WO2012130314A1 - Composition comprising docetaxel - Google Patents

Abstract

The present invention relates to a composition comprising docetaxel or a solvate thereof and a phenylsulfonamide compound of the formula (I) as described herein. The invention also relates to said composition for use as a medicament, especially for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, to the use of said composition for preparing a medicament for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, and to a method for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, by administering said composition. wherein R¹ is selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and C₁-C₃-haloalkoxy; R² is selected from hydrogen and C₁-C₃-alkyl; and R³ is selected from C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy and C₁-C₃-haloalkoxy.

Description

Composition comprising docetaxel

The present invention relates to a composition comprising docetaxel or a solvate thereof. The invention also relates to said composition for use as a medicament, especially for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, to the use of said composition for preparing a medicament for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, and to a method for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, by administering said composition.

Background of the invention

Docetaxel (also known under the trade name Taxotere® from Sanofi Aventis) is a well- known anti-mitotic chemotherapy agent mainly used in the treatment of non-small cell lung, breast, ovarian, advanced stomach, head and neck and metastatic prostate cancer. Docetaxel belongs to the taxanes and is a semisynthetic analogue of paclitaxel. It is synthesized by esterification of 10-deacetyl baccatin III, which is in turn extracted from European yew tree.

The antitumor activity of docetaxel is attributed to its effect on microtubule dynamics: It stabilizes GDP-bound tubulin in the microtubule, thus blocking dynamic instability and preventing depolymerisation (i.e. it works as a polymerization agonist), even if hydrolysis of GTP reaches the tip of the microtubule. As a result, mitosis in the respective tumor cell is blocked.

WO 2010/075859 describes sulphonanilide compounds which are supposed to act as inhibitors of tubulin polymerization (i.e. they work as a polymerization antagonist). Their antitumor activity is thus based on depolymerisation of tubulin, which leads to mitotic arrest and apoptosis of the tumor cell.

Summary of the invention

Although docetaxel has a good microtubule-targeting activity, due to possible side effects and the possible development of drug resistance, there is an ongoing need to provide further active compounds or compositions with an improved activity in the treatment of hyperproliferative diseases, such as cancer diseases. It was surprisingly found that the combined administration of docetaxel or solvate thereof and certain sulphonanilide compounds described in WO 2010/075859, namely the compounds of the formula I described hereinbelow, provides a higher

antiproliferative activity than the administration of the single compounds, although docetaxal and the sulphonanilide compounds should have an antipodal activity on microtubule dynamics.

Thus, the invention relates to a composition comprising docetaxel or a solvate thereof and at least one compound of formula I or a pharmacologically acceptable salt thereof

wherein

R¹ is selected from Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; R² is selected from hydrogen and Ci-C3-alkyl; and

R³ is selected from Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy.

According to a further aspect, the present invention relates to a pharmaceutical composition comprising the composition of the invention and at least one

physiologically acceptable carrier and/or auxiliary substance.

According to a further aspect, the present invention relates to the composition of the invention for the use as a medicament and to the composition of the invention for treating or preventing a hyperproliferative disease.

According to a further aspect, the present invention relates to the use of docetaxel or a solvate thereof in combination with at least one compound I or a pharmacologically acceptable salt thereof for the preparation of a medicament for treating or preventing a hyperproliferative disease. In other words, the present invention relates to the use of a composition according to the invention for the preparation of a medicament for treating or preventing a hyperproliferative disease.

According to a further aspect, the present invention relates to a method for treating or preventing a hyperproliferative disease, said method comprising administering an effective amount of docetaxel or a solvate thereof in combination with an effective amount of at least one compound of formula I or a pharmacologically acceptable salt thereof to a subject in need thereof. In other words, the present invention relates to a method for treating or preventing a hyperproliferative disease, said method comprising administering an effective amount of a composition according to the invention to a subject in need thereof.

The combined administration of docetaxel or a solvate thereof with the compounds of the formula I described herein, as well as the compositions of the present invention provide a higher antiproliferative activity than the administration of the single compounds. This could be demonstrated by in vivo data showing that combined administration of docetaxel or a solvate thereof with the compounds of the formula I provide a significant reduction of tumor growth in warm blooded animals. This is rather surprising as docetaxal and the compounds of formula I should have an antipodal activity on microtubule dynamics, due to their mechanism of action. Surprisingly, an increased antiproliferative activity could not be observed in in-vitro assays.

Detailed description of the invention

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (lUPAC Recommendations)", Leuenberger, H.G.W., Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations, such as "comprises" and "comprising", will be understood to imply the inclusion of a stated component, integer or step or group of components, integers or steps, but not the exclusion of any other component, integer or step or group of components, integers or steps. If not stated otherwise, the term "docetaxel" intends to include both the compound (2R,3S)-4-Acetoxy-2a-benzyloxy-13-[3-(N-tert-butoxycarbonyl)amino-2-hydroxy-3- phenyl]propionyl-5p,20-epoxy-1 ,7p,10p-trihydroxy-9-oxotax-1 1 -en-13a-ylester (lUPAC) and the solvates thereof as defined below. The chemical entity Docetaxel may also be termed as (2R,3S)-N-(tert-Butoxycarbonyl)-2-hydroxy-3-phenyl-p-alanin-(4-acetoxy-2a- benzoyloxy-5p,20-epoxy-1 ,7β, 10p-trihydroxy-9-oxo-1 1 -taxen-13a-ylester),

Benzenepropanoic acid, beta-(((1 ,1 -dimethylethoxy)carbonyl)amino)-alpha-hydroxy-, (2aR,4S,4aS,6R,9S,1 1 S,12S,12aR,12bS)-12b-(acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,1 1 ,12,12a,12b-dodecahydro-4,6,1 1 -trihydroxy-4a,8,13,13- tetramethyl-5-oxo-7,1 1 -methano-1 H-cyclodeca(3,4)benz(1 ,2-b)oxet-9-yl ester,

(alphaR,betaS)- (National Library of Medicine); Benzenepropanoic acid, beta-(((1 ,1 - dimethylethoxy)carbonyl)amino)-alpha-hydroxy-, 12b-(acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,1 1 ,12,12a,12b-dodecahydro-4,6,1 1 -trihydroxy-4a,8,13,13- tetramethyl-5-oxo-7,1 1 -methano-1 H-cyclodeca(3,4)benz(1 ,2-b)oxet-9-yl ester (Medical Subject Headings File); Benzenepropanoic acid, beta-(((1 ,1 -dimethylethoxy)- carbonyl)amino)-alpha-hydroxy-, 12b-(acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9,10,1 1 ,12,12a,12b-dodecahydro-4,6,1 1 -trihydroxy-4a,8,13,13- tetramethyl-5-oxo-7,1 1 -methano-1 H-cyclodeca(3,4)benz(1 ,2-b)oxet-9-ylester, (2aR- (2a-alpha,4-beta,4a-beta,6-beta,9-alpha(alpha-R^*,beta-S^*), 1 1 -alpha, 12-alpha, 12a- alpha, 12b-alpha))- (Reg. of Toxic Eff. of Chem. Sub.).

The terms "compound I" and "compound of (the) formula I" are used as synonyms.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific

publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

The composition according to the invention may be a physical mixture of docetaxel or a solvate thereof and the at least one compound of the formula I or its salt. Accordingly, the invention also provides a mixture comprising docetaxel or a solvate thereof and at least one compound of the formula I or a pharmacologically acceptable salt thereof. However, the composition may also be any combination of docetaxel or a solvate thereof and at least one compound I, it not being required for docetaxel or a solvate thereof and compound(s) I to be present together in the same formulation.

An example of a composition according to the invention, in which the docetaxel or a solvate thereof and at least one compound I are not present together in the same formulation, is a kit of parts. In a kit of parts, two or more components of a kit are packaged separately, i.e., not p re-formulated. As such, kits include one or more separate containers, such as blister packages, vials, cans, bottles, pouches, bags or canisters, each container containing a separate component of the composition. Accordingly the present invention also relates to kit of parts comprising docetaxel or a solvate thereof and at least one compound I or a pharmacologically acceptable salt thereof. One example is a two-component kit. Accordingly, the present invention also relates to a two-component kit, comprising a first component which, in turn, comprises docetaxel or a solvate thereof and optionally a liquid or solid carrier and, if appropriate, at least one customary auxiliary, and a second component which, in turn, comprises at least one compound I or a pharmacologically acceptable salt thereof and optionally a liquid or solid carrier and, if appropriate, at least one customary auxiliary. Suitable liquid and solid carriers and customary auxiliaries are described below.

Preferably, the composition of the invention is not a physical mixture of docetaxel or a solvate thereof and the at least one compound of formula I or its salt, but any combination of docetaxel or a solvate thereof and at least one compound I, in which the two components are not present together in the same formulation, such a kit of parts, especially a two-(or more)-component-kit.

The above remarks apply analogously to the pharmaceutical composition of the invention. The "combined" use of docetaxel or a solvate thereof and the at least one compound of the formula I or the treatment according to the invention with docetaxel or a solvate thereof "in combination with" the at least one compound I or its salt on the one hand can be understood as using a physical mixture of docetaxel or a solvate thereof and the at least one compound I or its salt. On the other hand, the combined use may also consist in using docetaxel or a solvate thereof and the at least one compound I or its salt separately, i.e. simultaneously or sequentially, but in any case within a sufficiently short time of one another, so that the desired effect can take place.

In case of a separate, sequential use of docetaxel or a solvate thereof and the at least one compound of formula I or its salt, the time interval between the treatment with docetaxel or a solvate thereof and the at least one compound I or its salt is preferably in the range of from some seconds up to one month, preferably from some seconds up to two weeks, more preferably from some seconds up to one week and in particular from some seconds up to three days. These time intervals refer to the shortest administration intervals of the single, different components within a therapeutic phase. It is, however, of course possible that in a therapeutic phase only one component of the composition of the invention is administered. But it is required that in at least one therapeutic phase of the whole treatment docetaxel or a solvate thereof and the at least one compound I or its salt are administered in combination. A therapeutic phase is characterized in that between two phases, administration of docetaxel or a solvate thereof and the at least one compound I or its salt is interrupted for at least one week, preferably for at least two weeks and more preferably for at least three weeks.

Alternatively it is possible to alternate therapeutic phases in which in a single phase only docetaxel or a solvate thereof or only the at least one compound I or its salt is administered. In this case, the time interval between the end of a phase and the beginning of the subsequent phase with a different active compound is preferably in the range of from one week to two months, preferably from two weeks to one month. In a preferred embodiment, docetaxel or a solvate thereof is administered as allowed by the regulatory agencies, and the at least one compound I or its salt is administered during the same time period once or several times, e.g. 4 to 35 times, preferably 6 to 30 times and specifically 6 to 15 times. Specifically, docetaxel or a solvate thereof is administered 1 , 2 or 3 times within three weeks with approximately equal intervals bet- ween the single administrations (if it is administered twice or thrice), and the at least one compound I or its salt is administered during this time 4 to 35 times, preferably 6 to 30 times and specifically 6 to 15 times, where the at least one compound I or its salt can be administered once or several times a day, e.g. once, twice or three times a day, specifically twice a day. This treatment regimen (= therapeutic phase) can be repeated once or several times, e.g. 1 , 2, 3, 4, 5 or 6 times; the time period between each repetition being preferably at least one week, e.g. 1 to 6 weeks; more preferably at least two weeks, e.g. 2 to 6 weeks; and in particular at least three weeks, e.g. 3 to 6 weeks. Examples for a treatment regimen within a therapeutic phase may be

- administering docetaxel or a solvate thereof once on day 1 and the at least one compound I or its salt twice on days 1 , 2, 3, 4, 5, 6, 7, 15, 16, 17, 18, 19, 20 and 21 ; or

- administering docetaxel or a solvate thereof once on day 1 and the at least one compound I or its salt twice on days 1 , 2, 3, 4, 5, 15, 16, 17, 18 and 19; or

- administering docetaxel or a solvate thereof once on day 1 and the at least one compound I or its salt twice on days 1 , 2, 3, 15, 16 and 17; or

- administering docetaxel or a solvate thereof once on days 1 , 8 and 15 and the at least one compound I or its salt twice on days 1 , 2, 3, 4, 5, 6, 7, 15, 16, 17, 18, 19, 20 and 21 ; or

- administering docetaxel or a solvate thereof once on days 1 , 8 and 15 and the at least one compound I or its salt twice on days 1 , 2, 3, 4, 5, 15, 16, 17, 18 and 19; or

- administering docetaxel or a solvate thereof once on days 1 , 8 and 15 and the at least one compound I or its salt twice on days 1 , 2, 3, 15, 16 and 17. The dosage schedule most suitable for the individual case depends, however, on several factors, such as the specific disorder to be treated and its state and severity and the patient, and is determined by the attending physician. The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix C_n-C_m indicates in each case the possible number of carbon atoms in the group. Ci-C3-Alkyl is a straight-chain or branched alkyl group having from 1 to 3 carbon atoms. Examples are methyl, ethyl, n-propyl and isopropyl.

Ci-C3-Haloalkyl is a straight-chain or branched alkyl group having 1 to 3 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1 , 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by halogen atoms as mentioned above. Examples are chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl,

difluoromethyl, trifluoromethyl, bromomethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-chloroethyl, 2- bromoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl,

pentafluoroethyl, 1 -chloropropyl, 1 -bromopropyl, 1-fluoropropyl, 2-chloropropyl, 2- bromopropyl, 2-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 1 ,1 - dichloropropyl, 1 ,1 -difluoropropyl, 2,2-dichloropropyl, 2,2-difluoropropyl, 2,3- dichloropropyl, 2,3-difluoropropyl, 1 ,3-dichloropropyl, 1 ,3-difluoropropyl, 3,3- dichloropropyl, 3,3-difluoropropyl, 1 ,1 ,2-trichloropropyl, 1 ,1 ,2-trifluoropropyl, 1 ,2,2- trichloropropyl, 1 ,2,2-trifluoropropyl, 1 ,2,3-trichloropropyl, 1 ,2,3-trifluoropropyl, 2,2,3- trichloropropyl, 2,2,3-trifluoropropyl, 3,3,3-trichloropropyl, 3,3,3-trifluoropropyl, 1 ,1 ,1 - trifluoroprop-2-yl, 1 -chlorobutyl, 1 -bromobutyl, 1 -fluorobutyl, 2-chlorobutyl, 2- bromobutyl, 2-fluorobutyl, 3-chlorobutyl, 3-bromobutyl, 3-fluorobutyl, 4-chlorobutyl, 4- bromobutyl, 4-fluorobutyl, and the like.

Ci-C3-Alkoxy is a straight-chain or branched alkyl group having from 1 to 3 carbon atoms, which is bound to the remainder of the molecule via an oxygen atom. Examples include methoxy, ethoxy, n-propoxy and isopropoxy.

Ci-C3-Haloalkoxy is a straight-chain or branched alkoxy group having from 1 to 3, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atoms, in particular fluorine atoms, such as in fluoromethoxy, difluoromethoxy, trifluoromethoxy, (R)-l -fluoroethoxy, (S)-l -fluoroethoxy, 2-fluoroethoxy, 1 .1 - difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, (R)-l -fluoropropoxy, (S)-l -fluoropropoxy, (R)-2-fluoropropoxy, (S)-2-fluoropropoxy, 3-fluoropropoxy, 1 ,1 -difluoropropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, (R)-2-fluoro-1 -methylethoxy, (S)-2-fluoro-1 -methylethoxy, (R)-2,2-difluoro-1 -methylethoxy, (S)-2,2-difluoro-1 -methylethoxy, (R)-1 ,2-difluoro-1 - methylethoxy, (S)-1 ,2-difluoro-1 -methylethoxy, (R)-2,2,2-trifluoro-1 -methylethoxy, (S)-2,2,2-trifluoro-1 -methylethoxy, 2-fluoro-1 -(fluoromethyl)ethoxy, 1 -(difluoromethyl)-

2.2- difluoroethoxy, and the like. Suitable pharmacologically acceptable salts used in the composition of the present invention are salts of compounds I, wherein R² is a hydrogen atom. This hydrogen atom is acidic and thus can be removed by a base. Suitable salts include alkali metal salts, such as the sodium or potassium salt, alkaline earth metal salts, such as the magnesium or calcium salt, and ammonium salts, such as ammonium or

tetraalkylammonium salts.

The neutral forms of the compounds may be regenerated by contacting the salt with an acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the compounds used according to the present invention can be used in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide docetaxel or a solvate thereof or a compound of general formula I. A prodrug is a pharmacologically active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound as used in this invention following administration of the prodrug to a patient.

Additionally, prodrugs can be converted to the compounds as used in the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds used in the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek, Drug Metabolism Reviews 16.5 (1988), and Bundgaard, Design of Prodrugs, Elsevier (1985). Examples of a masked acidic anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as compounds I, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 0 039 051 (Sloan and Little, Apr. 1 1 , 1981 ) discloses

Mannich-base hydroxamic acid prodrugs, their preparation and use.

The compounds used in the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Especially docetaxel can be used in unsolvated form or as a solvate, preferably as a hydrate and especially as its trihydrate. Thus, the term "docetaxel" as used in the context of the present invention relates both to the unsolvated form of docetaxel as well as to its solvates, preferably hydrates and especially its trihydrate.

Certain compounds used in the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses

contemplated by the present invention and are intended to be within the scope of the present invention.

The compounds used in the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope, such as ³H or ¹⁴C, is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes, such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agent of the present invention and

pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. All isotopic variations of the compounds and compositions of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Docetaxel, its solvates and methods for its preparation are known in the art; and the compound is moreover commercially available.

Compounds of formula I and salts thereof as well as and methods for their preparation are known in the art and are for example described in WO 2010/075869.

In compounds I, R¹ is preferably Ci-C3-alkoxy or Ci-C3-haloalkoxy and more preferably Ci-C3-alkoxy. In particular it is methoxy.

R² is preferably hydrogen or methyl and in particular hydrogen.

R³ is preferably Ci-C3-alkyl or Ci-C3-haloalkyl, more preferably Ci-C3-alkyl and is in particular methyl.

In particular, in compounds I, R¹ is methoxy, R² is hydrogen and R³ is methyl.

In a preferred embodiment, the compound of formula I is a compound of formula la

where R¹, R² and R³ have one of the above-given general or, in particular, one of the above-given preferred meanings.

Preferably, in compounds la, R¹ is methoxy, R² is hydrogen and R³ is methyl.

In the composition according to the invention, docetaxel (calculated as trihydrate) and the at least one compound of formula I (or la) are preferably contained in a weight ratio of from 20:1 to 1 :20, more preferably from 5:1 to 1 :20, even more preferably from 2:1 to 1 :15, in particular from 1 :1 to 1 :15 and specifically from 1 :2 to 1 :15, e.g. 1 :5 to 1 :15 or 1 :5 to 1 :13. In case that the composition of the invention is not a physical mixture or a kit of parts, the above weight ratios refer to the total amount of docetaxel (calculated as trihydrate) and the at least one compound of formula I (or la) used in a therapeutical phase or during the whole therapy. In case that in a therapeutical phase only one component is used, the weight ratios refer to the total amounts of docetaxel (calculated as trihydrate) and the at least one compound of formula I (or la) used during the whole therapy.

The invention also relates to a pharmaceutical composition comprising the composition according to the invention and at least one physiologically acceptable carrier and/or auxiliary substance.

As a further aspect, the invention provides a therapeutical composition which, in addition to docetaxel or a solvate thereof and the at least one compound of formula I or its salt, comprises at least one further pharmaceutically active compound that is useful to treat one of the aforementioned or below mentioned diseases or disorders. Such therapeutical compositions are useful because the therapeutic efficiency of the composition of the invention can be amplified by the presence of said at least one further pharmaceutically active compound and vice versa.

In a further aspect, the present invention relates to a pharmaceutical composition comprising docetaxel or a solvate thereof, at least one compound I or a salt thereof and a further therapeutic agent useful for the treatment or prevention of a disease or disorder selected from hyperproliferative diseases or disorders, and, optionally, a pharmaceutically acceptable carrier or excipient. Such compositions are also useful to obtain synergistic therapeutic effects and also to prevent drug resistance of tumor cells, for example. It is also for these reasons, that current chemotherapy generally involves administering a cocktail of different cytotoxic and/or cytostatic compounds to improve the effectiveness of the treatment and reduce the possibility of tumor cell adaptation.

In a further aspect, the present invention relates to a pharmaceutical composition comprising docetaxel or a solvate thereof and at least one compound of formula I or a salt thereof in combination with radiation therapies.

Any composition of the present invention may be admixed with a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof. Even though docetaxel or a solvate thereof and the at least one compound of formula I or its salt can be administered as such, i.e. as pure substances or as a mixture of pure substances, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy.

The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.

Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the "Handbook of Pharmaceutical Excipients", 2nd Edition, (1994), edited by A Wade and PJ Weller. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

Suitable pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 80%, more preferably from 20% to 70% of total active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

The term "preparation" is intended to include the formulation of the active compounds with encapsulating material as a carrier providing a capsule in which the active component(s), with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component(s) is/are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. Liquid forms are particularly preferred for topical applications to the eye. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component(s) in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component(s) in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium

carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component(s), colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical composition is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Interestingly, HIF inhibitors can prevent the development of tumor resistance towards chemotherapeutic drugs and can make cancer cells more sensitive towards radiotherapy (see e.g. Palayoor ST, et al., Int J Cancer, 2008 Nov 15;123(10):2430-7 and Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3). Thus, useful further therapeutic agents that can be combined with the composition of the invention to produce the pharmaceutical composition of the invention include, without limitation, a HIF-1 inhibitor, a cytotoxic compound and cytostatic compounds. A HIF-1 inhibitor can be e.g. selected from the group consisting of PX-478 (S-2-amino- 3-[4'-A/,A/,-bis(2-chloroethyl)amino]phenyl propionic acid A/-oxide dihydrochloride); a topoisomerase-1 inhibitor, such as 8,9-dimethoxy-5-(2-A/,A/-dimethylaminoethyl)-2,3- methylenedioxy-5/-/-dibenzo[c, ?][1 ,6] naphthyridin-6-one (also known as ARC-1 1 1 or topovale) or (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H-pyrano[3',4':6,7] indolizino [1 ,2-t)]quinoline-3,14-(4/-/ ,12H)-dione monohydrochloride (also referred to as tropotecan); echinomycin; chetomin (NSC289491 ); cyclosporine A; 3-[2-[4-[bis(4-fluoro- phenyl)methylene]-1 -piperidinyl]-2,3-dihydro-2thioxo-4(1 H)-quinazolinone (R59949); an inhibitor of the PI K3K/Akt/mTor signalling cascade, e.g., LY294002, wortmannin or rapamycin; an inhibitor of the MAPK signalling cascade, e.g. the MEK1 inhibitor PD98059; a soluble guanyl cyclase stimulator such as 3-(5'hydroxymethyl-2'-furyl)- 1 -benzylindazole (YC-1 ); a heat-shock protein 90 inhibitor, in particular radicicol, the radicicol analogue KF58333 or geldanamycin; a microtubule disrupting agent, in particular, e.g. taxol, vincristine or 2-methoxyestradiol; a histone deacetylase inhibitor, e.g. FK228; a thioredoxin inhibitor, in particular, PX-12 or pleurotin; UCNO-1 ;

diphenylene iodonium, genestein and carboxyamido-triazole.

Many cytotoxic or cytostatic compounds are known to the expert artisan skilled in the therapy of hyperproliferative diseases or disorders such as a tumor or cancer disease. For example, cytotoxic and cytostatic compounds include, but are not limited to, pure or mixed anti-estrogens, such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II); any compound that acts through inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HER2 signalling, such as herceptin; any compound that interchelates DNA, such as doxorubicin. Particularly preferred cytostatic or cytotoxic drugs, which can be combined with the compounds of the present invention are alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle- dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or

lipoxygenases, biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, aclarubicine, ambazone, aminoglutethimide, L- asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine,

cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin,

hydroxyprogesteronecaproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon γ , irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, rapamycin, rofecoxib, rosiglitazone, salazosulfapyridine, scriflavinium chloride, semustine streptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole,

sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, UCN-01 , vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or their respective derivatives or analogs thereof. Several of the above indicated drugs are now

administered simultaneously for cancer therapy and, consequently, it is also envisioned that more than one cytostatic and/or cytotoxic drug can be comprised in compositions of the present invention.

As mentioned above, HIF inhibitors render cancer cells more vulnerable to

chemotherapy and radiation therapy. Thus, to effectively treat a hyperproliferative disease or disorder, the composition of the present invention can be co-administered with other active medicinal agents and/or administered in conjunction with other anticancer, antitumor, or antiproliferative disease therapies. In one aspect, the invention provides a method for treating a hyperproliferative disease or disorder comprising administering a compound according to the invention to a patient prior to, during and/or after said patient was subjected to a radiation therapy, a chemotherapy, an immunotherapy, a laser/microwave thermotherapy or a gene therapy using antisense DNA and RNA (for examples see Moeller et al., Cancer Cell 2004 5429-441 ). In a further aspect, the invention provides, as already outlined above, the use of the composition according to the invention or of a therapeutic or pharmaceutical composition according to the invention for the preparation of a medicament for the therapy, including the treatment or prevention, of a disease or disorder selected from hyperproliferative diseases or disorders.

The composition of the invention shows anti-proliferative effects. The hyperproliferative disease is preferably selected from tumour or cancer diseases, precancerosis, dysplasia, histiocytosis, vascular proliferative diseases and virus-induced proliferative diseases. Thus, in one preferred embodiment of the invention the hyperproliferative disease is a tumor or cancer disease selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T-cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, glioma, bone cancer and soft-tissue sarcomas, common solid tumors of adults, such as head and neck cancers (e.g., oral, laryngeal and

esophageal), genitourinary cancers (e.g., prostate, bladder, renal (in particular malignant renal cell carcinoma (RCC)), uterine, ovarian, testicular, rectal, and colon), lung cancer (e.g., small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin carcinoma, squamous cell carcinoma of both ulcerating and papillary type, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary carcinoma, osteosarcoma, soft-tissue sarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, glioblastoma, papillary adenocarcinomas, cystadenocarcinoma, bronchogenic carcinoma, seminoma, embryonal carcinoma, Wilms' tumor, small cell lung carcinoma, epithelial carcinoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,

neuroblastoma, retinoblastoma, glaucoma, hemangioma, heavy chain disease and metastases. The precancerosis treatable with the composition of the present invention are preferably selected from the group consisting of precancerosis, in particular actinic keratosis, cutaneaous horn, actinic cheilitis, tar keratosis, arsenic keratosis, x-ray keratosis, Bowen's disease, bowenoid papulosis, lentigo maligna, lichen sclerosus, and lichen rubber mucosae; precancerosis of the digestive tract, in particular erythroplakia, leukoplakia, Barrett's esophagus, Plummer-Vinson syndrome, crural ulcer, gastropathia hypertrophica gigantea, borderline carcinoma, neoplastic intestinal polyp, rectal polyp, porcelain gallbladder; gynaecological precancerosis, in particular carcinoma ductale in situ (CDIS), cervical intraepithelial neoplasia (CIN), endometrial hyperplasia (grade III), vulvar dystrophy, vulvar intraepithelial neoplasia (VI N), hydatidiform mole; urologic precancerosis, in particular bladder papillomatosis, Queyrat's erythroplasia, testicular intraepithelial neoplasia (TIN), carcinoma in situ (CIS); precancerosis caused by chronic inflammation, in particular pyoderma, osteomyelitis, acne conglobata, lupus vulgaris, and fistula.

Dysplasia is frequently a forerunner of cancer, and is can be found in e.g. the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where there exists chronic irritation or inflammation. Dysplastic disorders which can be treated with the composition of the present invention include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia,

craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis heminelia, dysplasia epiphysialis multiplex, dysplasia epiphysalis punctata, epithelial dysplasia, faciodigitogenital dysplasia, familial fibrous dysplasia of jaws, familial white folded dysplasia, fibromuscular dysplasia, fibrous dysplasia of bone, florid osseous dysplasia, hereditary renal-retinal dysplasia hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary dysplasia, mandibulofacial dysplasia, metaphysical dysplasia, Mondini dysplasia, monostotic fibrous dysplasia, mucoepithelial dysplasia, multiple epiphysial dysplasia, oculoauriculovertebral dysplasia, oculodentodigital dysplasia, oculovertebral dysplasia, odontogenic dysplasia, ophthalmomandibulomelic dysplasia, periapical cemental dysplasia, polyostotic fibrous dysplasia, pseudoachondroplastic spondyloepiphysial dysplasia, retinal dysplasia, septo-optic dysplasia, spondyloepiphysial dysplasia, and ventriculoradial dysplasia. The progesterone receptor (PR), also known as NR3C3 (nuclear receptor subfamily 3, group C, member 3), is an intracellular steroid receptor that specifically binds progesterone. In humans, PR is encoded by a single PGR gene residing on chromosome 1 1 q22, it has two main forms, A and B, that differ in their molecular weight. Progesterone and the progesterone receptor have been implicated in many diseases, such as cancer, diabetes and hormone resistance syndromes. It was found that the compound of the formula I, as defined herein, acts as an antagonist of the progesterone receptor and is capable of inhibiting progesterone receptor-mediated transcriptional activity. Thus, the composition of the invention can be used to treat said diseases.

Thus, in a further preferred embodiment, the hyperproliferative disorders treatable according to the invention are those which benefit from a reduced progesterone receptor signalling, i.e. disorders associated with an increased progesterone receptor signalling, if compared to healthy tissue. This particular suitability of the composition of the present invention is based on the fact that the composition of the present invention potentially through inhibiting cellular replication, but possibly also through an additional activity exerts an inhibition of progesterone receptor signalling. Thus, preferred diseases, conditions and/or disorders which can be treated are selected from the group consisting of mammary tumors (see e.g. David MW Cork et al., Alternative splicing and the progesterone receptor in breast cancer, Breast Cancer Research 2008, 10, 207), endometrial tumors, tumors of the uterus and lung cancers (for the latter see Y. Jeong et al., Nuclear Receptor Expression defines a Set of Prognostic Biomarkers for Lung Cancer, Plos Medicine, December 2010, 7(12)). Whether a disease is associated with an increased progesterone receptor activity can be measured by a variety of art known methods including determination of PR expression level in the diseased tissue by, e.g. immunological methods, which determine the amount of expressed protein, by methods determining the amount of transcribed PR encoding nucleic acids, e.g. RT- PCR, Northern-blots, nuclear run-ons etc., and determining the activity of a nucleic acid construct comprising a PR-receptor recognition element, which drives expression of a detectable reporter, e.g. CAT, luciferase, GFP etc as described in more detail in the Experimental Section below. Preferably, the disorders which benefit from a reduced progesterone receptor signalling are those which show in the diseased tissue an increase in progesterone receptor signalling by at least 10%, preferably by at least 20%, 30%, 40%, 50%, 60%, 70%, if compared to healthy tissue. Preferably, this increase is measured on the basis of a nucleic acid comprising a PR-receptor recognition element and the increase of the expression of a reporter driven by this element. The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor. Testosterone, dihydrotestosterone and the androgen receptor have been implicated in many diseases such as cancer. It was found that the compound of the formula I, as defined herein, acts as an antagonist of the androgen receptor and is capable of inhibiting androgen receptor-mediated activity. Thus, the composition of the invention can be used to treat diseases associated with androgen receptor-mediated activity.

Thus, in a further preferred embodiment, the hyperproliferative disorders treatable according to the invention are those which benefit from a reduced androgen receptor signalling, i.e. disorders associated with an increased androgen receptor signalling, if compared to healthy tissue. This particular suitability of the composition of the present invention is based on the fact that the composition of the present invention potentially through inhibiting cellular replication, but possibly also through an additional activity exerts an inhibition of androgen receptor signalling. Thus, preferred diseases, conditions and/or disorders which can be treated are prostate cancer.

The hyperproliferative diseases and disorders to be treated according to the present invention are preferably selected from tumor or cancer disease and precancerosis.

More preferably, they are selected from lung cancer, (e.g. small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and

adenocarcinoma), breast cancer (including metastatic breast cancer and node positive breast cancer) and prostate cancer. In particular, the hyperproliferative diseases are selected from non-small cell lung cancer, metastatic breast cancer and node positive breast cancer and prostate cancer. Specifically, the composition of the invention is used for treating prostate cancer.

The composition according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes. Parenteral administration and particular intravenous

administration, preferably by depot injection, is preferred. Depending on the route of administration different pharmaceutical formulations are required and some of those may require that protective coatings are applied to the drug formulation to prevent degradation of the compounds present in the composition of the invention in, for example, the digestive tract. Thus, preferably, the composition of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation.

Preferably, the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.

Particular preferred pharmaceutical forms for the administration of the composition of the invention are forms suitable for injection and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the final solution or dispersion form must be sterile and fluid. Typically, such a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils. The composition of the invention can also be formulated into liposomes, in particular for parenteral

administration. Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug. Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like antibacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal. Further, isotonic agents, such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.

Production of sterile injectable solutions containing one or more of the compounds of the composition of the invention is accomplished by incorporating the respective compound(s) in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary. Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions. Preferred carriers are cocoa butter and vitebesole. Besides the preferred excipients mentioned already above, also the following excipients can be chosen, without limitation, to be used with the various pharmaceutical forms of a composition of the invention: a) binders, such as lactose, mannitol, crystalline sorbitol, dibasic phosphates,

calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like;

b) lubricants, such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates,

c) disintegrants, such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.

Other suitable excipients can be found in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association, which is herein incorporated by reference.

It is to be understood that depending on the severity of the disorder and the particular type which is treatable with the composition of the invention, as well as on the respective patient to be treated, e.g. the general health status of the patient, etc., different doses of the composition are required to elicit a therapeutic or prophylactic effect. The determination of the appropriate dose lies within the discretion of the attending physician. Docetaxel (as well as its solvates) is preferably administered as is recommended by the producer, i.e. preferably in an amount of from 60 to 100 mg/m², more preferably from 70 to 80 mg/m², specifically about 75 mg/m² per single

administration (single dose), calculated as docetaxel trihydrate. The average single administration (single dose) of the compound I or its salt in the therapeutic or prophylactic use of the invention is preferably in the range from 10 to 100, preferably from 20 to 70, more preferably from 25 to 60, in particular from 25 to 50 mg/m², calculated as free compound I. As to the frequency of the administration of the active compounds and specific therapy regimen, reference is made to what has been said above.

Generally, treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. The duration of therapy and the dosing frequency with the composition of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient. As is known in the art, the pharmaceutically effective amount of a given compound or composition will also depend on the administration route. In general, the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower, if the route of administration is parenteral, e.g. intravenous.

If a person is known to be at risk of developing a disorder treatable with the

composition of the invention, a prophylactic administration of the pharmaceutical composition according to the invention may be possible. In these cases, the composition of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, the composition of the invention will be administered once a disease/disorder has been diagnosed. In these cases, it is preferred that a first dose of the composition of the invention is administered one, two, three or four times daily. Preferably, the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or until they are improving.

Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention. Examples

Abbreviations:

b.i.d. twice a day

i.v. intravenous p.o. orally

q.d. once daily

T/C treatment/control relative tumour volume 1 . Progesterone and androgen receptor antagonistic activity of compounds of

formula I

The compound of formula I. a, wherein R¹ is methoxy, R² is hydrogen and R³ is methyl, was tested in in vitro standard binding assays (commercial tests carried out by Cerep).

The specific ligand binding to the receptors is defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabelled ligand. The results are expressed as a percent of control specific binding (measured specific binding/control specific binding) x 100) obtained in the presence of the above compound.

The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting (Y = D + [(A - D)/(1 + (C/C₅o)^nH)], where Y = specific binding, D = minimum specific binding, A = maximum specific binding, C = compound concentration, C50 = IC50, and nH = slope factor). This analysis was performed using a software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot^® 4.0 for Windows^® (© 1997 by SPSS Inc.). The inhibition constants (K,) were calculated using the Cheng Prusoff equation (K, =

IC5O/(1 +(L/KD)), where L = concentration of radioligand in the assay, and KD = affinity of the radioligand for the receptor). A scatchard plot was used to determine the Kd.

The tested compound was found to be an antagonist of the progesterone and androgen receptor. In the progesterone assay the IC50 value was 3.1 x10^-8 M, the Ki value was 2.5x10^"8 M and ΠΗ was 0.9. In the androgen assay the IC50 value was 9.6x10^"8 M, the Ki value was 4.3x10^"8 M and n_H was 0.9.

2. Antitumor activity in an androgen receptor positive prostate cancer model

(CWR22)

Docetaxel and the compound of formula la.1 ,

described as example 73 in WO 2010/075869 were tested either alone or in combination with each other.

Docetaxel was obtained as the clinical formulation from SanofiAventis, solution 80 mg/mg, purchased from local Pharmacy. The compound of formula la.1 was synthesized as described in WO 2010/075869. The compound of formula la.1 was formulated for oral administration in 10% DMSO, 10% cremaphor EL and 80% H₂0.

CWR22 tumors were taken from an in vivo passage, cut into small fragments and transplanted s.c. into the flank of 88 nude mice. At day 13 tumors were palpable. Mice were randomized to 10 groups with 8 mice each and treatment was initiated according to the protocol. The b.i.d. treatments were performed daily at 7 a.m. and 5 p.m.; the injection volume was 5 ml/kg. The different groups were sacrificed at different days for ethical reasons (large tumors). The treatments are compiled in the table below.

Table 1

No. Treatment Dose T/C [%] Schedule

[mg/kg]

1 - (vehicle control)^* - - -

2 Docetaxel 12 40 i.v. q.d. 1 ,8,15

3 Compound la.1 12 50 P.o. b.i.d. 7 days on/ 7 days off/

7 days on

4 Compound la.1 12 24⁺ P.o. b.i.d. 7 days on/7 days off/

7 days on

Docetaxel 12 i.v. q.d. 1 , 8, 15

5 Compound la.1 15 45 P.o. b.i.d. 7 days on/ 7 days off/

7 days on

6 Compound la.1 15 23⁺ P.o. b.i.d. 7 days on/ 7 days off/ No. Treatment Dose T/C [%] Schedule

[mg/kg]

7 days on

Docetaxel 12 i.v. q.d. 1 , 8, 15

7 Compound la.1 12 57 P.o. b.i.d. 5 days on/ 2 days off

8 Compound la.1 12 22⁺ P.o. b.i.d. 5 days on/2 days off (3x)

Docetaxel 12 i.v. q.d. 1 , 8, 15

9 Compound la.1 15 49 P.o. b.i.d. 5 days on/2 days off (3x)

10 Compound la.1 15 25⁺ P.o. b.i.d. 5 days on/2 days off (3x)

Docetaxel 12 i.v. q.d. 1 , 8, 15

^* 10%DMSO; 10% cremaphor EL and 80% H₂0

+ significantly different to Docetaxel alone p > 0.05

Results:

Control tumors grew well and relatively fast. Mice had to be sacrificed at day 24 because of large tumors and strong body weight loss.

Docetaxel led to a moderate and borderline significant (p = 0.04) inhibition of tumor growth.

The compound of formula la.1 induced a moderate but not significant (p > 0.05) tumor growth delay. That effect was slightly dependent on dose, but not clearly on schedule.

The treatments were well tolerated with only minimum body weight changes (BWC).

The combined treatment with the compound of formula la.1 and docetaxel revealed a distinct tumor growth inhibition, which was significantly better than each single drug as can be seen from table 1 . The effect was not clearly dependent on dose or schedule. The treatments were well tolerated with only one unclear death in group I. The body weight loss in the combinations was tolerable but always higher than in the single treatment groups.

As the results show, the compound of formula la.1 clearly improved efficacy of docetaxel in a docetaxel moderately responsive prostate carcinoma.

Claims

Claims:

1. A composition comprising docetaxel or a solvate thereof and at least one

compound of formula I or a pharmacologically acceptable salt thereof

wherein

R¹ is selected from Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and C1-C3- haloalkoxy;

R² is selected from hydrogen and Ci-C3-alkyl; and

R³ is selected from Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and C1-C3- haloalkoxy.

2. The composition as claimed in claim 1 , where the composition is a mixture.

3. The composition as claimed in claim 1 , where the composition is a kit of parts.

4. The composition as claimed in any of the preceding claims, where R¹ is C1-C3- alkoxy.

5. The composition as claimed in claim 4, where R¹ is methoxy.

6. The composition as claimed in any of the preceding claims, where R² is

hydrogen.

7. The composition as claimed in any of the preceding claims, where R³ is methyl.

8. The composition as claimed in any of the preceding claims, where the compound of the formula I is a compound of formula la

where R¹, R² and R³ are as defined in any of the preceding claims.

9. The composition as claimed in claim 8, where R¹ is methoxy, R² is hydrogen and R³ is methyl.

10. The composition as claimed in any of the preceding claims, containing docetaxel and the compound of formula I in a weight ratio of from 20:1 to 1 :20.

1 1 . The composition as claimed in claim 10, containing docetaxel and the compound of formula I in a weight ratio of from 2:1 to 1 :15, preferably from 1 :1 to 1 :15.

12. A pharmaceutical composition comprising the composition as defined in any of the preceding claims and at least one physiologically acceptable carrier and/or auxiliary substance.

13. The composition as claimed in any of claims 1 to 1 1 for use as a medicament.

14. The composition as claimed in any of claims 1 to 1 1 for treating or preventing a hyperproliferative disease.

15. The composition as claimed in claim 14, where the hyperproliferative disease is a tumor or cancer disease or a precancerosis.

16. The composition as claimed in claim 15, where the tumor or cancer disease is selected from breast cancer, lung cancer and prostate cancer.

17. The composition as claimed in claim 16, where the tumor or cancer disease is selected from metastatic breast cancer, node positive breast cancer, non-small cell lung cancer and prostate cancer.

18. The use of docetaxel in combination with at least one compound of formula I as defined in any of claims 1 to 1 1 or a pharmacologically acceptable salt thereof for preparing a medicament for treating or preventing a disease which is as defined in any of claims 14 to 17.

19. A method for treating or preventing hyperproliferative diseases, which method comprises administering an effective amount of docetaxel in combination with an effective amount of at least one compound I as defined in any of claims 1 to 1 1 or a pharmacologically acceptable salt thereof to a subject in need thereof.

20. The method as claimed in claim 19, where the hyperproliferative disease is a tumor or cancer disease or a precancerosis,

21 . The method as claimed in claim 20, where the tumor or cancer disease is

selected from breast cancer, lung cancer and prostate cancer.

22. The composition as claimed in claim 21 , where the tumor or cancer disease is selected from metastatic breast cancer, node positive breast cancer, non-small cell lung cancer and prostate cancer.