CN104592105B - Regorafenib and manufacture method thereof - Google Patents

Regorafenib and manufacture method thereof Download PDF

Info

Publication number
CN104592105B
CN104592105B CN201510069175.2A CN201510069175A CN104592105B CN 104592105 B CN104592105 B CN 104592105B CN 201510069175 A CN201510069175 A CN 201510069175A CN 104592105 B CN104592105 B CN 104592105B
Authority
CN
China
Prior art keywords
compound
formula
acid
content
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510069175.2A
Other languages
Chinese (zh)
Other versions
CN104592105A (en
Inventor
李阅东
唐建飞
沈如杰
何海珍
马雯霞
姚成娥
张群
赵福斌
张婧
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Original Assignee
HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd filed Critical HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Priority to CN201510069175.2A priority Critical patent/CN104592105B/en
Publication of CN104592105A publication Critical patent/CN104592105A/en
Application granted granted Critical
Publication of CN104592105B publication Critical patent/CN104592105B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to Regorafenib and a manufacture method thereof and particularly relates to a compound shown in formula (I) or a pharmaceutical salt or a hydrate. The compound shown in formula (I) or the pharmaceutical salt or the hydrate can be used as a pharmaceutical bulk drug. The invention also relates to a method for preparing the compound shown in formula (I) or the pharmaceutical salt or the hydrate, and a pharmaceutical composition containing the compound shown in formula (I) or the pharmaceutical salt or the hydrate. The compound shown in formula (I) or the pharmaceutical salt or the hydrate can be used as a novel anti-tumour medicine for effectively treating the diseases mediated by abnormal VEGFR, PDGFR, raf, p38 and/or flt-3 kinase signal and the disease symptoms.

Description

Rui Gefeini and its preparation method
Technical field
The present invention relates to a kind of new antineoplastic, more particularly to a kind of Rui Gefeini, it can be used for treatment by exception Vegfr, pdgfr, raf, p38 and/or flt-3 kinase signal mediation disease and disease symptomses.The invention still further relates to it is described The antineoplastic particularly preparation method of Rui Gefeini.
Background technology
The activation of ras signal transduction pathway means that cell proliferation, differentiation and conversion have the event of profound influence Cascade reaction.Raf kinases as ras downstream effect is that from cell surface receptor, these signals are delivered to nuclear one Individual key transmitter.It has been proved that by using the inactivation antibody of raf kinases or dominant raf kinases or dominant mek The coexpression of (substrate of raf kinases) suppresses raf kinase signal pathway to suppress the effect activating ras can lead to the cell converting Revert to normal growth phenotype.Kolch etc. further demonstrates and has blocked film phase by the suppression that antisense rna expresses to raf Close the cell proliferation that oncogene causes.Similarly, have confirmed the suppression of raf kinases in tube assay and experiment in vivo (by ASON) is related to the growth inhibition of multiple human tumor types.
Size is maintained to need functioning stroma more than the continued tumor growth of the tumour cell of 1-2mm3, this is including becoming fine Dimension cell, smooth muscle cell, the support structures of endothelial cell, extracellular matrix proteins and soluble factors.Tumour passes through secretion The soluble growth factor such as pdgf and transforming growth factor β (tgf- β) causes the formation of interstitial tissue, described growth factor Each stimulation of host cell secretion such as fibroblast growth factor (fgf), EGF (egf) and blood vessel endothelium life The complementary factors such as the long factor (vegf).These stimulating factors cause new Angiogenesiss, and this provides oxygen and nutriment to tumour And so that it is grown and provide route for metastases.Believe that some treatment methods being formed for suppression interstitial can be many to being derived from The growth planting the epithelial tumor of histological type is suppressed.However, due to the complexity of its property and multiple growth factor Participate in angiogenesis and tumor progression, a kind of material for single signal approach may only have limited effect.Wish Can tumour be used in host stroma cause multiple key signaling pathways of Angiogenesiss to provide treatment method.These approach bags Include pdgf (the effective stimulus factor that interstitial is formed), (chemokine of fibroblast and endothelial cell and rush have silk to fgf Mitogen) and vegf (angiopoietic effective regulatory factor).
Pdgf is a kind of key regulator that interstitial is formed, and it is secreted and promoted into paracrine form by kinds of tumors The growth of fibrocyte, smooth muscle and endothelial cell, thus promote interstitial to be formed and Angiogenesiss.Pdgf is initially as ape and monkey Sarcoma viral v-sis oncogene products are identified.This growth factor is made up of 2 peptide chains being referred to as a chain or b chain, Peptide chain primary amino acid sequences have 60% homology.Peptide chain warp disulfide bond is connected to form by aa, bb or ab homology or heterologous The maturation protein of the 30kda of dimer composition.It is found that high-caliber pdgf in blood platelet, and pdgf can be by endothelial cell And Expression of Vascular Smooth Muscle Cell.Additionally, under hypoxia condition found in the not enough tumor tissues of such as vascularization The generation of pdgf is raised.Pdgf is combined with pdgf acceptor (pdgfr) with high-affinity, and this receptor is 1106 amino acid structures The transmembrane tyrosine kinase acceptor of the 124kda becoming.Pdgfr is homology or heterodimer peptide chain form, and peptide chain is in its amino 30% homology is generally had on acid sequence, and there is between its kinase domain 64% homology.Pdgfr is tool There is the member of the tyrosine kinase receptor family of separate kinase domain, this family includes vegfr2 (kdr), vegfr-3 (flt-4), c-kit and flt-3.Pdgfr is mainly in fibroblast, smooth muscle cell and pericyte (pericyte) upper table Reach, and express on a small quantity on nerve cell, the schwann cell of messangial cell, leydig cell and central nervous system.One Denier and receptor binding, pdgf causes Receptor dimerization and experiences the self-phosphorylation of tyrosine residue and mutual phosphorylation, this energy Improve the kinase activity of acceptor and promote the downstream effect factor to pass through to activate raising of sh2 protein binding domain.Including pi-3 Kinases, phosphide enzyme c- γ, src and gap (for the GTP acid ras GTPase activating protein ras-GTP of p21-ras) divide in interior multi-signal Son forms compound with the pdgfr of activation.By activating pi-3 kinases, pdgf activation rho cellular pathways are thus cause cell to transport Move and migrate, and cause the mitosis by the activation of p21-ras and mapk signal pathway by activating gap.
In adult, the Main Function of pdgf is to promote and improve the speed of wound healing and keep putting down in vivo of blood vessel Weighing apparatus.It is found that the pdgf of high concentration in blood platelet, it is for fibroblast, smooth muscle cell, neutrophil cell and huge It is a kind of effective chemokine for phagocyte.In addition to it is in the effect in wound healing, pdgf assists in keeping The homeostasis of blood vessel.In new vessels growth course, pdgf raises the pericyte peace required for blood vessel structure integrality Sliding myocyte.Pdgf is considered to play similar effect in tumor angiogenesis.As it played in Angiogenesiss A part for effect, pdgf passes through it and adjusts blood vessel to the regulation of phoirocyte and the interphase interaction of extracellular matrix Permeability and control the Fluid pressure of tissue space.The activity of suppression pdgfr can reduce the pressure of tissue space and promote thin Born of the same parents' toxin flows into tumour and improves the antitumor efficacy of these materials.
Pdgf can directly stimulate pdgfr on interstitial cell or tumour cell or by being subject to by paracrine or autocrine The signal of body amplifies or promotes tumour growth through recombination activation acceptor.The melanoma cells that the pdgf of overexpression can make one and The cell type that keratinocyte both does not express pdgf acceptor may be formed to interstitial by pdgf and induction of vascular generation Direct effect and convert.Tumour expression pdgf but the not colon cancer of expressed receptor, lung cancer, breast cancer and prostate wherein The paracrine that also been observed this mesenchyma stroma of tumors in the tumours such as cancer stimulates.In spongioblastoma, soft-tissue tumor, ovary It has been reported that autocrine stimulation to growth of tumour cell in cancer, prostate cancer, cancer of pancreas and lung cancer, wherein most through point The tumor cells expression pdgf part of analysis and acceptor.The receptor activation of non-ligand-dependent type finds less, but in chronic grain list It has been reported that wherein a chromosome translocation is between class ets transcription factor tel and pdgf acceptor in monocytic leukaemia (cmml) Form fusion protein.Additionally, having discovered that in gastrointestinal stromal tumor the activation in the pdgfr unrelated with c-kit activation is dashed forward Become.Pdgfr inhibitor can disturb mesenchyma stroma of tumors to develop and suppress growth and metastasis of tumours without excessive side effect.
VEGF (vegf, also referred to as Vascular Permeability Factor vpf) be another kind of in embryonic development and The newborn main regulatory factors with blood vessel generation of disease medium vessels that some Angiogenesiss rely on.Vegf represents due to selectivity Rna montage and with homodimer form exist mitogenesis former isomers family.Vegf isomers is for blood vessel endothelium It is high special for cell.
Vegf expression is many by anoxic and interleukin-11, interleukin 6, EGF and TGF etc. Plant cell factor and growth factor-induced.It is reported that vegf and vegf family member and following three kinds of transmembrane receptor junket at present One or more of histidine kinase combines: vegf acceptor 1 (also referred to as flt-1 (class fms EGFR-TK 1)), vegfr-2 (also referred to as acceptor containing Kinase insert Domain (kdr), the mouse analog of kdr is referred to as tire liver kinases 1 (flk-1)) and vegfr- 3 (also referred to as flt-4).Have confirmed, vegfr-2 and flt-1 has different signal transduction properties.Therefore, vegfr-2 is complete Experience the strong tyrosine phosphorylation of ligand-dependent in whole cell, and flt-1 shows weak response.It is therefore believed that it is complete for inducing For the biological answer-reply of vegf mediation of scope, being combined with vegfr-2 is key request.
Vegf plays central role in blood vessel generation in vivo, and causes angiogenesis and Vascular permeability.It is not added with adjusting Vegf expression cause multiple diseases, it is characterized in that abnormal angiogenesis and/or high osmosis effect.Believe some materials Regulation to the signal transduction cascade of vegf mediation can provide and effectively control to abnormal angiogenesis and/or high osmosis effect System.Anti-tumor cell in tumor hypoxia region passes through to stimulate vegf production to react, and this causes the endothelial cell of silence Activation is to stimulate new vascularization.Ras can be promoted to believe additionally, the vegf in the tumor region not having angiogenesis produces Number transduction pathway.In situ hybridization research shows, include lung cancer, thyroid cancer, breast cancer, gastroenteric tumor, kidney and tumor of bladder, Oophoroma, cervical carcinoma and hemangioma and the notable rise of several ICT vegf mrna in interior various human tumors. Neutrality vegfr-2 monoclonal antibody is proved to be effective in blocking neonate tumour blood vessel.
The overexpression (for example under the conditions of extreme oxygen deficiency) of vegf can cause angiogenesis in eyeball, leads to blood vessel excessive Hyperplasia, ultimately results in blind.Including diabetic retinopathy, ischemic retinal vein obturation and premature retinal Disease and age related macular degeneration observed such cascade reaction in interior multiple retinopathies.
In rheumatic arthritis (ra), the generation of angiogenesis factor can with mediate vascular screen to growth.Ra suffers from There is in the synovia of person high-caliber immunoreactivity vegf, and in other forms arthritis or degenerative joint disease patient Vegf low SI in synovia.Anti-rat collagen induction type arthritis model has confirmed, AI agm-170 Hinder the neovascularization in joint.
Formed in psoriasis and bullous pemphigoid, erythema multiforme and dermatitis herpetiformis etc. and subepidermal blister Also the raising of vegf expression is shown in related herpes diseases.
VEGF (vegf, vegf-c, vegf-d) and its acceptor (vegfr2, vegfr3) are not only tumour Angiogenesiss and be the key regulator of lymphatic vessel generation.Vegf, vegf-c and vegf-d are main in most of tumour During tumour growth and often with the abundant horizontal expression improving.Vegf expression is caused by anoxic, cell factor, such as ras Oncogene or the stimulation by the inactivation of tumor suppressor gene.
The BA of vegf is mediated by the combination with its acceptor.Vegfr3 (also referred to as flt-4) mainly exists Express on lymphatic endothelial cells in normal adult tissue.Being formed for new lymphatic vessel needs vegfr3 function, but for Already present lymphatic vessel is maintained then not need.Vegfr3 is also raise on the vascular endothelial cell of tumour.Recently, vegfr3 Part vegf-c and vegf-d be confirmed as the regulatory factor of lymphatic vessel generation in mammal.The related lymphatic vessel life of tumour The lymphatic vessel generation becoming factor induction may promote new vessel growth to enter tumour, and this provides entrance system for tumour cell The passage of circulation.Invade vasculolymphatic cell and blood circulation may be entered by ductus thoracicus.It is right that tumour expression study has allowed for Vegf-c, vegf-d and vegfr3 expression clinicopathologia factor directly related with same primary tumo(u)r diffusivity (is for example drenched Fawn on transfer, lymphatic vessel invades, Secondary cases shifts and DFS phase) directly compared.In many cases, these researchs Illustrate the correlation statistically between lymphatic vessel generation factor expression and primary entity tumor transfer ability.
For vegf in malignant cell produces, anoxic is it appear that a kind of important stimulating factor.For tumour cell For response being produced to anoxic and inducing vegf, need the activation of p38map kinases.Except being participated in by adjusting vegf secretion Beyond Angiogenesiss, p38map kinases passes through to adjust collagenase activity and the expression of urokinase Plasminogen Activator promotes Malignant cell invades the migration with different tumor types.
The suppression of mitogenesis former activated protein kinase (mapk) p38 is demonstrated to thin in test tube and/or internal suppression Intracellular cytokine forms (such as tnf, il-1, il-6, il-8) and protease produces (such as mmp-1, mmp-3).Mitogenesis is former Activated protein kinase p38 participates in il-1 and tnf signal pathway.
Clinical research produces and/or TNF (tnf) to many including rheumatoid arthritis Plant disease to link up.Additionally, being found that the tnf of excessive levels in multiple inflammatories and/or immunological regulation class disease.These Disease includes acute rheumatic fever, bone information, PMO, pyaemia, septic shock, endotoxic shock, general Inflammatory reaction disease, asthma etc..Tnf is also related to infectious diseases, and these diseases include pulmonary tuberculosis, the pylorus during gastric ulcer Pylori (Hp) infection etc..
Numerous disease be considered as by excessive or unwanted matrix destruction metalloproteinases (mmp) activity or by The proportional imbalance of the tissue depressant (tmp) of mmp and metalloproteinases is mediated.These diseases include osteoarthritis, rheumatism Property arthritis, septic arthritis, metastases, periodontosis, cornea come off, the rupture of albuminuria, atherosclerotic plaque The coronary artery thrombosis that causes, aortic aneurysm, infertile, EBD, after traumatic joint injury Degenerative cartilage disappearance, the demyelinating disease of the osteoporosis, jawbone arthropathy and nervous system of mmp activity mediation.
Because suppression p38 leads to tnf to form the suppression being formed with mmp it is believed that the suppression former activator protein of mitogenesis swashs Enzyme p38 can provide the above-mentioned disease including osteoporosis and inflammation disease for the treatment of such as rheumatoid arthritis and copd The means of disease.
For vegf in malignant cell produces, anoxic is it appear that a kind of important stimulating factor.For tumour cell For response being produced to anoxic and inducing vegf, need the activation of p38map kinases.Except being participated in by adjusting vegf secretion Beyond Angiogenesiss, p38map kinases passes through to adjust collagenase activity and the expression of urokinase Plasminogen Activator promotes Malignant cell invades the migration with different tumor types.As a result, it may also be desirable to suppression p38 kinases passes through interference and Angiogenesiss and evil Property cell invade related signal cascade impact tumour growth.
The serine-threonine kinase inhibitor that some ureas are had and/or tyrosine kinase inhibitor activity are It is described.Especially have been proven that and some ureas are used for cancer, blood vessel life as the active component of pharmaceutical composition Become disease, the treatment of inflammatory disease.
This area still expects there is effective antitumour medicine, and for example it can be used for situation mentioned above.And it is such The beneficial preparation method of antineoplastic.
Formula (i) compound 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] carbamyl } amino) -3- fluorophenoxy] - N- picoline -2- formamide, i.e. 4- [4- ({ [4-chloro-3- (trifluoromethyl) phenyl] carbamoyl } Amino) -3-fluorophenoxy]-n-methylpyridine-2-carboxamide is disclosed in wo2005009961:
The monohydrate of formula (i) compound is that Rui Gefeini (regorafenib) is listed with trade name stivarga, is used for Treatment excess proliferative disease, such as cancer, tumour, lymthoma, sarcoma and leukaemia.The molecular formula of Rui Gefeini is c21h15clf4n4o3·h2O, molecular weight is 500.83.
The Rui Gefeini of monohydrate form refers in wo2008043446.Additionally, the salt of formula (i) compound, such as Its hydrochloride, mesylate and phenylbenzimidazole sulfonic acid salt refer in wo2005009961, and can be by using corresponding acid treatment Formula (i) compound is forming.Formula (i) compound is described for treating excess proliferative disease, such as cancer, tumour, pouring Bar knurl, sarcoma and leukaemia.
Wo2005009961 describes a kind of method of formula (i) compound, and it is illustrated in following scheme:
In the first step, 4- amino -3- fluorophenol is processed with potassium tert-butoxide, and add 4- chloro- n- methyl -2- pyridine carboxylic Solution in n, n- dimethylacetylamide for the acid amides, to form 4- (4- amino -3- fluorophenoxy) pyridine-2-carboxylic acids methyl acyl Amine；
After extraction it is finally used isocyanic acid (4- chloro- 3- (trifluoromethyl) phenyl) ester at the solution in toluene Reason, to form 4 { 4- [3- (4- chloro- 3- trifluoromethyl)-urea groups] -3- fluorophenoxy }-pyridine-2-carboxylic acids methyl nitrosourea, It is formula (i) compound.
Although method disclosed in prior art can be effectively used for formula (i) compound, its monohydrate, hydrochloric acid in itself Salt, mesylate and phenylbenzimidazole sulfonic acid salt, but such as purity, product yield, the factor pair of method efficiency, security and economy It is very important for the method for plant-scale drug products.
Content of the invention
It is an object of the invention to provide a kind of formula (i) compound and its salt and monohydrate commercial scale (kilogram Level more than) method, its meet the standard applied aborning and provide purity, environmental suitability, industrial applicibility, Secure context and the improvement of volume yield aspect.Especially, for the preparation of medicine, purity and secure context are to need checking Consider.This purpose is achieved by the present invention.Formula (i) compound of the present invention is that have the fluoro- 4- of the 2- being combined with urea The omega-carboxyaryl diphenyl urea of (2- (n- methylcarbamoyl) -4- pyridine epoxide) phenylene group, it be raf kinases, Effective inhibitor of vegfr kinases, p38 kinases and pdgfr kinases, described kinases is all to include cancer to treatment and prevention to exist Molecular target interested for interior osteoporosis, inflammatory disease, excess proliferative disease and Angiogenesiss disease.
The preparation of formula (i) compound of the present invention is shown in following scheme.
First aspect present invention provides with following formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate:
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, it is Medicinal crude drug.Or Person, first aspect present invention provides a kind of Medicinal crude drug, and it is formula (i) compound or pharmaceutically acceptable salt thereof of the present invention or Hydrate.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein comprise micro work For impurity with following formula (x) compound:
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein change with respect to formula (i) For the weight of compound, the content of formula (x) compound is less than 0.2%, e.g., less than 0.15%, e.g., less than 0.1%, for example little In 0.05%.
It has been unexpectedly discovered that being less than 0.2% for formula (x) compound (with respect to formula (i) compound) content Medicinal crude drug, it has significantly more excellent stability, for example its bulk drug or add the preparation of auxiliary material in long-term storage During active component be significantly able to maintain that higher level.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, it is as follows by including The method of step prepares:
(1) make in the reactive mixture with following formula (iv) compound
React with following formula (v) compound
Obtain formula (i) compound；Then, optionally,
(2) make gained formula (i) compound acid treatment to form the pharmaceutical salts of formula (i) compound；Then, optionally,
(3) step (2) gained pharmaceutical salts alkaline aqueous solution is made to process to be settled out the monohydrate of formula (i) compound.
In formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein step (3), The monohydrate making formula (i) compound at a temperature of 35 DEG C to 45 DEG C precipitates.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, are wherein also included step (4) it may be assumed that making the monohydrate drying under reduced pressure of step (3) gained formula (i) the compound step to form formula (i) compound.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein comprise the formula dissolving The solution of i material that () compound and the salt from formula (i) compound are settled out is reactant mixture or from reactant mixture In isolate formula (i) compound after preparation formula (i) compound single solution.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein said acid so adds Enter: after forming formula (i) compound, mixed in reaction by adding proton material and acid precursors in reactant mixture (i.e. in-situ preparation) is produced on the spot in thing.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein said proton material It is alcohol and described acid precursors are acid chlorides.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein said acid so adds Enter: after forming formula (i) compound, by the addition alcohol in reactant mixture and acid chloride in the reactive mixture Ground produces (i.e. in-situ preparation).
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein said alcohol is methyl alcohol Or ethanol and described acid chloride is chloroacetic chloride.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, are wherein carried out in step (1) During formula (iv) compound is reacted with formula (v) compound, also it is added with alkanoic acid with formula (iv) compound.At one In embodiment, formula (iv) compound is 1:0.1～0.2 with the mol ratio of alkanoic acid.In one embodiment, alkanoic acid is Glacial acetic acid.Surprisingly it has been found that adding appropriate alkanoic acid in condensation reaction to contribute to reduction formula (x) compound Generate.
Formula (iv) compound is known.Certainly it also can be prepared by the following method and obtain.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, its Chinese style (iv) compound Through the following steps that preparation:
Make formula (iii) compound
Wherein r1 and r2 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected and Form 4 to 7 yuan of cycloalkyl rings together with the carbon atom being connected with them,
React in the presence of base with following formula (ii) compound,
It is subsequently added acid with production (iv) compound.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, its Chinese style (iii) compound In the solution of suitable organic solvent using and be to react generation by making 4- amino -3- fluorophenol and formula (vi) compound 's
Wherein r1 and r2 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected and Form 4 to 7 yuan of cycloalkyl rings together with the carbon atom being connected with them.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, its Chinese style (ii) compound The solution of suitable organic solvent uses, described solution is by being prepared with the hydrochloride with formula (ii) compound in alkali 's.
Formula (i) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein by formula (ii) chemical combination Thing is dissolved in suitable organic solvent, with the acid treatment by adding proton material and acid precursors in-situ generation, is precipitated as formula (ii) salt of compound, and by adding the aqueous solution neutralization of alkali.
Further, second aspect present invention provides and prepares with following formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate Method:
It comprises the steps:
(1) make in the reactive mixture with following formula (iv) compound
React with following formula (v) compound
Obtain formula (i) compound；Then, optionally,
(2) make gained formula (i) compound acid treatment to form the pharmaceutical salts of formula (i) compound；Then, optionally,
(3) step (2) gained pharmaceutical salts alkaline aqueous solution is made to process to be settled out the monohydrate of formula (i) compound.
Method according to a second aspect of the present invention, wherein said formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate are medicine Use bulk drug.Or, second aspect present invention provide preparation Medicinal crude drug method, this Medicinal crude drug its be the present invention Described formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate.
In method according to a second aspect of the present invention, its obtained formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate, Comprise micro as impurity with following formula (x) compound
In method according to a second aspect of the present invention, its obtained formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate, For the weight of formula (i) compound, the content of formula (x) compound is less than 0.2%, e.g., less than 0.15%, for example little In 0.1%, e.g., less than 0.05%.
In method according to a second aspect of the present invention, wherein step (3), formula (i) is made to change at a temperature of 35 DEG C to 45 DEG C The monohydrate precipitation of compound.
Method according to a second aspect of the present invention, is wherein also included step (4) it may be assumed that making step (3) gained formula (i) change The step to form formula (i) compound for the monohydrate drying under reduced pressure of compound.
Method according to a second aspect of the present invention, wherein comprises formula (i) compound and the salt from formula (i) compound dissolving The solution of the material being settled out is reactant mixture or prepares after isolating formula (i) compound from reactant mixture The single solution of formula (i) compound.
Method according to a second aspect of the present invention, wherein said acid so adds: after forming formula (i) compound, Produce (i.e. in-situ preparation) by adding proton material and acid precursors in reactant mixture on the spot in the reactive mixture.
Method according to a second aspect of the present invention, wherein said proton material is alcohol and described acid precursors are acid chlorides.
Method according to a second aspect of the present invention, wherein said acid so adds: after forming formula (i) compound, Produce (i.e. in-situ preparation) by adding alcohol and acid chloride in reactant mixture on the spot in the reactive mixture.
Method according to a second aspect of the present invention, wherein said alcohol is methyl alcohol or ethanol and described acid chloride is acetyl Chlorine.
Method according to a second aspect of the present invention, wherein anti-with formula (v) compound in step (1) progressive form (iv) compound During answering, also it is added with alkanoic acid with formula (iv) compound.In one embodiment, formula (iv) compound and chain The mol ratio of alkanoic acid is 1:0.1～0.2.In one embodiment, alkanoic acid is glacial acetic acid.
Method according to a second aspect of the present invention, its Chinese style (iv) compound through the following steps that preparation:
Make formula (iii) compound
Wherein r1 and r2 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected and Form 4 to 7 yuan of cycloalkyl rings together with the carbon atom being connected with them,
React in the presence of base with following formula (ii) compound,
It is subsequently added acid with production (iv) compound.
Method according to a second aspect of the present invention, its Chinese style (iii) compound makes in the solution of suitable organic solvent With and be to react generation by making 4- amino -3- fluorophenol and formula (vi) compound
Wherein r1 and r2 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected and Form 4 to 7 yuan of cycloalkyl rings together with the carbon atom being connected with them.
Method according to a second aspect of the present invention, its Chinese style (ii) compound makes in the solution of suitable organic solvent With described solution is by being prepared with the hydrochloride with formula (ii) compound in alkali.
Method according to a second aspect of the present invention, wherein formula (ii) compound is dissolved in suitable organic solvent, uses By adding the acid treatment of proton material and acid precursors in-situ generation, it is precipitated as the salt of formula (ii) compound, and by adding alkali The aqueous solution neutralization.
Further, third aspect present invention provides a kind of pharmaceutical composition, wherein comprises first aspect present invention arbitrary Medicinal crude drug described in embodiment, and pharmaceutically acceptable auxiliary material.
Or, further, third aspect present invention provides a kind of pharmaceutical composition, wherein contained (i) compound or Its pharmaceutical salts or monohydrate, and pharmaceutically acceptable auxiliary material.
Pharmaceutical composition according to a third aspect of the present invention, wherein comprise micro as impurity with following formula (x) chemical combination Thing
Pharmaceutical composition according to a third aspect of the present invention, wherein for the weight of formula (i) compound, formula (x) The content of compound is less than 0.2%, e.g., less than 0.15%, e.g., less than 0.1%, e.g., less than 0.05%.
According to the either side of the present invention, whether described Medicinal crude drug or pharmaceutical composition, wherein with respect to formula I, for the weight of () compound, the content of formula (x) compound is 0.0001%～0.2%, for example, 0.0001%～ 0.15%, for example, 0.0001%～0.1%, for example, 0.0001%～0.05%.According to the either side of the present invention, no matter It is described Medicinal crude drug or pharmaceutical composition, wherein for the weight of formula (i) compound, formula (x) compound Content is 0.0005%～0.2%, for example, 0.0005%～0.15%, for example, 0.0005%～0.1%, for example, 0.0005%～0.05%.According to the either side of the present invention, whether described Medicinal crude drug or pharmaceutical composition, wherein For the weight of formula (i) compound, the content of formula (x) compound is 0.001%～0.2%, for example, 0.001%～ 0.15%, for example, 0.001%～0.1%, for example, 0.001%～0.05%.It has been found by the present inventors that formula (x) is changed It is technically extremely difficult that the content of compound drops to 0.0001%, and the yield of object can be caused drastically to decline.Therefore formula X () compounds content is beneficial at acceptable (i.e. lower limit) to controlled (i.e. the upper limit).
Arbitrary technical characteristic that any embodiment of either side of the present invention or this either side has is equally applicable Other any embodiment or any embodiment of other either side, as long as they will not be conflicting, certainly mutual Between where applicable, if necessary can individual features be made suitably modify.Make into one with feature to various aspects of the present invention below The description of step.
All documents recited in the present invention, their full content is incorporated herein by, and if these are civilian When implication expressed by offering is inconsistent with the present invention, it is defined by the statement of the present invention.Additionally, the present invention use various terms and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term referring to and phrase if any inconsistent with common art-recognized meanings, with institute of the present invention table The implication stated is defined.
In the present invention, if not otherwise indicated, the % being related to is w/w percentage.
A kind of method that the present invention comprises formula (i) compound, its salt or monohydrate, the method is passed through mixed in reaction By formula (iv) compound (it is 4- (4- amino -3- fluorophenoxy)-n- picoline -2- carboxylic acid amides) in compound
Processed with formula (v) compound (it is isocyanic acid (4- chloro- 3- trifluoromethyl-phenyl) ester),
Then by formula (i) the compound acid treatment of dissolving, to form the salt of formula (i) compound, (it is from the formula containing dissolving It is precipitated out in the solution of (i) compound), then optionally the salt alkaline aqueous solution of formula (i) compound is processed to precipitate The monohydrate of formula (i) compound, and optionally by this monohydrate drying under reduced pressure, until forming formula (i) compound.
During progressive form (iv) compound is reacted with formula (v) compound, also add with formula (iv) compound There is alkanoic acid.In one embodiment, formula (iv) compound and the mol ratio of alkanoic acid are 1:0.1～0.2.Implement at one In scheme, alkanoic acid is glacial acetic acid.
The salt of formula (i) compound can be prepared by following steps: uses formula (iv) compound in the reactive mixture Formula (v) compound treatment, then by formula (i) the compound acid treatment of dissolving to form the salt of formula (i) compound, it is from containing It is precipitated out in the solution of formula (i) compound of dissolving.
The monohydrate of formula (i) compound can be prepared by following steps: changes formula (iv) in the reactive mixture Compound formula (v) compound treatment, then salt (its to form formula (i) compound by formula (i) the compound acid treatment of dissolving It is precipitated out from the solution of formula (i) compound containing dissolving), then preferably in 35 DEG C to 45 DEG C of temperature, most preferably exist 38 DEG C to the 42 DEG C salt alkaline aqueous solutions by formula (i) compound are processed to be settled out the monohydrate of formula (i) compound.
Formula (i) compound can be prepared by following steps: in the reactive mixture by formula (iv) compounds having formula (v) Compound treatment, then by formula (i) the compound acid treatment of dissolving, to form the salt of formula (i) compound, (it is from containing dissolving The solution of formula (i) compound in be precipitated out), then by the salt of formula (i) compound with alkaline aqueous solution process with precipitating type The monohydrate of (i) compound, and preferably in 85 DEG C to 120 DEG C of temperature, and preferably should in the pressure less than 30mbar Monohydrate drying under reduced pressure, until forming formula (i) compound.
According to method described above, the thing being settled out containing formula (i) compound dissolving and the salt from formula (i) compound The solution of matter may be preferred that reactant mixture, or can be the single solution containing formula (i) compound.This is individually molten Liquid can (for example be passed through according to being described in such as wo2005009961 isolating formula (i) compound from reactant mixture In the post-processing approach of standard and formula (i) compound is dissolved in suitable organic solvent) after preparation.
In the preferred embodiment of the method for formula (i) compound as described above, its monohydrate or salt, Described acid by add in reactant mixture proton material and acid precursors in the solution of formula (i) compound containing dissolving just Ground produces.
In the further preferred embodiment of the method for formula (i) compound, its monohydrate or salt, described acid is passed through Alcohol and acid precursors are added to produce on the spot in the reactive mixture after the generation of formula (i) compound in reactant mixture.
In the most preferred embodiment of the method for formula (i) compound, its monohydrate or salt, described acid is passed through Add in reactant mixture alcohol and acid chloride (preferably chloroacetic chloride) after the generation of formula (i) compound in the reactive mixture Ground produces.
In the method for formula (i) compound, its monohydrate or salt, formula (iv) compound and formula (v) compound Reaction in suitable organic solvent (for example in oxolane), higher than 15 DEG C and be less than 70 DEG C of temperature (preferably 15 DEG C to 60 DEG C of temperature, more preferably at 15 DEG C to 50 DEG C, most preferably in room temperature) occur.Preferably first formula (iv) compound is added Enter to suitable organic solvent (for example in oxolane), and mix 30 to 300 minutes with formula (v) compound, preferably 60 To 150 minutes, most preferably 80 to 100 minutes, preferably dissolve or be suspended in suitable organic solvent (such as toluene), described molten Agent can be differently configured from the organic solvent that the first is suitable for.After forming formula (i) compound, add the acid to reactant mixture In.Preferably described acid by such as 5 to 60 minutes, add in preferably 10 to 30 minutes proton material (such as water and/or alcohol, Preferred alcohols) and acid precursors (preferably acid chloride) (thus in-situ generation accordingly acid) produce on the spot in the reactive mixture.Preferably It is firstly added proton material.The salt of formula (i) compound can be separated by precipitation.
For the monohydrate of formula (i) compound, the salt of formula (i) compound is used further alkaline aqueous solution (excellent Mixture from organic solvent and alkaline aqueous solution) process.The monohydrate of formula (i) compound can be divided by precipitation From preferably in 35 DEG C to 45 DEG C of temperature, most preferably carrying out to 42 DEG C at 38 DEG C.
For formula (i) compound, the monohydrate of formula (i) compound is dried, preferably in 85 DEG C to 120 DEG C of temperature Spend and at reduced pressure conditions, more preferably carry out under the pressure less than 30mbar.
In the method for formula (i) compound, its monohydrate or salt formed acid-addition salts suitably acid include but It is not limited to inorganic acid, carboxylic acid and sulfonic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, TFMS, ethyl sulfonic acid, first Benzene sulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzene Formic acid.Preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, TFMS, ethyl sulfonic acid, toluenesulfonic acid, benzene sulfonic acid and naphthalene two Sulfonic acid, more preferably hydrochloric acid, benzene sulfonic acid, toluenesulfonic acid or methanesulfonic acid, most preferably hydrochloric acid.
Salt (it is pharmaceutically acceptable salt) including but not limited to inorganic acid, carboxylic acid and the sulfonic acid of formula (i) compound Acid-addition salts, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, TFMS, ethyl sulfonic acid, toluenesulfonic acid, benzene sulfonic acid, Naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic salt.Preferably salt The salt of acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, TFMS, ethyl sulfonic acid, toluenesulfonic acid, benzene sulfonic acid and naphthalenedisulfonic acid, more The salt of preferably hydrochloric acid, benzene sulfonic acid, toluenesulfonic acid or methanesulfonic acid, most preferably hydrochloride.
According to the present invention, alcohol is the organic substance carrying at least one oh group.Alcohol includes but is not limited to methyl alcohol, second Alcohol, normal propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol, isobutanol, n-amyl alcohol, glycerine or its mixture.Preferably by methyl alcohol, ethanol and Isopropanol is used as the alcohol in this method.
In order to prepare acid on the spot, suitable acid precursors include but is not limited to organic acyl halide, preferably acyl halide, such as acid chloride And acid bromide RCOBr, more preferably chloroacetic chloride, acetyl bromide, propionyl chloride or propionyl bromide, most preferably chloroacetic chloride.
Preferably method described above, wherein prepares acid in the absence of water on the spot.
In the method for formula (i) compound, its monohydrate or salt, suitable organic solvent includes but is not limited to four Hydrogen furans, toluene, ethyl acetate, dioxane, methyl tertiary butyl ether(MTBE), dimethoxy-ethane, dimethyl sulfoxide, dimethylformamide, 1-Methyl-2-Pyrrolidone or the mixture of above-mentioned solvent.More preferably using oxolane, toluene and its mixture.
In the method for the monohydrate of formula (i) compound, suitable alkaline aqueous solution includes but is not limited to alkali metal The aqueous solution of hydroxide, alkaline earth metal hydroxide, alkali metal alcoholates, alkaline-earth alkoxides, organic amine and ammonia, preferably hydrogen-oxygen Change the aqueous solution of sodium and potassium hydroxide, the more preferably aqueous solution of NaOH.Alkaline aqueous solution can with organic solvent, such as third Ketone, ethyl acetate, oxolane mixing, are preferably mixed with acetone.
The method that the present invention equally comprises a kind of formula (iv) compound, the method is by making formula (iii) compound
Wherein r1 and r2 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected simultaneously And, form 4 to 7 yuan of cycloalkyl rings together with the carbon atom being connected with them,
React in the presence of base with formula (ii) compound (it is 4- chloro- n- methyl -2- pyridine carboxamides),
It is subsequently added acid with production (iv) compound.
In the preferred embodiment of the method for formula (iv) compound, formula (iii) compound is suitable organic In the solution of solvent using and be to react formation by making 4- amino -3- fluorophenol and formula (vi) compound,
Wherein r1 and r2 independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, The tert-butyl group, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected simultaneously And, form 4 to 7 yuan of cycloalkyl rings together with the carbon atom being connected with them.
In the further preferred embodiment of the method for formula (iv) compound, formula (ii) compound is suitable Use in the solution of organic solvent, described solution is by with alkali, preferably using NaOH, more preferably using the water-soluble of NaOH Prepare with the hydrochloride of formula (ii) compound in liquid.
In the method for formula (iv) compound, 4- amino -3- fluorophenol and formula (vi) compound are at 20 ° to up to The temperature of reflux temperature, preferably in 50 DEG C of temperature to up to reflux temperature, most preferably in the backflow temperature of formula (vi) compound Degree is lower to react, and described formula (vi) compound can be excessively used and as solvent.It is optionally possible to add other different molten Agent, such as toluene, ethyl acetate, hexamethylene or its mixture.Can be removed by optional azeotropic distillation at reduced pressure conditions and wave The property sent out reactive component.Formula (iii) compound being formed can in the solution of suitable organic solvent (preferably 1- methyl- In 2-Pyrrolidone solution) use, and in the presence of base use 4- chloro- n- methyl -2- pyridine carboxamides (preferably with suitable In the solution of organic solvent use, more preferably in 1-Methyl-2-Pyrrolidone solution using) process.By reactant mixture plus The temperature of heat to 50 DEG C to up to 150 DEG C, preferably 80 DEG C to up to 120 DEG C of temperature.After 1 to 5h, preferably 2 to 4h Afterwards, by temperature adjustment to 50 DEG C to up to 90 DEG C, preferably 70 DEG C to up to 90 DEG C, and acid is added (to be preferable in water Acetic acid).After cooling, it is preferably cooled to 0 DEG C to 10 DEG C of temperature, and optionally use the crystal of formula (iv) compound to sow, Precipitate and separate formula (iv) compound can be passed through.
Preferred formula (vi) compound, wherein r1 and r2 independently selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, Form 4 to 7 yuan of cycloalkyl rings together with the carbon atom that isobutyl group, sec-butyl or r1 with r2 are connected and, are connected with them. More preferably formula (vi) compound is selected from 4-methyl-2 pentanone, 3- methyl -2- butanone, 2- butanone, 2 pentanone, 4- heptanone, 2,4- bis- Methyl-propione and cyclohexanone.
In the method for formula (iv) compound, suitable organic solvent includes but is not limited to 1- methyl -2- pyrrolidines Ketone, dimethylformamide, n, n- dimethylacetylamide, the mixture of dimethyl sulfoxide, sulfolane or mentioned solvent.Preferably make With 1-Methyl-2-Pyrrolidone and/or dimethylformamide.
The alkali being suitable in the method for formula (iv) compound is alkali metal hydroxide and alkali metal alcoholates.Preferably uncle Butanol potassium.Potassium tert-butoxide preferably uses in the solution, uses more preferably in tetrahydrofuran solution.
In order to provide formula (ii) compound of high-purity forms, it is dissolved in suitable organic solvent, with by adding Enter proton material and the acid treatment of acid precursors in-situ generation, be precipitated as formula (ii) compound salt (preferred formula (ii) compound Hydrochloride), and by adding the aqueous solution neutralization of alkali.
For this purpose, chloro- for initial compounds 4- n- methyl -2- pyridine carboxamides are dissolved in suitable organic solvent In (preferably in toluene), and with the acid of in-situ generation (by adding proton material (such as water and/or alcohol, preferred alcohols) and acid Precursor (preferably acid chloride) for example in 5 to 60 minutes, preferably in 10 to 30 minutes, thus in-situ generation accordingly acid) place Reason.Preferably it is firstly added proton material.The salt of 4- chloro- n- methyl -2- pyridine carboxamides, preferably 4- chloro- n- methyl -2- pyridine carboxylic The hydrochloride of acid amides can pass through precipitate and separate.The salt of the purifying of chloro- for such 4- n- methyl -2- pyridine carboxamides is dissolved in In suitable organic solvent (preferably in toluene), and by adding in the aqueous solution aqueous solution of NaOH (preferably) of alkali With.After separating each phase, optionally reduced pressure concentration organic phase, and add suitable organic solvent (preferably 1- methyl -2- pyrroles Alkanone) to prepare a kind of solution, it is used directly for formula (iv) compound (as described above).
In the method preparing 4- chloro- n- methyl -2- pyridine carboxamides, suitable organic solvent includes but is not limited to tetrahydrochysene Furans, toluene, ethyl acetate, dioxane, methyl tertiary butyl ether(MTBE), dimethoxy-ethane, dimethyl sulfoxide, dimethylformamide, 1- N-methyl-2-2-pyrrolidone N or the mixture of mentioned solvent.More preferably using oxolane, toluene and its mixture.
According to the present invention, alcohol is the organic substance carrying at least one oh group.Alcohol includes but is not limited to methyl alcohol, second Alcohol, normal propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol, isobutanol, n-amyl alcohol, glycerine or its mixture.Preferably by methyl alcohol, ethanol and Isopropanol is used as the alcohol in the inventive method.
In order to prepare acid on the spot, suitable precursor includes but is not limited to organic acyl halide, preferably acyl halide, such as acid chloride and Acid bromide RCOBr, more preferably chloroacetic chloride, acetyl bromide, propionyl chloride or propionyl bromide, most preferably chloroacetic chloride.
Preferably prepare described acid in the absence of water on the spot.
Alternative is, formula (ii) compound and its hydrochloride can according to be described in wo2005009961 or Method in bankston et al. (organic process research＆development, 2002,6,777-781) is making Standby.. formula (v) compound (its be isocyanic acid (4- chloro- 3- trifluoromethyl-phenyl) ester) can be according to being described in wo2000042012 In method preparation.
Pharmaceutical composition according to a third aspect of the present invention, its be in tablet, the preparation shape such as capsule, granule, powder Formula.
Pharmaceutical composition according to a third aspect of the present invention, including: active pharmaceutical compounds, diluent, disintegrant, Adhesive, lubricant；Described active pharmaceutical compounds are with following formula (i) compound or its salt, monohydrate:
Pharmaceutical composition according to a third aspect of the present invention, it is solid composite medicament.
Pharmaceutical composition according to a third aspect of the present invention, it is the solid composite medicament in tablet form.
Pharmaceutical composition according to a third aspect of the present invention, wherein said diluent includes but is not limited to: calcium monohydrogen phosphate, height Ridge soil, dextrin, lactose, mannitol, sucrose, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbierite and starch and Its derivative (such as cornstarch, potato starch, amylum pregelatinisatum, modified starch, pregelatinized starch etc.), erythritol, wood Sugar alcohol, fructose etc. and combinations thereof.
Pharmaceutical composition according to a third aspect of the present invention, the active pharmaceutical compounds wherein comprising are with formula (i) compound It is calculated as 40 weight portions, the amount of described diluent is 50～500 weight portions；The amount of for example described diluent is 50～400 weight portions； The amount of for example described diluent is 50～300 weight portions；The amount of for example described diluent is 50～200 weight portions.
Pharmaceutical composition according to a third aspect of the present invention, wherein said disintegrant includes but is not limited to: low-substituted hydroxypropyl Base cellulose, PVPP, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, Ac-Di-Sol etc. with And combinations thereof.
Pharmaceutical composition according to a third aspect of the present invention, the active pharmaceutical compounds wherein comprising are with formula (i) compound It is calculated as 40 weight portions, the amount of described disintegrant is 50～500 weight portions；Such as 50～400 weight portions；Such as 50～300 weight Part；Such as 50～200 weight portions.
Pharmaceutical composition according to a third aspect of the present invention, wherein said adhesive is such as, but not limited to: hydroxy propyl cellulose (molecular weight is 5000～50000 pvp, for example pvp k15, pvp for element, hydroxypropyl methyl cellulose, polyvinylpyrrolidone K17, pvp k25, pvp k30 etc.), polyvinyl alcohol, Arabic gum, alginic acid, sodium alginate, gelatin etc. and their group Close.Preferred inclusion hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone or polyvinyl alcohol.
Pharmaceutical composition according to a third aspect of the present invention, the active pharmaceutical compounds wherein comprising are with formula (i) compound It is calculated as 40 weight portions, the amount of described adhesive is 50～500 weight portions；Such as 50～400 weight portions；Such as 100～300 weight Part；Such as 100～200 weight portions.Adhesive can be added by dry method, and prepares piece using typical compressing dry granulation Agent；Adhesive can be added by dry method, and it is right to carry out wet granulation for wetting agent to whole material using water or hydrous ethanol Prepare tablet afterwards again；Adhesive can also be used water or hydrous ethanol wiring solution-forming as binder solution, then with this bonding Agent solution carries out wet granulation and then prepares tablet again；Adhesive can also be dissolved in suitable solvent together with active medicine In (such as ethanol and/or acetone), more spray-dried for this solution technique is added in diluent and/or disintegrant.These Different types of adhesive feed postition be all well known to a person skilled in the art, and be easily able to.
Pharmaceutical composition according to a third aspect of the present invention, wherein said lubricant is also referred to as glidant in this area, Generally it is referred to as lubricant.Lubricant includes but is not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid Shape paraffin, polyethylene glycol, silica, cataloid, superfine silica gel powder, talcum powder, starch, hydrogenated vegetable oil etc. or its Combination.
Pharmaceutical composition according to a third aspect of the present invention, the active pharmaceutical compounds wherein comprising are with formula (i) compound It is calculated as 40 weight portions, the amount of described lubricant is 1～50 weight portion；The amount of for example described lubricant is 1～25 weight portion；For example The amount of described lubricant is 1～20 weight portion；The amount of for example described lubricant is 1～10 weight portion；For example described lubricant Measure as 2～8 weight portions.
Pharmaceutical composition according to a third aspect of the present invention, the pharmaceutically acceptable salt bag of wherein said formula (i) compound Include traditional nontoxic salt, the salt for example obtaining by methods known in the art from inorganic or organic acid.Such as formula (i) chemical combination The sulfate of thing, phosphate, fluoroform sulphonate, tosilate, 1-naphthalene sulfonic aicd salt, trifluoroacetate, malate, richness Horse hydrochlorate, benzoate, salicylate, phenylacetate, acetate, adipate, alginates, ascorbate, asparagine Hydrochlorate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphor hydrochlorate, camsilate, cinnamic acid Salt, cipionate, double gluconate, lauryl sulfate, isethionic acid, fumarate, glucose enanthate, glycerine Phosphate, Hemisulphate, enanthate, caproate, hydrochloride, hydrobromate, hydriodate, 2- hydroxyethanesulfonic acid salt, clothing health Hydrochlorate, lactate, maleate, mandelate, methane sulfonates, 2- naphthalene sulfonate, nicotinate, nitrate, oxalates, double hydroxyl Naphthoate, pectate, persulfate, 3- phenpropionate, picrate, pivalate, propionate, succinate, sulphur Hydrochlorate, tartrate, rhodanate, toluenesulfonic acid and undecylate are in interior acid-addition salts.
Pharmaceutical composition according to a third aspect of the present invention, the solvent of wherein said formula (i) compound or pharmaceutically acceptable salt thereof closes Thing can be its any acceptable solvate thereof.The hydrate of such as formula (i) compound, the such as monohydrate of formula (i) compound Deng.
Pharmaceutical composition according to a third aspect of the present invention, the polymorphic of wherein said formula (i) compound or pharmaceutically acceptable salt thereof, Can be any crystal formation disclosed in prior art, the i crystal formation of for example known formula (i) compound, etc..
Pharmaceutical composition according to a third aspect of the present invention, it is to be prepared by conventional preparation process.
Pharmaceutical composition according to a third aspect of the present invention, it is the form in coated tablet.
Pharmaceutical composition according to a third aspect of the present invention, it is the form in coated tablet, and described clothing layer is film Clothing.
Pharmaceutical composition according to a third aspect of the present invention, wherein said clothing layer accounts for the 1～5% of total weight of tablet, example As 1～4%, such as 2～3%.
Pharmaceutical composition according to a third aspect of the present invention, the main filmogen of the coating material of wherein said clothing layer is selected from: Ethyl cellulose, hydroxypropyl methyl cellulose and methacrylic acid-alkyl acrylate copolymer；Further, the main one-tenth of coating material Membrane material is hydroxypropyl methyl cellulose, is, for example, its aqueous dispersion；Further, coating material isIt is hydroxypropyl Ylmethyl cellulose aqueous dispersion；Further, coating material is selected from With
Pharmaceutical composition according to a third aspect of the present invention, the main filmogen of the coating material of wherein said clothing layer is Polyvinyl alcohol.In one embodiment, they can be interim before tablet is coated according to the conventional amount used of this area with water Prepared, can also easily be buied from market.For example, it is possible to buy from card happy Kanggong department, such asFilm bag Clothing premix formula, such as powder pinAgain for example, it is possible to buy from Ai Leyi medical material company, such asSeries of products, for exampleA kind of typical coating material composition includes: colouring agent (example As iron oxide red and/or iron oxide yellow or other), phosphatide (such as Fabaceous Lecithin), polyethylene glycol (such as PEG3350), poly- Vinyl alcohol, talcum powder, titanium dioxide etc..The pink colour for example buied from card happy Kanggong departmentWherein contain portion Divide the polyvinyl alcohol (accounting for the 44% of total weight of the mixture) hydrolyzing, peg3350 (accounting for the 12.4% of total weight of the mixture), beans phosphorus Fat, iron oxide (iron oxide red and iron oxide yellow), talcum powder, titanium dioxide.
The purposes of the present composition
The invention provides one or more letter being related to raf, vegfr, pdgfr, p38 and/or flt-3 kinases can be adjusted The pharmaceutical composition of number transduction pathway.Raf is to participate in important thin of many including cell growth, cell survival and intrusion The important signaling molecule of the regulation and control of born of the same parents' process.It is ras/raf/mek/erk approach member.This approach is present in major part In tumour cell.Vegfr, pdgfr and flt-3 are the acceptor molecules of cross-film, when it can be triggered by suitable ligand stimulation Ras/raf/mek/erk Cell signal transduction pathway, leads to intracellular cascade reaction.These acceptor molecules all have tyrosine-kinase enzyme activity Property.
Vegfr acceptor is stimulated by VEGF (vegf), and is in endothelial cell development and function point analysis Important control point.Pdgf beta receptor is adjusting cell proliferation and survival in the various kinds of cell type including mesenchymal cell. Flt-3 is the acceptor of fl part.It is similar to that c-kit, and adjusts the growth of multipotency hematopoietic cell, thus affect t cell, B cell and the growth of dendritic cells.
Any gene of raf, vegfr, pdgfr, p38 and/or the flt-3 including wild type and saltant type or isomery Body can be adjusted according to the present invention.Raf or raf-l kinases is serine/threonine kinase family, and it includes at least 3 Family member (a-raf, b-raf and c-raf or raf-1).C-raf and b-raf is the preferred of pharmaceutical composition of the present invention Target spot.Authenticated the activated mutant (such as v599e mutant) of b-raf in the kinds of tumors including melanoma, and Pharmaceutical composition as described herein can be used for suppressing its activity.
Term " regulation " refer to described pharmaceutical composition do not exist when normal activity compared with change described approach (or Its component) functional activity.This effect includes the regulation in any quantity or degree, and this includes improving, activates, strengthens, increasing Plus, promote, stimulate, reducing, hindering, suppression, reduce, reduce, antagonism etc..
Pharmaceutical composition of the present invention can also adjust following one or more process, and these processes include but is not limited to For example cell growth (including such as differentiation, cell survival and/or propagation), growth of tumour cell (include such as differentiation, cell to deposit Live and/or breed), tumor regression, endothelial cell growth (including such as differentiation, cell survival and/or propagation), Angiogenesiss (angiogenic growth), lymphatic vessel generation (lymphatic growth) and/or hematopoiesis function (such as t cell and b cell development, dendritic cells Develop etc.).
While not wishing to be subject to the constraint of any mechanism of action or mechanism it has been found that pharmaceutical composition of the present invention has There is the ability adjusting kinase activity.However, method of the present invention is not limited to any concrete mechanism or described drug regimen How thing realizes its therapeutic action.Term " kinase activity " refers to wherein turn a γ phosphate radical from atriphos (atp) Move on to the catalysis activity on one of protein substrate amino acid residue (such as serine, threonine or tyrosine).Medicine group Compound can adjust kinase activity, for example, suppressed its activity, passed through by the atp binding site that direct and atp compete kinases Producing conformation change in the structure of enzyme affects its activity (for example passing through to destroy the three-dimensional structure with BA) etc..
Conventional determining can be carried out using common detection methods to kinase activity.Kinase assays generally include kinases, Substrate, buffer solution and detecting system component.Typical kinase assay includes protein kinase and peptide substrate and as p-atp Atp reacts to produce the end-product (phosphorylated protein for example when using peptide substrate) of phosphorylation.Can be using any suitable Method final product is detected.When using radioactivity atp, can be by radioactivity mark using affinity membrane or gel electrophoresis The phosphorylated protein of note is separated with unreacted γ -32p-atp, and is subsequently developed on gel using autoradiograph or use Scintillation counter detects.Non-radioactive methods can also be used.Can be using antibody (for example anti-phosphoric acid of identification phosphorylated substrate Phosphotyrosine antibody).For example, can there is atp and kinase buffer liquid and described kinases available phosphorus acidifying institute with substrate in kinases It is incubated under conditions of stating substrate.Reactant mixture (for example passing through electrophoresis) can be separated, and subsequently can be with the phosphoric acid of detection substrate Change (for example by using the Western blot of antiphosphotyrosine antibody).Described antibody can be with detectable mark substance markers (the such as enzyme of such as hrp, Avidin or biotin, chemical illuminating reagent etc.).Other methods can adopt elisa, parent With UF membrane, fluorescence polarization method, luminescence method etc..
Another kind of method outside radioactive form is time-resolved fluorescence resonant energy transfer (tr-fret).Described side Method is reacted according to standard kinase, and wherein substrate (for example biotinylated poly- (GluTyr)) is deposited in atp by protein phosphatase Phosphorylation under the conditions.Final product subsequently can be with phospho-specif iotac antibodies (anti-phosphotyrosine or the phosphoric acid of europium chelating Serine/threonine) and the streptavidin-apc that is combined with biotinylated substrate detected.Above-mentioned two component is when combining It is spatially near, and the fluorescence producing homogeneous form to the energy transmission of acceptor (sa-apc) from phospho-specif iotac antibodies is read Number.
Pharmaceutical composition of the present invention can be used for treat and/or prevent be related to raf, vegfr, pdgfr, p38 and/or Any disease or illness that the one or more cellular signal transduction pathways of flt-3 are mediated.Term " treatment " is conventional according to it Meaning uses, for example, for the symptom resisting, mitigating, reduce, release, improve disease or dysfunction etc. purpose, patient is entered Row processes or looks after.Described pharmaceutical composition for preventing and/or can also treat the disease being mediated by described signaling molecule And/or illness is described.Term " mediation " represent for example described signaling molecule be abnormal in described disease and/or illness or A part for not normal approach.
Treatable disease and illness include any disease mentioned above and below and:
Raf relevant disease including such as cell generation disorders, cancer, tumour etc.；
Including such as cancer, tumour growth, inflammation disease, rheumatic arthritis, retinopathy, psoriasis, glomerulonephritis Disease, asthma, chronic bronchitis, arteriosclerosis, graft rejection, be related to the illness of Angiogenesiss etc. vegfr-2 related Disease；
Include such as cancer, disease of cornea, cornea redness, corneal transplantation, lymph gland hyperplasia, be related to the illness of lymphatic vessel generation Etc. vegfr-3 relevant disease；
Including the disease being for example characterised by that cell proliferation, cellular matrix formation, cell movement and/or extracellular matrix are formed Disease or the pdgfr- ss related diseases of illness.Specific example includes such as tumour, malignant tumour, cancer, cancer metastasis, chronic Myelomatosis, inflammation, ephrosis, diabetic nephropathy, mesangium hyperplastic glomerular ephrosis, fibrotic conditions, artery are hard Change disease, heart lobe ISR, hypertension related arteriosclerosis, venous bypass graft artery sclerosis, chorionitis, interstitial lung disease, cunning Liquid disease, arthritis, leukaemia, lymthoma etc.；
Including such as immune correlated disease, blood cell disease, (for example t cell, b cell, dendron shape are thin to be related to hematopoietic cell Born of the same parents) develop illness, cancer, anaemia, hiv, the flt-3 relevant disease of acquired immunodeficiency disease etc.；
Including inflammation disease, immunoregulatory disorder and other and the generation or different of abnormal cell factor (particularly tnf α) The p38 relevant disease of the related other diseases of normal mmp activity.These diseases include but is not limited to rheumatic arthritis, chronic Obstructive lung disease (copd), osteoporosis, Crohn disease and psoriasis.
Additionally, pharmaceutical composition of the present invention can be used for treating for example following illness and disease: glomerulosclerosis, Interstitial nephritis, interstitial pulmonary fibrosis, arteriosclerosis, wound scar and chorionitis.
Pharmaceutical composition of the present invention also has extensive therapeutic activity in order to treat or to prevent the progress of various diseases, These diseases such as inflammatory disorders, coronary restenosis, tumor-associated vessels generation, arteriosclerosis, autoimmunity disease, inflammation The disease some ephrosis related to glomerulus or mesangial cell propagation and the illness in eye related with retinal vessel proliferation, silver Bits disease, cirrhosis, diabetes, arteriosclerosis, ISR, vascular graft restenosis, in-stent restenosis, Angiogenesiss, eye Disease, lung fiber disease, bronchiolitis obliterans, glomerulus ephrosis, rheumatic arthritis.
The present invention also provides treatment, prevention, adjusts for the illness of one or more of people and/or other mammals Etc.: include diabetic retinopathy, the view of ischemic retinal vein obturation, retinopathy of prematurity and age related macular degeneration Film disease；Rheumatic arthritis, psoriasis or form related bullous disease to subcutaneous bubble and (include bullous pemphigoid, multiform Erythema or dermatitis herpetiformis), rheumatic fever, bone information, PMO, pyaemia, Gram-negative pyaemia, purulence blood Property shock, endotoxin shock, Toxin shock syndrom, Systemic inflammatory syndrome, inflammatory bowel disease (Crohn disease and ulcer Property colitis), Herxheimer reaction, asthma, adult respiratory distress wait group, Acute Lung fibrotic disease, sarcoidosis of lung, mistake Hepatopathy in quick property respiratory disease, silicosis, coal miner pneumoconiosis, alveolar damage, hepatic failure, acute inflammation, severe Alcoholic Hepatitis, malaria (Plasmodium falciparum malaria and brain malaria), Non-Insulin Dependent Diabetes Mellitus (neddm), congestive cardiac decline Exhaust, damage, arteriosclerosis, Alzheimer disease, acute encephalitis, brain damage, multiple sclerosis (multiple sclerosis after heart disease In demyelinate and few BMDC disappearance), TCA, malignant lymphoma, pancreatitis, in infection wound healing weaken, Inflammation and cancer, myelodysplastic syndrome, systemic loupus erythematosus, biliary cirrhosis, bowel necrosis, radiational injury/give (ischemia reperfusion injury and kidney, liver, heart and skin are same for toxicity after monoclonal antibody, host-transplant reaction Kind of allograft rejection), lung allograft rejection (bronchitis obliterans), total hip displacement complication and Summer Graves disease that helicobacter pylori infections in pulmonary tuberculosis, gastric ulcer, Ku Shi Trypanosoma cruzi infection cause, coli-infection Cause shiga-like toxin effect, staphy lococcus infection cause enterotoxin a effect, the infectious diseases of meningococcal infection, with And the huge virus of lyme disease spirochete, Leptospira, cell, influenza virus, theiler's encephalomyelitis virus and human immune deficiency Infection that viral (hiv) causes, papilloma, bud shape glioma, Kaposi's sarcoma, melanoma, lung cancer, oophoroma, Prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, carcinoma of urinary bladder, breast cancer, colorectal cancer, thyroid cancer, pancreas Cancer, cancer of the stomach, hepatocellular carcinoma, leukaemia, lymthoma, Hodgkin's disease, Hugh Burkitt disease, arthritis, rheumatic arthritis, diabetes regard Nethike embrane disease, Angiogenesiss, ISR, in-stent restenosis, vascular graft restenosis, pulmonary fibrosis, cirrhosis, artery sclerosis Disease, glomerulus ephrosis, diabetic nephropathy, graft rejection, psoriasis, diabetes, wound healing, inflammation and neurodegenerative disease, Excessive immune disease, hemangioma, myocardial angiogenesis, crown and the formation of brain collateral, ischemic, keratonosus, iridopathy, new green blood Pipe glaucoma, premature labor ARM retinopathy, wound healing, Helicobacter pylori ulcers relevant disease, fracture, endometrium Dystopy, diabetic symptom, cat scratch fever, thyroid gland hypertrophy, asthma or burnt degree edema, wound, chronic lung disease, apoplexy, polyp, capsule Swollen, synovitis, chronic and allergic inflammation, ovary be high to stimulate syndrome, lung and brain edema, cheloid, cystic fibrosis, hard Change, carpal tunnel syndrome, adult respiratory distress syndrome, ascites, illness in eye, cardiovascular disease, Ke-richness (poems) syndrome, Crow grace Disease, glomerulus ephrosis, osteoarthritis, multiple sclerosis, graft rejection, Lyme arthritis, pyaemia, Feng Xi-woods Er Shi are comprehensive Simulator sickness, pemphigoid, Paget disease, MCKD, sarcoidosis, thyroiditis, hyperviscosity syndrome, osier-weber- Rendir disease, chmnic. obstructive's tuberculosis, radiation, anoxic, pre-eclampsia, menorrhalgia, mullerianosis, herpe simplex sense Dye, ischemic retinopathies, corneal vessels generation, herpes zoster, human immunodeficiency virus, parapoxvirus, protozoan, arch Parasitosis and related the oozing out and oedema of tumour.
Pharmaceutical composition of the present invention can have more than one described activity and therefore can be directed to a plurality of letter Number transduction pathway.Therefore, can realize being typically only capable to could when using different pharmaceutical combination of compositions for these pharmaceutical compositions The treatment and prevention effect obtaining.For example, formed (for example with vegfr-2 by using the new conduit of single medicine composition suppression It is connected with vegfr-3 function) (such as blood vessel and/or lymphatic vessel) (be for example connected with raf and pdgfr β function with cell proliferation ) be particularly useful in treating cancer and other cell proliferation exceptions of being promoted by new vascularization.Therefore, the present invention More particularly, at least there is suppressing cell reproduction and the pharmaceutical composition of Anti- angiogenesis (suppressing Angiogenesiss) activity.According to The present invention can benefit from vessel growth and the disease of cell inhibitory effect or illness is treated to any.Due to can be more smart Really define its field of activity, be also advantageous using single medicine composition.
Pharmaceutical composition of the present invention can be treated to any tumour, and these tumours include but is not limited in raf, ras And/or there is in flt-3 and its any upstream of signal pathway of being participated in or downstream member the swollen of one or more mutation Knurl.As it was earlier mentioned, tumour can be treated with pharmaceutical composition of the present invention and not considered its corresponding mechanism.Can Treated with the tumour to any organ, this including but not limited to such as colon cancer, cancer of pancreas, breast cancer, prostate cancer, bone Cancer, liver cancer, kidney, lung cancer, carcinoma of testis, cutaneum carcinoma, cancer of the stomach, colorectal cancer, clear-cell carcinoma, hepatocellular carcinoma, melanoma etc..
The example of breast cancer includes but is not limited to IDC, ILC, DCIS and original position leaflet Cancer.
The example of respiratory cancer includes but is not limited to cellule and non-small cell lung cancer and bronchial adenoma and pleura lung Blastoma.
The example of the cancer of the brain includes but is not limited to brain stem and hypophtalmic glioma, cerebellum and cerebral astrocytoma, becomes neural Solencyte knurl, ependymoma and the outer embryoma of nerve and pine nut adenoma.
Genital orgnas,male's tumour includes but is not limited to prostate cancer and carcinoma of testis.Tumors of female reproductive organ include but not It is limited to carcinoma of endometrium, cervical carcinoma, oophoroma, carcinoma of vagina and carcinoma of vulva and sarcoma of uterus.
Tumor in digestive tract includes but is not limited to cancer of anus, colon cancer, colorectal cancer, cancer of the esophagus, carcinoma of gallbladder, cancer of the stomach, straight Intestinal cancer, carcinoma of small intestine and salivary-gland carcinoma.
Urethral system tumour includes but is not limited to carcinoma of urinary bladder, carcinoma of penis, kidney, carcinoma of renal pelvis, carcinoma of ureter and carcinoma of urethra.
Cancer eye includes but is not limited to intraocular melanoma and retinoblastoma.
The example of liver cancer includes but is not limited to hepatocellular carcinoma (with or without the hepatocellular carcinoma of fibrolamellar form), courage Solencyte cancer and mixed type liver cell cholangiocellular carcinoma.
Cutaneum carcinoma include but is not limited to squamous cytoma, Kaposi sarcoma, chromoma, Merkel cell skin cancer with And non-melanoma cutaneum carcinoma.
Head and neck cancer includes but is not limited to laryngocarcinoma, hypopharyngeal cancer, nasopharyngeal carcinoma and/or oropharyngeal cancer and lip and carcinoma of mouth.
Lymthoma includes but is not limited to aids associated lymphoma, NHL, Cutaneous T-cell Lymphoma, Huo Qi Gold disease and central nervous system lymphoma.
Sarcoma includes but is not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and horizontal stroke Line muscle tumor.
Leukaemia including but not limited to acute myeloid leukemia, Acute Lymphoblastic Leukemia, chronic lymphocytic is white Blood disease, chronic myelogenous leukemia and hairy cell leukemia.
Except suppressing tumor cell proliferation, pharmaceutical composition of the present invention also can cause tumor regression, and such as tumour is big The reduction of little reduction or tumour distribution in vivo.
Specific embodiment
The following examples being provided are only used for task of explanation rather than are used for, and are also not necessarily to be construed as limiting by any way The present invention processed.Spectrometer using bruker is composed in room temperature record 1h-nmr.Deuterated dimethyl sulfoxide is used as solvent, described solvent Including tetramethylsilane as internal standard (if in addition referring to).Using water this and applied biosystems Spectrometer record ms composes.Give relative signal intensity (representing with the percentage based on main peak).Carried out using favour spectrum hp1100 hplc.The respective working Examples of conditions accompanying determining are given.
Embodiment 1:4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl)-phenyl] amino } carbonyl) amino] -3- fluorophenoxy } - The preparation of n- picoline -2- carboxylic acid amides, its hydrochloride and its monohydrate
Stage 1:
4- chloro- n- methvl-pyridinium -2- carboxamide hydrochloride:
Will be molten in toluene for chloro- for the 4- of 420g n- picoline -2- carboxylic acid amides (according to wo2006/034796 preparation) Liquid (about 30%w/w) and 48.8g ethanol add to reaction flask.It is less than with reaching the temperature of reactant mixture in stirring 67.2g chloroacetic chloride is added under conditions of 30 DEG C of degree.After being further stirred at room temperature 1.5h, product is leached, use first Benzene (212g) washing drying under reduced pressure (30 DEG C, 80mbar).In this way, obtain the chloro- n- methyl of 156.3g (quantitative yield) 4-- Pyridine -2- carboxamide hydrochloride.173.7-174.5 DEG C of fusing point.
1H-nmr (500mhz, dmso-d6): δ [ppm]=2.96 (d, 3h), 7.79-7.97 (m, 1h), 8.13-8.26 (m, 1h), 8.73 (d, 1h), 9.06 (br.s., 1h), 13.16 (br.s., 1h).
Ms [dci, nh3]: m/e=171 [m+h]+(m=free alkali).
Hplc: fixing phase: nucleodur gravity c18 (150mm length, 3mm id, 3.0 μm of particle diameters)；Mobile phase a: The o- phosphoric acid of 1.15g diammonium hydrogen phosphate+0.68ml (85% solution in water)/ll water；Mobile phase b: acetonitrile；Uv detects: 254nm；Oven temperature: 45 DEG C, volume injected: 3 μ l, flow velocity: 0.5ml/min.；Linear gradient: 5%b- > 80%b (20min.), in 10 minutes retention times of 80%b；Purity: > 98% (rt=17.8min.).
Stage 2:
4- (4- amino -3- fluorophenoxy)-n- picoline -2- carboxylic acid amides
Method 2a:
To in the reaction flask have agitator add 41.4g 4- chloro- n- methvl-pyridinium -2- carboxamide hydrochloride and 100g toluene as solvent.After adding 68.4g water and 19.6g sodium hydrate aqueous solution (45%w/w), by reaction mixing Thing stirs 30 minutes.Two phases were separated and discards water layer.Organic layer is concentrated and by toluene 1- methyl -2- pyrrole through vacuum distillation Pyrrolidone (70g) replaces, and obtains solution in 1-Methyl-2-Pyrrolidone for the 4- chloro- n- methvl-pyridinium -2- carboxylic acid amides.
Add in the second reaction flask have agitator the 4- methyl of the 4- amino -3- fluorophenol of 26.7g and 100g - 2 pentanone.By being heated to backflow and additionally stirring 1 hour, remove water through azeotropic distillation.Then by excessive 4- methyl -2- penta Ketone removes through vacuum distillation and uses 1-Methyl-2-Pyrrolidone (70g) to replace to prepare the imines chemical combination containing with good grounds formula (iii) The solution of thing.Add 4- chloro- n- methvl-pyridinium -2- carboxylic acid amides in gained reactant mixture in 1-Methyl-2-Pyrrolidone Solution.Reactant mixture is heated approximately at 100 DEG C.Dropping (in about 70 minutes) 123.2g potassium tert-butoxide is in tetrahydrochysene furan Solution (20%w/w) in muttering, simultaneously through oxolane is distilled off.Thereafter, reactant mixture is extra in 100 DEG C of stirrings 3 hours to complete to react.Adjusting to 80 DEG C afterwards, adding 350ml toluene, 392ml water and 8g acetic acid.By mixture at 80 DEG C Stirring 10 minutes, is cooled to 50 DEG C and the crystal sowing with 4- (4- amino -3- fluorophenoxy)-n- picoline -2- carboxylic acid amides. It is being cooled to 0 DEG C afterwards, suspension is being stirred about 30 minutes.Product is leached, with methanol/water (1:3v/v, 144ml) washing And drying under reduced pressure (30 DEG C, 80mbar).In this way, obtain 40.4g (the 78% of theoretical value) 4- (4- amino -3- fluorobenzene oxygen Base)-n- picoline -2- carboxylic acid amides is brown crystal.
140.8-141.4 DEG C of fusing point
1H-nmr (100mhz, dmso-d6): δ [ppm]=2.87 (d, 3h), 5.24-5.35 (s, 2h), 6.80-6.85 (m, 1h), 6.87-6.99 (m, 1h), 7.01-7.09 (m, 1h), 7.09-7.14 (m, 1h), 7.45 (d, 1h), 8.49 (d, 1h), 8.75-8.85 (m, 1h) .ms [es]: m/e=262 [m+h]+
Hplc: fixing phase: agilent zorbax sb-aq (150mm length, 3mm id, 3.5 μm of particle diameters)；Mobile phase a: The o- phosphoric acid of 1.40g dipotassium hydrogen phosphate+5.8ml (8.5% solution in water)/ll water；Mobile phase b: acetonitrile；Uv detects: 268nm；Oven temperature: 50 DEG C, volume injected: 3 μ l, flow velocity: 0.8ml/min；Linear gradient in two steps: 10%b- > 37%b (10min.), 37%b- > 80%b (10min.), in 10 minutes retention times of 80%b；Purity: > 97% (rt= 9.22min.).
Method 2b:
To in the reaction flask have agitator add 41.4g 4- chloro- n- methvl-pyridinium -2- carboxamide hydrochloride and 100g toluene as solvent.After adding 68.4g water and 19.6g sodium hydrate aqueous solution (45%w/w), by reaction mixing Thing stirs 30 minutes.Two phases were separated and discards water layer.Organic layer is concentrated and by toluene 1- methyl -2- pyrrole through vacuum distillation Pyrrolidone (70g) replaces, and obtains solution in 1-Methyl-2-Pyrrolidone for the 4- chloro- n- methvl-pyridinium -2- carboxylic acid amides.
Add in the second reaction flask have agitator the 3- methyl of the 4- amino -3- fluorophenol of 26.7g and 100g - 2- butanone.By being heated to backflow and additionally stirring 3 hours, remove water through azeotropic distillation.Then by excessive 3- methyl -2- fourth Ketone removes through vacuum distillation and uses 1-Methyl-2-Pyrrolidone (70g) to replace to prepare the imines chemical combination containing with good grounds formula (iii) The solution of thing.Add 4- chloro- n- methvl-pyridinium -2- carboxylic acid amides in gained reactant mixture in 1-Methyl-2-Pyrrolidone Solution.Reactant mixture is heated approximately at 100 DEG C.Dropping solution (20% in oxolane for the 123.2g potassium tert-butoxide W/w) (in about 3 hours), simultaneously through oxolane is distilled off.Thereafter, reactant mixture is extra in 100 DEG C of stirrings 2.5 hours to complete to react.Adjusting to 80 DEG C afterwards, adding 350ml toluene, 392ml water and 8g acetic acid.By mixture 80 DEG C stirring 10 minutes, be cooled to 50 DEG C and broadcast with the crystal of 4- (4- amino -3- fluorophenoxy)-n- picoline -2- carboxylic acid amides Kind.It is being cooled to 0 DEG C afterwards, suspension is being stirred about 30 minutes.Product is leached, with methanol/water (1:3v/v, 144ml) Washing drying under reduced pressure (30 DEG C, 80mbar).In this way, obtain 44.6g (the 84% of theoretical value) 4- (4- amino -3- fluorobenzene Epoxide)-n- picoline -2- carboxylic acid amides is light-brown crystals.141.9-142.6 DEG C of fusing point.
1H-nmr (400mhz, dmso-d6): δ [ppm]=2.83 (d, 3h), 5.27 (s, 2h), 6.77-6.83 (m, 1h), 6.86-6.94 (m, 1h), 7.01-7.07 (m, 1h), 7.09-7.13 (m, 1h), 7.41 (d, 1h), 8.49 (d, 1h), 8.71- 8.87 (m, 1h) .ms [es]: m/e=262 [m+h]+
Hplc: fixing phase: agilent zorbax sb-aq (150mm length, 3mm id, 3.5 μm of particle diameters)；Mobile phase a: The o- phosphoric acid of 1.40g dipotassium hydrogen phosphate+5.8ml (8.5% solution in water)/ll water；Mobile phase b: acetonitrile；Uv detects: 268nm；Oven temperature: 50 DEG C, volume injected: 3 μ l, flow velocity: 0.8ml/min；Linear gradient in two steps: 10%b- > 37%b (10min.), 37%b- > 80%b (10min.), in 10 minutes retention times of 80%b；Purity: > 99% (rt= 9.16min.).
Method 2c:
To in the reaction flask have agitator add 41.4g 4- chloro- n- methvl-pyridinium -2- carboxamide hydrochloride and 100g toluene as solvent.After adding 68.4g water and 19.6g sodium hydrate aqueous solution (45%w/w), by reaction mixing Thing stirs 30 minutes.Two phases were separated and discards water layer.Organic layer is concentrated and by toluene 1- methyl -2- pyrrole through vacuum distillation Pyrrolidone (70g) replaces, and obtains solution in 1-Methyl-2-Pyrrolidone for the 4- chloro- n- methvl-pyridinium -2- carboxylic acid amides.
Add in the second reaction flask have agitator the 4- amino -3- fluorophenol of 26.7g, 73g hexamethylene and 20.6g cyclohexanone.By being heated to backflow and additionally stirring 3 hours, remove water through azeotropic distillation.Then by solvent hexamethylene and Excessive cyclohexanone removes through vacuum distillation and uses 1-Methyl-2-Pyrrolidone (70g) to replace to prepare containing with good grounds formula (iii) Group with imine moiety solution.Add 4- chloro- n- methvl-pyridinium -2- carboxylic acid amides in 1- methyl -2- in gained reactant mixture Solution in pyrrolidones.Reactant mixture is heated approximately at 100 DEG C.Dropping (in about 40 minutes) 126g potassium tert-butoxide Solution (20%w/w) in oxolane, simultaneously through oxolane is distilled off.Thereafter, reactant mixture is stirred at 100 DEG C Mix extra 3 hour to complete to react.Adjust to 80 DEG C after, addition 350ml toluene, 392ml water and 8g acetic acid.To mix Thing stirs 10 minutes at 80 DEG C, is cooled to 50 DEG C and with 4- (4- amino -3- fluorophenoxy)-n- picoline -2- carboxylic acid amides Crystal is sowed.It is being cooled to 3 DEG C afterwards, suspension is being stirred about 30 minutes.Product is leached, with methanol/water (1:3v/v, 144ml) washing drying under reduced pressure (30 DEG C, 80mbar).In this way, obtain 40.1g (the 76% of theoretical value) 4- (4- amino- 3- fluorophenoxy)-n- picoline -2- carboxylic acid amides is light-brown crystals.
141.4 DEG C of fusing point
1H-nmr (400mhz, dmso-d6): δ [ppm]=2.84 (d, 3h), 5.27 (s, 2h), 6.78-6.85 (m, 1h), 6.86-6.94 (m, 1h), 7.01-7.04 (m, 1h), 7.09-7.14 (m, 1h), 7.45 (d, 1h), 8.49 (d, 1h), 8.71- 8.87 (m, 1h) .ms [es]: m/e=262 [m+h]+
Hplc: fixing phase: agilent zorbax sb-aq (150mm length, 3mm id, 3.5 μm of particle diameters)；Mobile phase a: The o- phosphoric acid of 1.40g dipotassium hydrogen phosphate+5.8ml (8.5% solution in water)/ll water；Mobile phase b: acetonitrile；Uv detects: 268nm；Oven temperature: 50 DEG C, volume injected: 3 μ l, flow velocity: 0.8ml/min；Linear gradient in two steps: 10%b- > 37%b (10min.), 37%b- > 80%b (10min.), in 10 minutes retention times of 80%b；Purity: > 98% (rt= 9.14min.).
Stage 3: preparation 4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl)-phenyl] amino } carbonyl) amino] -3- fluorobenzene oxygen Base }-n- picoline -2- carboxylic acid amides monohydrate (monohydrate)
4- (4- amino -3- the fluorobenzene that stage 2 method 2a of 20.0g is obtained is added in the reaction flask have agitator Epoxide)-n- picoline -2- carboxylic acid amides (i.e. formula (iv) compound), the glacial acetic acid (mol ratio of formula (iv) compound and glacial acetic acid For 1:0.15) and the 180g oxolane as solvent.Drip 18.7g isocyanic acid (the chloro- 3- of 4- in room temperature in about 90 minutes Trifluoromethyl-phenyl) ester and 21.1g toluene solution.Resulting solution is stirred 3 hours to complete to react.Then by 30g tetrahydrochysene Furans and 7.8g methyl alcohol add to reactant mixture.Then in 15 minutes, 9.0g chloroacetic chloride is dropped to reactant mixture In.In extra stirring about 2 hours afterwards, suspension is filtered and by solid oxolane (18.2g) and acetone (136.4g) wash.40 DEG C by solid add to acetone (268.6g), water (55.8g) and sodium hydrate aqueous solution (8.2g, In mixture 45%w/w).Stir the mixture for extra 30 minute.So pass through with 4- { 4- [({ [4- chloro- 3- (fluoroform Base)-phenyl] amino carbonyl) amino] -3- fluorophenoxy-n- picoline -2- carboxylic acid amides monohydrate crystal sowing draw Send out crystallization.It is being cooled to 20 DEG C afterwards, adding 31.6g water.Suspension is cooled to about 3 DEG C and stirs 30 minutes.By product Leach, washed with the cold mixture of acetone (106g) and water (44g) and drying under reduced pressure (30 DEG C, 80mbar).In this way, obtain To 31.6g (the 83% of theoretical value) 4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl)-phenyl] amino } carbonyl) amino] -3- fluorobenzene oxygen Base }-n- picoline -2- carboxylic acid amides monohydrate is white crystal.
1H-nmr. (500mhz, methyl alcohol-d4): δ [ppm]=2.95 (s, 3h), 6.96-7.01 (m, 1h), 7.05-7.11 (m, 2h), 7.49-7.53 (m, 1h), 7.55-7.59 (m, 1h), 7.61-7.65 (m, 1h), 8.00-8.03 (m, 1h), 8.15- 8.20 (m, 1h), 8.46-8.50 (m, 1h) .ms [es]: m/e=483 [m+h]+
The present invention uses following [hplc-a method] to measure formula (i) compounds content in various forms bulk drug or its preparation (i.e. purity) and the content of related impurities.[hplc-a method] is as follows:
Fixing phase: eclipse xdb-c8 (150mm length, 2.1mm id, 3.5 μm of particle diameters)；Mobile phase a:1.0g hexane -1- Sulfonate sodium+1.0ml trifluoroacetic acid/1l water；Mobile phase b: acetonitrile；Uv detects: in 232nm；Oven temperature: 43 DEG C, injecting body Long-pending: 3 μ l, flow velocity: 0.5ml/min；Linear gradient in 3 steps: 5%b- > 36%b (14.5min.), 36%b- > 44% B (6min.), 44%b- > 80%b (9.5min.), in 10 minutes retention times of 80%b；
By external standard method with the content of calculated by peak area raw material or composition Chinese style (i) compound；
Relative for formula (i) compound with calculated by peak area raw material or composition Chinese style (x) compound phase by external standard method Content；
The retention time of formula (i) compound is about 25.5min；
Formula (x) compound phase is 0.86～0.90 for the relative retention time (rrt) of formula (i) compound.
After measured, the purity 99.82% in the Medicinal crude drug of formula (i) compound monohydrate that the above stage 3 obtains (i.e. formula (i) compound monohydrate accounts for the content of bulk drug gross weight)；
After measured, Medicinal crude drug Chinese style (x) compound phase of formula (i) the compound monohydrate that the above stage 3 obtains Relative amount for formula (i) compound monohydrate is that 0.063% (it is with respect to the content of bulk drug gross weight 0.0631%).
Complementary testing 1: 4- (4- amino -3- the fluorophenoxy)-n- picoline -2- carboxylic that operational phase 2 method 2b is obtained Acid amides (i.e. formula (iv) compound), other raw material, obtain with reference to the method in above " stage 3 " with a batch of using with the stage 3 To formula (i) compound monohydrate (yield 83%)；After measured, this Medicinal crude drug purity 99.94%, formula (x) compound phase It is 0.007% to content.
Complementary testing 2: 4- (4- amino -3- the fluorophenoxy)-n- picoline -2- carboxylic that operational phase 2 method 2c is obtained Acid amides (i.e. formula (iv) compound), other raw material, obtain with reference to the method in above " stage 3 " with a batch of using with the stage 3 To formula (i) compound monohydrate (yield 81%)；After measured, this Medicinal crude drug purity 99.93%, formula (x) compound phase It is 0.016% to content.
Complementary testing 3: using with the stage 3 with a batch of raw material, with reference to the method in above " stage 3 ", different only It is that the consumption of glacial acetic acid adding is: formula (iv) compound is 1:0.2 with the mol ratio of glacial acetic acid, obtains formula (i) compound one Hydrate (yield 86%)；After measured, this Medicinal crude drug purity 99.86%, formula (x) compound relative amount is 0.036%.
Complementary testing 4: using with the stage 3 with a batch of raw material, with reference to the method in above " stage 3 ", different only It is that the consumption of glacial acetic acid adding is: formula (iv) compound is 1:0.1 with the mol ratio of glacial acetic acid, obtains formula (i) compound one Hydrate (yield 85%)；After measured, this Medicinal crude drug purity 99.86%, formula (x) compound relative amount is 0.168%.
Complementary testing 5: using with the stage 3 with a batch of raw material, with reference to the method in above " stage 3 ", different only It is that the consumption of glacial acetic acid adding is: formula (iv) compound is 1:0.5 or 1:1 with the mol ratio of glacial acetic acid, obtains formula (i) chemical combination Thing monohydrate (yield is respectively 75% and 63%)；After measured, this Medicinal crude drug purity 99.89%, formula (x) compound phase It is 0.108% and 0.094 to content.Show to effectively improve product purity when increasing glacial acetic acid consumption, but can be right The yield of product produces significant harmful effect.
Complementary testing 6: using with the stage 3 with a batch of raw material, with reference to the method in above " stage 3 ", different only It is without glacial acetic acid, obtain formula (i) compound monohydrate (yield 84%)；After measured, this Medicinal crude drug purity 99.23%, formula (x) compound relative amount is 0.47%；
Complementary testing 7: with reference to the method for above " complementary testing 1 ", different is only without glacial acetic acid, obtains formula (i) Compound monohydrate (yield 82%)；After measured, this Medicinal crude drug purity 99.16%, formula (x) compound relative amount is 0.63%；
Complementary testing 8: with reference to the method for above " complementary testing 2 ", different is only without glacial acetic acid, obtains formula (i) Compound monohydrate (yield 83%)；After measured, this Medicinal crude drug purity 99.24%, formula (x) compound relative amount is 0.44%；
Complementary testing 9: using with the stage 3 with a batch of raw material, with reference to the method in above " stage 3 ", different only It is that glacial acetic acid is changed to formic acid, obtain formula (i) compound monohydrate (yield 86%)；After measured, this Medicinal crude drug purity 99.23%, formula (x) compound relative amount is 0.39%.
Complementary testing 10: using with the stage 3 with a batch of raw material, with reference to the method in above " stage 3 ", different only It is that the methyl alcohol forming acid with chloroacetic chloride reaction in-situ uses ethanol instead, obtain formula (i) compound monohydrate (yield 76%)；Through surveying Fixed, this Medicinal crude drug purity 99.79%, formula (x) compound relative amount is 0.057%.
Stage 4: preparation 4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl)-phenyl] amino } carbonyl) amino] -3- fluorobenzene oxygen Base }-n- picoline -2- carboxylic acid amides (anhydride)
4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl)-phenyl] amino } carbonyl) the amino] -3- that the 10.2g stage 4 is obtained Fluorophenoxy }-n- picoline -2- carboxylic acid amides monohydrate, in 90 DEG C of drying under reduced pressure (21mbar) 3 hours, in this way, obtains 4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl)-phenyl] amino } carbonyl)-amino] -3- fluorophenoxy }-n- methyl pyrrole to 9.8g Pyridine -2- carboxylic acid amides, is white crystal.187.3-188.1 DEG C of fusing point.
1H-nmr (400mhz, methyl alcohol-d4): δ [ppm]=2.94 (s, 3h), 6.94-7.13 (m, 3h), 7.51 (d, 1h), 7.58 (d, 1h), 7.61-7.67 (m, 1h), 8.01 (d, 1h), 8.17 (t, 1h), 8.45-8.53 (m, 1h) .ms [es]: m/e= 483[m+h]+
After measured, the purity 99.84% in the Medicinal crude drug of formula (i) compound anhydride that the above stage 4 obtains；
After measured, Medicinal crude drug Chinese style (x) compound phase pair of formula (i) the compound anhydride that the above stage 4 obtains It is that 0.054% (it is with respect to material Chinese style (i) compound anhydride gross weight in the relative amount of formula (i) compound anhydride Content be 0.0541%).
Complementary testing example 11: with reference to the method in above " stage 4 ", different complementary testing examples 1 above of using instead is tried to supplementary The product testing example 10 gained various formula (i) compound monohydrate is raw material, obtains the anhydride of 10 batch (i) compounds；Warp [hplc-a method] measures, and they are all no bright in purity and formula (x) compound relative amount with monohydrate raw material used by it respectively Aobvious change, purity difference is less than 0.1%, and formula (x) compound phase is less than 0.003% to content difference.
Embodiment 2: the study on the stability of bulk drug
Respectively by the formula of the various different purity preparing in above example 1, its each stage and each complementary testing example I () compound monohydrate and the medicinal aluminum plastic composite membrane of formula (i) compound anhydride medicinal raw material pack, put 45 DEG C of perseverances 4 months are placed to carry out high-temperature treatment in incubator.Measure purity when 0 month and during April for each bulk drug and formula (x) compound Relative amount, and it is respectively compared the purity of every batch sample and the changing value of formula (x) compound relative amount, changed with purity respectively Value and relative amount percent change characterize this change.The calculating formula of two parameter is as follows:
Purity changing value=0 month purity-April purity
Relative amount percent change=[(- 0 month relative amount of April relative amount) 0 month relative amount of ÷] × 100%
Result shows:
All the purity when April for the bulk drug and this batch of bulk drug purity when 0 month has no significant change, purity change , all in 0.2 percentage ranges, the Medicinal crude drug of such as stage 3 gained formula (i) compound monohydrate, when its 0 month for value Purity 99.82%, purity 99.67% during April, purity changing value is only 0.15%, shows to say simultaneously from the angle changing of principal component Do not occur significantly reducing；But, the relative amount percent change of formula (x) compound but presents with itself in bulk drug The related variation tendency of relative amount, specifically: formula (x) compound relative amount is less than to 0.2% whole medical raw Material medicine, their relative amount percent change is below 13%, the such as medicine of stage 3 gained formula (i) compound monohydrate It is 8.7% with the relative amount percent change of bulk drug its Chinese style (x) compound after high-temperature treatment April；But formula (x) is changed Whole Medicinal crude drug that compound relative amount is more than 0.2%, they are in its Chinese style (x) compound after high-temperature treatment April Relative amount percent change all in the range of 52～183%, and the higher bulk drug of relative amount of formula (x) compound its Formula (x) compound phase is bigger to changes of contents percentage, and for example formula (x) compound phase of complementary testing 8 product is to changes of contents Percentage is 146%.
Embodiment 3: prepare the pharmaceutical composition of tablet form
With reference to the step a) of page 19 embodiments 1 of wo2014039677a1, formula b), c) and preparation method, respectively using this The Medicinal crude drug of formula (i) the compound monohydrate of invention example 1 above preparation or formula (i) compound anhydride is activity Composition, prepares coated tablet (every contained (i) compound 40mg).
Each for gained tablet is packed with aluminum plastic composite membrane respectively, puts and place 4 months in 45 DEG C of insulating boxs to carry out High-temperature treatment.With reference to the method in above example 2, measure formula (i) compounds content when 0 month and during April for each tablet With formula (x) compound phase to (in formula (i) compound) content, and it is respectively compared formula (i) compound residues of every batch sample and contains Amount and the changing value of formula (x) compound relative amount, respectively with formula (i) compound residues content and formula (x) compound phase to containing Amount percent change characterizes this change.The calculating formula of two parameter is as follows:
Formula (i) compound residues content=(0 month relative amount of April content ÷) × 100%
Relative amount percent change=[(- 0 month relative amount of April relative amount) 0 month relative amount of ÷] × 100%
Result shows: all formula (i) the compound residues contents when April for the tablet are all higher than 95%, all 95%～ In the range of 99%, show to say the no obvious stability difference of each tablet, such as stage 3 gained formula from the angle changing of active component I tablet that () compound monohydrate Medicinal crude drug is made, its April up-to-date style (i) compound residues content is 97.8%；But It is, the relative amount percent change of formula (x) compound, but variation tendency in bulk drug similar to it, presents and it The related variation tendency of body relative amount in tablets, specifically: 0.2% is less than for formula (x) compound relative amount Whole tablets that bulk drug is made, their relative amount percent change is below 15%, and such as stage 3 gained formula (i) is changed The relative amount change of tablet its Chinese style (x) compound after high-temperature treatment April that compound monohydrate Medicinal crude drug is made Percentage is 9.7%；But formula (x) compound relative amount is more than whole tablets that 0.2% bulk drug is made, and they are in warp After high-temperature treatment April, the relative amount percent change of its Chinese style (x) compound is all in the range of 64～197%, and formula (x) Its formula (x) compound phase of tablet that the relative amount of compound is higher is bigger to changes of contents percentage, and such as complementary testing 9 is produced Formula (x) compound phase of thing is 133% to changes of contents percentage.
Above by present pre-ferred embodiments, the spirit of the present invention is elaborated.Those skilled in the art manage Solution, every any modification, equivalent variations and modification substantially above example made according to the technology of the present invention, all fall within this In bright protection domain.

Claims (24)

1. preparation is with the method for following formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate:
It comprises the steps:
(1) make in the reactive mixture with following formula (iv) compound
React with following formula (v) compound
Wherein it is added with glacial acetic acid, formula (iv) compound and ice with formula (iv) compound The mol ratio of acetic acid is 1: 0.1～0.2, obtains formula (i) compound；Then, optionally,
(2) make gained formula (i) compound acid treatment to form the pharmaceutical salts of formula (i) compound；Then, optionally,
(3) step (2) gained pharmaceutical salts alkaline aqueous solution is made to process to be settled out the monohydrate of formula (i) compound.
2., in method according to claim 1, wherein step (3), at a temperature of 35 DEG C to 45 DEG C, make the one of formula (i) compound Hydrate deposition.
3. method according to claim 1, wherein also includes step (4): make a water of step (3) gained formula (i) compound Compound drying under reduced pressure is to form formula (i) compound.
4. method according to claim 1, wherein comprises formula (i) compound of dissolving and the salt from formula (i) compound is settled out Material solution be reactant mixture or after isolating formula (i) compound from reactant mixture preparation formula (i) The single solution of compound.
5. method according to claim 1, acid described in step (2) is such addition: after forming formula (i) compound, By adding proton material and acid precursors in reactant mixture and in-situ preparation in the reactive mixture.
6. method according to claim 5, wherein said proton material is alcohol and described acid precursors are acid chlorides.
7. method according to claim 6, wherein said alcohol is methyl alcohol or ethanol and described acid chloride is chloroacetic chloride.
8. the method according to any one of claim 1-7, its obtained formula (i) compound or pharmaceutically acceptable salt thereof or monohydrate In, comprise micro as impurity with following formula (x) compound
9. method according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound is 0.0001%～0.2%.
10. method according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.0001%～0.15%.
11. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.0001%～0.1%.
12. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.0001%～0.05%.
13. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.0005%～0.2%.
14. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.0005%～0.15%.
15. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.0005%～0.1%.
16. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.0005%～0.05%.
17. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.001%～0.2%.
18. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.001%～0.15%.
19. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.001%～0.1%.
20. methods according to claim 8, wherein for the weight of formula (i) compound, the content of formula (x) compound For 0.001%～0.05%.
21. according to the method for any one of claim 1-7 it is characterised in that: its Chinese style (iv) compound through the following steps that Preparation:
Make formula (iii) compound
Wherein r1 and r2 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary fourth Base, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected and and it The carbon atom that connected form 4 to 7 yuan of cycloalkyl rings together,
React in the presence of base with following formula (ii) compound,
It is subsequently added acid with production (iv) compound.
22. methods according to claim 21, its Chinese style (iii) compound in the solution of suitable organic solvent using and It is to react generation by making 4- amino -3- fluorophenol and formula (vi) compound
Wherein r1 and r2 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary fourth Base, n-pentyl, 2- amyl group, 3- amyl group, neopentyl, n-hexyl, 2- hexyl and 3- hexyl, or r1 with r2 be connected and and it The carbon atom that connected form 4 to 7 yuan of cycloalkyl rings together.
23. methods according to claim 21, its Chinese style (ii) compound uses in the solution of suitable organic solvent, described Solution is by being prepared with the hydrochloride with formula (ii) compound in alkali.
24. methods according to claim 21, wherein formula (ii) compound are dissolved in suitable organic solvent, with by adding Enter proton material and the acid treatment of acid precursors in-situ generation, be precipitated as the salt of formula (ii) compound, and by adding the water-soluble of alkali Liquid neutralizes.
CN201510069175.2A 2015-02-10 2015-02-10 Regorafenib and manufacture method thereof Active CN104592105B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510069175.2A CN104592105B (en) 2015-02-10 2015-02-10 Regorafenib and manufacture method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510069175.2A CN104592105B (en) 2015-02-10 2015-02-10 Regorafenib and manufacture method thereof

Publications (2)

Publication Number Publication Date
CN104592105A CN104592105A (en) 2015-05-06
CN104592105B true CN104592105B (en) 2017-01-18

Family

ID=53118211

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510069175.2A Active CN104592105B (en) 2015-02-10 2015-02-10 Regorafenib and manufacture method thereof

Country Status (1)

Country Link
CN (1) CN104592105B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106674097A (en) * 2015-11-06 2017-05-17 江苏先声药业有限公司 Regorafenib impurity preparation method
CN107118153A (en) * 2016-02-25 2017-09-01 石药集团中奇制药技术（石家庄）有限公司 A kind of Rui Gefeini monohydrate crystal forms and preparation method thereof
CN109438336B (en) * 2018-11-27 2019-11-22 广东安诺药业股份有限公司 A kind of preparation method of Rui Gefeini hydrate
CN109438337B (en) * 2018-11-27 2019-08-09 广东安诺药业股份有限公司 A kind of preparation process of Rui Gefeini intermediate
CN109820851A (en) * 2019-03-22 2019-05-31 南开大学 Application of the Rui Gefeini hydrate in preparation treatment pulmonary fibrosis disease drug
CN109796401B (en) * 2019-04-04 2023-10-17 新乡双鹭药业有限公司 Preparation method of regorafenib bulk drug
CN110294706A (en) * 2019-07-25 2019-10-01 李斌 Anti-tumor drug and its preparation method and purposes
CN112159351B (en) * 2020-09-21 2021-12-07 广州南鑫药业有限公司 Preparation method of multi-target antitumor drug
CN114315710B (en) * 2022-01-07 2024-04-26 江苏豪森药业集团有限公司 Method for preparing or purifying regorafenib

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012012404A1 (en) * 2010-07-19 2012-01-26 Bayer Healthcare Llc Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR081060A1 (en) * 2010-04-15 2012-06-06 Bayer Schering Pharma Ag PROCEDURE TO PREPARE 4- {4 - [({[4-CHLORINE-3- (TRIFLUOROMETIL) PHENYL] AMINO} CARBONYL) AMINO] -3-FLUOROPHENOXY} -N-METHYLPIRIDIN-2-CARBOXAMIDE
WO2011130728A1 (en) * 2010-04-17 2011-10-20 Bayer Healthcare Llc Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012012404A1 (en) * 2010-07-19 2012-01-26 Bayer Healthcare Llc Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions

Also Published As

Publication number Publication date
CN104592105A (en) 2015-05-06

Similar Documents

Publication Publication Date Title
CN104592105B (en) Regorafenib and manufacture method thereof
ES2297490T3 (en) OMEGA-CARBOXIARILDIFENILUREA FLUORO REPLACED FOR THE TREATMENT AND PREVENTION OF DISEASES AND AFFECTIONS.
JP5215666B2 (en) Thermodynamically stable form of BAY 43-9006 tosylate
AU2014236820B2 (en) JAK2 and ALK2 inhibitors and methods for their use
US20110124680A1 (en) Novel anthranilamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors
CN103079567A (en) Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions
JP6671552B2 (en) Novel pyrimidine compound, method for preparing the same, and pharmaceutical composition containing the pyrimidine compound for preventing or treating cancer and inflammatory diseases
KR20140016889A (en) Diarylacetylene hydrazide containing tyrosine kinase inhibitors
CN104546776B (en) Rui Gefeini troche medical compositions and preparation method
JP2012500269A (en) Compounds as kinase inhibitors
JP6921877B2 (en) New pyrazole derivative as an ALK5 inhibitor and its use
WO2014040242A1 (en) 3-chloro- and 3-methoxy-n-methyl-2-pyridine carboxamide compound and application thereof as anticancer medicament
CN107383016A (en) The preparation and application of the Pyrrolopyrimidine compounds of the structure containing heteroaryl amide
CN110054584B (en) 1-aryl-3- {4- [ (pyridin-2-ylmethyl) thio ] phenyl } urea compound and application thereof
CN102108078A (en) 1,4-substituted phthalazine compound and preparation method and applications thereof
CN109553581A (en) Replace carbamide compound, its pharmaceutically acceptable salt or its solvate, its application, drug and pharmaceutical composition
KR101663335B1 (en) 6-1--1--4--2-3-5-2--4----2---2--3- novel polymorphic forms of 6-1-methyl-1h-pyrazol-4-yl-2-3-5-2-morpholin-4-yl-ethoxy-pyrimidin-2-yl-benzyl-2h-pyridazin-3-one dihydrogenphosphate and processes of manufacturing thereof
JP2017516867A (en) 1H-1,8-naphthyridin-2-one as an antiproliferative compound
CN113444074B (en) Compound with EGFR (epidermal growth factor receptor) and Wnt dual inhibition effects as well as preparation method and application thereof
JP7477846B2 (en) N-containing heteroaryl derivative and pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient
CN104586808B (en) Antineoplastic pharmaceutical compositions
CN110294706A (en) Anti-tumor drug and its preparation method and purposes
CN107056754B (en) WNT pathway inhibitor with embedded urea structure
CN115894486B (en) Hydrogenated pyridoquinazoline compound, composition and application thereof
WO2017211216A1 (en) Fused pyrimidinopiperidine derivative, and manufacturing method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant