CN106279176B - Deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine and application thereof - Google Patents

Deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine and application thereof Download PDF

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CN106279176B
CN106279176B CN201510319730.2A CN201510319730A CN106279176B CN 106279176 B CN106279176 B CN 106279176B CN 201510319730 A CN201510319730 A CN 201510319730A CN 106279176 B CN106279176 B CN 106279176B
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段文虎
耿美玉
詹正生
艾菁
丁健
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Shanghai Institute of Materia Medica of CAS
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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
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    • 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
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    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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Abstract

The invention relates to deuterated 3- [ (6-quinolyl) difluoromethyl]-6- [ (1-methyl) -4-pyrazolyl][1,2,4]Triazolo [4,3-b]The application of pyridazine (formula I) or crystal form and pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the compound or the crystal form or the pharmaceutically acceptable salt thereof in preparing medicines for preventing or treating diseases mediated by protein tyrosine kinase, especially c-Met kinase signal.

Description

Deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine and application thereof
Technical Field
The invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to application of deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine or crystal form and pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the compound or the crystal form or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating diseases mediated by protein tyrosine kinase, especially c-Met kinase signal.
Background
The known [1,2,4] triazolo [4,3-b ] pyridazine compounds are selective c-Met inhibitors and have been disclosed in patents WO2007075567A1 and WO2008155378A1 for the treatment of neoplastic diseases caused by dysregulation of tyrosine kinases including c-Met kinase.
Protein Tyrosine Kinases (PTKs) are a class of enzymes that regulate a variety of important biological functions, including cell growth, differentiation, organ formation, neovascularization, tissue repair and regeneration, and the like. Protein tyrosine kinases exert their biological effects by catalyzing the phosphorylation of protein tyrosine residues, which then modulate the biological activity of substrate proteins. Dysregulation of one class of protein tyrosine kinases may lead to tumor formation and growth, and further play an important role in tumor survival and progression (Blume J P, Hunter T. oncogeneic kinase signaling [ J ] Nature,2001,411(6835): 355-. Therefore, protein tyrosine kinases closely related to tumors represent one of the most important protein targets for cancer therapy and drug development.
c-Met is Hepatocyte Growth Factor Receptor (HGFR), encoded by the MET proto-oncogene. c-Met is highly expressed in most cancers and partial sarcomas and is closely related to poor prognosis, such as lung cancer, breast cancer, colon cancer, prostatic cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, renal cancer, glioma, melanoma and the like. c-Met activates tyrosine kinase in intracellular segment through interaction with ligand HGF/SF or other ways, induces cell proliferation, invasion and migration, inhibits apoptosis, promotes angiogenesis, and plays an important role in the process of generating and developing tumors.
In view of the above, there is an urgent need in the art to develop novel drugs having protein tyrosine kinase inhibitory activity, particularly c-Met inhibitory activity.
Disclosure of Invention
The invention aims to provide a novel medicine with protein tyrosine kinase inhibitory activity, in particular with c-Met inhibitory activity.
In a first aspect of the present invention, there is provided a compound represented by the following formula (i):
Figure BDA0000736295950000021
in the formula:
d represents a deuterium atom;
R1、R2、R3、R4、R5、R6、R7、R8、R9each independently is a hydrogen atom or a deuterium atom;
R10selected from the group consisting of: CH (CH)3、CH2D、CHD2Or CD3。
In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.
In another preferred embodiment, all or substantially (e.g., N, C, F, etc.) of the elements other than H in the compound of formula (I)>99 wt.%) is the most abundant naturally occurring element, e.g.14N、12C and19F。
in another preferred embodiment, R1、R2、R3、R4、R5、R6、R7、R8、R9Are each a hydrogen atom;
R10is CH3。
In another preferred embodiment, the compound of formula I is the following compound II.
Figure BDA0000736295950000022
In a second aspect of the present invention, there is provided a process for preparing a pharmaceutical composition, the process comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound according to the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to form a pharmaceutical composition.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula I as described in the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula II, namely 3- [ (2-deuterium-6-quinolinyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine, or a crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof:
Figure BDA0000736295950000031
and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises a therapeutically effective amount of other active ingredients, and the other active ingredients comprise one or more active ingredients selected from the group consisting of: cytotoxic agents, signal transduction inhibitors, and other anti-tumor substances.
In another preferred embodiment, the pharmaceutical composition is for the treatment or prevention of a disease associated with tyrosine kinase activity or expression, preferably with c-Met activity or expression.
In another preferred embodiment, the disease is selected from the group consisting of: papilloma, gemma 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 tract cancer, brain cancer, genital cancer, cancer of the digestive tract, cancer of the urinary tract, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and distant metastases thereof, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma, non-small cell lung cancer.
In another preferred embodiment, the pharmaceutical composition is a formulation selected from the group consisting of: tablets, capsules, pills, powders, granules or injections; preferably tablets, capsules, or intravenous injections.
In another preferred embodiment, when the pharmaceutical composition is a tablet, the pharmaceutical composition comprises a carrier selected from the group consisting of: colloidal silicon dioxide, magnesium stearate, modified starch, microcrystalline cellulose, lactose, or combinations thereof.
In another preferred embodiment, 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.
In another preferred embodiment, when the pharmaceutical composition is an intravenous injection, the pharmaceutical composition comprises a carrier selected from the group consisting of: sterile water for injection.
In another preferred embodiment, the pharmaceutical composition is a depot formulation.
In a fourth aspect of the present invention, there is provided the use of a compound of formula (I), as described in the first aspect of the present invention, or a crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a pharmaceutical composition for the treatment of tyrosine kinases, especially c-Met mediated diseases.
In another preferred embodiment, the disease is selected from the group consisting of: papilloma, gemma 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 tract cancer, brain cancer, genital cancer, cancer of the digestive tract, cancer of the urinary tract, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and distant metastases thereof, lymphoma, sarcoma, colon cancer, bone cancer, kidney cancer, testicular cancer, skin cancer, renal cell carcinoma, non-small cell lung cancer.
In a fifth aspect of the invention, there is provided a process for the preparation of 3- [ (2-deuterium-6-quinolinyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine, a compound of formula II according to the first aspect of the invention,
Figure BDA0000736295950000041
the method is characterized by comprising the following steps:
Figure BDA0000736295950000042
and (3) carrying out a ring closing reaction on the compound of the formula (VII) and the compound of the formula (VIII) in an organic solvent to obtain the compound of the formula (II).
In another preferred embodiment, the ring closure reaction is carried out in the presence of dioxane and methanesulfonic acid.
In another preferred embodiment, the organic solvent is a solvent selected from the group consisting of: dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, N-butanol, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
In another preferred embodiment, the reaction is carried out at 60 to 130 ℃.
In another preferred embodiment, the reaction time is 8 to 16 hours.
In another preferred embodiment, the compound of formula (VII) is prepared by the following process:
Figure BDA0000736295950000051
reacting the compound of formula (VI) with ethyl difluorobromoacetate and hydrazine hydrate in an organic solvent to obtain the compound of formula (VII).
In another preferred embodiment, the reaction is carried out in the presence of copper powder; preferably, compound (VI) is condensed with ethyl difluorobromoacetate in the presence of copper powder and then reacted with hydrazine hydrate to give compound of formula (VII).
In another preferred embodiment, the organic solvent is a solvent selected from the group consisting of: dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, N-butanol, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
In another preferred embodiment, the reaction is carried out at 60-100 ℃.
In another preferred embodiment, the reaction time is 18 to 30 hours.
In another preferred embodiment, the compound of formula (VI) is prepared by the following process:
Figure BDA0000736295950000052
reacting a compound of formula (V) with an iodinating agent in an organic solvent to obtain a compound of formula (VI); preferably, the iodinating agent is sodium iodide, cuprous iodide and N, N-dimethylethylenediamine.
In another preferred embodiment, the organic solvent is a solvent selected from the group consisting of: dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, N-butanol, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
In another preferred embodiment, the reaction is carried out at 80-140 ℃.
In another preferred embodiment, the reaction time is 8 to 16 hours.
In another preferred embodiment, the compound of formula (V) is prepared by the following process:
Figure BDA0000736295950000053
carrying out reduction reaction on a compound shown in a formula (IV) and a reducing agent in an organic solvent to obtain a compound shown in a formula (V); preferably, the reducing agent is iron powder; more preferably, the reduction reaction is carried out in the presence of glacial acetic acid.
In another preferred embodiment, the organic solvent is a solvent selected from the group consisting of: dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, N-butanol, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
In another preferred embodiment, the reaction is carried out at 80-140 ℃.
In another preferred embodiment, the reaction time is 1 to 5 hours.
In another preferred embodiment, the compound of formula (IV) is prepared by the following process:
Figure BDA0000736295950000061
carrying out deuteration reaction on the compound of the formula (III) in an organic solvent to obtain a compound of a formula (IV); preferably, the deuteration reaction is carried out in the presence of heavy water and/or sodium tert-butoxide.
In another preferred embodiment, the organic solvent is a solvent selected from the group consisting of: dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, N-butanol, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
In another preferred embodiment, the reaction is carried out at 70-130 ℃.
In another preferred embodiment, the reaction time is 8 to 16 hours.
In another preferred embodiment, the compound of formula (III) is prepared by the following process:
Figure BDA0000736295950000062
carrying out oxidation reaction by using 6-bromoquinoline in an organic solvent to obtain a compound (III); preferably, the oxidation reaction uses m-chloroperoxybenzoic acid as an oxidizing agent.
In another preferred embodiment, the organic solvent is a solvent selected from the group consisting of: dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, N-butanol, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, glacial acetic acid, or a combination thereof.
In another preferred embodiment, the reaction is carried out at 10-40 ℃.
In another preferred embodiment, the reaction time is 8 to 16 hours.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 plasma concentration-time curves of cynomolgus monkeys gavage 10mg/kg Compound II and JNJ38877605, respectively;
FIG. 2 shows the growth inhibitory effect of Compound II and JNJ38877605 on human lung carcinoma EBC-1 nude mouse transplantable tumors.
Detailed Description
The inventors of the present invention have conducted extensive and intensive studies for a long time, and have unexpectedly found that deuterated [1,2,4] triazolo [4,3-b ] pyridazine compounds have excellent protein tyrosine kinase inhibitory activity, remarkably improved pharmacokinetics, and higher exposure to animals after administration, thereby having better therapeutic effects. Based on the above findings, the inventors have completed the present invention.
Term(s) for
Unless otherwise specified, in the present invention, the deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.
Deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine
The invention provides a novel compound with c-Met inhibitory activity and better pharmacodynamic performance and application thereof, namely deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine shown in a formula (I), a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:
Figure BDA0000736295950000071
in the formula:
d represents a deuterium atom;
R1、R2、R3、R4、R5、R6、R7、R8、R9each independently is a hydrogen atom or a deuterium atom;
R10is CH3、CH2D、CHD2Or CD3；
Preferably, R1、R2、R3、R4、R5、R6、R7、R8、R9Are each a hydrogen atom, R10Is CH3The compound is the following compound II:
Figure BDA0000736295950000081
preparation of deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine
Deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine according to the invention can be prepared by a method commonly used in the art for preparing deuterated compounds, for example, in a preferred embodiment of the invention, the method for preparing the compound II comprises the following steps: starting from 6-bromoquinoline, obtaining an intermediate (VII) through oxidation, deuteration, reduction, iodine substitution, coupling and hydrazinoation, and then closing a ring with a compound (VIII) to obtain a target product.
Figure BDA0000736295950000082
Specifically, the preparation method comprises the following steps:
starting from 6-bromoquinoline, oxidizing by m-chloroperoxybenzoic acid to obtain a compound (III);
reacting the compound (III) with sodium tert-butoxide by using heavy water to obtain a deuterated compound (IV);
the compound (IV) is reduced into a compound (V) by iron powder in the presence of glacial acetic acid;
compound (V) is converted into compound (VI) in the presence of sodium iodide, cuprous iodide and N, N-dimethylethylenediamine;
condensing the compound (VI) with ethyl difluorobromoacetate in the presence of copper powder, and then reacting with hydrazine hydrate to obtain an intermediate (VII);
and (5) carrying out ring closure on the intermediate (VII) and the intermediate (VIII) in the presence of methane sulfonic acid to obtain a compound (II).
Active ingredient
As used herein, the term "compounds of the present invention" refers to compounds of formula (I). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (i).
The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for salt formation include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
Pharmacokinetic and pharmacodynamic evaluation of Compound II (compare with prototype JNJ 38877605)
JNJ38877605 is a c-Met inhibitor developed by Johnson & Johnson company, and the compound II prepared by deuteration of the compound II has obviously better pharmacokinetic and/or pharmacodynamic properties than the compound JNJ38877605, so the compound II is more suitable for being used as a compound for inhibiting c-Met kinase and is further more suitable for preparing medicines for treating cancers and related diseases.
Figure BDA0000736295950000091
The pharmacokinetic results show that the plasma peak concentration C of the compound II in the cynomolgus monkey is equal to the administration dosagemaxAnd exposure AUC0-t1.56 times and 2.29 times of JNJ38877605 respectively; pharmacodynamic results in a human lung cancer EBC-1 nude mouse transplantation model showed that the drug concentration was 5mg/kg per mouseAfter the compound II is continuously administrated for 21 days under the treatment dosage of twice a day, the tumor growth inhibition rate (TGI) of the compound II is 90.4 percent, and the compound II is obviously superior to the inhibition effect of JNJ38877605 (the TGI is 83.8 percent) on the tumor growth under the same dosage.
The results show that the compound II has obviously better pharmacokinetic and pharmacodynamic properties than JNJ38877605, and has potential value in developing antitumor drugs accepted by human bodies.
Application method
The present invention provides compounds capable of modulating signal transduction pathways mediated by protein tyrosine kinases, particularly 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. Dysregulation of the c-Met signaling pathway is the most prevalent occurrence in human cancers. Disruption of c-Met signal was demonstrated in many solid and hematological tumors. The most compelling evidence linking c-Met and cancer is the over-expression of c-Met in almost all initially discovered bodies of patients with hereditary renal Papilloma (PRCC). Chromosome 7 trisomy carrying the HGF and c-Met genes is ubiquitous in PRCC patients. The c-Met mutation has also been reported to occur in many cancers, such as gastric cancer, brain tumor, liver cancer, ovarian cancer, non-small cell lung cancer, thyroid cancer, and the like. The potential carcinogenicity of several c-Met mutants has been confirmed in preclinical models. The compounds described herein may be used to inhibit their activity.
The term "modulate" refers to a change in the functional activity of the pathway (or a component thereof) as compared to the normal activity in the absence of the compound. Such effects include modulation of any amount or degree, including enhancement, stimulation, activation, enhancement, increase, promotion, reduction, hindrance, inhibition, antagonism, and the like.
The compounds of the invention may also modulate one or more processes including, but not limited to, for example, cell growth (including, e.g., differentiation, cell survival and/or proliferation), tumor regression, and the like.
While not wishing to be bound by any mechanism or mechanism of action, it has been found that the compounds of the present invention have the ability to modulate kinase activity. However, the methods of the invention are not limited to any particular mechanism or how the compounds achieve their therapeutic effect. The term "kinase activity" refers to a catalytic activity in which a gamma phosphate is transferred from Adenosine Triphosphate (ATP) to an amino acid residue (e.g., serine, threonine or tyrosine) in a protein substrate. The compounds can modulate kinase activity, for example, by directly competing with ATP for its ATP-binding site, inhibiting its activity by producing a conformational change in the structure of the enzyme (e.g., by disrupting a three-dimensional structure with biological activity), and the like.
The compounds of the present invention may be used in the treatment and/or prevention of any disease or condition in which an abnormality in the cellular signal transduction pathway mediated by a protein tyrosine kinase, especially c-Met kinase, is implicated. The term "treating" is used in its conventional sense, e.g., to treat or care for a patient for the purpose of combating, alleviating, reducing, eliminating, ameliorating the symptoms of a disease or disorder, and the like. The compounds may also be described for use in the prevention and/or treatment of diseases and/or conditions mediated by the signaling molecule. The term "mediate" means, for example, that the signaling molecule is part of a pathway that is abnormal or aberrant in the disease and/or disorder.
Diseases and conditions that may be treated include any of the diseases mentioned above and below as well as related diseases caused by abnormalities in c-Met including, for example, cell proliferation disorders, cancer, tumors, and the like. The disease includes papilloma, 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, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, hemangioma, keloid.
The methods of the invention include modulating tumor cell proliferation, including inhibiting cell proliferation. The latter means that the growth and/or differentiation of the tumor cells is reduced, diminished, weakened, slowed down, etc. The term "proliferation" includes any process involving cell growth and division, and includes differentiation and apoptosis. As described above, c-Met kinase plays an important role in the activation of cytoplasmic signaling cascades involved in cell proliferation, differentiation and apoptosis.
The methods of the present invention include methods of using a compound described above (a compound of formula (I)), including or crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates thereof, and compositions thereof, to treat a hyperproliferative disease in a mammal, including a human in need thereof, in an amount effective to treat the disease. Hyperproliferative diseases include, but are not limited to, solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and distant metastases thereof. These diseases also include lymphomas, sarcomas and leukemias.
Any tumor may be treated, including but not limited to tumors having one or more mutations in c-Met and any upstream or downstream members of the signaling pathway in which it is involved. As previously mentioned, tumors can be treated with the compounds of the present invention without regard to their corresponding mechanism. Tumors 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, gastric cancer, colorectal cancer, renal cell carcinoma, hepatocellular carcinoma, melanoma, and the like.
Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to, small and non-small cell lung cancers, as well as bronchial adenomas and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to, brain stem and pituitary gliomas, medulloblastomas, cerebellum and brain astrocytomas, ependymomas, as well as extraneural and pineal adenomas.
Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of female reproductive organs include, but are not limited to, ovarian, endometrial, cervical, vaginal, and vulvar cancers, as well as uterine sarcomas.
Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, rectal, stomach, small intestine, and salivary gland cancers.
Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (with or without the presence of a fibrolamellar form of hepatocellular carcinoma), cholangiocellular carcinoma, and mixed hepatocellular cholangiocellular carcinoma.
Skin cancers include, but are not limited to, kaposi's sarcoma, squamous cell tumor, malignant melanoma, merkel cell skin cancer, and non-melanoma skin cancer.
Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, and/or oropharyngeal cancer, as well as lip and oral cancer.
Lymphomas include, but are not limited to, non-hodgkin's lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, hodgkin's disease, and central nervous system lymphoma.
Sarcomas include, but are not limited to, chondrosarcoma, histiocytoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and villous cell leukemia.
In addition to inhibiting tumor cell proliferation, the compounds of the present invention can also cause tumor regression, e.g., a decrease in tumor size or a decrease in the spread of tumors in vivo.
Pharmaceutical compositions based on the compounds of the invention
The invention also relates to a pharmaceutical composition containing the compound or the crystal form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof, and the pharmaceutically acceptable salt thereof. These compositions can be administered to a patient in need thereof to achieve a desired pharmacological effect. It is an object of the present invention that the patient be a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention includes a pharmaceutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the present invention or a salt thereof. A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and harmless to the patient at concentrations commensurate with the effective activity of the active ingredient so that any side effects caused by the carrier do not detract from the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is an amount that produces an effect or exerts an effect on the particular condition being treated. The compounds of the present invention may be administered orally, parenterally, topically, ocularly, nasally, sublingually, rectally, vaginally, etc., in any effective conventional dosage unit form, including fast-release, sustained-release and timed-release formulations, in a pharmaceutically acceptable carrier well known in the art.
For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, dragees, lozenges, powders, melts, solutions, emulsions or suspensions, and may be prepared according to methods known in the art for the manufacture of pharmaceutical compositions. The solid unit dosage form may be a conventional soft or hard shell gelatin-type capsule containing, for example, surfactants, lubricants and inert fillers such as sucrose, lactose, corn starch and calcium phosphate.
In another embodiment, the compounds of the present invention may be formulated with conventional tablet bases such as lactose, sucrose and corn starch in combination with binders such as acacia, gelatin or corn starch; disintegrants for assisting in tablet splitting and dissolution after administration such as potato starch, corn starch, alginic acid, and guar gum, gum arabic, gum tragacanth and the like; lubricants such as talc, stearic acid or magnesium stearate, calcium or zinc, which are used to enhance the tablet granulation flow and prevent sticking of the tablet material to the tablet dies and tablet press; the tablets are prepared with a combination of dyes, colorants, and flavoring agents such as wintergreen oil, peppermint oil, or cherry flavoring to improve the appearance and quality of the tablets and make them more acceptable to the patient. Suitable excipients for oral solid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyethylene glycol) with or without pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Various other materials may be present in sugar coated form or to otherwise 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 preparing aqueous suspensions. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable wetting or dispersing agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents such as those described above, may also be present.
The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifiers may be (1) natural phospholipids, such as soya lecithin and lecithin, (2) natural gums, such as gum arabic and tragacanth, (3) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate, (4) fatty acids and hexitol anhydrides in the form of esters or partial ester derivatives, for example sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example olive oil, arachis oil, coconut oil or sesame oil, or in a mineral oil such as liquid paraffin. The oily suspensions 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 paraben or ethyl paraben; one or more colorants; one or more flavoring agents; and one or more sweetening agents such as saccharin or sucrose.
Syrups or elixirs may be formulated with sweetening agents, for example propylene glycol, glycerol, sucrose or sorbitol. Such formulations may also contain a demulcent and a preservative such as propyl and methyl parabens, as well as flavoring and coloring agents.
The compounds of the present invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or intraperitoneally, in an injectable dose of the compound in a physiologically acceptable diluent comprising a pharmaceutical carrier which may be a sterile liquid or liquid mixture of an alcohol such as water, saline, aqueous glucose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecanol, a glycol such as propylene glycol or polyethylene glycol, a glycerol ketal such as 2, 2-methyl-1, 1-dioxolane-4-methanol, an ether such as polyethylene glycol 400, an oil, a fatty acid ester or glyceride, or an acetylated glyceride of a fatty acid, with or without a pharmaceutically acceptable surfactant or detergent such as a fatty acid salt, such as a carbomer, a pharmaceutically acceptable carrier, a pharmaceutically acceptable surfactant or detergent, such as a carbomer, a pharmaceutically acceptable carrier, a pharmaceutically, Pectin, methyl cellulose, carboxymethyl cellulose or hydroxypropyl methyl cellulose, or emulsifying agent, and other pharmaceutical adjuvants.
Examples of oils which may be used in the parenteral dosage forms of the invention are petroleum, oils of synthetic origin, animal or vegetable oils, for example, 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 ammonium and fatty acid triethylamine, and suitable surfactants include cationic surfactants such as alkylpyridines halides and alkylamines acetate, dimethyldialkylammonium halides; anionic surfactants such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates; nonionic surfactants such as fatty amine oxides, alkanolamide fatty acids, and poly (oxyethylene-oxypropyl) or oxyethylene or oxypropylene copolymers; and amphoteric surfactants such as 2-alkylimidazoline quaternary ammonium salts and alkyl-beta-aminopropionates, and mixtures thereof.
The parenteral compositions of the invention will generally comprise from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be conveniently employed. To minimize or eliminate irritation at the injection site, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance constant (HLB) between about 12 and about 17. The surfactant is present in such dosage forms in an amount of between about 5% to 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.
Examples of surfactants for use in the parenteral dosage form are polyethylene sorbitol fatty acid ester surfactants such as sorbitol monooleate and high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene glycol with propylene peroxide.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. Such suspensions may be formulated in accordance with known procedures using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide, for example polyoxyethylene stearate, with a fatty acid, a condensation product of ethylene oxide, for example heptadecaethylene-oxycetanol, with a long chain aliphatic alcohol, a condensation product of ethylene oxide, for example polyoxyethylene sorbitol monooleate, with a partial ester derived from a fatty acid and a hexitol, or a condensation product of ethylene oxide, for example polyoxyethylene sorbitan monooleate, with a partial ester derived from a fatty acid and a hexitol anhydride.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent. Diluents or solvents which can be used are, for example, water, ringer's solution, isotonic glucose solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. Any non-irritating, non-volatile oil including synthetic mono-or diglycerides may be used for this purpose. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. 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 will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.
Another dosage form for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or intermittent infusion of controlled amounts of the compounds of the present invention. The construction and use of transdermal patches for drug delivery is well known in the art (see, e.g., U.S. Pat. No.5,023,252, published 1991, 6, 11, incorporated by reference). Such ointments may be constructed for continuous, pulsed, or on-demand drug delivery.
It may be desirable or necessary to administer the pharmaceutical composition to a patient via a mechanical delivery device. The construction and use of mechanical delivery devices for drug delivery is well known in the art. Direct delivery techniques, such as direct delivery to the brain, typically involve placing a delivery catheter in the ventricular system of the patient to bypass the blood brain barrier. One such implantable delivery system for delivering a substance to a specific anatomical region of the body is described in U.S. patent No.5,011,472, published 30/4 1991.
Controlled release formulations for parenteral administration include liposome, polymer microparticle and polymer colloid formulations known in the art.
The compositions of the present invention may also contain conventional pharmaceutically acceptable compounding ingredients, often referred to as carriers or diluents, where necessary or desired. Conventional procedures for preparing such compositions in suitable dosage forms may be employed. Such compositions and processes include those described in the following references, incorporated by reference in this specification: powell, M.F., et al, "excipient overview for parenteral dosage forms" (Complex of Excipients for parenteral formulations), PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-; strickley, R.G Parenteral dosage forms of Small Molecule drugs Marketed in the United States, first Part 1999 (scientific Formulations of Small molecular Therapeutics marked in the United States (1999) -Part-l), PDA Journal of Pharmaceutical Science & Technology1999,53(6), 324-349; and Nenia, S. et al excipient and Use thereof in Products for injection (excipients and therapeutic Use in Injectable Products), PDA Journal of Pharmaceutical Science & Technology 1997,51(4), 166-.
Common pharmaceutical ingredients for which the designed route of administration matches the dosage form of the composition include:
● acidulants (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
● alkalizing agents (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, CCl2F2、F2ClC-CClF2And CClF3)；
● air displacement agents (examples include, but are not limited to, nitrogen and argon);
● antioxidant (examples 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, sodium metabisulfite);
● antifungal preservatives (examples include but are not limited to benzoic acid, butyl paraben, methyl paraben, propyl paraben, ethyl paraben, sodium benzoate);
● antimicrobial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorobutanol, benzyl alcohol, phenethyl alcohol, cetylpyridinium chloride, phenol, phenylmercuric nitrate, and sodium thimerosal);
● buffer (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, sodium citrate dihydrate);
● adhesive materials (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);
● carrier (examples include but are not limited to acacia syrup, aromatic elixir, cherry syrup, orange syrup, cocoa syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection);
● chelating agents (examples include but are not limited to edetic acid and edetate disodium);
● coloring agents (examples 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 Red iron oxide);
● clarifying agents (examples include but are not limited to acacia, polyethylene glycol, cetyl alcohol, glyceryl monostearate, lecithin, polysorbate monooleate, polyoxyethylene 50 monostearate);
● Capsule (examples include but are not limited to gelatin and cellucotton);
● flavoring essence (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);
● humectants (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, yellow ointment, and rose water ointment);
● oil (examples include, but are not limited to, arachis oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil);
● penetration enhancers (transdermal drug delivery) (examples include, but are not limited to, monohydric or polyhydric alcohols, monovalent or polyvalent alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);
● solvent (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for infusion);
● plasticizers (examples include but are not limited to diethyl phthalate and glycerol);
● hardener (examples include, but are not limited to, cetyl alcohol, cetyl esters, waxes, microcrystalline waxes, paraffin waxes, stearyl alcohol, white waxes, and yellow waxes);
● suppository base (examples include but are not limited to cocoa butter and polyethylene glycol (mixtures));
● surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, oxoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);
● suspending agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum (veegum));
● sweetening agents (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);
● tablet binder (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sucrose, ethylcellulose, gelatin, liquid glucose, methylcellulose, and gelatinized starch);
● tablet detackifiers (examples include, but are not limited to, magnesium stearate and talc);
● tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch);
● tablet coating agents (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate, and shellac);
● tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate);
● tablet disintegrating agents (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrilin potassium (polacrillin potassium), sodium alginate, sodium starch glycolate, and starch);
● tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);
● tablet glidants (examples include, but are not limited to, colloidal silica, corn starch, and talc);
● tablet polishes (examples include, but are not limited to, carnauba wax and white wax);
● tablet/capsule opacifiers (examples include but are not limited to titanium dioxide);
● thickening agents (examples include but are not limited to beeswax, cetyl alcohol, and paraffin wax);
● viscosity enhancing agents (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and tragacanth);
● tonicity agents (examples include but are not limited to dextrose and sodium chloride);
● moisturizers (examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
Dosage of the pharmaceutical composition of the present invention
The effective dose of the compounds of the present invention for the treatment of each of the desired indications can be readily determined by routine toxicity testing and by routine pharmacological testing procedures for determining the efficacy of the above-mentioned symptoms in mammals, based on known, routine laboratory techniques for evaluating compounds for use in the treatment of any of the above-mentioned diseases, and by comparing these results with those of known drugs for treating these symptoms. The amount of the active ingredient administered in the treatment of one of these conditions may vary widely depending upon such factors as the particular compound and dosage unit used, the mode of administration, the course of treatment, the age and sex of the patient being treated and the nature and extent of the condition being treated.
The total amount of active ingredient administered may be between about 0.01 mg/kg to about 50 mg/kg, and preferably between about 0.1 mg to about 10mg 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 5mg per kg body weight. The daily dose administered by injection (including intravenous, subcutaneous, intramuscular and parenteral) and using infusion techniques should preferably be between 0.1 and 5 milligrams per kilogram of body weight. The daily rectal dosage regimen should preferably be between 0.1 and 15 mg per kg body weight. The daily topical regimen should preferably be between 0.1 and 5mg/kg administered 1 to 4 times per day. Transdermal concentrations should preferably be maintained at a daily dose of 0.1 to 3 mg/kg. The daily inhalation regimen should preferably be 0.1 to 5mg per kg body weight. Other dosages and amounts may be routinely selected.
The specific initial and sustained dosage regimen will vary from patient to patient, depending upon the identity and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and physical condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, and the like. The mode of treatment required, as well as the number of doses of a compound of the invention or a pharmaceutically acceptable salt or composition thereof, can be determined by one skilled in the art using routine therapeutic testing.
In combination with other active ingredients
The compounds of the present invention may be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse results. This may be particularly useful for treating hyperproliferative diseases such as cancer. In this case, the compounds of the present invention may be used in combination with known cytotoxic agents, signal transduction inhibitors, or with other anti-tumor substances and mixtures and compositions thereof.
In one embodiment, the compounds of the present invention may be used in combination with cytotoxic anti-tumor agents. Examples of such substances can be found in the ink Index 11 th edition (Merck Index (1996)). These include, but are not limited to, asparaginase, levoasparaginase, bleomycin, carboplatin, cisplatin, mechlorethamine, carmustine, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin, epirubicin, doxorubicin, etoposide, 6-mercaptopurine, methotrexate, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, leucovorin, lomustine, mesna, mitomycin C, mitoxantrone hydrochloride, procarbazine, raloxifene, streptozotocin, tamoxifen, thioguanine, topotecan, irinotecan, prednisolone, prednisone, vinblastine, vincristine, vindesine.
Other cytotoxic agents suitable for use in combination with The compounds of The invention include, but are not limited to, those compounds described in "Pharmacological Basis of drugs" by Goodman and Oilman (The Pharmacological Basis of Therapeutics (NinthEdition,1996, McGraw-Hill)) which are generally recognized for The treatment of neoplastic diseases. These include, but are not limited to, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, plicamycin, docetaxel, erythrohydroxynonyladenine, estriol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluorometholone, flutamide, hydroxyprogesterone hexanoate, paclitaxel, demethoxydaunorubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, N-dioxaphosphatyl-L-aspartate (PALA), pentostatin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uracil, and vinorelbine.
Other cytotoxic antineoplastic agents suitable for use in combination with the compounds of the present invention also include newly discovered cytotoxic agents such as gemcitabine, capecitabine, epothilones, oxaliplatin and its natural and synthetic derivatives, temozolomide, tositumomab (Bexxar), trabedectin, and inhibitors of the kinesin spindle protein Eg 5.
In another embodiment, the compounds of the present invention may be used in combination with other signal transduction inhibitors. Of particular interest are signal transduction inhibitors directed against the EGFR family (such as EGFR, HER-2 and HER-4) and their respective ligands. Examples of such substances include, but are not limited to, antibody drugs such as herceptin (trastuzumab), ebitux (cetuximab), and pertuzumab (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 series of advantages over the compounds known in the prior art which do not carry deuterium. The main advantages of the invention include:
(1) the compounds of the present invention have excellent inhibitory activity against tyrosine kinases such as c-Met.
(2) The compounds of the invention are less readily metabolized in the animal body than non-deuterated compounds, which results in a reduction in first-pass effect, and thus can be varied in dosage and form depot formulations, which can also improve applicability in the form of depot formulations.
(3) The pharmacokinetic effects are also altered by deuteration, so that the distribution of the compounds of the invention in the organism is clearly different from that of non-deuterated compounds.
(4) The compound of the invention has higher drug concentration in animal bodies, thereby improving the drug effect.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 13 preparation of- [ (2-deuterium-6-quinolinyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine (II)
Step 1: 6-Bromoquinoline-1-oxy (III)
Figure BDA0000736295950000211
20 g of 6-bromoquinoline are dissolved in 200 ml of dichloromethane, 200 ml of dichloromethane solution containing 21.5 g of m-chloroperoxybenzoic acid is added dropwise under stirring in an ice bath, and after the addition is finished, the mixture is stirred at room temperature overnight. The reaction was washed with saturated sodium thiosulfate solution and the organic phase was concentrated to dryness to give 19.4 g of a light brown solid with a yield of 90%.1H-NMR(300Hz,DMSO-d6):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).
Step 2: 2-deuterium-6-bromoquinoline-1-oxy (IV)
Figure BDA0000736295950000212
A mixture of 10 g of 6-bromoquinoline-1-oxide, 10.7 g of sodium tert-butoxide and 33 ml of deuterium solution was heated in an oil bath at 100 ℃ for 12 hours. The reaction was cooled to room temperature, extracted with dichloromethane, and the organic layer was concentrated to dryness to give a pale yellow solid 6.7 g, yield 67%.1H-NMR(300Hz,DMSO-d6):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.
And step 3: 2-deuterium-6-bromoquinoline (V)
Figure BDA0000736295950000213
4 g of 2-deuterium-6-Bromoquinoline-1-oxide was dissolved in 70 ml of glacial acetic acid, 8 g of iron powder were added in portions, and heated under reflux for 3 hours. The reaction was concentrated to dryness, the residue was dissolved in water, pH was adjusted to 8 with sodium carbonate solid, extracted with dichloromethane, and the organic layer was concentrated to dryness to give 2.5 g of light brown oil in 67% yield.1H-NMR(300Hz,CDCl3):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).
And 4, step 4: 2-deuterium-6-iodoquinoline (VI)
Figure BDA0000736295950000214
A mixture of 1 g of 2-deuterium-6-bromoquinoline, 182 mg of cuprous iodide, 1.43 g of sodium iodide, 0.22 ml of N, N-dimethylethylenediamine and 10ml of 1, 4-dioxane was refluxed overnight. The reaction was cooled to room temperature, filtered, the filter cake washed with ethyl acetate and the filtrate concentrated to dryness to give a pale yellow solid 1.1 g with a yield of 90%.1H-NMR(300Hz,CDCl3):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).
And 5: 2- (2-deuterium-6-quinolinyl) -2, 2-difluoroacetohydrazide (VII)
Figure BDA0000736295950000221
Heating and stirring 3 g of 2-deuterium-6-iodoquinoline, 3 ml of ethyl difluorobromoacetate, 2.08 g of nano copper powder and 30 ml of dimethyl sulfoxide at 80 ℃ for overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, and the organic layer was concentrated to dryness to give a brown oil.
The brown oily substance obtained above was dissolved in 30 ml of methanol, 0.7 ml of hydrazine hydrate (85%) was added, reaction was carried out at 80 ℃ for 1 hour, the reaction solution was concentrated to dryness, and column chromatography was carried out on the residue to obtain 1.1 g of a pale yellow solid, with a yield of 39.4%.1H-NMR(300Hz,DMSO-d6):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)
Step 6: 3- [ (2-deuterium-6-quinolinyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine (II)
Figure BDA0000736295950000222
3 g of 2- (2-deuterium-6-quinolyl) -2, 2-difluoroacetohydrazide, 1.64 g of 3-chloro-6- (1-methyl-1H-pyrazol-4-yl) pyridazine, 1.5 g of methanesulfonic acid and 33 ml of n-butanol were placed in a sealed tube, and the mixture was heated at 90 ℃ and stirred overnight. The reaction was concentrated to dryness, dissolved in water, adjusted to pH 8 with ammonia, extracted with dichloromethane, the organic layer was concentrated to dryness, and the residue was subjected to column chromatography to give 2.5 g of a yellow solid with a yield of 79%.1H-NMR(300Hz,CDCl3):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.
EXAMPLE 2 Metabolic Studies of Compound II in monkey liver S9
Each in vitro incubation system was incubated in a total volume of 200. mu.L in a medium of 100mM phosphate buffer (PBS, pH7.4) including JNJ38877605 or Compound II at a final concentration of 3. mu.M and 2mM NADPH in a 37 ℃ water bath. After pre-incubation for 3min, adding monkey liver S9 protein into the buffer solution-substrate-cofactor mixture to initiate reaction, and adding ice-cold acetonitrile with the same volume after reaction for 60min to terminate the reaction. The experimental conditions of the control group were the same as above, except that NADPH was replaced by PBS; in addition, in the blank control group, the S9 protein was subjected to high temperature inactivation treatment. All hatching samples were double samples.
Combining 200 μ L of each sample, adding 400 μ L of acetonitrile, vortex mixing for 1min, centrifuging for 5min (14000rpm), taking out all supernatant, transferring into a 10mL plastic tube, drying under 40 ℃ nitrogen flow, dissolving the residue with 80 μ L of acetonitrile-water (10:90, v/v), and taking 10 μ L for UPLC-UV/Q-TOF MS analysis.
The UPLC-UV/Q-TOF MS method is adopted to identify possible metabolites in a JNJ38877605 and a compound II monkey liver S9 hatching system, and the result shows that the proportion of prototype drugs of the compound II is 31.8% higher than that of the JNJ 38877605. The pharmacokinetic property of the compound II is obviously superior to that of JNJ 38877605.
EXAMPLE 3 in vivo pharmacokinetic testing of Compound II after intragastric administration in cynomolgus monkeys
The cynomolgus monkeys 4 were individually gavaged to administer the test compounds, specifically arranged as follows:
Figure BDA0000736295950000231
taking 0.8mL of venous blood from veins of limbs before administration (0h) and after administration (0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12 and 24 h), placing in an EDTA anticoagulation test tube, centrifuging at 3500rpm for 10min, separating plasma, and freezing and storing in a refrigerator at-70 deg.C.
The concentration in plasma was determined by LC/MS/MS method and potential metabolites in plasma, and urine were identified by UPLC-Q/TOF-MS method.
Pharmacokinetic parameters after administration were calculated using a non-compartmental model of WinNonlin 6.3 software (Pharsight, usa).
The plasma concentration-time curves after gastric gavage of 10mg/kg compound II and JNJ38877605, respectively, in cynomolgus monkeys are shown in FIG. 1.
Exposure of Compound II to cynomolgus monkeys after intragastric administration CmaxAnd AUC0-tIs 1.56 times and 2.29 times of JNJ38877605 respectively.
From the above results, it can be seen that the compounds of the present invention have better pharmacokinetics in animals and thus will have better pharmacodynamics and therapeutic effects.
EXAMPLE 4 growth inhibition of Compound II on human Lung cancer EBC-1 nude mouse subcutaneous transplantation tumors
BALB/cA nude mice. Number of animals per group: negative control group 6, administration group 6.
The right axillary fossa of the nude mouse is inoculated with the human lung cancer EBC-1 cell strain with the cell inoculation amount of 5 × 106After the formation of the graft tumor, the tumor was used after 1 passage in nude mice.
Cutting tumor tissue in vigorous growth stage into 1.5mm3Left and right, inoculated to the right axillary skin of nude mice under aseptic conditionThe following steps. Measuring the diameter of the transplanted tumor by using a vernier caliper for the nude mouse subcutaneous transplanted tumor until the average tumor volume grows to 176mm3The animals were randomized after the left and right, compound ii and JNJ38877605 were administered at 5mg/kg twice daily orally for 21 days continuously, the solvent control group was given an equal amount of solvent, the transplanted tumor diameter was measured 2 times a week during the whole experiment, and the mouse body weight was measured at the same time, and the calculation formula of the tumor volume was that TV is 1/2 × a × b2Wherein a and b represent length and width, respectively. Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows: RTV ═ Vt/V0. Wherein V0When administered separately from the cage (i.e. d)0) Measurement of the resulting tumor volume, VtFor the tumor volume at each measurement.
The evaluation indexes of the antitumor activity are as follows:
1) the relative tumor proliferation rate T/C (%) was calculated as follows: T/C (%) ═ TRTV/CRTV)×100％，TRTV: treatment group RTV; cRTV: negative control group RTV;
2) the tumor volume increase inhibition rate GI% is calculated according to the following formula: TGI% [1- (TV) ]t-TV0)/(CVt-CV0)]×100％，TVtTumor volume measured for each treatment group; TV (television)0Tumor volume obtained when cage-administered as a therapeutic component; CV oftTumor volume measured for each time for the control group; CV of0Tumor volume obtained when cage-administered as control component;
3) the tumor weight inhibition rate is calculated according to the following formula: tumor weight inhibition ratio%C-WT)/WC×100％，WC: tumor weight of control group, WT: the treated group had heavy tumor.
The results of the experiment are shown in FIG. 2. The compound II and JNJ38877605 are orally administered twice a day for 21 days under the administration dosage of 5mg/kg, and have extremely obvious inhibition effect on the growth of subcutaneous transplantation tumors of human lung cancer EBC-1 nude mice. Wherein the compound II gave a T/C percentage of 9.98% at day 21 and a Tumor Growth Inhibition (TGI) of 90.4%, while JNJ38877605 gave a T/C percentage of 21.56% at day 21 and a Tumor Growth Inhibition (TGI) of 83.8%. Mice were well-behaved in each group of the study during the treatment period.
EXAMPLE 5 pharmaceutical composition
Tablet(s)
Figure BDA0000736295950000251
The materials are mixed evenly and 1000 tablets are prepared by the conventional process. Suitable aqueous or non-aqueous coatings may be used to enhance palatability, improve appearance and stability, or delay absorption.
Capsule
Compound II (example 1) 30g
140g of starch
Microcrystalline cellulose 60g
Mixing the above materials uniformly according to conventional method, and making into 1000 capsules.
Sterile IV solution
0.2g of Compound II (example 1)
Sterile water for injection 50mL
Compound ii was formulated in a 4 mg/ml solution with sterile water for injection and the pH adjusted as required. It is administered by intravenous infusion diluted with 5% sterile dextrose to 1.5-2.0 mg/ml.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (8)

1. A process for the preparation of a compound of formula (I):
Figure FDA0002577456760000011
in the formula:
d represents a deuterium atom;
R1、R2、R3、R4、R5、R6、R7、R8、R9each independently is a hydrogen atom;
R10selected from the group consisting of: CH (CH)3；
The compound is prepared by the following method:
Figure FDA0002577456760000012
(1) carrying out deuteration reaction on the compound of the formula (III) in an organic solvent to obtain a compound of a formula (IV); the deuteration reaction is carried out in the presence of heavy water and sodium tert-butoxide;
Figure FDA0002577456760000013
(2) carrying out reduction reaction on a compound shown in a formula (IV) and a reducing agent in an organic solvent to obtain a compound shown in a formula (V);
Figure FDA0002577456760000014
(3) reacting a compound of formula (V) with an iodinating agent in an organic solvent to obtain a compound of formula (VI);
Figure FDA0002577456760000021
(4) reacting a compound shown in a formula (VI) with ethyl difluorobromoacetate and hydrazine hydrate in an organic solvent to obtain a compound shown in a formula (VII);
Figure FDA0002577456760000022
(5) and (3) carrying out a ring closing reaction on the compound of the formula (VII) and the compound of the formula (VIII) in an organic solvent to obtain the compound of the formula (II).
2. The method of claim 1, wherein in step (2), the reducing agent is iron powder.
3. The method of claim 1, wherein in step (2), the reduction reaction is carried out in the presence of glacial acetic acid.
4. The method of claim 1, wherein in step (3), the iodinating agent is a combination of sodium iodide, cuprous iodide, and N, N-dimethylethylenediamine.
5. The method of claim 1, wherein in step (4), the reaction is carried out in the presence of copper powder, and the reaction comprises: the compound (VI) is condensed with ethyl difluorobromoacetate in the presence of copper powder and then reacts with hydrazine hydrate to obtain the compound shown in the formula (VII).
6. The method according to claim 1, wherein in the step (5), the ring closure reaction is carried out in the presence of dioxane and methanesulfonic acid.
7. The process of claim 1, wherein the compound of formula (III) is prepared by:
Figure FDA0002577456760000023
carrying out oxidation reaction by using 6-bromoquinoline in an organic solvent to obtain a compound (III).
8. The process of claim 7, wherein the oxidation reaction uses m-chloroperoxybenzoic acid as the oxidizing agent.
CN201510319730.2A 2015-06-11 2015-06-11 Deuterated 3- [ (6-quinolyl) difluoromethyl ] -6- [ (1-methyl) -4-pyrazolyl ] [1,2,4] triazolo [4,3-b ] pyridazine and application thereof Active CN106279176B (en)

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
氘代作用在药物研究中的应用;江文峰 等;《齐鲁药事》;20101231;第29卷(第11期);第682-684页 *

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