JP2012097032A - Concomitant medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a concomitant medicine which is useful for preventing or treating cancer, and also has excellent efficacy.SOLUTION: The medicine for preventing or treating cancer is obtained by combining 6-ethyl-N-[1-(hydroxyacetyl)piperidine-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroetoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide or its salt with rapamycin or its derivative or its salt.

Description

  The present invention relates to 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2, 2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof and rapamycin or a derivative or a salt thereof in combination to prevent cancer Alternatively, the present invention relates to a medicament for treatment and a method for preventing or treating cancer using such a combination medicament.

[Background of the invention]
Patent Document 1 (WO2009 / 107850) has 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] as a compound having Hedgehog signal transduction system inhibitory activity and useful for the prevention or treatment of cancer. -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2- c] Pyridine-2-carboxamide is described.

Rapamycin (CAS Registry Number 53123-88-9; also called Sirolimusu) is a macrolide antibiotic produced by Streptomyces hygroscopics. Patent Document 2 (WO02 / 066019) describes that rapamycin or a derivative thereof is useful for treatment of solid tumors. Patent Document 3 (WO2007 / 059106) includes mTOR inhibitors such as rapamycin, AP23573 (also referred to as Deforolimus), CC1779 (also referred to as Temsirolimus), RAD001 (also referred to as Everolimus), and the like. A method of treating cancer has been described.
Non-Patent Document 1 (GASTROENTEROLOGY, 2009, 137, 1102-1113) shows that treatment with a combination of cyclopamine or CUR199691, which is an Hedgehog signaling inhibitor, rapamycin, and gemcitabine is performed in vitro and in vivo. In both cases, pancreatic cancer stem cells were removed.

International Publication No. 2009/107850 International Publication No. 02/0666019 International Publication No. 2007/059106

GASTROENTEROLOGY, 2009, 137, 1102-1113

  Development of a medicine that is useful for the prevention and treatment of cancer and has an excellent medicinal effect is desired.

  We have prepared 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- ( 2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide and rapamycin have been found to have excellent antitumor activity, Intense research has been conducted and the present invention has been completed.

That is, the present invention
[1] 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2 , 2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof and rapamycin or a derivative or a salt thereof in combination to prevent cancer or Medicine to treat;
[2] 6-Ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2 , 2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof and a therapeutically effective amount of rapamycin or a derivative thereof or a salt thereof. A method for preventing or treating cancer in a mammal, which comprises administering to the mammal;
Etc.

  6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2- When trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof and rapamycin or a derivative or a salt thereof are used alone Compared with, it is possible to obtain excellent effects such as improvement or prevention of cancer and reduction of side effects.

Detailed Description of the Invention
In the present specification, “6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- ( 2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof and rapamycin or a derivative or a salt thereof in combination The "medicament for preventing or treating" may be referred to as "the medicament of the present invention".
In the present specification, “6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- ( 2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof may be referred to as “compound (A)”.
In the present specification, “6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- ( 2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide ”may be referred to as“ compound (Aa) ”.
In the present specification, “rapamycin or a derivative thereof or a salt thereof” may be referred to as “compound (B)”.

In the present specification, “metal salt” means, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; and aluminum salt.
In this specification, “organic base” means, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. It means a salt with ethylenediamine or the like.
In the present specification, “inorganic acid” means, for example, a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
In the present specification, “organic acid” means, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene It means a salt with sulfonic acid, p-toluenesulfonic acid and the like.
In the present specification, “basic amino acid” means, for example, a salt with arginine, lysine, ornithine and the like.
In the present specification, “acidic amino acid” means, for example, a salt with aspartic acid, glutamic acid or the like.
In the present specification, the “pharmaceutically acceptable salt” means, for example, an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt ( Examples include inorganic salts such as calcium salts and magnesium salts, and ammonium salts. When the compound has a basic functional group, for example, inorganic substances such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid Means a salt with an acid or a salt with an organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid To do.

In the present specification, the term “prodrug” refers to a compound (ie, enzymatically) that is converted into an active substance (eg, compound (A), compound (B)) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo. A compound that undergoes oxidation, reduction, hydrolysis, etc. to change into an active substance, or a compound that undergoes hydrolysis or the like by gastric acid or the like to become an active substance.
Specific examples of prodrugs include compounds in which the amino acid in the active substance is acylated, alkylated, or phosphorylated (for example, the amino acid in the active substance is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2- Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound); active body hydroxy is acylated, alkyl Activated, phosphorylated, borated compounds (eg, compounds in which the active substance hydroxy is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated); active Compounds in which the carboxy of the main body is esterified or amidated (for example, Carboxy of active body is ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2 -Oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound); and the like.
Such prodrug compounds can be produced from the active substance by a method known per se.
In addition, the prodrug may be a substance that changes into an active substance under physiological conditions as described in Hirokawa Shoten 1990 "Pharmaceutical Development", Volume 7, Molecular Design, pages 163 to 198.

  In this specification, examples of the salt in the compound (A) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic amino acids, and acidic amino acids. And the like. Of these, pharmaceutically acceptable salts are preferred.

  Compound (A) can be produced by a method known per se according to the description in WO2009 / 107850.

Examples of the derivative of rapamycin in the compound (B) include derivatives such as Everolimus (CAS registration number 159351-69-6) described in WO94 / 09010, Temsirolimus (Temsirolimus) described in WO95 / 28406 ( Derivatives such as CAS registry number 162635-04-3), derivatives such as Deforolimus described in US 7,091,213 (CAS registry number 572924-54-0), derivatives described in WO95 / 16691, WO96 / 41807 And the derivatives described in the above.
Rapamycin and its derivatives can be produced by a method known per se. For example, rapamycin can be prepared according to US 3,929,992, everolimus according to WO 94/09010, temsirolimus according to WO 95/28406, and deforolimus according to US 7,091,213.

  Examples of the salt in the compound (B) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic amino acids, salts with acidic amino acids, and the like. It is done. Of these, pharmaceutically acceptable salts are preferred.

  In one embodiment, compound (B) is preferably rapamycin, everolimus, temsirolimus, deforolimus or a salt thereof.

The compound (A) and the compound (B) may be crystals, and may be a single crystal form or a crystal form mixture.
Compound (A) and compound (B) may also be co-crystals.
Compound (A) and compound (B) may also be hydrated, non-hydrated, solvated or non-solvated.
Compound (A) and compound (B) may also be labeled with an isotope (eg, ² H, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I).
Compound (A) and compound (B) may also be prodrugs.
When the compound (A) and the compound (B) have an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., even if it is any one isomer, It may be a mixture.

The medicament of the present invention is used for cancer (eg, colon cancer (eg, colon cancer, rectal cancer, anal cancer) in mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human). , Familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, Pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, esophageal cancer, gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (eg, invasive ductal carcinoma) , Noninvasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low grade tumor), testicular tumor, prostate cancer (eg, Hormone-dependent prostate cancer, hormone-independent prostate cancer), liver cancer (eg, hepatocellular carcinoma, primary liver cancer, bile duct cancer) Extrahepatic bile duct cancer), thyroid cancer (eg, medullary thyroid cancer), kidney cancer (eg, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), uterine cancer (eg, cervical cancer, endometrial cancer, Uterine sarcoma), brain tumors (eg, medulloblastoma, glioma, pineal astrocytoma, ciliary astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary fibroma) Retinoblastoma, skin cancer (eg, basal cell tumor, malignant melanoma), sarcoma (eg, rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma), malignant bone tumor, bladder cancer, blood cancer (eg, multiple occurrences) It is used as a pharmaceutical agent such as a growth inhibitor of cancerous myeloma, leukemia, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disease), cancer of unknown primary), a cancer metastasis suppressor, an apoptosis promoter.
In particular, the medicament of the present invention is effective for brain tumor, skin cancer, lung cancer, pancreatic cancer, liver cancer, prostate cancer, esophageal cancer, gastric cancer, colon cancer, sarcoma and breast cancer, among which glioma, medulloblast It is effective for cell tumor, basal cell tumor, small cell lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, gastric cancer, colon cancer, rhabdomyosarcoma and breast cancer.

The administration form of the medicament of the present invention is not particularly limited, and it may be administered so that the compound (A) and the compound (B) coexist in vivo.
Such dosage forms include, for example,
(1) Administration of a single preparation obtained by simultaneously compounding compound (A) and compound (B);
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating compound (A) and compound (B);
(3) Administration of two types of preparations obtained by separately formulating compound (A) and compound (B) with a time difference in the same administration route (for example, compound (A), then compound (B ) In the order of) or vice versa);
(4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating compound (A) and compound (B);
(5) Administration of two types of preparations obtained by separately formulating compound (A) and compound (B) at different administration routes (for example, compound (A) and then compound (B) Administration in the order of) or administration in the reverse order).

The medicament of the present invention can be administered orally or parenterally with compound (A) and compound (B) as they are or in combination with a pharmacologically acceptable carrier.
Examples of dosage forms for oral administration of compound (A) and compound (B) include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (soft capsules, microcapsules) Syrup, emulsion, suspension and the like.
Examples of the dosage form when the compound (A) and the compound (B) are administered parenterally include injections, infusions, drops, suppositories and the like.
In addition, the compound (A) and the compound (B) may be converted into a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, butyric acid polymer and glycolic acid polymer). It is also effective to prepare a sustained-release preparation in combination with a mixture with polyglycerol fatty acid ester).

  As a method for producing the pharmaceutical of the present invention into the above-mentioned dosage form, a known production method generally used in the art can be applied. In addition, when manufacturing into the above-mentioned dosage forms, excipients, binders, disintegrants, lubricants, sweeteners, interfaces usually used in the pharmaceutical field when manufacturing into the dosage forms, if necessary. An appropriate amount of additives such as an activator, a suspending agent, and an emulsifier can be appropriately contained.

For example, the compound (A) and the compound (B)
(1) When manufactured as a tablet, the compound (A) and / or compound (B) can be manufactured by containing an excipient, a binder, a disintegrant, a lubricant and the like;
(2) When manufactured as a pill and a granule, the compound (A) and / or compound (B) can be manufactured by containing an excipient, a binder, a disintegrant, and the like;
(3) When manufactured as a powder and capsule, the compound (A) and / or compound (B) can be manufactured by containing an excipient or the like;
(4) When produced as a syrup, the compound (A) and / or compound (B) can be produced by adding a sweetener or the like;
(5) In the case of producing an emulsion or suspension, the compound (A) and / or compound (B) can be produced by adding a surfactant, suspending agent, emulsifier and the like.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
Examples of the binder include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
Examples of disintegrants include starch and calcium carbonate.
Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
Examples of emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.

  Furthermore, when producing the medicament of the present invention into the above-mentioned dosage form, an appropriate amount of a colorant, a preservative, a fragrance, a corrigent, a stabilizer, a thickener, etc., which are usually used in the pharmaceutical field, if necessary. Can be added.

  In addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous infusions, and the like are included as injections, and sustained-release preparations include iontophoretic transdermal agents and the like.

  Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying Compound (A) and / or Compound (B) in a sterile aqueous or oily liquid. Aqueous solutions for injection include isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride) containing physiological saline, glucose and other adjuvants, and suitable solubilizers such as alcohol (Eg, ethanol), polyalcohol (eg, propylene glycol, polyethylene glycol), nonionic surfactant (eg, polysorbate 80, HCO-50) and the like may be used in combination. Examples of the oily liquid include sesame oil and soybean oil. As a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride), stabilizers (eg, human serum albumin, polyethylene glycol), preservatives (eg, , Benzyl alcohol, phenol) and the like. The prepared injection solution is usually filled in an ampoule.

The compounding ratio of the compound (A) and the compound (B) in the medicament of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound (A) in the medicament of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 99.99% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. %, More preferably about 0.5 to 20% by weight.
The content of compound (B) in the medicament of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 99.99% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to 20% by weight.
The content of the additive in the medicament of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
Moreover, the same content may be sufficient also when formulating a compound (A) and a compound (B) separately, respectively.

  The medicament of the present invention can be safely used with stable and low toxicity. The daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc. For example, in the case of oral administration to a patient for the purpose of cancer treatment, the daily dose for an adult (body weight approximately 60 kg) Is usually about 1 to about 1000 mg, preferably about 3 to about 300 mg, more preferably about 10 to about 200 mg as compound (A) and compound (B), respectively, and these are used once or 2 to 3 Can be administered in divided doses.

  When the pharmaceutical of the present invention is administered parenterally, it is usually administered in the form of a liquid (eg, injection). The single dose varies depending on the administration subject, target organ, symptom, administration method, and the like. For example, in the case of an injection, each of the compound (A) and the compound (B) is usually about 0 per kg of body weight. 0.01 to about 100 mg, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg can be administered by intravenous injection.

The combination of compound (A) and compound (B) may be used in combination with other drugs.
Such other drugs include hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or agents that inhibit the action of cell growth factors and their receptors.
Or you may combine a compound (A) and multiple types of compound (B).

  Examples of the `` hormone therapeutic agent '' include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, Raloxifene, olmeroxifene, levormeroxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, buserelin acetate) , Leuprorelin), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydrochloride, anastrozole, letrozo) , Exemestane, borozole, formestane), antiandrogens (eg, flutamide, bicalutamide, nilutamide), 5α-reductase inhibitors (eg, finasteride, epristeride), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone) ), Androgen synthesis inhibitors (eg, abiraterone), drugs that retard the metabolism of retinoids and retinoids (eg, riarosol), thyroid hormones, their DDS (Drug Delivery System) preparations, and the like.

  Examples of the “chemotherapeutic agent” include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.

  Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Prednimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide, Roh statins scan chima Lamar, adozelesin, cystemustine, Bizereshin, DDS preparations thereof, and the like are used.

  Examples of the “antimetabolite” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emiteful, capecitabine), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbpyramide, pendant Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and their D S formulation, or the like is used.

  Examples of the “anticancer antibiotic” include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations.

  As the “plant-derived anticancer agent”, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and their DDS preparations are used.

  Examples of the “immunotherapy agent (BRM)” include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacteria Umparbum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody and the like are used.

The “cell growth factor” in the “drug that inhibits the action of the cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less. Peptides include factors that exert their effects at low concentrations by binding to receptors. Specifically,
(1) EGF (epidermal growth factor) or a substance having substantially the same activity [eg, TGFα], (2) insulin or a substance having substantially the same activity [eg, insulin, IGF (insulin- like growth factor) -1, IGF-2], (3) FGF (fibroblast growth factor) or a substance having substantially the same activity as it [eg, acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF -10], (4) Other cell growth factors (eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor) ), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiopoietin] It is.

  The “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor. Specifically, EGF receptor, heregulin receptor (eg, HER3 ), Insulin receptor inhibitor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (eg, Tie2), PDGF receptor, c -MET, c-Kit, Trk, etc. are used.

  “Agents that inhibit the action of cell growth factors and their receptors” include EGF inhibitors, TGFα inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Body, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibition Agents, PKC inhibitors, Trk inhibitors, Ret inhibitors, mTOR inhibitors, MEK (MEK1 / 2) inhibitors, MET inhibitors, Akt inhibitors, ERK inhibitors and the like are used. More specifically, anti-VEGF antibody (eg, Bevacizumab), anti-HER2 antibody (eg, Trastuzumab, Pertuzumab), anti-EGFR antibody (eg, Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-VEGFR antibody, Imatinib mesylate, Erlotinib , Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4- (4-Fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (1-pyrrolidinyl) propoxy] quinazoline (AZD-2171), Lestaurtinib, Pazopanib, Canertinib, Tandutinib, 3- (4-Bromo-2,6-difluorobenzyloxy) -5- [3- [4- (1-pyrrolidinyl) butyl] ureido] isothiazole- 4-carboxamide (CP-547632), Axitinib, N- (3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2- (pyridin-4-ylmethylamino) pyridine-3- Carboxamide (AMG-706), Nilotinib, 6- [4- (4-Ethylpiperazin-1-ylmethyl) phenyl] -N- [1 (R)- Phenylethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (AEE-788), Vandetanib, Enzastaurin, N- [4- [4- (4-methylpiperazin-1-yl) -6- (3-Methyl-1H-pyrazol-5-ylamino) pyrimidin-2-ylsulfanyl] phenyl] cyclopropanecarboxamide (VX-680), phosphate 2- [N- [3- [4- [5- [N- (3-Fluorophenyl) carbamoylmethyl] -1H-pyrazol-3-ylamino] quinazolin-7-yloxy] propyl] -N-ethylamino] ethyl ester (AZD-1152), 4- [9-chloro-7- ( 2,6-difluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ylamino] benzoic acid (MLN-8054), N- [2-methoxy-5-[(E) -2 -(2,4,6-Trimethoxyphenyl) vinylsulfonylmethyl] phenyl] glycine sodium salt (ON-1910Na), 4- [8-cyclopentyl-7 (R) -ethyl-5-methyl-6-oxo-5 , 6,7,8-Tetrahydropteridin-2-ylamino] -3-methoxy -N- (1-methylpiperidin-4-yl) benzamide (BI-2536), 5- (4-bromo-2-chlorophenylamino) -4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxam Acid 2-hydroxyethyl ester (AZD-6244), N- [2 (R), 3-dihydroxypropoxy] -3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901 ) Etc. are used.

In addition to the above drugs, cell cycle inhibitors (eg, Aurora A inhibitor, Aurora B inhibitor, PLK inhibitor, CDK inhibitor), apoptosis inducers (eg, Bcl-2 inhibitor, IAP inhibitor, Nedd -8 inhibitor) Proteasome inhibitor (eg, bortezomib), hedgehog signal inhibitor (eg, Vismodegib, LDE225, IPI-926), Wnt signal inhibitor (eg, β-catenin / TCF inhibitor, anti-Wnt antibody) , Notch signal inhibitor (eg, anti-Notch antibody, γ-secretase inhibitor), L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin-cobalt complex, mercury hematoporphyrin sodium, topoisomerase I inhibitor (eg, irinotecan, topotecan) ), Topoisomerase II inhibitors (eg, sobuzoxane), differentiation Inducing agents (eg, retinoids, vitamin Ds), other angiogenesis inhibitors (eg, fumagillin, shark extract, COX-2 inhibitor), α-blockers (eg, tamsulosin hydrochloride), bisphosphonic acids (eg, pamidronate) Zoledronate), thalidomide, 5-azacytidine, decitabine, anti-tumor antibodies such as anti-CD20 antibody, toxin-labeled antibodies, and the like can also be used.

  The invention is further illustrated by the following examples, which are not intended to limit the invention and may be varied without departing from the scope of the invention.

Example 1
6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2- Evaluation of the combined antitumor effect of trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide (“Compound (Aa)”) and rapamycin -04 (under laboratory animal central laboratory) nude mouse subcutaneous transplant model.

(Test compound)
Compound (Aa) was synthesized according to Example 143 of WO2009 / 107850.
Rapamycin was obtained from LKB Laboratories (St. Paul, MN, USA).

(Combination antitumor test of test compounds)
A PAN-04 tumor mass (about 8 mm ³ ) was transplanted subcutaneously into an 8-week-old female nude mouse with a trocar, and the tumor was grown subcutaneously in the mouse. When the tumor size reached 126 to 236 mm ³ , the mice were divided into (1) Vehicle administration group (n = 5), (2) Compound (Aa) administration group (25 mg / kg, PO, QD, n = 5 ), (3) Rapamycin administration group (1 mg / kg, IP, QD, n = 5), and (4) Compound (Aa) (25 mg / kg, PO, QD) and rapamycin (1 mg / kg, IP , QD) was grouped into the combined administration group (n = 5). As vehicle, 0.5% methylcellulose was used for compound (Aa), 0.5% PEG400, 5% Tween 80 was used for rapamycin, and both of these vehicles were administered to the vehicle administration group. Administration was carried out once a day for 15 days, and the tumor size and body weight were measured before administration and on days 2, 6, 9, 12, and 15 of administration. The significant difference test was performed by 1-tailed Dunnett's test between the vehicle and each test compound administration group, and a case where p ≦ 0.025 was determined to be a significant difference. In addition, a Student's t-test was performed between the combination administration group and the single administration group, and a case where p ≦ 0.05 was determined as a significant difference. Antitumor activity is T / C = ((tumor size at the end of administration in the compound administration group) − (tumor size at the start of administration in the compound administration group)) / ((tumor size at the end of administration in the control group) − (Tumor size at the start of administration in the control group)) × 100.
When compound (Aa) and rapamycin were each administered alone, significant antitumor activity was observed (T / C = 53% and 27%, respectively). When the compound (Aa) and rapamycin were used in combination, stronger antitumor activity (T / C = 9%) was observed than each single agent. The antitumor activity at the time of combined use was significantly improved as compared with either the compound (Aa) alone or the antitumor activity of rapamycin alone.
These results indicate that the antitumor activity when the compound (Aa) is combined with rapamycin is superior to the antitumor activity of each single agent.

  According to the present invention, by combining the compound (A) and the compound (B), superior effects such as prevention of cancer or improvement of therapeutic effect and reduction of side effects are obtained as compared with the case where each is used alone. Obtainable. Therefore, the combination of the compound (A) and the compound (B) can be used as a new combined drug for cancer prevention or treatment methods.

Claims (2)

  6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2- To prevent or treat cancer comprising a combination of (trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof and rapamycin or a derivative or a salt thereof. Medicines.   6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2- Trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide or a salt thereof and a therapeutically effective amount of rapamycin or a derivative or salt thereof to a mammal A method for preventing or treating cancer in the mammal, which comprises administering the method.