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WO2011040212A1 - Agent thérapeutique pour une tumeur cérébrale - Google Patents

Agent thérapeutique pour une tumeur cérébrale Download PDF

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Publication number
WO2011040212A1
WO2011040212A1 PCT/JP2010/065674 JP2010065674W WO2011040212A1 WO 2011040212 A1 WO2011040212 A1 WO 2011040212A1 JP 2010065674 W JP2010065674 W JP 2010065674W WO 2011040212 A1 WO2011040212 A1 WO 2011040212A1
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WIPO (PCT)
Prior art keywords
carcinoma
salt
ethyl
amino
pyrrolo
Prior art date
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Ceased
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PCT/JP2010/065674
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English (en)
Inventor
Yoshikazu Ohta
Toshiya Tamura
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Filing date
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Publication of WO2011040212A1 publication Critical patent/WO2011040212A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to an agent for the prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue, comprising N- ⁇ 2- [4- ( ⁇ 3-chloro- 4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3,2- d] pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof.
  • WO2005/118588 discloses that a compound represented by the formula:
  • A is an optionally substituted aryl group or an optionally substituted heteroaryl group
  • X 1 is -NR 3 -Y-, -0-, -S-, -SO-, -S0 2 - or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to a carbon atom or a hetero atom on the aryl group or the
  • heteroaryl group represented by A to form an optionally substituted ring structure
  • Y 1 is a single bond or an optionally substituted C1-4 alkylene or an optionally substituted -0-(Ci_ 4 alkylene)-,
  • R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom
  • R 2 is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or
  • R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, provided that the ompounds represented by the formulas
  • WO2008/044782 discloses a combination drug using such fused pyrimidine compound.
  • WO2008/156153 discloses a combination drug using such fused pyrimidine compound.
  • an agent for the prophylaxis or treatment of trastuzumab-resistant cancer comprising such fused pyrimidine compound.
  • WO2009/113560 discloses that a compound represented by the formula:
  • ring A is an optionally substituted benzene ring
  • ring B is an optionally substituted benzoisothiazole ring
  • R 1 is a hydrogen atom, a halogen atom, or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom;
  • R 2 is a hydrogen atom, or an optionally substituted group bonded via a carbon atom or a sulfur atom
  • R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group
  • R 1 and R 2 , or R 2 and R 3 are optionally bonded to each other to form an optionally substituted ring structure; or
  • R 3 is optionally bonded to the carbon atom on ring A to form an optionally substituted ring structure
  • the present invention aims to provide an agent for the prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue.
  • N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) henoxy] henyl ⁇ amino) -5H-pyrrolo [3, 2- d]pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof is useful as an agent for the prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue.
  • metastatic tumor has spread from breast carcinoma
  • metastatic tumor has spread from breast carcinoma and is trastuzumab-resistant;
  • [4] a method for the prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue in a mammal, which comprises administering, to said mammal, an effective amount of N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] henyl ⁇ amino) -5H-pyrrolo [3,2- d] yrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof;
  • a pharmaceutical agent comprising N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3, 2- d]pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof, or N-[2-(4- ⁇ [4- (1, 2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3, 2-d]pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof is useful for the
  • prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue are prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue.
  • Fig, 1 shows changes in the amount of luminescence of each mouse due to intracerebral tumor growth of HER2 high expressing human breast carcinoma cell line, wherein the vertical axis shows the amount of luminescence of each mouse, and the horizontal axis shows the number of days after cell inoculation.
  • Fig. 2 (A) and (B) show changes in the amount of luminescence of each mouse due to intracerebral tumor growth of trastuzumab-resistant HER2 high expressing human breast carcinoma cell line, wherein the vertical axis shows the amount of luminescence of each mouse, and the horizontal axis shows the number of days after cell inoculation.
  • Fig.2 (C) shows the amount of luminescence of control group and compound A group due to intracerebral tumor growth of trastuzumab-resistant HER2 high expressing human breast carcinoma cell line at day 22 and day 29 after cell
  • Fig. 3 (A) shows a prophylactic effect of compound A on the brain metastasis of BTBR3 cell line, wherein the ' vertical axis shows brain metastasis-free survival (%) , and the horizontal axis shows the number of days after inoculation (Kaplan-Meier curve) .
  • Fig.3 (B) shows an IVIS image, wherein the upper figure shows one example of the control group, the lower figure shows one example of the compound A administration group, and the upper and lower figures show representative examples of each group.
  • the agent of the present invention comprises N- ⁇ 2-[4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] henyl ⁇ amino) -5H- pyrrolo [3, 2-d] pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3- methylbutanamide or a salt thereof or a prodrug thereof, or N- [2- (4- ⁇ [4- (1, 2-benzoisothiazol-4-yloxy) -3-chlorophenyl] amino ⁇ - 5H-pyrrolo [3, 2-d] pyrimidin-5-yl) ethyl] -2-methylalaninamide or a salt thereof or a prodrug (hereinafter sometimes to be
  • the compound of the present invention referred to as the compound of the present invention.
  • the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like.
  • salts with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine,
  • salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • salts with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • salts for example, inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt etc.), calcium salts (e.g., magnesium salt, calcium salt, magnesium salt etc.), alkaline earth metal salts (e.g., magnesium salt, magnesium salt etc.), magnesium salts (e.g., magnesium salt, magnesium salt etc.), magnesium salts, magnesium salts, magnesium salts, magnesium salts, magnesium salts, magnesium salts, magnesium salts, magnesium salt etc.
  • alkali metal salts e.g., sodium salt, potassium salt etc.
  • alkaline earth metal salts e.g., calcium salt, calcium salt, calcium salt etc.
  • salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like
  • salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,
  • N- ⁇ 2-[4- ( ⁇ 3-chloro-4-[3- (trifluoromethyl) phenoxy] henyl ⁇ amino) -5H-pyrrolo [3,2- d]pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof can be produced according the method . described in
  • N- [2- (4- ⁇ [4- (1, 2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3,2-d]pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof can be produced according to the following Example 1.
  • N- ⁇ 2-[4- ( ⁇ 3-chloro-4-[3- (trifluoromethyl) phenoxy] henyl ⁇ amino) -5H-pyrrolo [3,2- d]pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof, or N- [2- (4- ⁇ [4- (1, 2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3, 2-d]pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof may be a crystal, and both a single crystal and crystal mixtures are encompassed in the compound of the present invention. Such crystal can be
  • N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3,2- d]pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof, or N- [2- (4- ⁇ [4- (l,2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3, 2-d]pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound of the present invention.
  • a compound labeled with an isotope e.g., 3 H, n C, 14 C, 18 F,
  • a prodrug of N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3,2- d] pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof, or N- [2- (4- ⁇ [4- (1, 2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3, 2-d] pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof means a compound which is converted to N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3,2- d] pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt
  • a prodrug for N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl)phenoxy]phenyl ⁇ amino) -5H-pyrrolo [3,2- d] pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof, or N- [2- (4- ⁇ [4- (1, 2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3,2-d]pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof includes a compound obtained by subjecting an amino group in N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3, 2- d]pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a
  • alkylation or phosphorylation e.g., a compound obtained by subjecting an amino group in N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3, 2- d]pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof, or N- [2- (4- ⁇ [4- (1, 2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3, 2-d]pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-l, 3- dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrroli
  • a prodrug for N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3,2- d] yrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt thereof, or N- [2- (4- ⁇ [4 ⁇ (1, 2-benzoisothiazol-4-yloxy) -3- chlorophenyl] amino ⁇ -5H-pyrrolo [3, 2-d]pyrimidin-5-yl) ethyl] -2- methylalaninamide or a salt thereof may also be one which is converted into N- ⁇ 2- [4- ( ⁇ 3-chloro-4- [3- (trifluoromethyl) phenoxy] phenyl ⁇ amino) -5H-pyrrolo [3,2- d] pyrimidin-5-yl] ethyl ⁇ -3-hydroxy-3-methylbutanamide or a salt
  • the compound of the present invention possesses tyrosine kinase-inhibiting activity and can be used for the prophylaxis or treatment of tyrosine kinase-dependent diseases in mammals.
  • Tyrosine kinase-dependent diseases include diseases characterized by increased cell proliferation due to abnormal tyrosine kinase enzyme activity.
  • the compound of the present invention specifically inhibits HER2 kinase and/or EGFR kinase and is therefore also useful as a therapeutic agent for suppressing the growth of HER2 and/or EGFR kinase- expressing cancer, or a preventive agent for preventing the transition of hormone-dependent cancer to hormone-independent cancer.
  • the compound of the present invention is useful as a pharmaceutical agent because it shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like) , high water solubility, and is superior in stability, pharmacokinetics (absorption,
  • the compound of the present invention possesses prophylactic or therapeutic effects against metastatic tumor that has spread to the brain from other tissue, and can be used for the prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like) .
  • the metastatic tumor (or brain tumor) in the present specification includes any tumors observed inside the cranium or in the central spinal canal.
  • metastatic tumor that has spread to the brain from other tissue includes metastatic tumors which have spread from various carcinomas in other tissue than the brain
  • breast carcinoma e.g., invasive ductal
  • carcinoma ductal carcinoma in situ, inflammatory breast carcinoma etc.
  • prostate carcinoma e.g., hormone-dependent prostate carcinoma, non-hormone dependent prostate carcinoma etc.
  • pancreatic carcinoma e.g., pancreatic duct carcinoma etc.
  • gastric carcinoma e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma etc.
  • lung carcinoma e.g., non-small cell lung carcinoma, small cell lung carcinoma, malignant mesothelioma etc.
  • colon carcinoma e.g., gastrointestinal stromal tumor etc.
  • rectal carcinoma e.g., gastrointestinal stromal tumor etc.
  • colorectal carcinoma e.g., familial colorectal carcinoma, hereditary nonpolyposis colorectal carcinoma, gastrointestinal stromal tumor etc.
  • small intestinal carcinoma e.g., non-Hodgkin lymphoma, gastrointestinal stromal tumor, etc.
  • oropharyngeal carcinoma hypopharyngeal carcinoma etc.
  • salivary gland carcinoma neurinoma
  • liver carcinoma e.g., primary liver carcinoma, extrahepatic bile duct carcinoma etc.
  • kidney carcinoma e.g., renal cell carcinoma
  • transitional cell carcinomas of renal pelvis and ureter etc. carcinoma of the bile duct, endometrial carcinoma, carcinoma of the uterine cervix, ovarian carcinoma (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor etc.), urinary bladder carcinoma, urethral carcinoma, skin carcinoma (e.g., ocular melanoma, Merkel cell carcinoma etc.),
  • hemangioma hemangioma, malignant lymphoma, malignant melanoma, thyroid carcinoma (e.g., medullary thyroid carcinoma etc.),
  • parathyroid carcinoma nasal cavity carcinoma, paranasal sinus carcinoma, bone tumors (e.g., osteosarcoma, Ewing' s tumor, uterus sarcoma, soft tissue sarcoma etc.), vascular fibroma, retinoblastoma, penile carcinoma, testis tumor, solid tumors (e.g., osteosarcoma, Ewing' s tumor, uterus sarcoma, soft tissue sarcoma etc.), vascular fibroma, retinoblastoma, penile carcinoma, testis tumor, solid
  • carcinoma in childhood e.g., Wilms' tumor, childhood kidney tumor, etc.
  • Kaposi's sarcoma Kaposi's sarcoma derived from AIDS
  • maxillary tumor fibrous histiocytoma
  • leiomyosarcoma rhabdomyosarcoma and the like
  • brain tumor that has spread from any of the above-mentioned various HER2/EGFR- positive carcinomas .
  • other tissue in the present specification means a tissue other than brain, and is exemplified by a tissue in which the above-mentioned various carcinomas are observed.
  • the other tissue includes, for example, breast, prostate, pancreas, lung, colon, kidney, skin, lymph tissue and bone marrow. Among all, breast is preferred.
  • the "metastatic tumor that has spread to the brain from other tissue” may be any of trastuzumab-resistant and
  • trastuzumab-non-resistant and is preferably trastuzumab- resistant.
  • agent of the present invention the agent which contains the compound of present invention is referred to as the "agent of the present invention”.
  • the agent of the present invention is particularly useful for the prophylaxis or treatment of brain tumor (said "brain tumor” has the same meaning as the metastatic tumor that has spread to the brain) that has spread from breast carcinoma, prostate carcinoma, pancreatic carcinoma, gastric carcinoma, lung carcinoma, colon carcinoma, colorectal carcinoma, kidney carcinoma and the like, and especially useful for the
  • the "brain tumor that has spread from breast carcinoma” includes trastuzumab-resistant brain tumor and trastuzumab-non-resistant brain tumor.
  • the agent of the present invention is useful for the prophylaxis or treatment of brain tumor that has spread from breast carcinoma and is trastuzumab-resistant.
  • proliferatives in the present specification also includes suppression or prevention of metastasis to the brain of a tumor in other tissue.
  • the agent of the present invention is also useful as an inhibitor of the metastasis of various carcinomas mentioned above to the brain.
  • the compound of the present invention can be used as a pharmaceutical agent as it is, or as a pharmaceutical
  • composition in admixture with a commonly known pharmaceutically acceptable carrier etc. in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like) .
  • mammals e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like.
  • the agent of the present invention may contain other active ingredients, e.g., the following hormonal therapeutic agents, anticancer agent (e.g., chemotherapeutic agents,
  • immunotherapeutic agents or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors, and the like.
  • the agent of the present invention can be administered orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules) , powders, granules and the like, or by a parenteral administration route in the form of injections, suppositories, pellets and the like.
  • parenteral administration route include intravenous,
  • the dose of the agent of the present invention varies depending on the route of administration, symptoms, etc.
  • its dose in terms of the compound of the present invention is, for example, 0.5 to 100 mg/kg body weight per day, preferably 1 to 50 mg/kg body weight per day, and more preferably 1 to 25 mg/kg body weight per day. This amount may be administered once or in 2 to 3 divided portions daily.
  • the compound of the present invention can be safely- administered to the mammals orally or parenterally (e.g., topical, rectal, intravenous administrations etc. ) as a single agent, or as a pharmaceutical composition containing a
  • Japanese Pharmacopoeia etc. such as tablet (including sugar- coated tablet, film-coated tablet) , powder, granule, capsule, liquid, emulsion, suspension, injection, suppository,
  • sustained release preparation plaster and the like.
  • a combination of (1) administering an effective amount of the agent of the present invention and (2) 1 to 3 selected from the group consisting of (i) administering an effective amount of other anticancer agents, (ii) administering an effective amount of hormonal therapeutic agents and (iii) non-drug therapy, can prevent and/or treat metastatic tumor that has spread to the brain from other tissue more effectively.
  • non-drug therapy for example, surgery, radiotherapy, gene therapy, thermotherapy, cryotherapy, laser cauterization, and the like are exemplified and two or more of these may be combined.
  • the agent of the present invention can be administered to the same subject simultaneously with hormonal therapeutic agents, anticancer agents (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors) (hereafter, these are referred to as a concomitant drug) .
  • hormonal therapeutic agents e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors
  • anticancer agents e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors
  • levormeloxifene e.g., levormeloxifene, anti-estrogens (e.g., tamoxifen citrate, toremifene citrate, and the like), ER down regulator (e.g., fulvestrant, and the like) , human menopausal gonadotrophin, follicle stimulating hormone, pill preparations, mepitiostane, testrolactone, aminoglutethimide, LH-RH agonists (e.g.,
  • aromatase inhibitors e.g., fadrozole hydrochloride, anastrozole, retrozole, exemestane, vorozole, formestane, and the like
  • anti-androgens e.g., flutamide, bicartamide
  • 5oc-reductase inhibitors e.g., finasteride, dutasteride, epristeride, and the like
  • finasteride e.g., finasteride, dutasteride, epristeride, and the like
  • adrenocorticohormone drugs e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, and the like
  • adrenocorticohormone drugs e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, and the like
  • androgen e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, and the like
  • synthesis inhibitors e.g., abiraterone, and the like
  • retinoid and drugs that retard retinoid metabolism e.g., liarozole, and the like
  • LH-RH agonists e.g., LH-RH agonists
  • goserelin acetate, buserelin, leuprorelin or its acetate are preferable.
  • alkylating agents examples include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.
  • alkylating agents there may be mentioned nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa,
  • antimetabolites there may be mentioned mercaptopurine, 6-mercaptopurine riboside, thioinosine,
  • methotrexate methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur, and the like) , aminopterine, leucovorin calcium, tabloid, butocine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide,
  • 5-FU drugs e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur, and the like
  • aminopterine e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, e
  • pentostatin pentostatin, piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine, and the like.
  • anticancer antibiotics there may be mentioned actinomycin-D, actinomycin-C, mitomycin-C,
  • hydrochloride epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin
  • plant-derived anticancer agents there may be mentioned etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and the like.
  • immunotherapeutic agents there may be mentioned picibanil, krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, and the like.
  • cell growth factors or cell growth factor receptors there may be mentioned any substances that promote cell proliferation, which are normally peptides having a molecular weight of not more than 20,000 that are capable of exhibiting their activity at low concentrations by binding to a receptor, including (1) EGF (epidermal growth factor) or
  • EGF EGF, heregulin (HER2 ligand) , and the like
  • insulin or substances possessing substantially the same activity as it e.g., insulin, IGF (insulin-like growth factor)-!, IGF-2, and the like
  • FGF fibroblast growth factor
  • other cell growth factors e.g., CSF (colony stimulating factor) , EPO (erythropoietin) , IL-2 (interleukin-2) , NGF (nerve growth factor) , PDGF (platelet-derived growth
  • TGFp transforming growth factor ⁇
  • HGF hepatocyte growth factor
  • VEGF vascular endothelial growth factor
  • HER2 heregulin receptor
  • IGF receptor insulin receptor
  • FGF receptor-1 FGF receptor-1 or FGF receptor-2, and the like.
  • trastuzumab Herceptin (trade mark) : HER2 antibody
  • imatinib mesilate ZD1839 or cetuximab
  • antibody to VEGF e.g.
  • bevacizumab antibody to VEGF receptor
  • gefitinib gefitinib
  • erlotinib erlotinib
  • L-asparaginase aceglatone
  • procarbazine hydrochloride protoporphyrin-cobalt complex salt
  • mercuric hematoporphyrin-sodium topoisomerase I inhibitors (e.g., irinotecan, topotecan, and the like)
  • topoisomerase II inhibitors e.g., sobuzoxane, and the like
  • differentiation inducers e.g., retinoid, vitamin D, and the like
  • angiogenesis inhibitors e.g., thalidomide, SU11248, and the like
  • ⁇ -blockers e.g., tamsulosin hydrochloride, naftopidil, urapidil, alfuzosin, terazosin, prazosin,
  • silodosin and the like
  • serine/threonine kinase inhibitor e.g., atrasentan, and the like
  • proteasome inhibitor e.g., bortezomib, and the like
  • Hsp 90 inhibitor e.g., 17-AAG, and the like
  • spironolactone minoxidil, lla-hydroxyprogesterone, bone resorption
  • inhibiting/metastasis suppressing agent e.g., zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid
  • zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid e.g., zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid
  • LH-RH agonist e.g., goserelin acetate, buserelin, leuprorelin or its acetate, and the like
  • trastuzumab HER2 antibody
  • the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention and the concomitant drug can be administered to the administration subject simultaneously, or may be administered at different times.
  • the dosage of the concomitant drug may be determined according to the administration amount clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • administration mode of the compound of the present invention and the concomitant drug is not particularly restricted, and it is sufficient that the compound of the present invention and the concomitant drug are combined in administration.
  • administration mode include the following methods:
  • concomitant drug are simultaneously produced to give a single preparation which is administered.
  • the compound of the present invention and the concomitant drug are separately produced to give two kinds of preparations which are
  • the compound of the present invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by the same administration route only at the different times.
  • the compound of the present invention and the concomitant drug are separately produced to give two kinds of preparations which are administered simultaneously by different administration routes.
  • the compound of the present invention and the concomitant drug are separately produced to give two kinds of preparations which are
  • Compound A was produced according to the method
  • a luciferase expression vector was constructed by
  • a cell line established by stable transfection of the above-mentioned luciferase expression vector into human breast carcinoma cell line BT-474 (ATCC (American Type Culture
  • BT-474/Luc the established cell line is hereinafter referred to as BT-474/Luc
  • BT-47 /Luc cell was treated with trypsin and suspended in
  • RPMI-1640 medium comprising 10% bovine fetus serum (Gibcolnvitrogen) .
  • mice BALB/cAJcl-nu/nu, female, 5-week-old mice were purchased from CLEA Japan, Inc. After 1 week of
  • the above-mentioned cell suspension for transplantation was injected into the brain (2 mm outwardly right from Bregma in brain, depth 3 mm) of 6- week-old mouse at a concentration of 2.5 x 10 s cells/5 pL/mouse.
  • estradiol propionate (0VAH0RM0N DEPOT 5 mg ASKA Pharmaceutical Co., Ltd.) was intramuscularly injected into the right hind leg at a dose of 50 ⁇ ,.
  • estradiol propionate was intramuscularly injected similarly into the left hind leg at a dose of 50 ⁇ ..
  • the index of intracerebral tumor growth the amount of luminescence of BT-474/Luc cell due to
  • luciferin (Wako chemical Co., # 126-05116) was prepared with PBS to 15 mg/mL and
  • methylcellulose solution (Shin-Etsu Chemical Co., Ltd., SM- 100) , and each suspension was orally administered to mice at 10 mL/kg.
  • the control group was orally administered with the same amount of 0.5% aqueous methylcellulose solution.
  • the medication was given twice a day (in the morning and in the afternoon) at administration intervals of 7 hours or longer by consecutive administration until the death was confirmed.
  • the amount of luminescence which is an index of tumor growth, was measure at least once a week using aforementioned method. The results are shown in Fig. 1.
  • compound A and compound B show an intracerebral tumor growth suppressive effect against HER2 high expressing BT-474 breast carcinoma cell.
  • the aforementioned luciferase expression vector was introduced into trastuzumab low sensitive/resistant BT-474 cells described in WO2008/156153 by using FuGENE ® 6
  • BT-474TR/Luc cell a cell line stably harboring the luciferase gene (hereinafter to be referred to as BT-474TR/Luc cell) , and the cell line was used for the following test.
  • trastuzumab-resistant breast carcinoma cell intracerebral transplantation model was investigated using the BT-474TR/Luc cell and in the same manner as in the method described in
  • Example 1 Changes in the amount of luminescence of luciferin relative to the number of days elapsed after BT-474TR/Luc cell transplantation is shown in Fig. 2.
  • BT-474/Luc cell suspended in HBSS (Cambrex Bio Science Walkersville, 10-527F) was filtered (BD FalconTM, Cell strainer, 352350), and prepared with HBSS to 1 x 10 7 cells/mL. Under anesthesia, the above-mentioned cell suspension was injected to the left ventricle of nude mouse (CLEA Japan, Inc., Jcl:
  • luciferin prepared to 15 mg/mL. Several weeks after the reaction
  • BTBR3 cell BTBR3 cells prepared with HBSS to 1*10 6 cells/100 ⁇ were transplanted into the left ventricle of nude mouse 5 hr after the administration of the below-mentioned drug.
  • compound A prepared to 20 mg/ml with 0.5% aqueous methylcellulose solution was orally administered to the nude mouse at a liquid amount of 10 mL/kg.
  • the control group was given the 0.5%
  • methylcellulose vehicle solution methylcellulose vehicle solution.
  • the administration was performed twice a day in the morning and afternoon at the intervals of 7 hr or longer for 15 cycles with once cycle being 5 day drug administration and 2 day cessation of the drug.
  • the intracerebral growth of BTBR3 cells was measured in the same manner as in the above-mentioned Example 1. Changes in the amount of luminescence of luciferin relative to the number of days elapsed after BTBR3 cell transplantation is shown in Fig. 3.
  • an agent for the prophylaxis or treatment of metastatic brain tumor comprising N- ⁇ 2-[4- ( ⁇ 3-chloro-4-[3-

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  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un agent destiné à la prophylaxie ou au traitement d'une tumeur métastasée qui s'est propagée vers le cerveau à partir d'un autre tissu, contenant du N-{2-[4-({3-chloro-4-[3-(trifluorométhyl)-phénoxy]phényl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]éthyl}-3-hydroxy-3-méthylbutanamide ou l'un de ses sels.
PCT/JP2010/065674 2009-10-01 2010-09-06 Agent thérapeutique pour une tumeur cérébrale Ceased WO2011040212A1 (fr)

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US61/247,671 2009-10-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473616A (zh) * 2016-11-23 2018-08-31 株式会社Lg化学 改性共轭二烯类聚合物及其制备方法

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Publication number Priority date Publication date Assignee Title
WO2005118588A1 (fr) 2004-06-02 2005-12-15 Takeda Pharmaceutical Company Limited Composé heterocyclique fusionné
WO2008044782A2 (fr) 2006-10-06 2008-04-17 Takeda Pharmaceutical Company Limited Médicament combiné
US20080214584A1 (en) * 2006-12-28 2008-09-04 Takeda Pharmaceutical Company Limited Method for treating cancer
WO2008156153A1 (fr) 2007-06-19 2008-12-24 Takeda Pharmaceutical Company Limited Médicament préventif/remède contre le cancer
WO2009113560A1 (fr) 2008-03-12 2009-09-17 武田薬品工業株式会社 Composé hétérocyclique fusionné

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Publication number Priority date Publication date Assignee Title
WO2005118588A1 (fr) 2004-06-02 2005-12-15 Takeda Pharmaceutical Company Limited Composé heterocyclique fusionné
WO2008044782A2 (fr) 2006-10-06 2008-04-17 Takeda Pharmaceutical Company Limited Médicament combiné
US20080214584A1 (en) * 2006-12-28 2008-09-04 Takeda Pharmaceutical Company Limited Method for treating cancer
WO2008156153A1 (fr) 2007-06-19 2008-12-24 Takeda Pharmaceutical Company Limited Médicament préventif/remède contre le cancer
WO2009113560A1 (fr) 2008-03-12 2009-09-17 武田薬品工業株式会社 Composé hétérocyclique fusionné

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Title
"Design of Molecules", vol. 7, 1990, HIROKAWA SHOTEN, article "IYAKUHIN no KAIHATSU", pages: 163 - 198
DATABASE WPI Week 200914, Derwent World Patents Index; AN 2009-B09565, XP002610123 *
LASFARGUES EY, IN VITRO, vol. 15, 1979, pages 723 - 729

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473616A (zh) * 2016-11-23 2018-08-31 株式会社Lg化学 改性共轭二烯类聚合物及其制备方法
US10808055B2 (en) 2016-11-23 2020-10-20 Lg Chem, Ltd. Modified conjugated diene-based polymer and method for preparing the same
CN108473616B (zh) * 2016-11-23 2020-10-23 株式会社Lg化学 改性共轭二烯类聚合物及其制备方法

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