WO2016197981A1 - 氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪及其应用 - Google Patents

氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪及其应用 Download PDF

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WO2016197981A1
WO2016197981A1 PCT/CN2016/085480 CN2016085480W WO2016197981A1 WO 2016197981 A1 WO2016197981 A1 WO 2016197981A1 CN 2016085480 W CN2016085480 W CN 2016085480W WO 2016197981 A1 WO2016197981 A1 WO 2016197981A1
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cancer
compound
formula
pharmaceutically acceptable
pharmaceutical composition
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PCT/CN2016/085480
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English (en)
French (fr)
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段文虎
耿美玉
詹正生
艾菁
丁健
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中国科学院上海药物研究所
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/50Pyridazines; Hydrogenated pyridazines
    • A61K31/5025Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to deuterated 3-[(6-quinolinyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1 , 2,4]triazolo[4,3-b]pyridazine, or a crystalline form thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutical combination comprising the compound or a crystalline form thereof or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable salt thereof Use in the preparation of a medicament for the prevention or treatment of a disease mediated by a protein tyrosine kinase, in particular a c-Met kinase signal.
  • Protein tyrosine kinases are a group of enzymes that regulate a variety of important biological functions, including cell growth, differentiation, organ formation, neovascularization, tissue repair, and regeneration. Protein tyrosine kinases exert their biological effects by catalyzing the phosphorylation of protein tyrosine residues and then modulating the biological activity of the substrate proteins. The dysregulation of a class of protein tyrosine kinases may lead to tumor formation and growth, and further play an important role in tumor survival and development (Blume J P, Hunter T. Oncogenic kinase signaling [J]. Nature, 2001, 411 (6835 ): 355-365). Therefore, protein tyrosine kinases, which are closely related to tumors, represent a class of protein targets of the most important cancer treatment and drug development.
  • c-Met is a hepatocyte growth factor receptor (HGFR) encoded by the MET proto-oncogene.
  • HGFR hepatocyte growth factor receptor
  • c-Met has high expression in most cancers and some sarcomas and is closely related to poor prognosis, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, stomach cancer, liver cancer, ovarian cancer, kidney cancer, nerve glue. Tumor, melanoma, etc.
  • c-Met induces cell proliferation, invasion, migration, inhibition of apoptosis, and promotes angiogenesis by interacting with its ligand HGF/SF or by other means to activate intracellular tyrosine kinase, in the process of tumor development. Play an important role.
  • D represents a halogen atom
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom or a halogen atom;
  • R 10 is selected from the group consisting of CH 3 , CH 2 D, CHD 2 , or CD 3 .
  • the cerium isotope content of the cerium at the cerium substitution site is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%.
  • the ground is greater than 95%, more preferably greater than 99%.
  • all elements other than H (such as N, C, F, etc.) in the compound of formula (I) are all or substantially (>99 wt%) being the most abundant naturally occurring element, for example 14 N, 12 C and 19 F.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each a hydrogen atom;
  • R 10 is CH 3 .
  • the compound of formula I is the following compound II.
  • a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier and a compound according to the first aspect of the invention, or a crystalline form thereof, pharmaceutically Acceptable salts, hydrates or solvates are mixed to form a pharmaceutical composition.
  • a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula I according to the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or solvate; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula II, ie 3-[(2-indol-6-quinolinyl)difluoromethyl]-6-[(1-A) (4-pyrazolyl)[1,2,4]triazolo[4,3-b]pyridazine, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • the pharmaceutical composition further comprises a therapeutically effective amount of the other active ingredient, and the other active ingredient comprises one or more active ingredients selected from the group consisting of cytotoxic agents, signal transduction Inhibitors, and other anti-tumor substances.
  • the pharmaceutical composition is for the treatment or prevention of a disease associated with tyrosine kinase activity or expression, preferably a disease associated with the activity or expression level of c-Met.
  • the disease is selected from the group consisting of papilloma, vaginal glioma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer , neck cancer, bladder cancer, breast cancer, colon straight Intestinal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloid, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer , head and neck cancer, thyroid cancer, parathyroid cancer and its distant metastases, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma, non-small cell lung cancer.
  • the pharmaceutical composition is a preparation selected from the group consisting of a tablet, a capsule, a pill, a powder, a granule or an injection; preferably a tablet, a capsule, or an intravenous injection.
  • the pharmaceutical composition when the pharmaceutical composition is a tablet, the pharmaceutical composition comprises a carrier selected from the group consisting of colloidal silica, magnesium stearate, modified starch, and microcrystalline fiber. , lactose, or a combination thereof.
  • the pharmaceutical composition when the pharmaceutical composition is a capsule, the pharmaceutical composition comprises a carrier selected from the group consisting of starch, microcrystalline cellulose, or a combination thereof.
  • the pharmaceutical composition when the pharmaceutical composition is an intravenous injection, the pharmaceutical composition comprises a carrier selected from the group consisting of sterile water for injection.
  • the pharmaceutical composition is a long acting preparation.
  • a compound of formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a therapeutic tyramine Use of a pharmaceutical composition of an acid kinase, especially a c-Met mediated disease.
  • the disease is selected from the group consisting of papilloma, vaginal glioma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer , neck cancer, bladder cancer, breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloid, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, Urethral cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and its distant metastases, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma Non-small cell lung cancer.
  • a compound of formula II 3-[(2-indol-6-quinolinyl)difluoromethyl]-6-[(1-), prepared according to the first aspect of the invention a method of methyl)-4-pyrazolyl][1,2,4]triazolo[4,3-b]pyridazine,
  • the ring closure reaction is carried out in an organic solvent with a compound of the formula (VII) and a compound of the formula (VIII) to give a compound of the formula (II).
  • the ring closure reaction is carried out in the presence of dioxane and methanesulfonic acid.
  • the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
  • reaction is carried out at 60-130 °C.
  • reaction time is 8-16 hours.
  • the compound of formula (VII) is prepared by the following method:
  • the reaction is carried out in the presence of copper powder; preferably, the compound (VI) is condensed with ethyl difluorobromoacetate in the presence of copper powder and then reacted with hydrazine hydrate to give a compound of the formula (VII). .
  • the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
  • reaction is carried out at 60-100 °C.
  • reaction time is 18-30 hours.
  • the compound of formula (VI) is prepared by the following method:
  • the compound of the formula (V) is reacted with an iodinating reagent in an organic solvent to obtain a compound of the formula (VI); preferably, the iodinating agent is sodium iodide, cuprous iodide and N,N-dimethyl Ethylenediamine.
  • the iodinating agent is sodium iodide, cuprous iodide and N,N-dimethyl Ethylenediamine.
  • the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
  • reaction is carried out at 80-140 °C.
  • reaction time is 8-16 hours.
  • the compound of formula (V) is prepared by the following method:
  • a reduction reaction is carried out with a compound of the formula (IV) and a reducing reagent to obtain a compound of the formula (V); preferably, the reducing agent is iron powder; more preferably, the reduction reaction is carried out in glacial acetic acid. Go on.
  • the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
  • reaction is carried out at 80-140 °C.
  • reaction time is from 1 to 5 hours.
  • the compound of formula (IV) is prepared by the following method:
  • the deuteration reaction is carried out with a compound of the formula (III) in an organic solvent to give a compound of the formula (IV); preferably, the deuteration reaction is carried out in the presence of heavy water and/or sodium t-butoxide.
  • the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
  • reaction is carried out at 70-130 °C.
  • reaction time is 8-16 hours.
  • the compound of formula (III) is prepared by the following method:
  • Oxidation with 6-bromoquinoline in an organic solvent gives compound (III); preferably, the oxidation reaction uses m-chloroperoxybenzoic acid as the oxidizing agent.
  • the organic solvent is a solvent selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, acetone, N,N-dimethylmethyl Amide, N,N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
  • reaction is carried out at 10 to 40 °C.
  • reaction time is 8-16 hours.
  • Figure 1 shows the plasma concentration-time curve of cynomolgus monkey after 10 mg/kg of compound II and JNJ38877605, respectively;
  • Figure 2 shows the growth inhibitory effect of compound II and JNJ38877605 on human lung cancer EBC-1 nude mice xenografts.
  • the yttrium isotope content of lanthanum at the yttrium substitution site is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. More preferably greater than 95%, more preferably greater than 99%.
  • the present invention provides a novel class of compounds having c-Met inhibitory activity and better pharmacodynamic properties and uses thereof, namely deuterated 3-[(6-quinolinyl)difluorocarbon represented by formula (I) Methyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[4,3-b]pyridazine, its crystalline form, pharmaceutically acceptable salt , hydrate or solvate:
  • D represents a halogen atom
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom or a halogen atom;
  • R 10 is CH 3 , CH 2 D, CHD 2 , or CD 3 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are each a hydrogen atom
  • R 10 is CH 3
  • the compound is the following compound II:
  • Deuterated 3-[(6-quinolinyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazole [4,3-b]pyridazines can be prepared by methods commonly used in the art for preparing deuterated compounds.
  • the method of preparing said compound II comprises the steps of: from 6- Starting from bromoquinoline, the intermediate (VII) is obtained by oxidation, deuteration, reduction, iodine substitution, coupling and deuteration, followed by ring closure with compound (VIII) to give the desired product.
  • the preparation method includes:
  • Compound (V) is converted to compound (VI) in the presence of sodium iodide, cuprous iodide and N,N-dimethylethylenediamine;
  • compound of the invention refers to a compound of formula (I).
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention which is formed with an acid or a base and which is suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for salt formation include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and horses.
  • Organic acids such as acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • JNJ38877605 is a c-Met inhibitor developed by Johnson & Johnson. On the basis of this, the inventors have significantly superior pharmacokinetic and/or pharmacodynamic properties compared to compound JNJ38877605. It is more suitable as a compound for inhibiting c-Met kinase, and is thus more suitable for the preparation of a medicament for treating cancer and related diseases.
  • the pharmacokinetic results showed that the plasma peak concentration C max and exposure AUC 0-t of compound II in cynomolgus monkeys were 1.56 times and 2.29 times that of JNJ38877605, respectively, at the same dose; human lung cancer EBC-1 naked
  • the pharmacodynamic results of the mouse transplantation model showed that the compound tumor inhibited tumor growth rate (TGI) was 90.4% at a therapeutic dose of 5 mg/kg twice daily for 21 days, which was significantly better than the same dose.
  • JNJ38877605 (83.8% TGI) inhibits tumor growth.
  • the invention provides compounds that modulate a signal transduction pathway mediated by a protein tyrosine kinase, particularly a c-Met kinase.
  • c-Met is an important signaling molecule involved in the regulation of many important cellular processes including cell growth, cell survival and invasion.
  • the HGF/c-Met signaling pathway is present in most tumor cells.
  • Disorders in the c-Met signaling pathway are most prevalent in human cancers.
  • the disorder of the c-Met signal has been confirmed in many solid tumors and hematomas.
  • the strongest evidence linking c-Met and cancer is the overexpression of c-Met in almost all patients with hereditary renal papilloma (PRCC).
  • PRCC hereditary renal papilloma
  • the chromosome 3 trisomy carrying the HGF and c-Met genes is ubiquitous in PRCC patients. It has also been reported that c-Met mutations occur in many cancers, such as gastric cancer, brain tumors, liver cancer, ovarian cancer, non-small cell lung cancer, and thyroid cancer. The potential carcinogenicity of multiple c-Met mutants has been confirmed in preclinical models.
  • the compounds described herein can be used to inhibit their activity.
  • modulate means that the functional activity of the pathway (or a component thereof) is altered as compared to the normal activity in the absence of the compound. This effect includes any number or degree of modulation, including enhancement, stimulation, activation, enhancement, increase, promotion, reduction, reduction, reduction, inhibition, inhibition, antagonism, and the like.
  • the compounds of the invention may also modulate one or more of the following processes, including but not limited to, for example, cell growth (including, for example, differentiation, cell survival and/or proliferation), tumor cell growth (including, for example, differentiation, cell survival, and/or Proliferation), tumor regression, etc.
  • cell growth including, for example, differentiation, cell survival and/or proliferation
  • tumor cell growth including, for example, differentiation, cell survival, and/or Proliferation
  • tumor regression etc.
  • kinase activity refers to a catalytic activity in which a gamma phosphate is transferred from adenosine triphosphate (ATP) to an amino acid residue (eg, serine, threonine or tyrosine) in a protein substrate.
  • ATP adenosine triphosphate
  • amino acid residue eg, serine, threonine or tyrosine
  • a compound can modulate kinase activity, for example by inhibiting its activity by directly ATP binding sites that compete with ATP, affecting its activity by producing a conformational change in the structure of the enzyme (e.g., by disrupting a biologically active three-dimensional structure), and the like.
  • the compounds of the invention may be used to treat and/or prevent any disease or condition involving a protein tyrosine kinase, particularly a c-Met kinase mediated cell signal transduction pathway.
  • treatment is used in its ordinary sense, for example to treat or care for a patient for the purpose of combating, alleviating, reducing, relieving, ameliorating the symptoms of a disease or dysfunction, and the like.
  • the compounds can also be described for the prevention and/or treatment of diseases and/or conditions mediated by the signaling molecules.
  • mediated means, for example, that the signaling molecule is part of a pathway that is abnormal or dysfunctional in the disease and/or condition.
  • Diseases and conditions that can be treated include any of the diseases mentioned above and below, as well as related diseases caused by c-Met abnormalities including, for example, cell proliferation disorders, cancer, tumors and the like.
  • the diseases include papilloma, vaginal glioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer , breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, stomach cancer, hepatocellular carcinoma, white blood Disease, lymphoma, hemangioma, keloid.
  • the methods of the invention comprise modulating tumor cell proliferation, which includes inhibiting cell proliferation.
  • the latter indicates that the growth and/or differentiation of tumor cells is reduced, reduced, weakened, slowed, and the like.
  • proliferation includes any process involving cell growth and division, and includes differentiation and apoptosis.
  • c-Met kinase plays an important role in the activation of the cytoplasmic signaling cascade involved in cell proliferation, differentiation and apoptosis.
  • the method of the present invention comprises the use of the above compound (compound of formula (I)), including a crystalline form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a combination thereof, for treating a mammal
  • a method of hyperproliferative disease comprising administering to a mammal, including a human in need thereof, an amount of a compound of the invention, a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or an amount thereof effective to treat the disease Solvate.
  • Hyperproliferative diseases include, but are not limited to, solid tumors such as breast cancer, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and Long-distance metastases. These diseases also include lymphoma, sarcoma and leukemia.
  • Any tumor can be treated, including but not limited to tumors having one or more mutations in any upstream or downstream member of c-Met and the signaling pathway in which it is involved.
  • tumors can be treated with the compounds of the invention regardless of the mechanism to which they correspond.
  • the tumor of any organ can be treated, including but not limited to, for example, colon cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, kidney cancer, lung cancer, testicular cancer, breast cancer, skin cancer, stomach cancer, colorectal cancer, kidney cells. Cancer, hepatocellular carcinoma, melanoma, etc.
  • breast cancer examples include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • respiratory cancer examples include, but are not limited to, small cell and non-small cell lung cancer, as well as bronchial adenoma and pleural pulmonary blastoma.
  • brain cancer examples include, but are not limited to, brainstem and pituitary gliomas, medulloblastoma, cerebellar and cerebral astrocytomas, tympanoma, and neuroectodermal and pineal adenomas.
  • Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer and vulvar cancer, and uterine sarcoma.
  • Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, rectal cancer, gastric cancer, small bowel cancer, and salivary gland cancer.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancer examples include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolat), cholangiocarcinoma, and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, Kaposi's sarcoma, squamous cell tumors, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, and/or oropharyngeal cancer, as well as lip and oral cancer.
  • Lymphomas include, but are not limited to, non-Hodgkin's lymphoma, AIDS-associated lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and central nervous system lymphoma.
  • Sarcomas include, but are not limited to, chondrosarcoma, tissue sarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, and villous cell leukemia.
  • the compounds of the invention can also cause tumor regression, such as tumor size The decrease or the extent of tumor distribution in the body.
  • composition based on the compound of the present invention
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable salt thereof.
  • These compositions can be administered to patients in need thereof to achieve the desired pharmacological effects.
  • a patient is a mammal, including a human, in need of treatment for a specific symptom or disease, which is the object of the present invention.
  • the invention includes a pharmaceutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention or a salt thereof.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic to the patient at a concentration which is compatible with the effective activity of the active ingredient so that any side effects caused by the carrier do not impair the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of a compound is that which is effective or effective in the particular condition being treated.
  • the compounds of the present invention can be administered orally, parenterally, topically, by any effective conventional dosage unit form, including rapid release, sustained release and timed release formulations, by pharmaceutically acceptable carriers well known in the art. Administration, eye, nose, sublingual, rectal, vaginal, etc.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, lozenges, powders, melts, solutions, emulsions or suspensions, and can be used in the art.
  • the methods for producing pharmaceutical compositions are known for their preparation.
  • the solid unit dosage form can be a conventional soft or hard shell gelatin capsule containing, for example, a surfactant, a lubricant, and an inert filler such as sucrose, lactose, corn starch, and calcium phosphate.
  • the compounds of the invention may be coated with conventional tablet bases such as lactose, sucrose, and corn starch with binders such as gum arabic, gelatin or corn starch; such as potato starch, corn starch, alginic acid, And guar gum, gum arabic, tragacanth and the like to disintegrate the tablet to help the tablet split and dissolve after administration; for example, talc, stearic acid or magnesium stearate, calcium or zinc for improving the tablet granulation flow And a lubricant that prevents the tablet material from sticking to the tablet mold and the tableting machine; a dye, a coloring agent, and a dye such as wintergreen oil, peppermint oil, or cherry flavoring for improving the appearance quality of the tablet and making it more acceptable to the patient.
  • binders such as gum arabic, gelatin or corn starch
  • binders such as gum arabic, gelatin or corn starch
  • binders such as gum arabic, gelatin or corn starch
  • binders such as gum arabic
  • Flavoring combinations are used to prepare tablets.
  • Suitable excipients for oral solid dosage forms include dicalcium phosphate and such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyethylene glycol) with or without pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Diluent of the agent.
  • Various other materials may be present in the form of a sugar coating or in other ways to modify the physical form of the dosage form. For example, tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of aqueous suspensions. They provide active ingredients in admixture with dispersing or wetting agents, suspending agents, and one or more preservatives. Suitable wetting or dispersing and suspending agents are exemplified by what has been mentioned above. Additional excipients such as those sweetening, flavoring, and coloring agents described above may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifiers may be (1) natural phospholipids such as soybean phospholipids and lecithin, (2) natural gums such as gum arabic and tragacanth, (3) condensation products of the partial esters with ethylene oxide, such as poly Oxyethylene monooleic sorbitan anhydride, (4) ester or partial ester derived form fatty acid and hexitol anhydride, such as sorbitan monooleate.
  • the emulsions may also contain sweeteners and flavoring agents.
  • the oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as olive oil, peanut oil, coconut oil or sesame oil or a mineral oil such as liquid paraffin.
  • the oily suspension may contain a thickening agent such as, for example, hard paraffin, beeswax or cetyl alcohol.
  • the suspension may also include one or more preservatives such as n-propyl p-hydroxybenzoate or ethyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; Or a variety of such as saccharin Or a sweetener of sucrose.
  • a syrup or elixir may be formulated with a sweetening agent such as, for example, propylene glycol, glycerin, sucrose or sorbitol.
  • a sweetening agent such as, for example, propylene glycol, glycerin, sucrose or sorbitol.
  • Such formulations may also contain a demulcent and preservative (such as propylparaben and methylparaben) as well as flavoring and coloring agents.
  • the compounds of the present invention may also be administered parenterally in an injection dose of the compound in a physiologically acceptable diluent, i.e., subcutaneous injection, intravenous injection, intraocular administration, intrasynovial administration, intramuscular administration.
  • a physiologically acceptable diluent i.e., subcutaneous injection, intravenous injection, intraocular administration, intrasynovial administration, intramuscular administration.
  • the diluent comprises, for example, water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, such as a glycerol ketal of 2,2-methyl-1,1-oxolan-4-methanol, an ether such as polyethylene glycol 400, an oil, a fatty acid, a fatty acid ester or a fatty acid glyceride, or an acetylated fatty acid glycerol
  • a pharmaceutical carrier of a sterile liquid or liquid mixture of esters with or without a pharmaceutically acceptable surfactant or detergent such as a fatty acid salt, such as carbomer, pectin, methylcellulose, carboxymethyl Suspension or emulsifier of cellulose or hydroxypropyl methylcellulose and other pharmaceutical adjuvants.
  • oils which may be used in the parenteral dosage form of the invention are petroleum, synthetically derived oils, animal oils or vegetable oils such as soft paraffin, mineral oil, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, isopropyl myristate and ethyl oleate.
  • Suitable fatty acid salts include fatty acid alkali metals, fatty acid ammoniums and fatty acid triethylamines, and suitable surfactants include cationic surfactants such as alkyl halides and alkyl acetates, dimethyldialkyl ammonium halides.
  • Anionic surfactants such as alkyl, aryl and alkene sulfonates, alkyl, olefin, diethyl ether and monoglyceride sulfates and sulfosuccinates; nonionic surfactants such as oxidized fatty amines; Alkanolamide fatty acid, and poly(oxyethylene-oxypropyl) or oxyethylene or oxypropylene copolymer; and amphoteric surfactants such as 2-alkylimidazoline quaternary ammonium salt and alkyl- ⁇ -aminopropionic acid Salt, and mixtures thereof.
  • compositions of the present invention should generally comprise from about 0.5% to about 25% by weight of active ingredient in solution. Preservatives and buffers can also be conveniently used. To minimize or eliminate irritation at the site of injection, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance constant (HLB) of between about 12 and about 17. The level of surfactant in such dosage forms is between about 5% and about 15% by weight.
  • the surfactant may be a single component having the above HLB or may be a mixture of two or more components having the desired HLB.
  • surfactants used in the parenteral dosage form are polyethylene sorbitan fatty acid ester surfactants, such as sorbitol monooleate and oxyethylene and a hydrophobic base formed by condensation of propylene glycol with peroxypropylene High molecular weight adduct.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous suspension.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and such as, for example, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium alginate, polyethylene a suspension of pyrrolidone, tragacanth and gum arabic;
  • the dispersing or wetting agent may be a natural phospholipid such as lecithin, a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, such as hepta-ethylene oxide a condensation product of oxyethylene of hexaol with a long-chain fatty alcohol, a condensation product of oxyethylene such as polyoxyethylene sorbitan monooleate with a partial ester derived from a fatty acid and a hexitol, or, for example, polyoxyethylene sorbitan A condensation product of a monooleate ethylene oxide with a
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents or solvents that can be used are, for example, water, Ringer's solution, isobaric glucose solution Liquid and isostatic sodium chloride solution.
  • sterile, fixed oils are usually employed as a solvent or suspension medium.
  • any non-irritating, non-volatile oil, including synthetic mono- or diglycerides, can be used.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions of the invention may also be administered in the form of a suppository for rectal administration.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and which can be melted in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and which can be melted in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and which can be melted in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery device a transdermal delivery device
  • Such transdermal patches can be used to provide controlled or continuous infusion of a controlled amount of a compound of the invention.
  • transdermal ointments for drug delivery are well known in the art (see, for example, U.S. Patent No. 5,023,252, issued Jun.
  • Such ointments can be constructed for continuous, pulsed, or on-demand drug delivery.
  • the construction and use of mechanical delivery devices for drug delivery are well known in the art.
  • Direct delivery techniques such as direct administration to the brain, typically involve placing a drug delivery catheter in the patient's ventricular system to bypass the blood-brain barrier.
  • Such an implant delivery system for transporting a substance to a particular anatomical region of the body is described in U.S. Patent No. 5,011,472, issued Apr. 30, 1991.
  • Controlled release formulations for parenteral administration include liposomes, polymeric microparticles and polymeric colloidal formulations known in the art.
  • compositions of the present invention may also contain, as needed or desired, conventional pharmaceutically acceptable intimate ingredients which are conventionally referred to as carriers or diluents.
  • conventional pharmaceutically acceptable intimate ingredients which are conventionally referred to as carriers or diluents.
  • Conventional processes for preparing such compositions in suitable dosage forms can be employed. Such ingredients and processes include those described in the prior art references.
  • Common pharmaceutical ingredients that are designed to match the dosage form of the composition include:
  • Acidifying agent examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid
  • Alkalinizing agent examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, ethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine;
  • adsorbents examples include, but are not limited to, powdered cellulose and activated carbon
  • Aerosol propellant examples include, but are not limited to, carbon dioxide, CCl 2 F 2 , F 2 ClC-CClF 2 , and CClF 3 );
  • Air displacement agents include, but are not limited to, nitrogen and argon
  • Antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, hypophosphorous acid, thioglycerol, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallic acid, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, partial Sodium bisulfite);
  • Antifungal preservatives include, but are not limited to, benzoic acid, butyl paraben, methyl paraben, propyl paraben, ethyl p-hydroxybenzoate, sodium benzoate);
  • Antibacterial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorobutanol, benzyl alcohol, phenylethyl alcohol, cetylpyridinium chloride, phenol, phenylmercuric nitrate, and sodium thiomersal );
  • Buffering agents include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, sodium citrate dihydrate);
  • Bonding materials include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);
  • Carriers include, but are not limited to, gum arabic syrup, aromatic syrup, aromatic tincture, cherry syrup, Orange syrup, syrup, cocoa syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection);
  • a chelating agent examples include, but are not limited to, edetic acid and disodium edetate;
  • Colorants include, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8 , caramel and iron oxide red);
  • clarifying agents examples include, but are not limited to, gum arabic, polyethylene glycol, cetyl alcohol, glyceryl monostearate, lecithin, polysorbate monooleate, polyoxyethylene 50 monostearate );
  • Capsules include, but are not limited to, gelatin and fiber vinegar
  • ⁇ food flavors examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin);
  • Moisturizers examples include, but are not limited to, glycerin, propylene glycol, and sorbitol
  • abrasives examples include, but are not limited to, mineral oil and glycerin
  • Ointment base examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, butter paste and rose red water ointment;
  • ⁇ oil examples include but are not limited to groundnut oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil;
  • Permeation enhancers include, but are not limited to, mono or polyhydric alcohols, monovalent or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids , essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones and ureas;
  • Solvents include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerin, isopropanol, mineral oil, oleic acid, peanut oil, pure water, water for injection, sterile water for injection, and sterile water for infusion);
  • plasticizers examples include, but are not limited to, diethyl phthalate and glycerin;
  • Hardener examples include, but are not limited to, cetyl alcohol, cetyl ester, wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);
  • a suppository base examples include, but are not limited to, cocoa butter and polyethylene glycol (mixture));
  • Surfactants include, but are not limited to, benzalkonium chloride, nonylphenol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitol monopalmitate);
  • Suspending agent examples include but are not limited to agar, bentonite, carbomer, sodium carboxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methyl cellulose , tragacanth and veegum;
  • Sweeteners include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);
  • Pill binders examples include, but are not limited to, gum arabic, alginic acid, sodium carboxymethylcellulose, compressible sucrose, ethylcellulose, gelatin, liquid glucose, methylcellulose, and gelatinized starch;
  • ⁇ tablet release agent examples include, but are not limited to, magnesium stearate and talc
  • Tablets and capsule diluents include, but are not limited to, calcium hydrogen phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol, and starch);
  • Pill coating agent examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, and insects gum;
  • tablet cracking agents examples include, but are not limited to, alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium glycolate starch, and starch;
  • tablet lubricants examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);
  • tablet slip agents examples include, but are not limited to, colloidal silica, corn starch, and talc;
  • Pill polishing agent examples include, but are not limited to, palm wax and white wax
  • tablet/capsule opacifiers examples include, but are not limited to, titanium dioxide
  • Thickeners include, but are not limited to, beeswax, cetyl alcohol, and paraffin);
  • Moisture enhancer examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and tragacanth;
  • Excipients include, but are not limited to, dextrose and sodium chloride);
  • Moisturizing agents include, but are not limited to, heptadecane oxyethylene hexadecanol, lecithin, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and polyoxyethylene stearate).
  • the effective dosage of the compounds of the invention for treating each of the desired indications can be conveniently determined.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely depending on, for example, the particular compound and dosage unit employed, the mode of administration, the course of treatment, the age of the patient being treated, and Factors such as gender and the characteristics and extent of the condition being treated.
  • the total amount of active ingredient administered can range from about 0.01 mg/kg to about 50 mg/kg, and preferably between about 0.1 mg to about 10 mg per kg of body weight per day.
  • the unit dose may preferably contain from about 1 mg to about 300 mg of the active ingredient, and may be administered one or more times per day.
  • the daily dose for oral administration should preferably be between 0.1 and 5 milligrams per kilogram of body weight.
  • the daily dose administered by injection (including intravenous, subcutaneous, intramuscular, and parenteral injections) and by infusion techniques should preferably be between 0.1 and 5 milligrams per kilogram of body weight.
  • the daily rectal administration regimen should preferably be between 0.1 and 15 milligrams per kilogram of body weight.
  • the daily topical dosage regimen should preferably be between 1 and 4 times daily, from 0.1 to 5 mg/kg.
  • the transdermal concentration should preferably be maintained at a daily dose of 0.1 to 3 mg/kg.
  • the daily inhalation dosing regimen should preferably be from 0.1 to 5 milligrams per kilogram of body weight. Other doses and amounts can be selected as usual.
  • the specific initial and sustained dosing regimen will vary from patient to patient, depending on the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and condition of the patient, the time of administration, and the administration. Routes, drug excretion rates, drug combinations, and more.
  • the mode required for treatment, as well as the dosage number of the compound of the present invention or a pharmaceutically acceptable salt or composition thereof, can be determined by those skilled in the art using conventional therapeutic tests.
  • the compounds of the invention may be administered in a single pharmaceutical form or in combination with one or more other pharmaceutical agents, wherein the combination does not cause unacceptable deleterious results. This may be especially useful for treating hyperproliferative diseases such as cancer. Its practical.
  • the compounds of the invention may be used in combination with known cytotoxic agents, signal transduction inhibitors, or with other anti-tumor substances, as well as mixtures and compositions thereof.
  • the compounds of the invention may be used in combination with a cytotoxic anti-tumor substance.
  • a cytotoxic anti-tumor substance include, but are not limited to, asparaginase, L-asparaginase, bleomycin, carboplatin, cisplatin, nitrogen mustard, carmustine, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin, epirubicin, doxorubicin, etoposide, 6-mercaptopurine, methotrexate, 5-fluorouracil, hexamethylamine, hydroxyurea, heterocyclic Phosphoramide, formyltetrahydrofolate, lomustine, mesna, mitomycin C, mitoxantrone hydrochloride, benzamidine, raloxifene, streptozotocin, tamoxifen, sulfur Guanine, topotecan,
  • cytotoxic drugs suitable for use in combination with the compounds described herein include, but are not limited to, those recognized for use in the treatment of neoplastic diseases. These include, but are not limited to, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxygenate Glycosides, pucamycin, docetaxel, erythrohydroxy adenine, estriol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluorotestosterone, fluoride Oreamine, hydroxyprogesterone capsaicin, paclitaxel, demethoxydaunorubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitoxantrone, N-diphosphoacety
  • cytotoxic antitumor agents suitable for use in combination with the compounds described herein also include newly discovered cytotoxic agents such as gemcitabine, capecitabine, epothilone, oxaliplatin and natural and synthetic derivatives thereof. , temozolomide, toximozumab (Bexxar), trabedectin, and an inhibitor of the kinesin spindle protein Eg5.
  • the compounds of the invention can be used in combination with other signal transduction inhibitors.
  • signal transduction inhibitors against the EGFR family such as EGFR, HER-2 and HER-4, and their respective ligands.
  • Examples of such materials include, but are not limited to, antibody drugs such as Herceptin (trastuzumab), Abitix (cetuximab), and pertuzumab.
  • Examples of such drugs also include, but are not limited to, small molecule kinase inhibitors such as ZD-1839/Iressa, CM033, OSI-774/Tarceva, CP-724, 714, EKB-569, and GW-2016.
  • the compounds of the present invention have a number of advantages over compounds known in the art that do not carry ruthenium.
  • the main advantages of the invention include:
  • the compound of the present invention has excellent inhibitory activity against a tyrosine kinase such as c-Met.
  • the compound of the present invention is less likely to be metabolized in animals than the undeuterated compound, which results in a decrease in the first-pass effect, so that the dosage can be changed and a long-acting preparation can be formed, which can also be long-acting.
  • the form of the formulation improves the suitability.
  • the compound of the present invention has a higher drug concentration in an animal, thereby improving the drug effect.
  • Step 6 3-[(2-Indol-6-quinolinyl)difluoromethyl]-6-[(1-methyl)-4-pyrazolyl][1,2,4]triazolo[ 4,3-b]pyridazine (II)
  • the total volume of each in vitro incubation system was 200 ⁇ L, and the medium was 100 mM phosphate buffer (PBS, pH 7.4), including JNJ38877605 or Compound II and 2 mM NADPH at a final concentration of 3 ⁇ M, and incubated with a 37 ° C water bath. After pre-incubation for 3 min, monkey liver S9 protein was added to the buffer-substrate-cofactor mixture to initiate the reaction. After 60 min, the reaction was stopped by adding the same volume of ice-cold acetonitrile. The experimental conditions of the control group were the same as above, but NADPH was replaced by PBS; in addition, in the blank control group, the S9 protein was subjected to high temperature inactivation treatment. All incubation samples were double samples.
  • Dosage dose (mg/kg) Dosing volume (mL/kg) 1 2 JNJ-38877605 10 5 2 2 Compound II 10 5
  • 0.8 mL of venous blood was taken from the extremities, placed in an EDTA anticoagulation tube, centrifuged at 3500 rpm for 10 min, and the plasma was separated, -70 Store in a freezer at °C for testing.
  • the concentration in plasma was determined by LC/MS/MS method, and plasma, and possible metabolites in urine were identified by UPLC-Q/TOF-MS.
  • the compounds of the present invention have better pharmacokinetics in animals and thus have better pharmacodynamics and therapeutic effects.
  • BALB/cA nude mice The number of animals in each group: 6 in the negative control group and 6 in the drug-administered group.
  • the human lung cancer EBC-1 cell line was inoculated subcutaneously into the right axilla of nude mice, and the inoculation amount was 5 ⁇ 10 6 /piece.
  • the transplanted tumor was formed and then used in nude mice for one generation.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the diameter of the transplanted tumor was measured with a vernier caliper in nude mice.
  • the animals were randomly divided into groups after the average tumor volume grew to about 176 mm 3 .
  • Compound II and JNJ38877605 were administered orally at a dose of 5 mg/kg twice a day for 21 days.
  • the solvent control group was given an equal amount of solvent.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • V 0 is the measured tumor volume at the time of sub-cage administration (i.e., d 0 )
  • V t is the tumor volume at each measurement.
  • the evaluation index of antitumor activity is:
  • T / C (%) (T RTV / C RTV ) ⁇ 100%, T RTV : treatment group RTV; C RTV : negative control group RTV;
  • TGI% [1-(TV t - TV 0 ) / (CV t - CV 0 )] ⁇ 100%
  • TV t is the tumor of each measurement group Volume
  • TV 0 is the tumor volume obtained when the therapeutic component is administered
  • CV t is the tumor volume measured in the control group at each time
  • CV 0 is the tumor volume obtained when the control group is administered in a cage
  • tumor weight inhibition rate % (W C - W T ) / W C ⁇ 100%, W C : control group tumor weight, W T : treatment group tumor weight.
  • the experimental results are shown in Figure 2.
  • Compound II and JNJ38877605 were orally administered twice a day at a dose of 5 mg/kg for 21 days, and had extremely significant inhibitory effects on the growth of subcutaneous xenografts of human lung cancer EBC-1 nude mice.
  • the percentage of T/C of compound II on day 21 was 9.98%
  • the tumor growth inhibition rate (TGI) was 90.4%
  • the percentage of T/C obtained on the 21st day of JNJ38877605 was 21.56%
  • the tumor growth inhibition rate (TGI) was 83.8%.
  • the mice in each of the administration groups were in good condition during the experimental treatment.
  • aqueous or non-aqueous coatings can be used to increase palatability, improve appearance and stability, or delay absorption.
  • Compound II was formulated into a 4 mg/ml solution with sterile water for injection and the pH was adjusted as needed.
  • the drug was diluted with 5% sterile dextrose to 1.5-2.0 mg/ml intravenous infusion.

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Abstract

一种如式(Ⅰ)所示的氘代3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪化合物、其晶型、药学上可接受的盐、及包含所述化合物或其晶型或其药学上可接受的盐的药物组合物在制备用于预防或治疗由蛋白酪氨酸激酶,尤其是c-Met激酶信号介导的疾病的药物中的应用。

Description

氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪及其应用 技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪、或其晶型、药学上可接受的盐、及包含所述化合物或其晶型或其药学上可接受的盐的药物组合物在制备用于预防或治疗由蛋白酪氨酸激酶,尤其是c-Met激酶信号介导的疾病的药物中的应用。
背景技术
已知的[1,2,4]三唑并[4,3-b]哒嗪类化合物是选择性c-Met抑制剂,已经在专利WO2007075567A1和WO2008155378A1中公开,用于治疗酪氨酸激酶包括c-Met激酶失调引起的肿瘤疾病。
蛋白酪氨酸激酶(PTKs)是一类具有调节多种重要的生物学功能的一组酶,包括细胞生长、分化、器官形成、新生血管形成、组织修复和再生等等。蛋白酪氨酸激酶通过催化蛋白酪氨酸残基的磷酸化发挥它们的生物学效应,然后调节底物蛋白的生物活性。一类蛋白酪氨酸激酶的失调可能导致肿瘤生成和增长,并进一步对肿瘤的生存和发展起着重要作用(Blume J P,Hunter T.Oncogenic kinase signaling[J].Nature,2001,411(6835):355-365)。因此,与肿瘤密切相关的蛋白酪氨酸激酶代表一类最重要的癌症治疗和药物发展相关的蛋白靶点。
c-Met是肝细胞生长因子受体(HGFR),由MET原癌基因编码。c-Met在绝大部分的癌及部分肉瘤中具有高表达且和预后差紧密相关,如肺癌、乳腺癌、结肠癌、前列腺癌、胰癌、胃癌、肝癌、卵巢癌、肾癌、神经胶质瘤、黑色素瘤等。c-Met通过与其配体HGF/SF相互作用或者通过其他途径激活胞内段的酪氨酸激酶,诱导细胞增殖、侵袭、迁移,抑制细胞凋亡,促进血管生成,在肿瘤的发生发展过程中发挥重要的作用。
综上所述,本领域迫切需要开发新的具有蛋白酪氨酸激酶抑制活性,特别是具有c-Met抑制活性的药物。
发明内容
本发明的目的是提供一种新的具有蛋白酪氨酸激酶抑制活性,特别是具有c-Met抑制活性的药物。
本发明的第一方面,提供了一种如下式(Ⅰ)所示的化合物:
Figure PCTCN2016085480-appb-000001
式中:
D代表氘原子;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地为氢原子或氘原子;
R10选自下组:CH3、CH2D、CHD2、或CD3
在另一优选例中,氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
在另一优选例中,式(I)化合物中的除H之外的其他元素(如N、C、F等)全部或基本上(>99wt%)为丰度最高的天然存在的元素,例如14N、12C和19F。
在另一优选例中,R1、R2、R3、R4、R5、R6、R7、R8、R9均为氢原子;
R10为CH3
在另一优选例中,所述的式I化合物为以下化合物Ⅱ。
Figure PCTCN2016085480-appb-000002
本发明的第二方面,提供了一种制备药物组合物的方法,所述方法包括步骤:将药学上可接受的载体与如本发明第一方面所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。
本发明的第三方面,提供了一种药物组合物,所述药物组合物包括:治疗有效量的如本发明第一方面所述的式I化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物;和药学上可接受的载体。
在另一优选例中,所述的药物组合物包括治疗有效量的式II化合物,即3-[(2-氘-6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪、或其晶型、药学上可接受的盐、水合物或溶剂合物:
Figure PCTCN2016085480-appb-000003
和药学上可接受的载体。
在另一优选例中,所述的药物组合物还包括治疗有效量的其他活性成分,且所述的其他活性成分包括选自下组的一种或多种活性成分:细胞毒剂、信号转导抑制剂,和其他抗肿瘤物质。
在另一优选例中,所述的药物组合物是用于治疗或预防与酪氨酸激酶活性或表达量相关的疾病,优选为与c-Met的活性或表达量相关的疾病。
在另一优选例中,所述的疾病选自下组:乳头状瘤、芽状神经胶质瘤、黑素瘤、肺癌、卵巢癌、前列腺癌、鳞状细胞癌、星细胞瘤、头癌、颈癌、膀胱癌、乳癌、结肠直 肠癌、甲状腺癌、胰腺癌、胃癌、肝细胞癌、白血病、淋巴瘤、血管瘤、瘢痕瘤、呼吸道癌、脑癌、生殖器官癌、消化道癌、尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、副甲状腺癌及其远距离转移灶、淋巴瘤、肉瘤、结肠癌、骨癌、肾癌、睾丸癌、皮肤癌、肾细胞癌、非小细胞肺癌。
在另一优选例中,所述的药物组合物是选自下组的制剂:片剂、胶囊剂、丸剂、散剂、颗粒剂或注射剂;优选为片剂、胶囊剂,或静脉注射剂。
在另一优选例中,当所述的药物组合物是片剂时,所述的药物组合物包括选自下组的载体:胶体二氧化硅、硬脂酸镁、改性淀粉、微晶纤维素、乳糖,或其组合。
在另一优选例中,当所述的药物组合物是胶囊剂时,所述的药物组合物包括选自下组的载体:淀粉、微晶纤维素,或其组合。
在另一优选例中,当所述的药物组合物是静脉注射剂时,所述的药物组合物包括选自下组的载体:无菌注射用水。
在另一优选例中,所述的药物组合物是长效制剂。
本发明的第四方面,提供了一种如本发明第一方面所述的式(I)化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物用于制备治疗酪氨酸激酶,尤其是c-Met介导的疾病的药物组合物的用途。
在另一优选例中,所述的疾病选自下组:乳头状瘤、芽状神经胶质瘤、黑素瘤、肺癌、卵巢癌、前列腺癌、鳞状细胞癌、星细胞瘤、头癌、颈癌、膀胱癌、乳癌、结肠直肠癌、甲状腺癌、胰腺癌、胃癌、肝细胞癌、白血病、淋巴瘤、血管瘤、瘢痕瘤、呼吸道癌、脑癌、生殖器官癌、消化道癌、尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、副甲状腺癌及其远距离转移灶、淋巴瘤、肉瘤、结肠癌、骨癌、肾癌、睾丸癌、皮肤癌、肾细胞癌、非小细胞肺癌。
本发明的第五方面,提供了一种制备如本发明第一方面所述的式II化合物3-[(2-氘-6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪的方法,
Figure PCTCN2016085480-appb-000004
其特征在于,包括步骤:
Figure PCTCN2016085480-appb-000005
在有机溶剂中,用式(VII)化合物和式(VIII)化合物进行关环反应,得到式(II)化合物。
在另一优选例中,所述的关环反应在二氧六环和甲烷磺酸存在下进行。
在另一优选例中,所述的有机溶剂是选自下组的溶剂:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸,或其组合。
在另一优选例中,所述的反应在60-130℃下进行。
在另一优选例中,所述的反应时间为8-16小时。
在另一优选例中,所述的式(VII)化合物是通过以下方法制备的:
Figure PCTCN2016085480-appb-000006
在有机溶剂中,用式(VI)化合物与二氟溴乙酸乙酯和水合肼反应,得到式(VII)化合物。
在另一优选例中,所述的反应在铜粉存在下进行;优选地,化合物(Ⅵ)在铜粉存在下与二氟溴乙酸乙酯缩合,然后与水合肼反应得到式(Ⅶ)化合物。
在另一优选例中,所述的有机溶剂是选自下组的溶剂:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸,或其组合。
在另一优选例中,所述的反应在60-100℃下进行。
在另一优选例中,所述的反应时间为18-30小时。
在另一优选例中,所述的式(VI)化合物是通过以下方法制备的:
Figure PCTCN2016085480-appb-000007
在有机溶剂中,用式(V)化合物与碘化试剂反应,得到式(VI)化合物;优选地,所述的碘化试剂为碘化钠、碘化亚铜和N,N-二甲基乙二胺。
在另一优选例中,所述的有机溶剂是选自下组的溶剂:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸,或其组合。
在另一优选例中,所述的反应在80-140℃下进行。
在另一优选例中,所述的反应时间为8-16小时。
在另一优选例中,所述的式(V)化合物是通过以下方法制备的:
Figure PCTCN2016085480-appb-000008
在有机溶剂中,用式(IV)化合物与还原试剂进行还原反应,得到式(V)化合物;优选地,所述的还原试剂是铁粉;更佳地,所述的还原反应在冰醋酸存在下进行。
在另一优选例中,所述的有机溶剂是选自下组的溶剂:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸,或其组合。
在另一优选例中,所述的反应在80-140℃下进行。
在另一优选例中,所述的反应时间为1-5小时。
在另一优选例中,所述的式(IV)化合物是通过以下方法制备的:
Figure PCTCN2016085480-appb-000009
在有机溶剂中,用式(III)化合物进行氘代反应,得到式(IV)化合物;优选地,所述的氘代反应在重水和/或叔丁醇钠存在下进行。
在另一优选例中,所述的有机溶剂是选自下组的溶剂:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸,或其组合。
在另一优选例中,所述的反应在70-130℃下进行。
在另一优选例中,所述的反应时间为8-16小时。
在另一优选例中,所述的式(III)化合物是通过以下方法制备的:
Figure PCTCN2016085480-appb-000010
在有机溶剂中,用6-溴喹啉进行氧化反应,得到化合物(Ⅲ);优选地,所述的氧化反应使用间氯过氧苯甲酸作为氧化剂。
在另一优选例中,所述的有机溶剂是选自下组的溶剂:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸,或其组合。
在另一优选例中,所述的反应在10-40℃下进行。
在另一优选例中,所述的反应时间为8-16小时。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1食蟹猴分别灌胃10mg/kg化合物Ⅱ和JNJ38877605后的血浆浓度-时间曲线;
图2化合物Ⅱ和JNJ38877605对人肺癌EBC-1裸小鼠移植瘤的生长抑制作用。
具体实施方式
本发明人经过长期而深入的研究,意外地发现,氘代的[1,2,4]三唑并[4,3-b]哒嗪类化合物在具有良好的蛋白酪氨酸激酶抑制活性的同时,在药代动力学上有显著的改善,给药后能够在动物体内的暴露量更高,因此具有更好的治疗效果。基于上述发现,发明人完成了本发明。
术语
除非特别说明,本发明中,氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015%),较佳地大于30%,更佳地大于50%,更佳地大于75%,更佳地大于95%,更佳地大于99%。
氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪
本发明提供了一类新型的具有c-Met抑制活性和更好药效学性能的化合物及其用途,即式(Ⅰ)所示的氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪、其晶型、药学上可接受的盐、水合物或溶剂合物:
Figure PCTCN2016085480-appb-000011
式中:
D代表氘原子;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地为氢原子或氘原子;
R10为CH3、CH2D、CHD2、或CD3
优选地,R1、R2、R3、R4、R5、R6、R7、R8、R9均为氢原子,R10为CH3,所述化合物为以下化合物Ⅱ:
Figure PCTCN2016085480-appb-000012
氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪的制备
本发明所述的氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪可以通过本领域常用的制备氘代化合物的方法制备,例如,在本发明的一个优选实施例中,制备所述的化合物Ⅱ的方法包括如下步骤:从6-溴喹啉出发,经氧化、氘代、还原、碘取代、偶联和肼代得到中间体(Ⅶ),接着与化合物(Ⅷ)关环得到目标产物。
Figure PCTCN2016085480-appb-000013
具体地说,所述制备方法包括:
从6-溴喹啉出发,经间氯过氧苯甲酸氧化,得到化合物(Ⅲ);
化合物(Ⅲ)经重水与叔丁醇钠反应,得到氘代的化合物(Ⅳ);
化合物(Ⅳ)被铁粉在冰醋酸存在下还原成化合物(Ⅴ);
化合物(Ⅴ)在碘化钠、碘化亚铜和N,N-二甲基乙二胺存在下转化成化合物(Ⅵ);
化合物(Ⅵ)在铜粉存在下与二氟溴乙酸乙酯缩合,然后与水合肼反应得到中间体(Ⅶ);
中间体(Ⅶ)和中间体(Ⅷ)在甲烷磺酸存在下关环得到化合物(Ⅱ)。
活性成分
如本文所用,术语“本发明化合物”指式(Ⅰ)所示的化合物。该术语还包括式(Ⅰ)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合成盐的酸包括但不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
化合物Ⅱ的药代动力学和药效学评价(与原型药物JNJ38877605比较)
JNJ38877605是由Johnson&Johnson公司研发的c-Met抑制剂,本发明人在此基础上通过氘化制备的化合物Ⅱ与化合物JNJ38877605相比具有明显更优异的药代动力学和/或药效学性能,因此更适合作为抑制c-Met激酶的化合物,进而更适用于制备治疗癌症以及相关疾病的药物。
Figure PCTCN2016085480-appb-000014
药代动力学结果显示,同等给药剂量下化合物Ⅱ在食蟹猴体内的血浆达峰浓度Cmax 和暴露量AUC0-t分别为JNJ38877605的1.56倍和2.29倍;在人肺癌EBC-1裸小鼠移植模型进行的药效学结果显示,在5mg/kg每日两次的治疗剂量下连续给药21天,化合物Ⅱ对肿瘤增长抑制率(TGI)为90.4%,同等剂量下明显优于JNJ38877605(TGI为83.8%)对肿瘤生长的抑制作用。
以上结果表明,化合物Ⅱ具有明显优于JNJ38877605的药代动力学和药效学性质,具有开发被人体接受的抗肿瘤药物的潜在价值。
使用方法
本发明提供了能调节涉及蛋白酪氨酸激酶,尤其是c-Met激酶介导的信号转导途径的化合物。c-Met是参与包括细胞生长、细胞存活和侵入在内的许多重要的细胞过程的调控的重要的信号分子。HGF/c-Met这条信号通路存在于大部分肿瘤细胞中。c-Met信号通路失调是人类癌症中最为普遍发生的。c-Met信号的错乱在许多实体瘤和血液瘤中均得到了证实。联系c-Met和癌症的最有力的证据是最初发现的几乎所有患有遗传性肾乳头瘤(PRCC)的病人机体中都存在着c-Met的过度表达。承载HGF和c-Met基因的7号染色体三体在PRCC病人中普遍存在。也有报道c-Met突变在许多癌症中有所发生,如胃癌、脑瘤、肝癌、卵巢癌、非小细胞肺癌和甲状腺癌等。多个c-Met突变体潜在的致癌性已在临床前模型中得到了确证。这里所描述的化合物可以用于抑制其活性。
术语“调节”是指与所述化合物不存在时的正常活性相比改变了所述途径(或其组分)的功能活性。这一作用包括任何数量或程度上的调节,这包括提高、刺激、激活、增强、增加、促进、降低、减少、减小、阻碍、抑制、拮抗等等。
本发明所述化合物也可以调节以下一个或多个过程,这些过程包括但不限于例如细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤消退等等。
虽然不希望受到任何作用机理或机制的束缚,已经发现本发明所述化合物具有调节激酶活性的能力。然而,本发明所述的方法不局限于任何具体机制或所述化合物如何实现其治疗作用。术语“激酶活性”是指其中将一个γ磷酸根从三磷酸腺苷(ATP)转移到蛋白底物中的一个氨基酸残基(例如丝氨酸、苏氨酸或酪氨酸)上的催化活性。化合物可以调节激酶活性,例如通过直接与ATP竞争激酶的ATP结合位点抑制其活性、通过在酶的结构上产生构象变化影响其活性(例如通过破坏具有生物学活性的三维结构)等等。
本发明所述化合物可以用于治疗和/或预防涉及蛋白酪氨酸激酶,尤其是c-Met激酶介导的细胞信号转导途径异常所导致的任何疾病或病症。术语“治疗”按照其常规意义使用,例如出于抗击、减轻、降低、解除、改善疾病或功能紊乱的症状等等目的对患者进行处理或照顾。所述化合物也可以以用于预防和/或治疗由所述信号分子介导的疾病和/或病症进行描述。术语“介导”表示例如所述信号分子是在所述疾病和/或病症中异常或失常的途径的一部分。
可以治疗的疾病和病症包括任何上面和下面所提及的疾病以及包括例如细胞增殖紊乱、癌症、肿瘤等等的c-Met异常导致的相关疾病。所述疾病包括乳头状瘤、芽状神经胶质瘤、卡波济氏肉瘤、黑素瘤、肺癌、卵巢癌、前列腺癌、鳞状细胞癌、星细胞瘤、头癌、颈癌、膀胱癌、乳癌、结肠直肠癌、甲状腺癌、胰腺癌、胃癌、肝细胞癌、白血 病、淋巴瘤、血管瘤、瘢痕瘤。
本发明所述方法包括调节肿瘤细胞增殖,这包括抑制细胞增殖。后者表示肿瘤细胞的生长和/或分化得到降低、减少、削弱、减缓等等。术语“增殖”包括涉及细胞生长和分裂的任何过程,并包括分化和凋亡。如上所述,c-Met激酶在涉及细胞增殖、分化和凋亡的细胞质信号级联的活化中发挥重要作用。
本发明所述方法中包括使用包括或其晶型、药学上可接受的盐、水合物或溶剂合物,及其组合物在内的上述化合物(式(I)所述化合物)以治疗哺乳动物过度增殖性疾病的方法,所述方法包括对包括需要的人在内的哺乳动物给予有效治疗所述疾病的量的本发明所述化合物、其晶型、药学上可接受的盐、水合物或溶剂合物。过度增殖性疾病包括但不限于实体肿瘤,诸如乳癌、呼吸道癌、脑癌、生殖器官癌、消化道癌、尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、副甲状腺癌及其远距离转移灶。这些疾病也包括淋巴瘤、肉瘤和白血病。
可以对任何肿瘤进行治疗,这些肿瘤包括但不限于在c-Met及其所参与的信号途径的任何上游或下游成员中具有一个或多个突变的肿瘤。如先前所述,肿瘤可以用本发明所述化合物进行治疗而不考虑其所对应的机制。可以对任何器官的肿瘤进行治疗,这包括但不限于例如结肠癌、胰腺癌、前列腺癌、骨癌、肝癌、肾癌、肺癌、睾丸癌、乳癌、皮肤癌、胃癌、结肠直肠癌、肾细胞癌、肝细胞癌、黑素瘤等等。
乳癌的例子包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌的例子包括但不限于小细胞及非小细胞肺癌、以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的例子包括但不限于脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤。
男性生殖器官肿瘤包括但不限于前列腺癌和睾丸癌。女性生殖器官肿瘤包括但不限于卵巢癌、子宫内膜癌、宫颈癌、阴道癌和外阴癌以及子宫肉瘤。
消化道肿瘤包括但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、直肠癌、胃癌、小肠癌以及唾液腺癌。
眼癌包括但不限于眼内黑素瘤和成视网膜细胞瘤。
肝癌的例子包括但不限于肝细胞癌(具有或不具有纤维板层形式的肝细胞癌)、胆管细胞癌以及混合型肝细胞胆管细胞癌。
皮肤癌包括但不限于卡波西肉瘤、鳞状细胞瘤、恶性黑素瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌。
头颈癌包括但不限于喉癌、下咽癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌。
淋巴瘤包括但不限于非霍奇金淋巴瘤、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病以及中枢神经系统淋巴瘤。
肉瘤包括但不限于软骨肉瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤。
白血病包括但不限于急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓白血病、慢性骨髓性白血病以及绒毛细胞白血病。
除了抑制肿瘤细胞增殖,本发明所述化合物也能引起肿瘤消退,例如肿瘤大小 的减小或肿瘤在体内分布范围的降低。
基于本发明所述化合物的药物组合物
本发明也涉及含本发明所述化合物或其晶型、药学上可接受的盐、水合物或溶剂合物,及其药学上可接受的盐的药物组合物。可以给予有此需要的患者这些组合物以达到所期望的药理学效果。患者是需要对具体症状或疾病进行治疗的包括人在内的哺乳动物是本发明所要达到的目的。因此,本发明包括含有药学上可接受的载体和本发明所述化合物或其盐的药物有效量的药物组合物。药学上可接受的载体是以与所述活性成分的有效活性相匹配的浓度对于患者相对无毒无害从而使载体引起的任何副作用不损害活性成分的有益作用的任何载体。化合物的药物有效量是对所治疗的具体症状产生效果或发挥作用的量。本发明所述化合物可以通过本领域所熟知的药学上可接受的载体使用包括快速释放制剂、缓释和定时释放制剂在内的任何有效的常规剂量单位形式经口服、非肠道、局部、眼部、眼球、鼻部、舌下、直肠、阴道等等方式给药。
对于口服给药,所述化合物可以配制成诸如胶囊、药丸、片剂、糖锭、锭剂、粉末、熔体、溶液、乳状液或悬浮液等固体或液体制剂,并且可以按照本领域内已知的用于生产药物组合物的方法进行制备。固体单位剂量形式可以是普通的软壳或硬壳的明胶类胶囊,包含例如表面活性剂、滑润剂以及诸如蔗糖、乳糖、玉米淀粉和磷酸钙的惰性填充剂。
在另一种实施方式中,本发明所述化合物可以用诸如乳糖、蔗糖和玉米淀粉等常规药片基质与诸如阿拉伯树胶、明胶或玉米淀粉等粘合剂;诸如马铃薯淀粉、玉米淀粉、褐藻酸、以及瓜尔豆胶、阿拉伯树胶、黄芪胶等用于给药后帮助药片分裂与溶解的崩解剂;例如滑石、硬脂酸或硬脂酸镁、钙或锌等用于提高药片制粒流并防止药片原料与药片模具及压片机粘连的滑润剂;用于提高药片外观质量并使其更为患者所接受的染料、着色剂、以及诸如冬青油、薄荷油、或樱桃调味剂等的调味剂组合制备片剂。用于口服固体剂型的适当的赋形剂包括磷酸二钙和诸如水和醇(例如乙醇、苯甲醇和聚乙二醇)的包含或不含药学上可接受的表面活性剂、悬浮剂或乳化剂的稀释剂。各种其他材料可以以糖衣形式或是为了以其他方式对剂型的物理形式进行修饰而存在。例如,药片、药丸或胶囊可以用虫胶、糖或这两者包被。
可分散粉末和颗粒适于制备水性悬浮液。它们提供了与分散剂或湿润剂、悬浮剂以及一种或多种防腐剂混合的活性成分。适当的湿润剂或分散剂和悬浮剂通过上面已经提到的内容举例。也可以存在额外的赋形剂,例如上述的那些甜味剂、调味剂和着色剂。
本发明所述药物组合物也可以是水包油乳剂形式的。油相可以是诸如液体石蜡的植物油或是植物油混合物。适当的乳化剂可以是(1)诸如大豆磷脂和卵磷脂的天然磷脂,(2)诸如阿拉伯树胶和黄芪胶的天然树胶,(3)所述部分酯与环氧乙烷的缩合产物,例如聚氧乙烯单油酸山梨醇酐,(4)酯或部分酯衍生形式脂肪酸和己糖醇酐,例如单油酸山梨醇酐。所述乳剂也可以包含甜味剂和调味剂。
油性悬浮液可以通过将活性成分在例如橄榄油、花生油、椰子油或芝麻油等植物油或诸如液体石蜡等矿物油中悬浮配制。油性悬浮液可以包含诸如例如硬石蜡、蜂蜡或鲸蜡醇等增稠剂。所述悬浮液也可以包括一种或多种例如对羟基苯甲酸正丙酯或对羟基苯甲酸乙酯的防腐剂;一种或多种着色剂;一种或多种调味剂;以及一种或多种诸如糖精 或蔗糖的甜味剂。
可以用诸如例如丙二醇、甘油、蔗糖或山梨醇等甜味剂配制糖浆或酏剂。这样的制剂也可以包含缓和剂和防腐剂(诸如对羟基苯甲酸丙酯和对羟基苯甲酸甲酯)以及调味剂和着色剂。
本发明所述的化合物也可以以生理上可接受的稀释剂中该化合物的注射剂量非肠道给药,即皮下注射、静脉内注射、眼内给药、滑膜内给药、肌内给药或腹膜给药,所述稀释剂包含可以是诸如水、盐水、水性葡萄糖和相关糖溶液、诸如乙醇、异丙醇或十六醇的醇、诸如丙二醇或聚乙二醇的甘醇、诸如2,2-甲基-1,1-恶茂烷-4-甲醇的甘油缩酮、诸如聚乙二醇400的醚、油、脂肪酸、脂肪酸酯或脂肪酸甘油酯、或乙酰化的脂肪酸甘油酯的无菌液体或液体混合物的药物载体,其中包含或不含诸如脂肪酸盐的药学上可接受的表面活性剂或去垢剂、诸如卡波姆、果胶、甲基纤维素、羧甲基纤维素或羟丙基甲基纤维素的悬浮剂、或乳化剂以及其他药物佐剂。
可以在本发明的非肠道剂型中使用的油的例子是石油、合成来源的油、动物油或植物油,例如软石蜡、矿物油、花生油、大豆油、芝麻油、棉籽油、玉米油和橄榄油。适当的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。适当的脂肪酸酯是例如肉豆蔻酸异丙酯和油酸乙酯。适当的脂肪酸盐包括脂肪酸碱金属、脂肪酸铵和脂肪酸三乙胺,并且适当的表面活性剂包括阳离子表面活性剂,例如卤化烷基吡啶和醋酸烷基胺、卤化二甲基二烷基铵;阴离子表面活性剂,例如烷基、芳基和烯烃磺酸盐、烷基、烯烃、乙醚和单酸甘油脂硫酸盐以及磺基琥珀酸盐;非离子型表面活性剂,例如氧化脂肪胺、链烷醇酰胺脂肪酸、和聚(氧乙烯-氧丙基)或氧乙烯或氧丙烯共聚物;以及两性表面活性剂,例如2-烷基咪唑啉季铵盐和烷基-β-氨基丙酸盐,及其混合物。
本发明所述非肠道组合物通常应在溶液中包含重量比从约0.5%到约25%的活性成分。也可以方便地使用防腐剂和缓冲液。为了最小化或消除注射位置上的刺激,这样的组合物可以包含具有介于约12到约17之间的亲水-亲脂平衡常数(HLB)的非离子表面活性剂。在这样的剂型中的表面活性剂的含量介于重量比约5%到约15%之间。所述表面活性剂可以是具有以上HLB的单一组分或可以是具有所需HLB的两种或更多组分的混合物。
在所述非肠道剂型中使用的表面活性剂的例子是聚乙烯山梨糖醇脂肪酸酯类表面活性剂,例如山梨糖醇单油酸酯和氧乙烯与疏水碱通过丙二醇与过氧丙烯缩合形成的高分子量加合物。
所述药物组合物可以是无菌注射用水性悬浮液形式的。这样的悬浮液可以按照已知方法进行配制,其中使用适当的分散剂或湿润剂和诸如例如羧甲基纤维素钠、羟丙基甲基纤维素、甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄芪胶和阿拉伯树胶的悬浮剂;分散剂或湿润剂可以是诸如卵磷脂的天然磷脂、例如聚氧乙烯硬脂酸酯的烯化氧与脂肪酸的缩合产物、例如十七-乙烯氧十六醇的氧乙烯与长链脂肪醇的缩合产物、诸如聚氧乙烯山梨醇单油酸酯的氧乙烯与由脂肪酸和己糖醇衍生的部分酯的缩合产物、或是例如聚氧乙烯山梨聚糖单油酸酯的乙烯氧与从脂肪酸和己糖醇酐衍生的部分酯的缩合产物。
所述无菌的注射用制剂也可以是位于无毒的非肠道给药允许的稀释剂或溶剂中的无菌的注射用溶液或悬浮液。可以使用的稀释剂或溶剂是例如水、林格溶液、等压葡萄糖溶 液和等压氯化钠溶液。此外,无菌的不挥发油通常被用作溶剂或悬浮用媒介。为此目的,可以使用包括合成的甘油单酯或甘油二酯在内的任何无刺激性的不易挥发的油。此外,诸如油酸的脂肪酸可以用于注射剂的制备。
本发明所述组合物也可以以用于直肠给药的栓剂形式进行给药。这些组合物可以通过将药物与适当的无刺激赋形剂混合进行制备,其中所述赋形剂在通常温度下是固体但在直肠温度下是液体并从而能在直肠中熔解以释放药物。这样的材料例如是可可油和聚乙二醇。
本发明所述方法中使用的另一种剂型采用透皮递药装置(“药膏”)。这样的透皮药膏可以用于提供受控量的本发明所述化合物的连续或间断灌注。用于药物递送的透皮药膏的构建和使用是本领域内所熟知的(参见例如通过参考结合在本说明书中的1991年6月11日出版的美国专利No.5,023,252)。可以构建这样的药膏用于连续、脉冲、或按要求的药物递送。
可能要求或需要将所述药物组合物通过机械递送装置向患者给药。用于药物递送的机械递送装置的构建和使用是本领域内所熟知的。例如直接向脑部给药的直接递药技术通常包括将给药导管置于患者脑室系统以绕过血脑屏障。1991年4月30日出版的美国专利No.5,011,472中描述了这样一种用于向身体的特定解剖学区域运输物质的植入递药系统。
用于非肠道给药的控释制剂包括本领域内已知的脂质体、聚合物微粒和聚合物胶体制剂。
在需要或希望的情况下本发明所述组合物也可以包含通常称为载体或稀释剂的常规的药学上可接受的混合成分。可以采用制备适当剂量形式的这样的组合物的常规工艺。这样的成分和工艺包括在现有技术的参考文献中所描述的内容。针对其设计的给药路线与组合物剂型相匹配的常用药物成分包括:
●酸化剂(例子包括但不限于醋酸、柠檬酸、富马酸、盐酸、硝酸);
●碱化剂(例子包括但不限于氨溶液、碳酸铵、二乙醇胺、乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺);
●吸附剂(例子包括但不限于粉末状纤维素和活性碳);
●气溶胶喷射剂(例子包括但不限于二氧化碳、CCl2F2、F2ClC-CClF2、以及CClF3);
●空气置换剂(例子包括但不限于氮气和氩气);
●抗氧化剂(例子包括但不限于抗坏血酸、抗坏血酸棕榈酸盐、次磷酸、硫代甘油、丁羟茴醚、丁羟甲苯、丙基没食子酸、抗坏血酸钠、重亚硫酸钠、甲醛次硫酸氢钠、偏亚硫酸氢钠);
●抗真菌防腐剂(例子包括但不限于苯甲酸、对羟基苯甲酸丁酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、对羟基苯甲酸乙酯、苯甲酸钠);
●抗菌防腐剂(例子包括但不限于苄烷氯铵、苄索氯铵、三氯叔丁醇、苯甲基醇、苯乙醇、氯化十六烷基吡啶、苯酚、硝酸苯汞和硫柳汞钠);
●缓冲剂(例子包括但不限于偏磷酸钾、磷酸氢二钾、醋酸钠、无水柠檬酸钠、二水柠檬酸钠);
●粘合材料(例子包括但不限于嵌段聚合物、天然及合成橡胶、聚丙烯酸酯、聚亚胺酯、硅树脂、聚硅氧烷和苯乙烯-丁二烯共聚物);
●承载剂(例子包括但不限于阿拉伯树胶糖浆、芳香糖浆、芳香酏剂、樱桃糖浆、 橙味糖浆、糖浆、可可糖浆、玉米油、矿物油、花生油、芝麻油、抑菌氯化钠注射剂及抑菌注射用水);
●螯合剂(例子包括但不限于依地酸和依地酸二钠);
●着色剂(例子包括但不限于FD&C Red No.3、FD&C Red No.20、FD&C Yellow No.6、FD&C Blue No.2、D&C Green No.5、D&C Orange No.5、D&C Red No.8、焦糖以及氧化铁红);
●澄清剂(例子包括但不限于阿拉伯树胶、聚乙二醇、十六烷基醇、单硬脂酸甘油酯、卵磷脂、单油酸聚山梨醇酯、聚氧乙烯50单硬脂酸酯);
●胶囊剂(例子包括但不限于明胶及纤维醋法酯);
●食用香精(例子包括但不限于茴芹油、肉桂油、可可、薄荷醇、桔油、胡椒薄荷油和香兰素);
●保湿剂(例子包括但不限于甘油、丙二醇和山梨醇);
●研磨剂(例子包括但不限于矿物油和甘油);
●油膏基质(例子包括但不限于羊毛脂、亲水油膏、聚乙二醇油膏、矿脂、亲水矿脂、白油膏、黄油膏以及玫瑰红水油膏);
●油(例子包括但不限于落花生油、矿物油、橄榄油、花生油、芝麻油和植物油);
●渗透增强剂(透皮递药)(例子包括但不限于单羟基或多羟基醇、单价或多价醇、饱和或不饱和脂肪醇、饱和或不饱和脂肪酯、饱和或不饱和二羧基酸、香精油、磷脂酰衍生物、脑磷脂、萜烯、酰胺、醚、酮和脲);
●溶剂(例子包括但不限于乙醇、玉米油、棉籽油、甘油、异丙醇、矿物油、油酸、花生油、纯水、注射用水、注射用无菌水和输液用无菌水);
●可塑剂(例子包括但不限于邻苯二酸二乙酯和甘油);
●硬化剂(例子包括但不限于十六烷基醇、十六烷基酯、蜡、微晶蜡、石蜡、硬酯醇、白蜡和黄蜡);
●栓剂基质(例子包括但不限于可可油和聚乙二醇(混合物));
●表面活性剂(例子包括但不限于苄烷氯铵、壬苯聚醇10、oxtoxynol 9、聚山梨醇酯80、十二烷基硫酸钠和山梨聚醇单棕榈酸酯);
●悬浮剂(例子包括但不限于琼脂、膨润土、卡波姆、羧乙基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、高岭土、甲基纤维素、黄芪胶和硅酸镁铝(veegum));
●甜味剂(例子包括但不限于阿斯巴甜糖、右旋糖、甘油、甘露醇、丙二醇、糖精钠、山梨醇和蔗糖);
●药片粘合剂(例子包括但不限于阿拉伯树胶、海藻酸、羧甲基纤维素钠、可压性蔗糖、乙基纤维素、明胶、液体葡萄糖、甲基纤维素和明胶化淀粉);
●药片防粘剂(例子包括但不限于硬脂酸镁和滑石粉);
●药片及胶囊稀释剂(例子包括但不限于磷酸氢钙、高岭土、乳糖、甘露醇、微晶纤维素、粉末化纤维素、沉淀的碳酸钙、碳酸钠、磷酸钠、山梨醇和淀粉);
●药片包被剂(例子包括但不限于液体葡萄糖、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、纤维醋法酯和虫胶);
●药片直接压缩赋形剂(例子包括但不限于磷酸氢钙);
●药片崩裂剂(例子包括但不限于海藻酸、羧甲基纤维素钙、微晶纤维素、波拉克林钾(polacrillin potassium)、藻酸钠、羟乙酸钠淀粉和淀粉);
●药片滑润剂(例子包括但不限于硬脂酸钙、硬脂酸镁、矿物油、硬脂酸和硬脂酸锌);
●药片滑动剂(例子包括但不限于胶体硅、玉米淀粉和滑石粉);
●药片抛光剂(例子包括但不限于棕榈蜡和白蜡);
●药片/胶囊不透明剂(例子包括但不限于二氧化钛);
●增稠剂(例子包括但不限于蜂蜡、十六烷醇和石蜡);
●粘性增强剂(例子包括但不限于海藻酸、膨润土、卡波姆、羧甲基纤维素钠、甲基纤维素、藻酸钠和黄芪胶);
●张性剂(例子包括但不限于右旋糖和氯化钠);
●增湿剂(例子包括但不限于十七烷乙烯氧十六醇、卵磷脂、山梨醇单油酸酯、聚氧乙烯山梨醇单油酸酯和聚氧乙烯硬脂酸酯)。
本发明所述药物组合物的剂量
在已知的对可以用于治疗任何上述疾病的化合物进行评价的常规实验室技术的基础上,通过常规毒性测试和通过用于确定哺乳动物中上述症状疗效的常规药理学检测方法,并通过将这些结果与用于治疗这些症状的已知药物的结果进行比较,可以方便地确定本发明所述化合物对治疗每种所需指征治疗的有效剂量。在对这些病症中的一种进行治疗中所述活性成分的给药量可以大范围地变化,这取决于诸如所使用的具体化合物和剂量单位、给药方式、疗程、所治疗患者的年龄和性别以及所治疗病症的特征和程度等因素。
所述活性成分总的给药量可以介于约0.01毫克/千克到约50毫克/千克之间,并且优选地介于每天约0.1毫克到约10毫克每千克体重之间。单位剂量可以优选地含约1毫克到约300毫克活性成分,并可以每天一次或多次给药。口服给药的每日剂量应优选地介于0.1到5毫克每千克体重。通过注射给药(包括静脉注射、皮下注射、肌内注射和非肠道注射)以及使用灌注技术给药的每日剂量应优选地介于0.1到5毫克每千克体重。每日直肠给药方案应优选地介于0.1到15毫克每千克体重。每日局部给药方案应优选介于0.1到5毫克/千克每日给药1到4次。透皮浓度应优选需要维持0.1到3毫克/千克的日剂量。每日吸入给药方案应优选0.1到5毫克每千克体重。其他剂量和数量可以按常规选择。
具体的初始及持续剂量方案对于每位患者有所不同,这取决于主治医生所确定的病症的特征及严重程度、所使用具体化合物的活性、患者的年龄及身体状况、给药时间、给药路线、药物排泄速度、药物组合等等。治疗所需的模式以及本发明所述化合物或其药学上可接受的盐或组合物的剂量数可以由精通本领域的人员使用常规治疗检测加以确定。
与其他活性成分的组合用药
本发明所述化合物可以以单一药剂形式或与一种或多种其他药剂组合给药,其中所述的组合不引起不能接受的有害结果。这对于治疗诸如癌症的过度增殖性疾病可能是尤 其实用的。在这种情况下,本发明所述化合物可以与已知的细胞毒剂、信号转导抑制剂、或与其他抗肿瘤物质及其混合物和组合物组合使用。
在一种实施方式中,本发明所述化合物可以与细胞毒抗肿瘤物质组合使用。这些物质包括但不限于天冬酰胺酶、左旋门冬酰胺酶、博莱霉素、卡铂、顺铂、氮芥、卡氮芥、苯丁酸氮芥、环磷酰胺、阿糖胞苷、达卡巴嗪、放射菌素D、柔红霉素、表阿霉素、阿霉素、依托泊苷、6-巯基嘌呤、甲氨喋呤、5-氟尿嘧啶、六甲密胺、羟基脲、异环磷酰胺、甲酰四氢叶酸、洛莫司汀、美司钠、丝裂霉素C、盐酸米托蒽醌、甲苄肼、雷洛昔芬、链脲菌素、它莫西芬、硫鸟嘌呤、托泊替康、伊利替康、泼尼松龙、波尼松、长春碱、长春新碱、长春地辛。
其他适于与本发明所述化合物组合使用的细胞毒药物包括但不限于公认的用于治疗肿瘤疾病的那些化合物。这些物质包括但不限于氨鲁米特、L-天冬酰胺酶、硫唑嘌呤、5-氮杂胞苷、克拉屈滨、白消安、己烯雌酚、2’,2’-双氟去氧胞苷、普卡霉素、多烯紫杉醇、赤羟壬基腺嘌呤、雌三醇、5-氟脱氧尿苷、5-氟脱氧尿苷单磷酸盐、磷酸氟达拉滨、氟甲睾酮、氟他胺、己酸羟孕酮、紫杉醇、去甲氧柔红霉素、干扰素、醋酸甲羟孕酮、醋酸甲地孕酮、美法仑、米托坦、N-二氧磷乙酰-L-天冬氨酸盐(PALA)、喷司他丁、司莫司汀、替尼泊甙、丙酸睾酮、噻替派、三甲基蜜胺、尿嘧啶以及长春瑞滨。
其他适于与本发明所述化合物组合使用的细胞毒抗肿瘤物质也包括新发现的细胞毒剂,诸如吉西他滨、卡培他滨、埃博霉素、奥沙利铂及其天然和合成的衍生物、替莫唑胺、托西莫单抗(Bexxar)、trabedectin、以及驱动蛋白纺锤体蛋白Eg5的抑制剂。
在另一种实施方式中,本发明所述化合物可以与其他信号转导抑制剂组合使用。特别感兴趣的是针对EGFR家族(诸如EGFR、HER-2和HER-4)及其各自的配体的信号转导抑制剂。这样的物质的例子包括但不限于诸如赫赛汀(曲妥珠单抗)、艾比特思(西妥昔单抗)和波替珠单抗(pertuzumab)的抗体药物。这样的药物的例子也包括但不限于小分子激酶抑制剂,诸如ZD-1839/Iressa、CM033、OSI-774/Tarceva、CP-724,714、EKB-569及GW-2016。
本发明的化合物与现有技术中已知的不携带氘的化合物相比,具有一系列的优点。本发明的主要优点包括:
(1)本发明化合物对酪氨酸激酶诸如c-Met具有优异的抑制活性。
(2)本发明的化合物相较于未氘化的化合物相比,在动物体内更不容易被代谢,这导致首过效应的降低,因此可以改变剂量并形成长效制剂,其也可以长效制剂的形式改善适用性。
(3)通过氘化还改变了药代动力学作用,使得本发明的化合物在生物体中的分布明显不同于未氘代的化合物。
(4)本发明的化合物在动物体内的药物浓度更高,从而提高了药效。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1 3-[(2-氘-6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪(Ⅱ)的制备
步骤1:6-溴喹啉-1-氧(Ⅲ)
Figure PCTCN2016085480-appb-000015
将20克6-溴喹啉溶于200毫升二氯甲烷中,于冰浴搅拌下滴加含21.5克间氯过氧苯甲酸的200毫升二氯甲烷溶液,加完后室温搅拌过夜。反应液以饱和硫代硫酸钠溶液洗,有机相浓缩至干,得浅棕色固体19.4克,收率90%。1H-NMR(300Hz,DMSO-d6)δ:8.63(d,J=6.3Hz,1H),8.42-8.47(m,2H),7.89-7.96(m,2H),7.51-7.56(m,1H).
步骤2:2-氘-6-溴喹啉-1-氧(Ⅳ)
Figure PCTCN2016085480-appb-000016
将10克6-溴喹啉-1-氧,10.7克叔丁醇钠,氘水33毫升的混合物于100℃油浴加热12小时。将反应液冷却至室温,以二氯甲烷萃取,有机层浓缩至干,得浅黄色固体6.7克,收率67%。1H-NMR(300Hz,DMSO-d6)δ:7.55(d,J=8.4Hz,1H),7.89-7.97(m,2H),8.42-8.47(m,2H).LRMS(ESI)m/z[M+H]+:225.3.
步骤3:2-氘-6-溴喹啉(Ⅴ)
Figure PCTCN2016085480-appb-000017
将4克2-氘-6-溴喹啉-1-氧溶于70毫升冰醋酸中,分批加入8克铁粉,加热回流3小时。将反应液浓缩至干,残余物加水溶解,以碳酸钠固体调pH=8,以二氯甲烷萃取,有机层浓缩至干,得浅棕色油状物2.5克,收率67%。1H-NMR(300Hz,CDCl3)δ:8.10(d,J=8.1Hz,1H),7.97-8.00(m,2H),7.81(dd,J=2.4,9.0Hz,1H),7.45(d,J=8.7Hz,1H).
步骤4:2-氘-6-碘喹啉(Ⅵ)
Figure PCTCN2016085480-appb-000018
将1克2-氘-6-溴喹啉,碘化亚铜182毫克,碘化钠1.43克,N,N-二甲基乙二胺0.22毫升,1,4-二氧六环10毫升的混合物回流过夜。将反应液冷却至室温,过滤,滤饼乙酸乙酯洗,滤液浓缩至干,得浅黄色固体1.1克,收率90%。1H-NMR(300Hz,CDCl3)δ:8.23(s,1H),8.07(d,J=8.1Hz,1H),7.97(dd,J=1.2,8.7Hz,1H),7.86(d,J=8.7Hz,1H),7.44(d,J=8.4Hz,1H).
步骤5:2-(2-氘-6-喹啉基)-2,2-二氟乙酰肼(Ⅶ)
Figure PCTCN2016085480-appb-000019
将2-氘-6-碘喹啉3克,二氟溴乙酸乙酯3毫升,纳米铜粉2.08克,二甲亚砜30毫升,于80℃加热搅拌过夜。将反应液冷却至室温,以乙酸乙酯稀释反应液,以饱和食盐水洗之,有机层浓缩至干,得棕色油状物。
将以上得到的棕色油状物溶于30毫升甲醇中,加入0.7毫升水合肼(85%),80℃反应1小时,将反应液浓缩至干,残余物柱层析,得浅黄色固体1.1克,收率39.4%。1H-NMR(300Hz,DMSO-d6)δ:10.39(br s,1H),8.57(d,J=8.4Hz,1H),8.28(s,1H),8.18(d,J=8.7Hz,1H),7.92(dd,J=1.8,8.7Hz,1H),7.66(d,J=8.4Hz,1H),4.73(br s,2H)
步骤6:3-[(2-氘-6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪(Ⅱ)
Figure PCTCN2016085480-appb-000020
将2-(2-氘-6-喹啉基)-2,2-二氟乙酰肼3克,3-氯-6-(1-甲基-1H-吡唑-4-基)哒嗪1.64克,甲烷磺酸1.5克,正丁醇33毫升置封管中,90℃加热搅拌过夜。将反应液浓缩至干,加水溶解,以氨水调pH=8,以二氯甲烷萃取,有机层浓缩至干,残余物柱层析,得黄色固体2.5克,收率79%。1H-NMR(300Hz,CDCl3)δ:8.24-8.28(m,3H),8.16(d,J=10.0Hz,1H),8.09(dd,J=2.0,8.8Hz,1H),7.98(d,J=9.6Hz,2H),7.51(d,J=8.4Hz,1H),7.42(d,J=9.6Hz,1H),4.01(s,3H).LRMS(EI)m/z[M]+:378.
实施例2 化合物Ⅱ在猴肝S9中代谢研究
每个体外孵化体系总体积为200μL,介质为100mM磷酸缓冲液(PBS,pH7.4),包括终浓度为3μM的JNJ38877605或化合物Ⅱ和2mM的NADPH,采用37℃水浴进行孵化。预孵化3min后,向缓冲液-底物-辅助因子混合物中分别加入猴肝S9蛋白起始反应,反应60min后加入同体积冰冷乙腈终止反应。对照组别实验条件同上,但NADPH以PBS代替;此外,空白对照组中,S9蛋白经过高温失活处理。所有孵化样本均为双样本。
取双样本各取200μL合并,加入400μL乙腈,涡流混合1min,离心5min(14000rpm),全部上清液取出,转移至10mL塑料管中,40℃氮气流下吹干,残留物以80μL乙腈-水(10:90,v/v)溶解,取10μL进行UPLC-UV/Q-TOF MS分析。
采用UPLC-UV/Q-TOF MS法鉴定了JNJ38877605和化合物Ⅱ猴肝S9孵化体系中可能的代谢产物,结果显示化合物Ⅱ的原型药物的比例比JNJ38877605高31.8%。表明化合物Ⅱ的药动学性质明显优于JNJ38877605。
实施例3 化合物Ⅱ灌胃给药后在食蟹猴体内药动学试验
食蟹猴4只,分别灌胃给予受试化合物,具体安排如下:
组别 动物数 给药化合物 给药剂量(mg/kg) 给药体积(mL/kg)
1 2 JNJ-38877605 10 5
2 2 化合物Ⅱ 10 5
给药前(0h)及给药后0.25、0.5、1.0、2.0、4.0、8.0、12和24h经四肢静脉取静脉血0.8mL,置EDTA抗凝试管中,3500rpm离心10min,分离血浆,–70℃冰箱中冷冻保存待测。
采用LC/MS/MS法测定血浆中的浓度,采用UPLC-Q/TOF-MS法鉴定血浆、和尿中可能代谢物。
采用WinNonlin 6.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
食蟹猴分别灌胃给予10mg/kg化合物Ⅱ和JNJ38877605后的血浆浓度-时间曲线见图1。
灌胃给药后,化合物Ⅱ在食蟹猴的暴露量Cmax和AUC0-t分别为JNJ38877605的1.56倍和2.29倍。
从上面结果看出,本发明化合物在动物体内具有更好的药物动力学,因而将具有更好的药效学和治疗效果。
实施例4 化合物Ⅱ对人肺癌EBC-1裸小鼠皮下移植瘤的生长抑制作用
BALB/cA裸小鼠。每组动物数:阴性对照组6只,给药组6只。
人肺癌EBC-1细胞株接种裸小鼠右侧腋窝皮下,细胞接种量为5×106/只,形成移植瘤后再在裸小鼠体内传1代后使用。
取生长旺盛期的瘤组织剪切成1.5mm3左右,在无菌条件下,接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径,待肿瘤平均体积生长至176mm3左右后动物随机分组。化合物Ⅱ和JNJ38877605以5mg/kg为给药剂量,每天口服给药两次,连续给药21天。溶剂对照组给等量溶剂。整个实验过程中,每周2次测量移植瘤直径,同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。
抗肿瘤活性的评价指标为:
1)相对肿瘤增殖率T/C(%),计算公式如下:T/C(%)=(TRTV/CRTV)×100%,TRTV:治疗组RTV;CRTV:阴性对照组RTV;
2)肿瘤体积增长抑制率GI%,计算公式如下:TGI%=[1-(TVt-TV0)/(CVt-CV0)]×100%,TVt为治疗组每次测量的瘤体积;TV0为治疗组分笼给药时所得瘤体积;CVt为对照组每次测量的瘤体积;CV0为对照组分笼给药时所得瘤体积;
3)瘤重抑制率,计算公式如下:瘤重抑制率%=(WC-WT)/WC×100%,WC:对照组瘤重,WT:治疗组瘤重。
实验结果如图2所示。化合物Ⅱ和JNJ38877605在5mg/kg给药剂量下,每天口服给药两次,连续给药21天,对人肺癌EBC-1裸小鼠皮下移植瘤的生长均有极其显著的抑制作用。其中化合物Ⅱ在第21天所得T/C百分数为9.98%,肿瘤增长抑制率(TGI)为90.4%,而JNJ38877605第21天所得T/C百分数21.56%,肿瘤增长抑制率(TGI)为83.8%。实验治疗期间各给药组小鼠均状态良好。
实施例5药物组合物
药片
Figure PCTCN2016085480-appb-000021
将上述物质混合均匀,通过常规工艺制备1000片药片。可以使用适当的水性或非水性包衣以提高适口程度、改善外观和稳定性或延缓吸收。
胶囊
化合物Ⅱ(实施例1)    30g
淀粉                 140g
微晶纤维素           60g
按常规方法,将上述物质混合均匀,装入普通明胶胶囊,制备1000颗胶囊。
无菌IV溶液
化合物Ⅱ(实施例1)    0.2g
无菌注射用水         50mL
将化合物Ⅱ用无菌的注射用水配制成4毫克/毫升溶液并按需要调节pH。用5%无菌右旋糖稀释至1.5-2.0毫克/毫升静脉输液给药。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种如下式(Ⅰ)所示的化合物:
    Figure PCTCN2016085480-appb-100001
    式中:
    D代表氘原子;
    R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地为氢原子或氘原子;
    R10选自下组:CH3、CH2D、CHD2、或CD3
  2. 如权利要求1所述的化合物,其特征在于,
    R1、R2、R3、R4、R5、R6、R7、R8、R9均为氢原子;
    R10为CH3
  3. 一种制备药物组合物的方法,其特征在于,包括步骤:将药学上可接受的载体与权利要求1或2所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合,从而形成药物组合物。
  4. 一种药物组合物,其特征在于,包括:治疗有效量的权利要求1或2所述的式I化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物;和药学上可接受的载体。
  5. 如权利要求4所述的药物组合物,其特征在于,包括治疗有效量的式II化合物即3-[(2-氘-6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪、或其晶型、药学上可接受的盐、水合物或溶剂合物:
    Figure PCTCN2016085480-appb-100002
    和药学上可接受的载体。
  6. 如权利要求4或5所述的药物组合物,其特征在于,所述的药物组合物还包括治疗有效量的其他活性成分,且所述的其他活性成分包括选自下组的一种或多种活性成分:细胞毒剂、信号转导抑制剂,和其他抗肿瘤物质。
  7. 一种如权利要求1所述的式(I)化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物的用途,其特征在于,用于制备治疗酪氨酸激酶,尤其是c-Met介导的疾病的药物组合物。
  8. 如权利要求7所述的用途,其特征在于,所述的疾病选自下组:乳头状瘤、芽状神经胶质瘤、黑素瘤、肺癌、卵巢癌、前列腺癌、鳞状细胞癌、星细胞瘤、头癌、颈 癌、膀胱癌、乳癌、结肠直肠癌、甲状腺癌、胰腺癌、胃癌、肝细胞癌、白血病、淋巴瘤、血管瘤、瘢痕瘤、呼吸道癌、脑癌、生殖器官癌、消化道癌、尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、副甲状腺癌及其远距离转移灶、淋巴瘤、肉瘤、结肠癌、骨癌、肾癌、睾丸癌、皮肤癌、肾细胞癌、非小细胞肺癌。
  9. 一种制备权利要求2所述的式II化合物3-[(2-氘-6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪的方法,
    Figure PCTCN2016085480-appb-100003
    其特征在于,包括步骤:
    Figure PCTCN2016085480-appb-100004
    在有机溶剂中,用式(VII)化合物和式(VIII)化合物进行关环反应,得到式(II)化合物。
  10. 如权利要求9所述的方法,其特征在于,所述的式(VII)化合物是通过以下方法制备的:
    Figure PCTCN2016085480-appb-100005
    在有机溶剂中,用式(VI)化合物与二氟溴乙酸乙酯和水合肼反应,得到式(VII)化合物。
PCT/CN2016/085480 2015-06-11 2016-06-12 氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪及其应用 WO2016197981A1 (zh)

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