The ratio of the total amounts of component (a) or (b) and component (c), which are administered as a combination of components, can vary, for example, depending on the type of subpopulation of patients being treated or on the condition of a particular patient, taking into account age, gender, body weight and etc. Preferably, at least one advantage of this combination is observed, for example, mutual enhancement of the action of the components of the combination (a) and (b), especially synergy, for example, a more effective action compared to a simple additive effect, as well as additional advantages in the form of reduced side effects and potentiation , i.e. there is a combined therapeutic effect with the introduction of ineffective doses of one or both components of the combination (a), (b) and (c), most preferably the extremely high synergy of the components of the combination (a), (b) and (c).

The term “solid tumor disease” used in the application description includes, but is not limited to, glioma, thyroid cancer, breast cancer, especially breast cancer, positive for overexpression of HER2 / neu, ovarian cancer, colon cancer and in general, gastrointestinal cancer, cervical cancer, lung cancer, especially small cell lung cancer and non-small cell lung cancer, head and neck cancer, bladder cancer, prostate cancer, hepatoma or Kaposi’s sarcoma. Depending on the type of tumor and the particular combination used, a reduction in tumor size can be achieved. The claimed combinations are also suitable for preventing tumor metastasis and the growth or development of micrometastases.

The term “proliferative disease” includes a disease associated with a solid tumor, a liquid tumor, such as leukemia, and psoriasis.

The term “solid tumor disease” primarily means breast cancer, colon cancer, and generally gastrointestinal cancer, including stomach cancer, hepatoma, lung cancer, especially small cell lung cancer and non-small cell lung cancer, cancer kidney, mesothelioma, glioma, squamous cell carcinoma of the skin, cancer of the head and neck, cancer of the genitourinary tract, for example cancer of the cervix, uterus, ovary, testis, prostate or bladder; Hodgkin's disease, carcinoid syndrome, or Kaposi’s sarcoma. In a preferred embodiment of the invention, the disease associated with a solid tumor to be treated is selected from the series: breast cancer, colorectal cancer, ovarian cancer, kidney cancer, lung cancer, especially non-small cell lung cancer, and glioma. Depending on the type of tumor and the particular combination used, a decrease in tumor size may be observed. The claimed combinations are also suitable for the prevention of tumor metastasis and the growth or development of micrometastases.

The term “microtubule active agents” refers to microtubule stabilizing or destabilizing agents selected from the group consisting of pink vinca alkaloids, for example vinblastine, especially vinblastine sulfate, vincristine, especially vincristine sulfate, vinorelbine and discodermolid. Vinblastine sulfate can be administered, for example, in the form of a commercial preparation, Vinblastin R.P. ™. Vincristine sulfate can be administered, for example, in the form of a commercial Farmistin ™ preparation. Discodermolide can be obtained, for example, as described in US 4939168 and 5618487 (Harbor Branch Oceanographic Institute) or chemical synthesis, as described, for example, in GB 2280677, WO 98/24429 and US 5789605 and 6031133, which are included in the description of the application by reference .

The term “protein kinase C inhibitors” means, in particular, staurosporin derivatives, preferably as claimed in US 5,093,330. Such compounds can be administered, for example, as described in WO 99/48896.

The term "anti-angiogenic compounds" used in the description of the application means thalidomide (Thalomid ™) and SU 5416.

The term “antiestrogens”, as used in the description of the application, means compounds that block the action of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form of a commercial Nolvadex ™ preparation. Raloxifene hydrochloride may be administered, for example, in the form of a commercial Evista ™ preparation. Fulvestrant may be prepared as described in US 4,659,516, or may be administered, for example, in the form of a commercial Faslodex ™ preparation.

The term “HER-1 or HER-2 antibody,” as used herein, means monoclonal antibodies that bind to the HER-1 or HER-2 receptor, especially the HER-2 receptor. Preferred antibodies are claimed in General terms and specifically in US 5677171, especially in the examples included in the description of the application by reference to the publication. Similarly, the present invention includes the claimed corresponding stereoisomers, as well as corresponding crystalline modifications, for example, solvates and polymorphic formations. Trastuzumab, which is manufactured under the trade name Herceptin ™, is more preferred.

The term “topoisomerase I inhibitors” as used in the application description includes, but is not limited to, topotecan, irinotecan, 9-nitrocamptothecin and high molecular weight camptothecin conjugate PNU-166148 (compound A1 in WO 99/17804). Irinotecan can be entered, for example, in the form of a commercial preparation Camptosar ™. Topotecan can be administered, for example, in the form of a commercial Hycamtin ™ preparation.

The term “topoisomerase II inhibitors” as used in the application description includes, but is not limited to, doxorubicin anthracyclines (including the liposomal form, for example, Caelyx ™), epirubicin, idarubicin and nemorubicin, anthraquinones mitoxantrone and losoxantrone, and podophyllotoxin etoposide and etoposide. Etoposide can be administered, for example, in the form of a commercial preparation Etopophos ™. Teniposide can be administered, for example, in the form of a commercial preparation VM 26-Bristol ™. Doxorubicin can be administered in the form of a commercial preparation Adriblastin ™. Epirubicin can be administered in the form of a commercial Farmorubicin ™ preparation. Idarubicin can be administered in the form of a commercial preparation Zavedos ™. Mitoxantrone may be administered in the form of a commercial Novantron ™ preparation.

The term “aromatase inhibitors” as used in the application description refers to compounds that inhibit the formation of estrogen, i.e. the conversion of substrates of androstenedione and testosterone to estrone and estradiol, respectively. The term includes, without limitation, steroids, especially exemestane and formestane, and preferably nonsteroids, especially aminoglutethimide, Vorozol, fadrozole, anastrozole, and most preferably letrozole. Exemestane can be administered in the form of a commercial Aromasin ™ preparation. Formestane can be administered in the form of a commercial Lentaron ™ preparation. Fadrozole may be administered in the form of a commercial Afema ™ preparation. Anastrozole can be administered in the form of a commercial Arimidex ™ preparation. Letrozole can be administered in the form of a commercial Femara ™ or Femar ™ preparation. Aminoglutetimide can be administered in the form of a commercial Orimeten ™ preparation.

The term “gonadorelin agonist” as used in the application description includes, but is not limited to, abarelix, goserelin and goselerin acetate. Goselerin is claimed in US 4,100,274 and may be administered in the form of a commercial Zoladex ™ preparation. Abarelix can be obtained as described in US 5843901.

The term “antiandrogens” as used in the description of the application includes, but is not limited to, bicalutamide (Casodex ™), which can be prepared as described in US 4,636,505.

The term "histone deacetylase inhibitors" used in the description of the application includes, but is not limited to, the preparations MS-275, Saha, FK228 (formerly FR901228), trichostatin A and the compounds claimed in WO 02/22577, especially the compound NVP-LAQ824 or its lactate.

The term "S-adenosylmethionine decarboxylase inhibitors" as used in the description of the application includes, without limitation, the compounds claimed in US 5461076.

The structure of the active ingredients indicated by code numbers, international patent names or trade names can be found in the latest edition of the standard catalog "The Merck Index" or in a data bank, for example Patents International (for example, IMS World Publications). Their respective contents are included in the description of the application by reference. A person skilled in the art is able to identify the active ingredients and, using the provided references, obtain and test pharmaceutical indications and properties on standard in vitro and in vivo models.

References to a combination of components (a), (b) and (c) are also intended to include pharmaceutically acceptable salts. If these components of combination (a) and (b) contain, for example, at least one basic group, then they can form acid addition salts. If necessary, the corresponding acid addition salts can also be obtained if the compounds contain an additional basic group. The components of combination (a) and (b) containing an acid group (e.g. COOH) can also form salts with bases. The components of combination (a) and (b), or a pharmaceutically acceptable salt thereof, can also be used in the form of a hydrate or in the form of solvates with other solvents used in the crystallization.

Compounds that are used as components (a) and (b) in the claimed combination can be obtained and administered by the methods described in the cited documents, respectively. Derivatives of epothilone of formula I, especially epothilone B, can be introduced as a component of the pharmaceutical compositions of WO 99/39694.

The combination of the invention, comprising an antitumor agent that is an aromatase inhibitor, is primarily used in the treatment of breast tumors with a positive response to the hormonal receptor.

Particularly preferred are combinations comprising an HER-1 or HER-2 antibody and an epothilone derivative.

Other preferred combinations are especially those combinations in which the antitumor agents are aromatase inhibitors or antiestrogens.

Other preferred combinations are, in particular, those in which the antitumor agents are topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, histone de-acetylene deacetylase inhibitors, and decarboxylases.

Preferred combinations are in particular those in which the antitumor agent is a topoisomerase I inhibitor, for example irinotecan, a topoisomerase II inhibitor, for example etoposide, or a microtubule active agent, for example, discodermolide, an aromatase inhibitor, for example letrozole.

Even more preferred combinations are those in which the HER-1 or HER-2 antibody is trastuzumab.

Other most preferred combinations are those in which the antitumor agent is a topoisomerase I inhibitor.

In addition, even more preferred combinations are those in which the antitumor agent is a topoisomerase II inhibitor.

Other most preferred combinations are those in which the antitumor agent is an aromatase inhibitor.

Other even more preferred combinations are those in which the antitumor agent is an agent active against microtubules.

A preferred embodiment of the invention is a combination that includes

(a) an HER-1 or HER-2 antibody; and

(b) an epothilone derivative of formula I

where A is O or NR _N , where R _N is hydrogen or (ness.) alkyl, R is hydrogen or (ness.) alkyl, R` is methyl, and Z is O or a chemical bond, the active ingredients (a) and (b) 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 for simultaneous, separate or sequential use.

Another preferred embodiment of the invention is a combination that includes (a) at least one antitumor agent selected from the group consisting of topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens , histone deacetylase inhibitors and S-adenosylmethionine decarboxylase inhibitors, and b) an epothilone derivative of formula I

where A is O or NR _N , where R _N is hydrogen or lower alkyl, R is hydrogen or lower alkyl, R 'is methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, a Z is O or a chemical bond, wherein the active ingredients (a) and (b) 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 for simultaneous, separate or sequential use.

Another preferred embodiment of the invention is a combination that includes (a) at least one antitumor agent selected from the group consisting of aromatase inhibitors and antiestrogens, and (b) an epothilone derivative of formula I

where A is O or NR _N , where R _N is hydrogen or lower alkyl, R is hydrogen or lower alkyl, R 'is methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, and Z is O or a chemical bond, wherein the active ingredients (a) and (b) 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 for simultaneous, separate or sequential use.

Another preferred embodiment of the invention is a combination that includes (a) an HER-1 or HER-2 antibody, or (b) at least one antitumor agent selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, histone deacetylase inhibitors and S-adenosylmethionine decarboxylase inhibitors, and c) an epothilone derivative of the formula I, where A is NR _N , where R _N is hydrogen or lower alkyl, or more preferably O, R is hydrogen or lower alkyl, most preferably methyl, R 'is methyl or methylthio, and Z is chemical a bond or preferably O, the active ingredients being present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use.

An even more preferred embodiment of the invention is a combination that includes (a) an HER-1 or HER-2 antibody, or (b) at least one antitumor agent selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, histone deacetylase inhibitors and S-adenosylmethionine decarboxylase inhibitors, and c) an epothilone derivative of the formula I, where A is NR _N , where R _N is hydrogen or lower alkyl or more preferably O, R is hydrogen or lower alkyl, most preferably methyl, R 'is methyl and Z is a chemical bond or preferably Oh, and 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 for simultaneous, separate or sequential use.

Another even more preferred embodiment of the invention is a combination that includes (a) an HER-1 or HER-2 antibody, or (b) at least one antitumor agent selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors , microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, histone deacetylase inhibitors and S-adenosylmethionine decarboxylase inhibitors, and c) an epothilone derivative f formulas I, where A is NR _N , where R _N is hydrogen or lower alkyl or more preferably O, R is hydrogen or lower alkyl, most preferably methyl, R 'is methylthio, and Z is a chemical bond or preferably O, the active ingredients being present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use.

An even more preferred embodiment of the invention is a combination that includes (a) an HER-1 or HER-2 antibody, or (b) at least one antitumor agent selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, histone deacetylase inhibitors and S-adenosylmethionine decarboxylase inhibitors, and c) epothilone B, with active ing The solvents 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 for simultaneous, separate or sequential use.

The nature of proliferative diseases, such as those associated with a solid tumor, depends on many factors. In some situations, drugs that act by various mechanisms can be combined. However, when using any combination of drugs with different mechanisms of action, the required effectiveness of the action is not always achieved.

Objects in the form of final products, pharmaceuticals, and claims as cited above are incorporated herein by reference. Similarly, the present invention includes the corresponding stereoisomers, as well as corresponding crystalline modifications, for example, solvates and polymorphic formations. Unless otherwise indicated, the compounds used as active ingredients in the claimed combinations can be prepared and administered as described in the cited documents, respectively.

Unexpected experimental data have also been obtained indicating that the in vivo administration of the combination of the invention not only has a beneficial effect, for example, attenuation of the tumor, suppression or regression of tumor development, or a prolonged tumor response, but also even more unexpected beneficial effects, for example, reduced side effects, improved quality of life and reduced mortality and morbidity compared to similar monotherapy with one of the pharmaceutically active ingredients the agents used in the combination of the invention, primarily in the treatment of a tumor resistant to other chemotherapeutic drugs known as antitumor agents.

Another advantage is the fact that in the combination according to the invention, lower doses of the active ingredients can be used, for example, in most cases, not only a lower dose of at least one component of the combination is used, but this dose is administered less often in order to reduce the development of side effects, which meets the wishes and requirements of the patient being treated.

When tested on models and especially on the models described in the text of the application, it was found that the combination according to the invention leads to more effective inhibition of progression or treatment of proliferative disease compared with the results observed when using one of the components of the combination. A person skilled in the art is able to select the appropriate model in order to confirm the above and below therapeutic indications and beneficial effects. The pharmacological activity of the combination according to the invention can, for example, be demonstrated in a clinical trial or analysis, as described below.

Suitable clinical trials include, but are not limited to, an open-label, randomized trial, dose-increase trials, or placebo and double-blind trials in patients with advanced solid tumors. Such tests primarily confirm the synergy of the active components of the combination according to the invention. The beneficial effect on proliferative disease can be determined directly from the results of these tests or by changing the test schedule, which is known to a person skilled in the art. Such tests are primarily suitable for comparing the effects of monotherapy using the active ingredients and the combination of the invention.

Preferably, the component of combination (a) is administered in a constant dose, and the doses of component (b) are increased to achieve the maximum tolerated dose (MTD). With such tests, treatment efficacy can be determined, for example, after 18 or 24 weeks with an X-ray examination of tumors every 6 weeks.

In another embodiment, to prove the benefits of the above combination according to the invention, you can use the double blind method in the control using placebo.

When tested with an increase in dose, an HER-1 or HER-2 antibody, for example, trastuzumab, is preferably administered in a constant dose, preferably 2 mg / kg of trastuzumab is administered by infusion for 30 minutes, for example, once a week, and doses of an epothilone derivative of formula I , for example epothilone B, increase. In a preferred embodiment, the epothilone derivative of formula I is administered intravenously once a week for three weeks, and then one week after the start of the test, for example, 0.5 mg / m ² epothilone B and increasing doses of 1.0 mg / m ² 1.5 mg / m ² , 2.0 mg / m ² and 2.5 mg / m ² until the maximum tolerated dose is reached. For one cycle, an interval equal to four weeks is taken. With such tests, treatment efficacy can be determined, for example, after 18 or 24 weeks with an X-ray examination of tumors every 6 weeks. In one of the variants of such clinical trials with increasing doses, preliminary treatment is carried out with the introduction of antibodies HER-1 or HER-2. Pretreatment means that before starting treatment with the combination of the invention, HER-1 or HER-2 antibody is administered to patients, preferably by infusion over 90 minutes at a weekly dose of about 4 mg / kg, for about one or two weeks.

Response criteria when evaluating pathological changes during clinical trials, for example when tested on breast cancer patients, as described above, include the following indicators: complete response (CR): disappearance of all pathological foci, partial response (PR): decrease the sum of the maximum diameters (LD) of the pathological foci of the targets is at least 30% compared with the initial amount of LD, stable state (SD): no noticeable decrease (the amount of LD) characteristic of PR, and a noticeable increase (sum we LD), characteristic of PD, compared with the minimum amount of LD pathological lesions recorded before treatment, progressive disease (PD): an increase in the amount of LD pathological foci of the targets by at least 20% compared with the minimum amount of LD recorded before initiation of treatment, or the appearance of one or more new lesions.

The first object of the present invention is a method of treating a proliferative disease with a combination of the invention having a higher CR, PR or SD compared with monotherapy with one of the components of the combination.

The combination of the invention can also be used in combination with surgery, moderate, prolonged hyperthermia of the whole organism and / or radiation therapy.

Another embodiment of the invention relates to the use of a combination of the invention for the treatment or for the manufacture of a medicament for the treatment of a disease associated with a solid tumor.

Another object of the present invention is a pharmaceutical composition comprising an amount which in total is therapeutically effective against a proliferative disease, including the combination of the invention. In this composition, components (a) or (b) and (c) can be administered together, sequentially or separately as a single combined unit dose or as two separate unit doses. The unit dose may also be a fixed combination.

The pharmaceutical compositions of the present invention can be obtained in a known manner; such compositions are suitable for enteral administration, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including humans, said compositions comprising a therapeutically effective amount of at least one pharmacologically active component alone or in combination with one or more pharmaceutically active carriers primarily carriers suitable for enteral or parenteral administration.

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 dosage forms for combination therapy for enteral or parenteral administration are, for example, standard forms such as sucrose-coated tablets, tablets, capsules or suppositories, as well as ampoules. Unless otherwise indicated, these forms are prepared in a known manner, for example by conventional mixing, granulation, sucrose coating, dissolution or lyophilization. It is contemplated that the standard amount of the combination component present in a single dose of each dosage form is not necessarily an effective amount, since the required effective amount is achieved by administering a plurality of unit doses.

In preparing the compositions for oral dosage form, any conventional pharmaceutical medium can be used, such as, for example, water, glycols, oils, alcohols, flavorings, preservatives, colorants; and in the case of solid oral forms, such as for example powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents and the like can also be used, moreover solid oral forms are preferred over liquid forms.

The therapeutically active amount of each component of the combination according to the invention can be administered simultaneously or sequentially and in any order, and the components can be administered separately or as a constant combination. For example, a method of treating a proliferative disease of the invention may include (I) administering the first component of the combination in free form or in the form of a pharmaceutically acceptable salt; and (II) administering the second component of the combination in free form or in the form of a pharmaceutically acceptable salt, simultaneously or sequentially, in any in order or together in therapeutically effective amounts, preferably in synergistically effective amounts, for example in the form of daily or weekly doses corresponding to those described and quantities. The individual components of the combination according to the invention can be administered separately at different times during the course of therapy or simultaneously in separate or single forms of combination. In addition, the term “administration” also includes the use of a prodrug of a combination component that is converted in vivo to a combination component. Therefore, it is intended that the present invention include all such schemes with simultaneous or alternating administration, and the term “administration” should be interpreted in accordance with the foregoing.

The effective dose of each of the components of the combination used in the combination according to the invention may vary depending on the particular compound or composition used, the route of administration, the condition to be treated, and the severity of the condition to be treated. Thus, the combination regimen of the invention is selected depending on a variety of factors, including the route of administration and the condition of the patient's kidneys and liver. A doctor, clinician or veterinarian can easily determine and prescribe an effective amount of one of the active ingredients needed to prevent, counteract or block the progression of a pathological condition. When optimizing the achieved concentration of active ingredients within a range that ensures efficacy in the absence of toxicity, schemes based on kinetic studies of the delivery of active ingredients to target tissues are used. Kinetic studies include distribution, balance, and elimination of active ingredients.

If the combination of the components according to the invention is used in the form of individual medicines, then, unless otherwise indicated, the dose and method of administration corresponds to the information provided on the package leaflet of the corresponding drug to achieve the described therapeutic effect.

If the warm-blooded animal is a human, the dose of the compound of formula I for an adult patient is preferably from about 0.25 to 75, preferably from 0.5 to 50, for example 2.5 mg / m ² , once a week for two to four , for example, for three weeks, and then follows a break for 6-8 days. In one embodiment of the invention, epothilone B is administered in accordance with the treatment regimen described in US 6302838, which is incorporated herein by reference.

Preferably, epothilone B is administered at a dose calculated by the formula (III):

single dose (mg / m ² ) = (from 0.1 to y) × N

where N means the number of weeks between courses of treatment, and y is 6, and epothilone B is administered for more than one treatment cycle with an interval between courses of treatment from one to six weeks.

In another preferred embodiment of the invention, epothilone B is administered weekly at a dose of from about 0.1 to 6 mg / m ² , preferably from 0.1 to 3 mg / m ² , for example 2.5 or 3.0 mg / m ² , for three weeks after a break from one to six weeks, especially with an interval of one week, after the previous course of treatment. In another embodiment of the invention, said epothilone B is preferably administered to the human body every 18 to 24 days at a dose of 0.3 to 12 mg / m ² .

Vinblastine can be administered to humans at a dose of about 1.5 to 10 mg / m ² / day.

Vincristine sulfate can be administered to humans at a dose of about 0.025 to 0.05 mg / kg body weight / week.

Vinorelbine can be administered to humans at a dose of from about 10 to 50 mg / m ² / day.

Etoposide phosphate can be administered to humans at a dose of 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 a person in a dose of from about 75 to 150 mg approximately every two weeks.

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

Epirubicin can be administered to humans at a dose of from about 10 to 200 mg / m ² / day.

Idarubicin can be administered to humans at a dose of from about 0.5 to 50 mg / m ² / day.

Mitoxantrone can be administered to humans at a dose of from about 2.5 to 25 mg / m ² / day.

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

Irinotecan can be administered to humans at a dose of from about 50 to 350 mg / m ² / day.

Bicalutamide can be administered to humans in a dose of from about 25 to 50 mg / m ² / day.

Fadrozole can be administered to humans at a dose of 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 a person in a dose of 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 is intended to be administered as a separate pharmaceutical composition, then it can be administered in the form claimed in GB 2177700.

Formestane can be administered to a person parenterally at a dose of from about 100 to 500 mg / day, preferably from about 250 to about 300 mg / day.

Anastrozole can be administered orally to a person in a dose of from about 0.25 to 20 mg / day, preferably from about 0.5 to about 2.5 mg / day.

Letrozole can be administered orally to a person in a dose of from about 1.0 to 2.5 mg / day, for example, about 2.5 mg / day.

Aminoglutemide can be administered to humans at a dose of from about 200 to 500 mg / day.

Tamoxifen citrate can be administered to humans at a dose of about 10 to 40 mg / day.

In addition, the present invention relates to the use of a combination according to the invention for the treatment of a proliferative disease and for the manufacture of a medicament for the treatment of a proliferative disease.

In addition, combinations are preferred that include (a) at least one antitumor agent selected from the group consisting of aromatase inhibitors and antiestrogens, and (b) an epothilone derivative of formula I, where A is NR _N , where R _N is hydrogen or ( ness.) alkyl or more preferably O, R is hydrogen or (ness.) alkyl, more preferably methyl, R` is methyl or methylthio, and Z is a chemical bond or preferably O.

In the compound of formula I, A preferably means O, R means (ness.) Alkyl, for example ethyl, or more preferably methyl, R` means methyl or methylthio, and Z preferably means O.

In addition, another object of the invention is the use of (a) an HER-1 or HER-2 antibody, or (b) at least one antitumor agent selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, protein kinase C inhibitors, antiangiogenic compounds, gonadorelin agonists, antiandrogens, histone deacetylase inhibitors and S-adenosylmethionine decarboxylase inhibitors, in combination with (c) an epothilone derivative of formula I

where A is O or nrn, where rn is hydrogen or lower alkyl, R is hydrogen or lower alkyl, R` is methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, and Z is O or a chemical bond, for the manufacture of a medicament for the treatment of a proliferative disease.

In one preferred embodiment of the invention, the combination of the invention comprises a Herceptin ™ preparation and epothilone B.

The combination of the invention may be a combination preparation or pharmaceutical composition.

Furthermore, the present invention relates to a method for treating a warm-blooded animal suffering from a proliferative disease, comprising administering to the animal a combination of the invention in an amount that is therapeutically effective against the proliferative disease, and the components of the combination may also be present in the form of pharmaceutically acceptable salts.

In addition, the present invention relates to the use of a combination of the invention for the treatment of a proliferative disease and for the manufacture of a medicament for the treatment of a proliferative disease.

In addition, the present invention provides a commercial package comprising, as active ingredients, a combination of the invention, together with recommendations for the simultaneous, separate or sequential use in the treatment of proliferative disease.

In another embodiment of the invention, the antidiarrheal agent is administered together with the combination according to the invention for the prevention, treatment or suppression of diarrhea, which is sometimes associated with the administration of epothilones, especially epothilone B. Thus, the present invention also relates to a method for the prevention or treatment of diarrhea associated with the administration epothilone derivatives of formula I, the method comprising administering an effective amount of an antidiarrheal agent to a patient who has been treated with the combination of the invention. Antidiarrheal agents and recommendations for their administration are known to those skilled in the art. Antidiarrheal agents suitable for use in the methods of the invention and compositions include, but are not limited to, natural opioids such as opium tincture, antiperistaltic tincture and codeine, synthetic opioids such as diphenoxylate, diphenoxin and loperamide, bismuth subsalicylate, ostreotide, for example, sold under the trade name Sandostatin ™, motilin antagonists and traditional antidiarrheal drugs such as kaolin, pectin, berberine and muscarinic agents. According to the information in the insert, loperamide or Sandostatin ™ can be used in particular.

Claims (12)

1. The combination intended for the treatment of proliferative diseases, comprising (a) at least one antitumor agent selected from the group comprising topoisomerase I inhibitors and topoisomerase II inhibitors, and (b) an epothilone B derivative of formula I

where A is O, R is methyl, R 'is methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, and Z is O, in which the active ingredients (a) and (b) 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, for simultaneous, separate or sequential use. 2. The combination according to claim 1, comprising (a) at least one antitumor agent selected from the group comprising topoisomerase I inhibitors and topoisomerase II inhibitors, and (b) an epothilone derivative B of formula I, where A is O, R 'is methyl or methylthio, R is methyl, and Z is O, in which the active ingredients (a) and (b) 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, for simultaneous separate or sequential of application. 3. The combination according to any one of claims 1 to 2, wherein the antitumor agent is a topoisomerase I. 4. The combination according to any one of claims 1 to 2, wherein the antitumor agent is a topoisomerase II inhibitor. 5. The combination according to any one of claims 1 to 3, wherein the antitumor agent is a topoisomerase I inhibitor selected from topotecan and PNU-166148. 6. The combination according to any one of claims 1 to 2 or 4, wherein the antitumor agent is a topoisomerase II inhibitor selected from Caelyx ™, epirubicin and mitoxantrone. 7. The combination according to any one of claims 1 to 6, which means a combined drug. 8. A pharmaceutical composition comprising an amount of a combination according to any one of claims 1 to 6, which in total is therapeutically effective against a proliferative disease, and at least one pharmaceutically acceptable carrier. 9. The use of the combination according to any one of claims 1 to 6 to obtain a medicinal product intended for the treatment of proliferative disease. 10. The use according to claim 9, where the proliferative disease is a disease associated with a solid tumor. 11. The use of (a) at least one antitumor agent selected from the group comprising topoisomerase I inhibitors and topoisomerase II inhibitors, in combination with (b) an epothilone B derivative of formula I,

where A is O, R is methyl, R 'is methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, and Z is O, for the manufacture of a medicament for treating a proliferative disease. 12. A commercial package comprising (a) at least one antitumor agent selected from the group consisting of topoisomerase I inhibitors and topoisomerase II inhibitors, and (b) an epothilone B derivative of formula I

where A is O, R is methyl, R 'is methyl, methoxy, ethoxy, amino, methylamino, dimethylamino, aminomethyl or methylthio, and Z is O, together with instructions for the simultaneous, separate or sequential use in the treatment of proliferative disease.