TW201420102A - Combination therapy - Google Patents

Abstract

A pharmaceutical combination comprising (a) a RTK inhibitor selected from the group consisting of compounds of Formula I or a tautomer thereof, compounds of Formula II or a tautomer thereof, compounds of Formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof; and (b) one or more CYP17 inhibitors such as abiraterone; and methods of treating a subject suffering from a proliferative disease comprising administering a therapeutically effective amount of such combination.

Description

Combination therapy

The present invention relates to a pharmaceutical combination comprising (a) at least one receptor tyrosine kinase (RTK) inhibitor compound that targets/reduces protein or lipid kinase activity, the compound being selected from the group consisting of: a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or And (b) one or more CYP17 inhibitors or pharmaceutically acceptable salts thereof, for example, (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (A Bitron, abiraterone), abiraterone acetate, 1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one, ketoconazole (ketoconazole) or VN/124-1 (TOK-001); use of the combination for treating or preventing a proliferative disease (such as prostate cancer); and a method for treating an individual suffering from a proliferative disease, comprising administering a therapeutically effective This combination of quantities.

Standard first-line androgen removal therapy (ADT) using medical castration (eg, using LHRH agonists) initially induces remission in 80% to 90% of patients with advanced prostate cancer. After the deterioration of medical castration, patients can usually be "re-induced" into remission by conventional second-line hormone ablation therapy (including non-steroidal antiandrogens (such as bicalutamide), ketoconazole, and DES). Successfully applied a series of androgen ablation therapy to achieve a median of 12 to 33 months without worsening survival, when the anti-castrated phenotype dominated. Prostate cancer is preferentially transferred to the bone, which induces significant pain, systemic symptoms, anemia, and death. Bone reaction. Until recently, in addition to cytotoxic chemotherapy, patients with metastatic anti-castration prostate cancer (mCRPC) had little choice after using standard androgen ablation therapy. However, unfortunately, chemotherapy only produces moderate survival benefits and is associated with significant toxicity.

Until recently, when the in-depth understanding of basic prostate cancer biology led to the rational integration of novel "targeted" agents involved in key growth-promoting pathways for the development of anti-castration disease, the success of efforts to advance treatment options other than chemotherapy Very little. Self-translating research has revealed three main points:

1) During the evolution of anti-castration disease, androgen biosynthesis is transferred from endocrine sources (test pills and adrenal glands) to paracrine/autocrine sources in the tumor-bone microenvironment. Intratumoral production of androgen (and endocrine) is effectively inhibited by novel CYP17 inhibitors such as abiraterone.

2) Androgen Receptor (AR) independence involved in normal prostate liposome development The "mesenchymal-epithelial" growth signaling pathway frequently becomes dysregulated during the development of anti-castration disease. Examples of such pathways include c-Met, NOTCH, and FGF signaling. These pathways present novel targets for small molecule therapeutics.

3) The relatively modest effectiveness of agents that block the interstitial-epithelial interaction pathway suggests that prolonged intratumoral androgen signaling drives the dominant survival pathway for anti-castration growth in bone. This line of reasoning has led to the hypothesis that effective inhibition of androgen signaling in tumors should be a key aspect of a rational combination strategy for small molecule therapeutics that target the interstitial-epithelial interaction pathway.

Abirate has recently been approved by the FDA for the treatment of mCRPC patients who have previously received docetaxel after a prolonged overall survival in a randomized phase III study. After a median follow-up of 12.8 months, the overall survival of the abiraterone-prednisone group was longer than that of the placebo-Pryson group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval) , 0.54 to 0.77; P < 0.001). Despite these encouraging results, as many as one-third of patients seem to have no response to Abitrone and the remaining 70% will eventually deteriorate. Molecular pathology analysis of bone marrow biopsy for tumor infiltration reveals that AR has a uniform and strong nuclear performance along with >10% CYP17 tumor performance was associated with longer treatment cessation (>4 months). Taken together, these findings indicate that the androgen receptor (AR) independent growth pathway promotes anti-castration growth after administration of abiraterone.

The compounds of Formula I, Formula II, and Formula III inhibit various protein kinases, such as the receptor tyrosine kinase (RTK). Receptor tyrosine kinase (RTK) is a transmembrane polypeptide that regulates the developmental cell growth, differentiation, remodeling and regeneration of adult tissues. A polypeptide ligand known as a growth factor or interleukin is known to activate RTK. Signaling RTK is involved in ligand binding and conformational transitions in the outer domain of the receptor, resulting in its dimerization. Binding of the ligand to the RTK causes the specific tyramine residue to undergo transphosphorylation and subsequent activation of the catalytic domain for phosphorylation of the cytoplasmic material.

Two RTK subfamilies are specific for vascular endothelium. These include the vascular endothelial growth factor (VEGF) subfamily and the Tie receptor subfamily. Class III RTKs include vascular endothelial growth factor receptor 1 (VEGFR-1), vascular endothelial growth factor receptor 2 (VEGFR-2), and vascular endothelial growth factor receptor 3 (VEGFR-3).

Inhibited tyrosine kinases include Cdc2 kinase (cell division cycle 2 kinase), Fyn (FYN oncogene kinase associated with SRC, FGR, YES), Lck (lymphocyte-specific protein tyrosine kinase), c-Kit (stem cell factor receptor or mast cell growth factor receptor), p60src (originally identified as the tyrosine kinase of the v-src oncogene of the rous sarcoma virus), c-ABL (representing the original from Adelson ( Adelson) tyrosine kinases of oncogene products isolated from leukemia virus, VEGFR3, PDGFRα (platelet-derived growth factor receptor alpha), PDGFRβ (platelet-derived growth factor receptor beta), FGFR3 (fibroblast growth factor receptor 3) ), FLT-3 (fms-like tyrosine kinase-3) or Tie-2 (tyrosine kinase with lg and EGF homology domains).

It has been found that a combination of the following drugs improves the anti-tumor activity of a CYP17 inhibitor (eg, abiraterone) by inhibiting FGF, an AR-independent signaling pathway that contributes to abiraterone resistance: (a) at least one targeting/ Receptor tyrosine that reduces protein or lipid kinase activity A kinase (RTK) inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, the compound a pharmaceutically acceptable salt, a pharmaceutically acceptable salt of the tautomer or a mixture thereof; and (b) one or more CYP17 inhibitors or a pharmaceutically acceptable salt thereof.

The invention relates to a pharmaceutical combination comprising (a) at least one RTK inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of a tautomer or a mixture thereof; and (b) one or more CYP17 inhibitors or a pharmaceutically acceptable salt thereof; For example (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (abiraterone), abiraterone acetate, 1-(2-chloro-pyridin-4-yl) --3-(4-Methyl-pyridin-3-yl)-imidazolidine-2-one, ketoconazole or VN/124-1 (TOK-001); for simultaneous, separate or sequential administration In particular, it is used to treat or prevent proliferative diseases.

The invention also relates to a combination, for example a combination preparation comprising the following pharmaceutical combinations: (a) at least one RTK inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or An isomer, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof; and (b) one or more CYP17 inhibitors Or a pharmaceutically acceptable salt thereof, for example, (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (abiraterone), abiraterone acetate, 1-( 2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one, ketoconazole or VN/124-1 (TOK-001).

The invention relates in particular to combinations of the invention which are useful in the treatment or prevention of proliferative disorders in an individual in need thereof.

The invention also relates to a combination of the invention for the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disorder in an individual in need thereof.

Unless otherwise expressly stated, the general terms used herein are defined to have the following meanings: unless otherwise indicated, the terms "include" and "include" are used herein in the open and non-limiting sense.

Unless otherwise stated herein or clearly contradicted by the context, the terms "a", "the" and "the" Both singular and plural. When a compound, a salt, and the like are used in the plural, this also means a single compound, a salt or the like.

The term "carrier" refers to a diluent, adjuvant or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids such as water and oil, including oils of such petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferred as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" (E.W. Martin).

The term "combination" or "pharmaceutical combination" as used herein, is defined as a fixed combination in the form of a dosage unit or a combination of non-fixed combinations (or portions) of a compound of formula I, formula II or formula III. And the combination partner (for example, a CYP17 inhibitor drug, also referred to as a "therapeutic agent" or "auxiliary agent" as explained below) can be administered simultaneously or separately at intervals, wherein the intervals are particularly Allows the combined partner to display synergistic effects, such as synergies. The term "combination administration" or the like as used herein is meant to encompass the administration of a selected combination partner to a single individual (eg, a patient) in need thereof, and is intended to include a treatment regimen that does not necessarily require the same administration route or concurrent administration of the agent. The term "fixed combination" means that the active ingredient (eg, a compound of Formula (I), Formula II or Formula III) and a combination partner are administered to a patient simultaneously in a single entity or dosage form. The term "non-fixed combination" or "Partial kit" means that the active ingredient (eg, a compound of Formula I, Formula II or Formula III) and a combination partner are administered to a patient as separate entities simultaneously, in parallel or sequentially and without specific time constraints, wherein This administration provides a therapeutically effective concentration of the two compounds in the patient. The latter also applies to cocktail therapy, for example by administering three or more active ingredients.

The term "CYP17 inhibitor" as used herein relates to a compound which inhibits cytochrome P450 17-α-hydroxylase 17-20 lyase (CYP17), a multifunctional enzyme that plays a key role in steroid hormone biosynthesis. The term includes, but is not limited to, (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (abiraterone), abiraterone acetate (Abitron has been discussed In patents such as: WO 200900132, WO 2008024485, WO 2006021776, WO 09509178, WO 09320097), 1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl) )-Imidazolidin-2-one, ketoconazole and VN/124-1 (TOK-001).

1-(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one

The term "RTK inhibitor" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or sulphate kinase inhibitors or lipid kinase inhibitors, for example: i) targeting, reducing or inhibiting A compound of vascular endothelial growth factor receptor (VEGF) activity, such as a compound that targets, decreases or inhibits VEGF activity, particularly a compound that inhibits the VEGF receptor, such as, but not limited to, 7H-pyrrolo[2,3-d]pyrimidine derivative (AEE788); BAY 43-9006; a heterocholine compound disclosed in WO 00/09495, such as (4-t-butyl-phenyl)-94-pyridin-4-ylmethyl-isoquinoline- a 1-amino)-amine (AAL881); and ii) a compound that targets, decreases or inhibits platelet-derived growth factor receptor (PDGFR) activity, such as a compound that targets, decreases or inhibits PDGFR activity, particularly inhibits PDGF receptor Compounds such as N -phenyl-2-pyrimidine-amine derivatives such as imatinib, SU101, SU6668 and GFB-111; iii) targeting, reducing or inhibiting fibroblast growth factor receptor (FGFR) Active compound; iv) a compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family; v) targets a compound that reduces or inhibits the activity of the FLT3 receptor tyrosine kinase family; and vi) a compound that targets, reduces or inhibits the activity of the C-kit receptor tyrosine kinase (part of the PDGFR family), such as targeting, reducing or inhibiting a compound active in the c-Kit receptor tyrosine kinase family, particularly a compound that inhibits the c-Kit receptor, such as imatinib; and vii) a compound that targets, decreases or inhibits protein-tyrosine kinase activity, such as Imatinib sulfonate (GLEEVEC); tyrphostin or pyrimidinyl benzamide and its derivatives (TASIGNA). The tyrosine phosphorylation inhibitor is preferably a low molecular weight (M _r <1500) compound or a pharmaceutically acceptable salt thereof, especially a compound selected from the group consisting of benzalmalononitrile or S-aryl phenylmalononitrile or A bi-substrate quinoline compound, more particularly a compound selected from the group consisting of tyrosine phosphorylation inhibitor A23/RG-50810, AG 99, tyrosine phosphorylation inhibitor AG 213, tyrosine Phosphorylation inhibitor AG 1748, tyrosine phosphorylation inhibitor AG 490, tyrosine phosphorylation inhibitor B44, tyrosine phosphorylation inhibitor B44(+) enantiomer, tyrosine phosphorylation inhibitor AG 555, AG 494, tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantane The base, NSC 680410, adafodine); the term "pharmaceutical composition" is defined herein to mean the inclusion of an individual (eg, a mammal or a human) in order to prevent or treat a particular disease or condition affecting the mammal. A mixture or solution of at least one therapeutic agent.

The term "pharmaceutically acceptable" is defined herein to mean that they are suitable for contact with mammalian (eg mammalian or human) tissues within reasonable medical judgment without excessive toxicity, irritation, allergic reactions and other problems. A compound, material, composition, and/or dosage form that is commensurate with a reasonable benefit/risk ratio.

The term "co-administered" or "combined administration" as used in the present invention is defined to encompass the administration of a selected therapeutic agent to a single patient, and is intended to include treatment regimens that are not necessarily administered by the same administration route or concurrently.

The term "treating or treating" as used herein encompasses treatment that reduces, attenuates, or slows down at least one symptom of an individual or delays the progression of the disease. For example, the treatment can be a reduction in one or several symptoms such as cancer or a complete eradication of the condition. Within the meaning of the present invention, the term "treatment" also means preventing, delaying the onset (i.e., the period prior to the clinical manifestation of the disease) and/or reducing the risk of developing or worsening the disease. The term "protection" is used herein to mean preventing, delaying the onset or persistence or aggravation of an individual's disease, or treating the condition or all such conditions as needed.

The term "prevent, prevention, or prevention" as used herein encompasses the prevention of at least one symptom associated with or caused by a prevented state, disease or condition.

The term "combination therapeutic activity" or "combination therapeutic effect" means that the therapeutic agent can preferably be administered separately at intervals of time (better synergistic) interaction (combination therapy effect) in the warm-blooded animal, especially human, to be treated ( In a long-term staggered manner, especially in a sequential manner). In any case, it can be determined, inter alia, by tracking blood concentrations, which indicates that the two compounds are present in the blood of the human being treated, at least during certain time intervals.

The term "pharmaceutically effective amount" or "clinically effective amount" of a combination of therapeutic agents is relative to The clinically observable signs and symptoms at the baseline of the condition treated with the combination are sufficient to provide an observable improved amount.

The term "individual" or "patient" as used herein includes an animal that is capable of suffering from or suffering from cancer or any condition that directly or indirectly involves cancer. Examples of individuals include mammals, for example, humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In a preferred embodiment, a system of humans, for example, a human suffering from, susceptible to, or likely to be able to develop cancer.

The term "about" or "approximately" shall have the meaning within 10%, more preferably within 5% of a given value or range.

Generally, when referring to an element such as hydrogen or H, it is meant to include all isotopes of that element. For example, if the R group is defined to include hydrogen or H, it also includes ruthenium and osmium.

The phrase "unsubstituted alkyl" means an alkyl group which does not contain a hetero atom. Thus, the phrase includes straight-chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl and the like. . The phrase also includes branched isomers of linear alkyl groups including, but not limited to, the following groups provided by way of example: -CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ), -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -C(CH ₂ CH ₃ ) ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ )( CH ₂ CH ₃ ), -CH ₂ CH(CH ₂ CH ₃ ) ₂ , -CH ₂ C(CH ₃ ) ₃ , -CH ₂ C(CH ₂ CH ₃ ) ₃ , -CH(CH ₃ )CH(CH ₃ (CH ₂ CH ₃ ), -CH ₂ CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ CH ₂ CH(CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ C(CH ₃ ) ₃ , -CH ₂ CH ₂ C(CH ₂ CH ₃ ) ₃ , -CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )CH( CH ₃ )CH(CH ₃ ) ₂ , -CH(CH ₂ CH ₃ )CH(CH ₃ )CH(CH ₃ )(CH ₂ CH ₃ ) and others. The phrase also includes cyclic alkyl groups such as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and such rings are straight as defined above Chains and branched alkyl substitutions. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl, norbornyl and bicyclo [2.2.2] octyl, and such rings are straight and branched as defined above. Substituted. Thus, the unsubstituted alkyl group includes a primary alkyl group, a secondary alkyl group, and a tertiary alkyl group. The unsubstituted alkyl group may be bonded to one or more of the carbon, oxygen, nitrogen and/or sulfur atoms of the parent compound. Preferred unsubstituted alkyl groups include straight chain and branched alkyl groups having from 1 to 20 carbon atoms and cyclic alkyl groups. More preferably, such unsubstituted alkyl groups have from 1 to 10 carbon atoms, and even more preferably such groups have from 1 to 5 carbon atoms. The most preferred unsubstituted alkyl group includes straight chain and branched alkyl groups having 1 to 4 or 1 to 3 carbon atoms and includes methyl, ethylpropyl and -CH(CH ₃ ) ₂ .

The phrase "substituted alkyl" refers to an unsubstituted alkyl group as defined above wherein one or more bonds bonded to carbon or hydrogen are replaced by a bond bonded to a bond other than a hydrogen and a non-carbon atom. Non-hydrogen and non-carbon atoms such as, but not limited to, halogen atoms in halides such as F, Cl, Br and I; oxygen atoms in groups such as: hydroxy, alkoxy, aryloxy and ester groups a sulfur atom in a group such as a thiol group, an alkyl group and an aryl sulfide group, a fluorenyl group, a sulfonyl group, and a fluorenylene group; a nitrogen atom such as the following: an amine, a guanamine , alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, quinones and enamines; ruthenium atoms in groups such as: trialkyl Alkyl, dialkylarylalkyl, alkyldiarylalkyl and triarylalkyl; and other heteroatoms in various other groups. The substituted alkyl group also includes a group in which one or more bonds bonded to a carbon or hydrogen atom are replaced by a bond bonded to a hetero atom such as a carbonyl group, a carboxyl group, and an ester group; Nitrogen in the group: imine, hydrazine, hydrazine and nitrile. Preferred substituted alkyl groups include, in particular, alkyl groups in which one or more bonds bonded to a carbon or hydrogen atom are replaced by one or more bonds bonded to a fluorine atom. An example of a substituted alkyl group is a trifluoromethyl group and other alkyl groups containing a trifluoromethyl group. Other alkyl groups include those in which one or more bonds bonded to a carbon or hydrogen atom are replaced by a bond bonded to an oxygen atom such that the substituted alkyl group contains a hydroxyl group, an alkoxy group, An aryloxy or heterocyclic oxy group. Still other alkyl groups include alkyl groups having the following groups: amines, alkylamines, dialkylamines, arylamines, (alkyl)(aryl)amines, diarylamines,heterocyclylamines, (alkanes) ()heterocyclyl)amine, (aryl)(heterocyclyl)amine or diheterocyclylamine.

The phrase "unsubstituted aryl" means an aryl group which does not contain a hetero atom. Thus, for example, the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, and naphthyl. Although the phrase "unsubstituted aryl" includes a group containing a fused ring, such as naphthalene, it does not include an aryl group having another group bonded to a ring member (for example, an alkyl group or a halogen group). It is because an aryl group such as a tolyl group is referred to herein as a substituted aryl group, as described below. A preferred unsubstituted aryl phenyl group. In some embodiments, the unsubstituted aryl has 6 to 14 carbon atoms. The unsubstituted aryl group can be bonded to one or more of the carbon atoms, oxygen atoms, nitrogen atoms and/or sulfur atoms in the parent compound.

The phrase "substituted aryl" has the same meaning as the unsubstituted alkyl group with respect to the unsubstituted alkyl group with respect to the unsubstituted alkyl group. However, substituted aryl also includes an aryl group in which one aromatic carbon is bonded to one of the above non-carbon or non-hydrogen atoms and also includes one or more aromatic carbons in which the aryl group is bonded to a substituent as defined herein. Or an unsubstituted alkyl, alkenyl or alkynyl aryl group. This includes the following bond arrangement: two carbon atoms of the aryl group are bonded to two atoms of an alkyl, alkenyl or alkynyl group to define a fused ring system (e.g., dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase "substituted aryl" includes, but is not limited to, groups such as tolyl and hydroxyphenyl.

The phrase "unsubstituted alkenyl" refers to straight-chain and branched and cyclic groups, such as those described above for unsubstituted alkyl groups as defined above, only between two carbon atoms. There is at least one double bond. Examples include (but are not limited to) _{ethenyl, -CH = CH (CH 3)} , - CH = C (CH 3) 2, -C (CH 3) = CH 2, -C (CH 3) = CH (CH ₃ ), -C(CH ₂ CH ₃ )=CH ₂ , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl. In some embodiments, the unsubstituted alkenyl group has 2 to 8 carbon atoms.

The phrase "substituted alkenyl" has the same meaning as the unsubstituted alkyl group with respect to the unsubstituted alkyl group. Substituted alkenyl groups include alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon bonded to another carbon and one of the non-carbon or non-hydrogen atoms is bonded to not participate in bonding to another carbon The alkenyl group of the carbon of the double bond.

The phrase "unsubstituted alkynyl" refers to both straight-chain and branched-chain groups, such as those described above for an unsubstituted alkyl group as defined above, except that at least one is present between two carbon atoms. Three keys. Examples include, but are not limited to, -C≡C(H), -C≡C(CH ₃ ), -C≡C(CH ₂ CH ₃ ), -C(H ₂ )C≡C(H),- C(H) ₂ C≡C(CH ₃ ) and -C(H) ₂ C≡C(CH ₂ CH ₃ ). In some embodiments, the unsubstituted alkynyl group has 2 to 8 carbon atoms.

The phrase "substituted alkynyl" has the same meaning as the unsubstituted alkynyl group with respect to the unsubstituted alkyl group with respect to the unsubstituted alkyl group. Substituted alkynyl groups include alkynyl groups wherein a non-carbon or non-hydrogen atom is bonded to a carbon bonded to another carbon and wherein none of the non-carbon or non-hydrogen atoms are bonded to participate in bonding to another carbon Alkynyl group of a triple bond carbon.

The phrase "unsubstituted heterocyclic group" means aromatic and non-aromatic ring compounds, including monocyclic, bicyclic and polycyclic compounds such as, but not limited to, quinone containing 3 or more ring members. A ring group in which one or more ring members are heteroatoms such as, but not limited to, N, O and S. Although the phrase "unsubstituted heterocyclic group" includes a fused heterocyclic ring, such as a benzimidazolyl group, it does not include a heterocyclic ring having another group bonded to a ring member (for example, an alkyl group or a halogen group). The reason is that a compound such as 2-methylbenzimidazolyl is a substituted heterocyclic group. Examples of heterocyclic groups include, but are not limited to, unsaturated 3 to 8 membered rings containing from 1 to 4 nitrogen atoms such as, but not limited to, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl , dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1, 2,3-Triazolyl, etc.), tetrazolyl (eg 1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms, such as, but not limited to, pyrrole Pyridyl, imidazolidinyl, hexahydropyridyl, hexahydropyrazinyl; fused unsaturated heterocyclic group containing from 1 to 4 nitrogen atoms, such as, but not limited to, fluorenyl, isodecyl, hydrazine Porphyrin group, pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, pyrazolyl, benzotriazolyl; unsaturated 3 containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms To an 8-membered ring, such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2,5-oxadiazolyl, etc.; a saturated 3 to 8 membered ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, but not limited to, morpholinyl; An unsaturated fused heterocyclic group of 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, a benzoxazolyl group, a benzooxadiazolyl group, a benzoxazinyl group (for example, 2H-1,4- a benzoxazinyl group, etc.; an unsaturated 3 to 8 membered ring containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms, such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (eg 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.; containing 1 to 2 a sulfur atom and a saturated 3 to 8 membered ring of 1 to 3 nitrogen atoms, such as, but not limited to, a tetrahydrothiazolyl group; a saturated and unsaturated 3 to 8 membered ring containing 1 to 2 sulfur atoms, for example (but Not limited to) thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; containing 1 to 2 sulfur atoms and 1 to An unsaturated fused heterocyclic ring of three nitrogen atoms, such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (eg, 2H-1,4-benzothiazinyl, etc.) , a dihydrobenzothiazinyl group (for example, 2H-3,4-dihydrobenzothiazinyl, etc.); an unsaturated 3 to 8 membered ring containing an oxygen atom, for example (but Not limited to) furanyl; unsaturated fused heterocyclic ring containing 1 to 2 oxygen atoms, such as benzodioxanyl group (for example, 1,3-benzodioxanyl group, etc.); containing oxygen atom and 1 to 2 sulfur Atomic unsaturation 3 to 8 membered rings, such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 members containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms Ring, such as 1,4-oxosulfur An unsaturated fused ring containing 1 to 2 sulfur atoms, such as a benzothienyl group, a benzodithiinyl group; and an unsaturated condensed group containing an oxygen atom and 1 to 2 sulfur atoms; A heterocyclic ring such as benzoxathiinyl. Heterocyclyl groups also include those described above, wherein one or more S atoms in the ring are double bonded to one or two oxygen atoms (anthracene and fluorene). For example, a heterocyclic group includes a tetrahydrothiophene oxide and a tetrahydrothiophene 1,1-dioxide. Preferably, the heterocyclic group contains a 5 or 6 ring member. More preferred heterocyclic groups include morpholine, hexahydropyrazine, hexahydropyridine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, Thimorpholine, thiomorpholine (wherein the S atom of thiomorpholine is bonded to one or more O atoms), pyrrole, homohexahydropyrazine, oxazolidin-2-one, pyrrolidin-2-one, evil Azole, quinuclidine ring, thiazole, isoxazole, furan and tetrahydrofuran.

The phrase "substituted heterocyclic group" refers to an unsubstituted heterocyclic group wherein one or more ring members are bonded to a non-hydrogen atom as defined above, for example, above substituted alkyl and substituted aryl Said. Examples include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzothiazolyl, N-alkylhexahydropyrazinyl (eg 1-methylhexa) Hydropyrazinyl, hexahydropyrazine-N-oxide, N-alkylhexahydropyrazine N-oxide), 2-phenoxy-thiophene and 2-chloropyridyl. Further, the substituted heterocyclic group also includes a bond in which a bond to a non-hydrogen atom is bonded to a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group or an unsubstituted heterocyclic group. a heterocyclic group of a carbon atom. Examples include, but are not limited to, 1-benzylhexahydropyridyl, 3-phenylthiomorpholinyl, 3-(pyrrolidin-1-yl)-pyrrolidinyl, and 4-(hexahydropyridin-1-yl) )-hexahydropyridyl. Such as N-alkyl substituted hexahydropyrazinyl (eg N-methylhexahydropyrazinyl), substituted morpholinyl and hexahydropyrazine N-oxide groups (eg hexahydropyrazine N-oxidation) The group such as N-alkyl hexahydropyrazine N-oxide) is an example of some substituted heterocyclic groups. Such as substituted hexahydropyrazinyl (eg N-alkyl substituted hexahydropyrazinyl, such as N-methylhexahydropyrazine and the like), substituted morpholinyl, hexahydropyrazine N-oxide Groups such as a group and an N-alkylhexahydropyrazine N-oxide group are some examples of substituted heterocyclic groups which are particularly suitable as the R ⁶ or R ⁷ group.

The phrase "unsubstituted heterocyclylalkyl" means a bond as defined above wherein the hydrogen bond or carbon bond of the unsubstituted alkyl group is bonded to a bond of a heterocyclic group as defined above. Substituted alkyl. For example, methyl (-CH ₃ ) is an unsubstituted alkyl group. If the hydrogen atom of the methyl group is replaced by a bond bonded to the heterocyclic group, for example, if the carbon of the methyl group is bonded to the carbon 2 of the pyridine (a carbon bonded to the N of the pyridine) or the carbon 3 or 4 of the pyridine, The compound is an unsubstituted heterocyclylalkyl group.

The phrase "substituted heterocyclylalkyl" has the same meaning as the unsubstituted arylalkyl group with respect to the unsubstituted aralkyl group relative to the unsubstituted heterocyclylalkyl group. However, the substituted heterocyclylalkyl group also includes a hetero atom in which a non-hydrogen atom is bonded to a heterocyclic group of a heterocyclylalkyl group (for example, but not limited to, a hexahydropyridylalkyl group in a hexahydropyridine ring). a group of nitrogen atoms). Further, the substituted heterocyclylalkyl group also includes a carbon bond or a hydrogen bond in which the alkyl moiety of the group is bonded to a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group. A group substituted by a bond. Examples include, but are not limited to, phenyl-(hexahydropyridin-1-yl)-methyl and phenyl-(morpholin-4-yl)-methyl.

The phrase "substituted heterocyclic oxy" refers to a hydroxy group (-OH) in which a bond bonded to a hydrogen atom is replaced by a bond bonded to a ring atom of a heterocyclic group which is otherwise substituted as defined above. .

The phrase "unsubstituted aryloxyalkyl" refers to an unsubstituted alkyl group as defined above wherein a carbon bond or a hydrogen bond is replaced by a bond bonded to an oxygen atom, the oxygen atom bonded to the above An unsubstituted aryl group is defined.

The phrase "substituted aryloxyalkyl" refers to a bond of a carbon or a hydrogen radical as defined above wherein the alkyl group bonded to the aryloxyalkyl group is bonded to a non-carbon and a non-hydrogen atom (as set forth above) An unsubstituted aryloxyalkyl group substituted by an aryl group as defined above wherein the alkyl group of the aryloxyalkyl group is substituted.

The phrase "unsubstituted heterocyclyloxyalkyl" refers to an unsubstituted alkyl group as defined above wherein a carbon bond or a hydrogen bond is replaced by a bond bonded to an oxygen atom, the oxygen atom bonded to An unsubstituted heterocyclic group as defined above.

The phrase "substituted heterocyclic oxyalkyl" refers to a bond or a hydrogen group bonded to a heterocyclyloxyalkyl group as defined above to a non-carbon and non-hydrogen atom. (as described above for the substituted alkyl group) or a heterocyclic group of the heterocyclyloxyalkyl group as above A heterocyclic group-substituted unsubstituted heterocyclic oxyalkyl group as defined.

The phrase "unsubstituted heterocyclylalkoxy" means a carbon bond or a hydrogen bond as defined above, which is replaced by a bond bonded to an oxygen atom (the oxygen atom is bonded to the parent compound) and wherein it is unsubstituted Another carbon bond or hydrogen bond of the alkyl group is bonded to the unsubstituted alkyl group of the unsubstituted heterocyclic group as defined above.

The phrase "substituted heterocyclylalkoxy" refers to a bond to a non-carbon and a non-hydrogen atom, as defined above, wherein the carbon or hydrogen group bonded to the alkyl group of the heterocyclylalkoxy group is bonded An unsubstituted heterocyclylalkoxy group substituted with a heterocyclic group as defined above for the substituted heteroalkyl group or a heterocyclic group of the heterocyclylalkoxy group. Further, the substituted heterocyclylalkoxy group also includes a group in which a carbon bond or a hydrogen bond bonded to the alkyl moiety of the group may be substituted with one or more other substituted and unsubstituted heterocyclic rings. Examples include, but are not limited to, pyridin-2-ylmorpholin-4-ylmethyl and 2-pyridin-3-yl-2-morpholin-4-ylethyl.

The phrase "unsubstituted alkoxyalkyl" refers to an unsubstituted alkyl group as defined above wherein a carbon bond or a hydrogen bond is replaced by a bond bonded to an oxygen atom, the oxygen atom bonded to the above An unsubstituted alkyl group is defined.

The phrase "substituted alkoxyalkyl" refers to a bond or a bond between a carbon group or a hydrogen group of an alkyl group and/or an alkoxy group bonded to an alkoxyalkyl group as defined above to a non-carbon and a non-carbon. An unsubstituted alkoxyalkyl group of a hydrogen atom as described above for a substituted alkyl group.

The term "protected" with respect to hydroxy, amine and thiol refers to a form of such functional groups that are protected from undesired reactions by protecting groups known to those skilled in the art, such as Equivalent to those described in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY (3rd edition, 1999), which can be added or removed using the procedures described therein. Examples of protected hydroxy groups include, but are not limited to, decyl ethers, such as those obtained by reacting a hydroxy group with a reagent such as, but not limited to, the following: tert-butyldimethyl-chlorodecane, trimethyl Chlorodecane, triisopropylchlorodecane, triethylchloromethane; substituted methyl ether and ethyl ether, examples Such as (but not limited to) methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, tert-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydrogen Pyryl ether, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzalkonate, formate, acetate, trichloroacetic acid Ester and trifluoroacetate. Examples of protected amine groups include, but are not limited to, decylamines, for example, formamide, acetamide, trifluoroacetamide, and benzamide; quinone imines such as quinone imine and dithiosuccinimide Amine; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl sulfide and S-4-pyridylmethyl sulfide; substituted S-methyl derivatives such as hemisulfur, disulfide and amine groups Thioacetal; and others.

The pharmaceutical combination of the invention comprises (a) at least one RTK inhibitor compound selected from the group consisting of a compound of formula I or a tautomer thereof, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof A pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof.

The RTK inhibitor compound may be selected from a compound of formula I, a tautomer of the compound, a salt of the compound, a salt of the tautomer or a mixture thereof, wherein the compound of formula I has the formula:

Wherein: R ¹ , R ² , R ³ and R ⁴ may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, -OR ¹⁰ groups, -NR ¹¹ R ¹² groups, substituted or Unsubstituted primary, secondary or tertiary alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted a heterocyclic group or a substituted or unsubstituted heterocyclylalkyl group; R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different and independently selected from H, Cl, Br, F, I, - OR ¹³ group, -NR ¹⁴ R ¹⁵ group, -SR ¹¹ group, substituted or unsubstituted one, two or three alkyl groups, substituted or unsubstituted aryl group, substituted or not Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted alkoxy An alkyl group, a substituted or unsubstituted aryloxyalkyl group or a substituted or unsubstituted heterocyclic oxyalkyl group; R ¹⁰ and R ¹³ may be the same or different and independently selected from substituted or unsubstituted Substituted alkyl group Or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl group, substituted or unsubstituted alkoxyalkyl group, substituted or unsubstituted Substituted aryloxyalkyl or substituted or unsubstituted heterocyclyloxyalkyl; R ¹¹ and R ¹⁴ may be the same or different and independently selected from substituted or unsubstituted alkyl, substituted Or unsubstituted aryl or substituted or unsubstituted heterocyclic group; R ¹² and R ¹⁵ may be the same or different and independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted An aryl group or a substituted or unsubstituted heterocyclic group; and R ^{16 is} selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group .

The RTK inhibitor compound may also be selected from a compound of formula II or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof, wherein the compound of formula II has formula:

Wherein: R ⁷ is a substituted or unsubstituted heterocyclic group. In some embodiments, R ⁷ is selected from substituted or unsubstituted heterocyclic groups of substituted or unsubstituted hexahydropyridyl, hexahydropyrazinyl or morpholinyl. In other embodiments, R ⁷ N- alkyl-based by-hexahydro-pyrazinyl, substituted or non-substituted. In other embodiments, R ⁷ N- alkyl-hexahydro-line by a substituted or unsubstituted pyrazinyl group, the N- alkyl and the alkyl group of the piperazine containing from 1 to 4 carbon atoms.

The RTK inhibitor compound may also be selected from a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof, wherein the compound of formula III has formula:

The compound of formula III includes 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2 (1H) -ketone (Compound A) and (4-Amino-5-fluoro-3-[6-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazol-2-yl]quinoline- 2(1H)-keto) (Compound B).

In a preferred embodiment, the pharmaceutical combination of the invention comprises at least one compound of formula I or a tautomer, a compound of formula II or a tautomer thereof, a compound of formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof The compound of formula III is compound A.

In another preferred embodiment, the pharmaceutical combination of the invention comprises at least one compound of the formula I or a tautomer thereof, a compound of the formula II or a tautomer thereof, a compound of the formula III or a tautomer thereof, a pharmaceutical of the compound An acceptable salt, a pharmaceutically acceptable salt of the tautomer or a mixture thereof, the compound of formula III being Compound B.

An RTK inhibitor compound of the formula I or a tautomer thereof, a compound of the formula II or a tautomer thereof, a compound of the formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, the tautomer A pharmaceutically acceptable salt or a mixture thereof; a formulation thereof and a process for the preparation thereof are described, for example, in WO2002/222598, WO2003/087095, WO2005/046589, WO2006/127926, WO2006/124413, WO2007/064719, WO2009/115562 and These cases are incorporated herein by reference in their entirety in WO 2012/001074.

The compounds of the invention may be administered in free form or as a pharmaceutically acceptable salt.

As used herein, "pharmaceutically acceptable salts" include inorganic base salts, organic base salts, mineral acid salts, organic acid salts or basic or acidic amino acid salts. As the inorganic base salt, the present invention includes, for example, an alkali metal salt such as sodium or potassium; an alkaline earth metal salt such as calcium and magnesium or aluminum; and an ammonia salt. As the organic base salt, the present invention includes, for example, a trimethylamine salt, a triethylamine salt, a pyridinium salt, a methylpyridine salt, an ethanolamine salt, a diethanolamine salt, and a triethanolamine salt. As the inorganic acid salt, the present invention includes, for example, a salt of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. As the organic acid salt, the present invention includes, for example, formate, acetate, trifluoroacetate, fumarate, oxalate, tartrate, maleate, lactate, citrate, succinate , malate, methanesulfonate, besylate and p-toluenesulfonate. As the basic amino acid salt, the present invention includes, for example, arginine, anisoamine, and aguanine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

The monolactates of the compounds of formula I exist in various polymorphic forms including, for example, monohydrate forms and anhydrous forms. Polymorphs are produced if the same composition of matter (including its monohydrates and solvates) is crystallized in a different crystal lattice to produce different thermodynamic and physical properties characteristic of a particular crystalline form.

Other pharmaceutically acceptable salts suitable for the compounds A and B of the present invention include the salts disclosed in WO2005/04658.

Unless otherwise stated or expressly indicated herein, reference is made to the therapeutic agents useful in the pharmaceutical compositions of the invention, including the free base of the compound and all pharmaceutically acceptable salts of the compound.

The structure of such compounds identified by number, generic or trade name may be from the current version of the standard "The Merck Index" or from, for example, Patents International (eg IMS World Publications) Wait for the database to get. The corresponding content is hereby incorporated by reference.

In each case where the citation of the patent application is given herein, the subject matter related to the compound is incorporated herein by reference. Compounds useful as therapeutic agents in the pharmaceutical compositions of the present invention can be prepared and administered as described in the cited documents, respectively. Also included are the pharmaceutically acceptable salts, corresponding racemic isomers, diastereomeric isomers, enantiomers, tautomers, and corresponding crystal modifications of the compounds disclosed above disclosed therein. Body, if present, for example, solvates, hydrates, and polymorphs. Combinations of two separate therapeutic agents as described above are also within the scope of the invention, i.e., a pharmaceutical combination within the scope of the invention may include three or more therapeutic agents.

According to the present invention, it is preferred that the combined mate system (a) is selected from the group consisting of RTK inhibitor compounds consisting of 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl) -1H-benzimidazol-2-yl]quinoline-2(1H)-one (Compound A) and (4-Amino-5-fluoro-3-[6-(4-methylhexahydropyrazine) -1-yl)-1H-benzimidazol-2-yl]quinoline-2(1H)-one) (Compound B), or a pharmaceutically acceptable salt thereof, and (b)(3β)-17- (pyridin-3-yl)androst-5,16-dien-3-ol or its medicine Acceptable salt. Preferably, the compounds are administered in a therapeutically effective amount which, when combined, provides a beneficial effect. The vote can be simultaneous or sequential.

In one embodiment, the proliferative disorder is cancer. The term "cancer" as used herein refers to a broad spectrum of tumors, including all solid tumors and hematological malignancies. Examples of such tumors include, but are not limited to, benign or malignant tumors: brain and central nervous system, lung (specifically small cell lung cancer and non-small cell lung cancer), bladder, prostate, stomach, pancreas, breast, head And neck, kidney (renal, kidney), ureter, ovary, prostate, colorectal, esophagus, testicular, gynecology (for example, ovary, uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer or vulva), thyroid , pancreas, bone, skin, melanoma, rectum, anus, colon, testicular, Hodgkin's disease, small intestine, endocrine system (eg, thyroid, parathyroid or adrenal gland), soft tissue and osteosarcoma, urethra , penis, leukemia, lymphoma, multiple myeloma, gallbladder, liver, neurofibromatosis, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and Kaposi's sarcoma.

According to still another aspect, the present invention provides a synergistic combination for administration to humans comprising (a) an RTK inhibitor compound selected from the group consisting of 4-amino-5-fluoro-3-[5-( 4-methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2(1H)-one (Compound A) and (4-Amino-5-fluoro-3- [6-(4-Methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2(1H)-one) (Compound B) or a pharmaceutically acceptable salt thereof And (b) (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol or a pharmaceutically acceptable salt thereof, wherein the dose range of each component corresponds to The synergistic range observed in a suitable tumor model (e.g., the tumor model described in the Examples below) is primarily used to identify synergistic interactions.

One object of the present invention is to provide a pharmaceutical composition comprising an amount effective in combination therapy for proliferative diseases comprising a combination of the invention. In this composition, the combination partners (a) and (b) can be administered in a single formulation or unit dosage form by any suitable route, but administered separately, or sequentially. The unit dosage form can also be a fixed combination.

Pharmaceutical compositions comprising the combination of the two, or a combination comprising a combination of the invention, for administration in a fixed combination (i.e., a single galenical composition) may be prepared in a manner known per se and are Suitable for enteral (eg, oral or rectal) and parenteral administration to a mammal, including a human, a warm-blooded animal, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone (eg, as above) Indicated) or a combination of the partner and one or more pharmaceutically acceptable carriers which are particularly suitable for enteral or parenteral administration.

The novel pharmaceutical compositions may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of the therapeutic agent.

Suitable pharmaceutical compositions for combination therapy by enteral or parenteral administration are, for example, those in unit dosage form, such as sugar-coated lozenges, lozenges, capsules or suppositories or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulation, sugar coating, dissolving, lyophilization processes or those skilled in the art. Production technology preparation. It will be appreciated that the unit content of the combination partner contained within individual dosages of each dosage form need not constitute an effective amount per se, since the necessary effective amount can be achieved by administering a plurality of dosage units.

The unit dosage form containing the individual agent or combination of agents may be in the form of a micro-tablet enclosed in a capsule, such as a gelatin capsule. For this purpose, gelatin capsules for use in pharmaceutical formulations, such as hard gelatin capsules known as CAPSUGEL (available from Pfizer) can be used. The unit dosage form of the invention may optionally comprise other conventional carriers or excipients for use in medicine. Examples of such carriers include, but are not limited to, disintegrants, binders, lubricants, slip agents, stabilizers and fillers, diluents, colorants, flavoring agents, and preservatives. One or more of the above carriers can be selected by a person skilled in the art by routine experimentation with respect to the particular desired properties of the dosage form without any excessive effort. The amount of each carrier used can vary within the range of practice in the art. The following references, which are hereby incorporated by reference, disclose the entire disclosure of the disclosure of the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of See The Handbook of Pharmaceutical Excipients , 4th edition, edited by Rowe et al., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro ed., Lippincott Williams & Wilkins (2003).

One or more conventional carriers may be included in the initial mixture prior to or during granulation or by combining one or more conventional carriers in an oral dosage form with granules of individual agents comprising a combination of agents or agents. Other optional carriers are included in the oral dosage form. In the latter embodiment, the combined mixture may be further blended, for example, via a V-shaped blender, and then compressed or molded into a tablet (eg, a tablet), encapsulated by a capsule, or Fill into the sachet.

Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starch; clay; cellulose; alginates; gums; crosslinked polymers such as crosslinked polyvinylpyrrolidone; crosslinked carboxymethyl fibers Cross-linked sodium carboxymethylcellulose or croscarmellose sodium, such as ACDI-SOL from FMC; and croscarmellose calcium; soybean polysaccharide; and guar gum. The disintegrant can be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1% to about 5% by weight of the composition.

Examples of pharmaceutically acceptable binding agents include, but are not limited to, starch; cellulose and its derivatives, such as microcrystalline cellulose (eg, AVICEL PH from FMC (Philadelphia, PA)), hydroxypropyl cellulose, Hydroxyethyl cellulose and hydroxypropyl methylcellulose METHOCEL from Dow Chemical Company (Midland, MI); sucrose; dextrose; corn syrup; polysaccharide; and gelatin. The binding agent can be present in an amount from about 0% to about 50% by weight (e.g., from 2 to 20% by weight) of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable slip agents include, but are not limited to, colloidal cerium oxide, magnesium tristearate, starch, talc, calcium phosphate, magnesium stearate, aluminum stearate , calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The lubricant may be present in an amount from about 0% to about 10% by weight of the composition. in. In one embodiment, the lubricant can be present in an amount from about 0.1% to about 1.5% by weight of the composition. The slip agent can be present in an amount from about 0.1% to about 10% by weight.

Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, powdered sugar, compressible sugars, glucan binding agents, dextrin, dextrose, lactose, mannitol, microcrystals Cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent may be present, for example, in an amount from about 0% to about 80% by weight of the composition.

In one embodiment, the invention is also directed to a combination of the invention for the manufacture of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disorder in an individual in need thereof.

In a further embodiment, the invention relates to the use of a combination of an RTK inhibitor compound selected from the group consisting of at least one antiestrogenic, in particular fulvestrant, or a pharmaceutically acceptable salt thereof: 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl)-1H-benzoimidazol-2-yl]quinoline-2(1H)-one (compound) A) and (4-Amino-5-fluoro-3-[6-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazol-2-yl]quinoline-2 (1H) a ketone) (Compound B) or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disorder in an individual in need thereof.

In accordance with the present invention, a therapeutically effective amount of each of the combination partners of the combinations of the invention can be administered simultaneously or sequentially and in any order, and the components can be administered separately or in a fixed combination. For example, a method of treating a proliferative disorder of the invention can comprise a therapeutically effective amount, preferably in a synergistically effective amount (eg, in a daily or intermittent dose corresponding to the amounts described herein), either simultaneously or in any order. (i) administration of the first agent (a) and (ii) in the form of a free form or a pharmaceutically acceptable salt (b) in the form of a free form or a pharmaceutically acceptable salt. The individual combination partners of the combinations of the invention may be administered separately at different times during the course of the therapy or simultaneously in a divided or single combination. In addition, the term "administering" also encompasses the use of a combination partner's prodrug, which is converted in vivo to the original combination partner. Therefore, the present invention should be understood to cover all such simultaneous or alternating treatments and the term "administration" should be understood accordingly.

The effective dosage of each combination partner for use in the combination of the invention will vary depending upon the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Thus, the dosage regimen of the combination of the invention should be selected based on a variety of factors, including the route of administration and the kidney and liver function of the patient. A clinician or physician with general skill can readily determine the effective amount of a single therapeutic agent needed to slow, counter or prevent the progression of the condition and prescribe.

The optimal ratios, individual and combined doses and concentrations of the combination partners (a) and (b) of the present invention to produce efficacy and non-toxicity are based on the kinetics of the availability of the therapeutic agent to the target site, and are used It is determined by methods known to those skilled in the art.

Each individual can empirically determine the optimal dosage of each combination partner for the treatment of a proliferative disease using known methods, and it will depend on a variety of factors including, but not limited to, the extent of disease progression; the age, weight, and overall of the individual. Health status, gender and diet; time and route of administration; and other medications the individual is taking. The optimal dosage can be determined using routine testing and procedures well known in the art.

The amount of each combination partner that can be combined with the carrier material to produce a single dosage form will vary depending on the individual being treated and the particular mode of administration. In some embodiments, a unit dosage form containing a combination of agents described herein will contain each of the agents typically administered in the amounts administered when the agent is administered separately.

The dosage frequency can vary depending on the compound employed and the particular condition being treated or prevented. In general, it is preferred to use a minimum dose sufficient to provide an effective therapy. The patient's therapeutic effectiveness can generally be monitored using an assay suitable for treating or preventing the condition, and such analysis should be familiar to those skilled in the art.

The invention further provides a commercially available package comprising a combination of the invention as a therapeutic agent and instructions for its simultaneous, separate or sequential use for delaying the progression or treatment of a proliferative disorder in an individual in need thereof.

The following examples illustrate the invention described above; however, it is not intended to be either The scope of the invention is limited. The beneficial effects of the pharmaceutical compositions of the present invention can also be determined by other test models known to those skilled in the art.

Example 1

Preclinical studies using human prostate cancer xenografts support the hypothesis that FGF signaling contributes to the evolution of AR-independent anti-castration disease. MDA PCa 118b is a metastatic prostate cancer xenograft obtained from advanced anti-castration patients. Molecular pathology analysis revealed that MDA PCa 118b cells did not exhibit AR but overexpressed high FGF9 levels. MDA PCa 118b cells induce proliferation of co-cultured osteoblasts in vitro and induce strong osteogenic responses in the FGF9-dependent manner in the bone of immunodeficient mice. MRI analysis of MDA PCa 118b orthotopic bone tumors 5 weeks after cell injection confirmed that mice treated with FGF9 neutralizing antibody produced tumors significantly smaller than the control. These clinical data of concern suggest the use of TKI258 to test FGF inhibition in human mCRPC patients.

The ongoing TKI258 clinical study includes patients with anti-castrated prostate cancer and bone metastases (mCPRC) with the goal of assessing bFGF signaling markers in bone marrow biopsy samples. The patient received 500 mg orally every day for 5 days, followed by a 2-day rest period. The reaction was evaluated every 28 days and every 56 days (8 weeks). The patient continues to take TKI258 until the disease worsens, the toxicity is unacceptable, or the consent is withdrawn. To date, 17 of the 40 patients have been registered. The median age was 68 years, all patients had bone metastases, 41% had lymph node and/or visceral metastases, and 82% had pre-accepted at least one cytotoxic chemotherapy regimen. The median follow-up was 63 days and the median PFS had not been reached. The most common treatment-related toxicity is 1/2, including fatigue (37%), nausea (50%), and diarrhea (50%). Grade 3 toxicity is rare, including fatigue (12%) and difficulty breathing (12%). There is no grade 4 toxicity to date. At the 8-week time point, 9/17 (52%) patients showed stable disease, 2/17 (10%) showed PR in the lymph nodes, and 2/17 (10%) discontinued the study due to radiographic deterioration, 3/17 ( 18% of patients discontinued the study due to clinical deterioration and 1/17 (6%) withdrew. So far, 4 out of 17 patients (25%) have experienced 4 months of long-term response and 3 active treatment. Preliminary molecular pathology analysis of bone marrow biopsy for tumor infiltration revealed TKI258-induced down-regulation of FGFR1 and its downstream target phospho-MAPK.

Based on these promising preliminary results, the following clinical hypothesis was explored: TI258 will improve the anti-tumor activity of abiraterone by inhibiting the AR-independent signaling pathway FGF that contributes to abiraterone resistance.

Main target/end point

In this study, the safety and clinical efficacy of the combination of TKI258 and abiraterone in human metastatic anti-castration prostate cancer will be determined. Primary endpoint:

1) To evaluate the tolerability and safety of the combination of TKI258 and abiraterone in this patient group.

2) Non-deteriorating survival (PFS) is the primary endpoint. PFS will be a composite endpoint defined as the time from entry into the study to the first occurrence of any of the following:

‧ The deterioration of the disease can be measured by the RECIST guidelines. In order to be considered measurable, baseline lymph nodes, visceral metastases, and soft tissue metastases must be the longest dimension 2cm. Suspected RECIST deterioration must be confirmed by tracking scans after >6 weeks.

• Two or more new regions attributable to prostate cancer (rather than redness) or new/increased size of soluble lesions as determined by CT scan or MRI as determined by bone scan. Suspicious deterioration of bone scans must be performed by other imaging modalities (eg, CT or MRI) and/or A confirmatory bone scan was performed 6 weeks later to confirm.

‧ need to involve more than one part of palliative radiation

‧Surgical or kyphoplasty for any tumorous bone lesion

‧ Cancer-related clinical deterioration, as determined by the treating physician.

PSA deterioration will not be used alone to define the deterioration.

3) Collecting and pooling blood and tissue samples for future hypothesis Research.

Secondary goal/end point

1) Overall survival

2) Radioactive reaction

3) Biomarker regulation (eg PSA, CTC, serum interleukin distribution, bone-specific alkaline phosphatase, urinary n-terminal peptide)

4) Tumor pharmacodynamic measurement (molecular pathology analysis of FGF and androgen-receptor (AR) signaling pathways using metastatic tissue samples).

Research design:

Prior to the Phase II study, a dose escalation Phase I protocol will be used to obtain safety data and select the optimal starting dose for the combination of TKI258 and Abiraterone.

As shown below, groups of 3 to 6 patients will be treated with TKI258 and abiraterone using a 28-day cycle. The starting dose of TKI258 (grade 0) will be 200 mg per day, of which 5 days will be taken, 2 days will be discontinued, and the dose of abiraterone will be 1000 mg per day. Presson will be administered twice daily with 5mg oral.

The dose escalation criteria as described in Table 1 must be met at each dose level during Cycle 1 to register and treat the patient at the next dosing level.

Using the 3+3 design, the first group consisting of 3 patients will be treated with dose level 0. The algorithm is as follows: (1) If all 3 patients have not experienced DLT, the next group consisting of 3 patients will be treated with the following higher dose level. (2) If one of the 3 patients develops DLT, the other 3 patients will be treated at the same dose level. If DLT no longer occurs at this dose, ie A DLT occurred in 1 of a total of 6 patients, and a group consisting of 3 patients continued to increase in dose. (3) At any given dose, if more than one of the three patients or more than one of the six patients experience DLT, the dose level exceeds the MTD, and if less than 6 patients are treated at that dose, The other 3 patients will be treated with the following lower dose. One of the 6 patients with MTD was the highest studied dose of DLT.

At each given dose level, there will be a one-week gap to assess the toxicity between the inclusion of the first patient and the inclusion of the next two patients.

Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD):

In order for the DLT to meet the requirements, clinical adverse events (AEs) or laboratory abnormalities should be associated with the drug, as evaluated by the treating physician, primary investigator, or sponsor. The DLT will be defined during the first treatment cycle (according to the NCI-CTCAE v 4 grading scale). Any drug-related grade 3 or 4 toxicity that occurs during the first cycle (excluding nausea, vomiting, or diarrhea controlled by standard therapy) is considered dose-limiting toxicity (DLT), which does not include secondary mineralocorticoids. Expected toxicity associated with excess syndrome (including hypertension, hypokalemia, and fluid excess). Toxicity associated with elevated mineralocorticoid concentrations will be controlled using a mineralocorticoid receptor antagonist (eplerenone 50 to 200 mg/d). If mineralocorticoid antagonism does not reverse these toxicities, ACTH is only inhibited by treatment with 0.5 mg dexamethasone daily.

After selecting the optimal starting dose for TKI258 and Abiraterone, the Phase II study will begin. Approximately 40 patients will receive study treatment until one of the following criteria is met:

‧ Disease worsens

‧ toxicity is unacceptable

‧The patient decided to quit

‧ palliative radiation involving more than one part

‧ According to the investigator's judgment, further treatment will not be in the best interests of the patient.

Number of patients and number of centers:

Total number of patients: 60

Number of patients in the treatment group: NA

Number of centers: MDACC

group:

Inclusion criteria

1) The patient or his or her legally authorized representative must provide written informed consent.

2) Age 18

3) ECOG performance status 2

4) Histological evidence of prostate adenocarcinoma

5) Metastatic anti-castration prostate cancer

6) The patient must have surgery or ongoing chemical castration (using an LHRH agonist or LHRH antagonist) with a baseline ketone concentration <50 ng/dL.

7) The patient must have evidence of a documented degenerative disease, as defined by any of the following:

‧PSA deterioration: get at least 2 ascents (3 measurements) with a minimum of 7 days, with the final result being at least 2.0ng/mL

‧New or increased non-bone disease (RECIST)

‧ Positive bone scan with 2 or more new lesions (PCWG2). Patients must have evidence of metastatic prostate cancer (ie, soft tissue, viscera, lymph nodes) as determined by bone scan and/or CT/MRI. If the only evidence of lymph node, visceral and/or soft tissue metastasis is transferred, then at least one lesion must have a diameter 2cm.

8) The following pre-treatment laboratory data within 14 days prior to enrollment: absolute neutrophil count (ANC) 1,500/ml

Platelet 100,000/ml

Total bilirubin Normal upper limit, except for isolated hyperbilirubinemia due to Gilbert's syndrome

SGPT, (ALT) and / or SGOT (AST) 1.5 x ULN. (If the patient has liver metastases, then 2.5×ULN)

9) Patient's creatinine clearance rate 30 ml/min, obtained using the Cockroft-Gault formula.

10) Men whose spouse is a fertile woman must be willing to agree to use effective contraception at the time of treatment and at least 3 months after treatment.

11) Patients may have received prior treatment with androgen ablation therapy (eg bicalutamide, ketoconazole, DES) and/or "targeted" therapy (eg tyrosine kinase inhibitor), but must be treated initially Pre-treatment drugs The therapy was stopped with a 5 x half-life.

12) Patients may have received up to 2 cytotoxic chemotherapy regimens for the treatment of metastatic anti-castration disease. At least one option must contain docetaxel.

Exclusion criteria

1) Histopathological evidence of small cell prostate cancer in patients

2) Pre-treatment with TKI258 or Abitron

3) Radiation therapy (including palliative radiotherapy for metastatic lesions) or major surgery within 28 days (eg, abdomen, pelvis, chest, orthopedics or nerves) within 14 days of the date of the first study drug administration Open surgery).

4) There is 钐-153 within 28 days after registration, or 锶-89 within 12 weeks (336 days) after registration. Patients who have received 2 or more doses of osteoporotic radioisotopes are unqualified.

5) Currently undergoing treatment for another therapeutic clinical trial

6) Imminent bone metastasis complications (fracture and/or umbilical cord compression). Allow proper treatment or stable fracture and/or umbilical cord compression.

7) There is an ongoing urinary tract obstruction requiring medical intervention (eg, urinary retention, renal edema). Urinary tract obstruction that allows proper treatment.

8) The patient has an uncontrolled disease (eg, uncontrolled diabetes, uncontrolled hypertension).

9) The patient has another serious medical or psychiatric disorder that, depending on the investigator, may potentially interfere with the patient's ability to provide informed consent or interfere with the completion of treatment according to the protocol.

10) The patient has a second active malignant disease, which according to the investigator may potentially interfere with the patient's ability to participate in and/or complete the trial.

Minimum/maximum age:

18 years old

Study duration:

The patient will receive study treatment until one of the following criteria is met:

‧ Disease worsens

‧ toxicity is unacceptable

‧The patient decided to quit

‧ palliative radiation involving more than one part

‧ According to the investigator's judgment, further treatment will not be in the best interests of the patient.

Based on my previous experience with patients

Research milestone date

Must enter the month and year

FCCV, LPFV and CSR dates required for NCC study code allocation

Research Beginning (FPFV): August 2012

End of Recruitment (LPFV): September 2014

End of Study (LPLV): March 2015

Completion of Clinical Research Report (CSR): preliminary summary data will be presented in January 2014

Open date: December 2015

The basis of the sample size:

This is an evaluation of the I/II laboratory trial of the combination of TKI258 and abiraterone for the safety and efficacy of patients with metastatic anti-castration prostate cancer. The main result is no deterioration Current (PFS). Based on a historical average PFS of 4 months, an average survival time of >6 months can be considered promising evidence of anti-disease activity. The planned sample size is approximately 60 patients (to complete Phase I and Phase II trials) and is expected to increase the rate of 3 patients per month. Based on historical experience gained with carefully selected candidates (based on evidence of participation in bone scans), it is expected that approximately 60% of patients will be positive for biopsy. Does not use the early stop rule according to the probability of PSA reaction, because it is not known whether the combination inhibition of the interstitial-epithelial interaction pathway will lead to a decrease in PSA (in contrast, the primary targeting of the epithelial compartment with abiraterone may result in The predicted PSA is reduced). Therefore, it may be the case that the PSA has not decreased but the PFS has been extended. Given the short PFS of these patients and the expected rate of increase for three patients per month, it is not feasible to implement an early stop rule in accordance with the observed PFS time. Thall and Sung methods (1998) will be used to monitor toxicity based on a historical ratio of 20% Grade 3 or Grade 4 toxicity of standard therapy. Unadjusted PFS time will be estimated using the Kaplan and Meier method (1958) and the effects of the following three potential prognostic covariates using logistic regression: FGF as determined by 4-week bone marrow biopsy Inhibition of AR signaling, bone markers (a) urinary NTX and (b) regulation of bone-specific alkaline phosphatase and FGF and AR signaling on FGF R-1, FGF R-3, FGF 9, AR and CYP17 Baseline mark.

Based on a historical ratio of 20% grade 3 or grade 4 toxicity of standard therapy, it will be assumed that p=Prob (level 3 or grade 4) follows the beta prior parameter (0.20, 0.80). Using the Thall and Suung methods, based on the observed toxicity data, if Pr (p > 0.20 | data) > 0.95, the increase in the test will be stopped early, this rule is applied after a continuous group of size 5. If [number of patients with grade 3 or 4 toxicity] / [number of patients evaluated] is greater than or equal to 3/5, 5/10, 7/15, 8/20, 9/25, 11/30, 12/35, then This rule indicates that the test is stopped.

Safety guidelines:

All patients who had received any dose of TKI258 were able to assess safety.

Clinically significant adverse events (including laboratory adverse events) that the investigator considers will be based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (4th edition) are graded and summarized.

Claims (8)

A pharmaceutical combination comprising: (a) an RTK inhibitor compound comprising a compound of formula II or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof, wherein the compound of formula II has the formula: and R ⁷ is a substituted or unsubstituted heterocyclic group: And (b) at least one CYP17 inhibitor or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential administration. A pharmaceutical combination comprising: (a) a compound of the formula III or a tautomer thereof, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer or a mixture thereof, wherein the formula III The compound has the formula: And (b) at least one CYP17 inhibitor or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential administration. The pharmaceutical combination of claim 2, wherein the RTK inhibitor is selected from the group consisting of 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazole- 2-yl]quinolin-2(1H)-one or a pharmaceutically acceptable salt thereof and (4-amino-5-fluoro-3-[6-(4-methylhexahydropyrazin-1-yl) -1H-benzimidazol-2-yl]quinolin-2(1H)-one) or a pharmaceutically acceptable salt thereof. The pharmaceutical combination according to claim 3, wherein the at least one CYP17 inhibitor is selected from the group consisting of (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (Abitron), 1 -(2-chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidine-2-one, ketoconazole, VN/124-1 (TOK- 001) and its pharmaceutically acceptable salts. A pharmaceutical combination comprising: 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazol-2-yl]quinoline-2 (1H)-ketone or a pharmaceutically acceptable salt thereof and (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (Abitron) or its medicinal Accept the salt. The pharmaceutical combination of claim 5 for use in the preparation of a medicament for the treatment of prostate cancer. One selected from the group consisting of 4-amino-5-fluoro-3-[5-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazol-2-yl]quinoline-2(1H)- Ketone and (4-amino-5-fluoro-3-[6-(4-methylhexahydropyrazin-1-yl)-1H-benzimidazol-2-yl]quinoline-2(1H)- The use of a ketone) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of prostate cancer, wherein The patient of the disease is administered the combination of the agent and at least one CYP17 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially. The use of claim 7, wherein the at least one CYP17 inhibitor is selected from the group consisting of (3β)-17-(pyridin-3-yl)androst-5,16-dien-3-ol (Abitron), 1- (2-Chloro-pyridin-4-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one, ketoconazole and VN/124-1 (TOK-001) Acceptable salt.