CN104592105A - Regorafenib and manufacture method thereof - Google Patents

Regorafenib and manufacture method thereof Download PDF

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Publication number
CN104592105A
CN104592105A CN201510069175.2A CN201510069175A CN104592105A CN 104592105 A CN104592105 A CN 104592105A CN 201510069175 A CN201510069175 A CN 201510069175A CN 104592105 A CN104592105 A CN 104592105A
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compound
formula
acid
monohydrate
weight
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CN104592105B (en
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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
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HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
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    • 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

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  • 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 method for making thereof
Technical field
The present invention relates to a kind of new antitumour drug, particularly relate to a kind of Rui Gefeini, it can be used for treating the disease that mediated by VEGFR, PDGFR, raf, p38 and/or flt-3 kinase signal of exception and disease symptoms.The invention still further relates to the preparation method of described antitumor drug particularly Rui Gefeini.
Background technology
The activation of ras signal transduction pathway means that on cell proliferation, differentiation and conversion have the cascade reaction of the event of profound influence.Raf kinases as Ras downstream effect is that these signals are delivered to a nuclear key transmitter from cell surface receptor.Verified, suppress the effect activating ras that the cellular-restoring transformed can be caused for grow phenotype normally by using the coexpression of raf kinase whose deactivation antibody or dominant raf kinases or dominant MEK (the kinase whose substrate of raf) to suppress raf kinase signal pathway.Kolch etc. further demonstrate and have blocked film by sense-rna to the suppression that raf expresses and to be correlated with the cell proliferation that oncogene causes.Similarly, in tube assay and experiment in vivo, confirmed that the kinase whose suppression of raf (by antisense oligonucleotide) is relevant to the growth-inhibiting of multiple human tumor types.
Maintain size and need functioning stroma more than the continued tumor growth of the tumour cell of 1-2mm3, this is the underwork comprising inoblast, smooth muscle cell, endotheliocyte, extracellular matrix proteins and soluble factors.Tumour causes the formation of stroma by secreting the soluble growth factor such as such as PDGF and transforming growth factor-beta (TGF-β), described somatomedin is the complementary factor such as stimulation of host emiocytosis such as fibroblast growth factor (FGF), Urogastron (EGF) and vascular endothelial growth factor (VEGF) separately.These stimulating factors cause new vasculogenesis, and this provides oxygen and nutritive substance to tumour and makes it grow and provide route for metastases.Believe that some methods for the treatment of for suppressing interstitial to be formed can be suppressed the growth of the epithelial tumor being derived from Various Tissues type.But, because the complicacy of its character and multiple somatomedin participate in angiogenesis and tumor progression, effect that a kind of material for single signal approach may be only limited.Wish to provide methods for the treatment of to multiple key signaling pathways of tumour for causing vasculogenesis in host stroma.These approach comprise PDGF (the effective stimulus factor that interstitial is formed), FGF (chemokine of inoblast and endotheliocyte and mitogenesis element) and VEGF (angiopoietic effective regulatory factor).
PDGF is a kind of key regulator that interstitial is formed, and it secrete with paracrine form by kinds of tumors and promotes the growth of inoblast, unstriated muscle and endotheliocyte, thus promotes interstitial formation and vasculogenesis.PDGF is identified as the v-sis oncogene products of simian sarcoma virus.This somatomedin is made up of 2 peptide chains being called as A chain or B chain, and peptide chain primary amino acid sequences has the homology of 60%.Peptide chain warp disulfide linkage is connected to form the maturation protein of the 30kDa be made up of AA, BB or AB homology or heterodimer.In thrombocyte, found high-caliber PDGF, and PDGF can by endotheliocyte and Expression of Vascular Smooth Muscle Cell.In addition, under the hypoxia condition found in the tumor tissues of such as vascularization deficiency, the generation of PDGF is raised.PDGF combines with high-affinity and pdgf receptor (PDGFR), and this receptor is the transmembrane tyrosine kinase acceptor of the 124kDa of 1106 Amino acid profiles.PDGFR is homology or heterodimer peptide chain form, and peptide chain always has the homology of 30% on its aminoacid sequence, and between its kinase domain, have the homology of 64%.PDGFR is the member of the tyrosine kinase receptor family with kinase domain separately, and this family comprises VEGFR2 (KDR), VEGFR-3 (flt-4), c-Kit and flt-3.PDGFR mainly in the upper expression of inoblast, smooth muscle cell and pericyte (pericyte), and expresses on a small quantity on the Schwann cell of neurocyte, messangial cell, Leydig cell and central nervous system.Once and receptors bind, PDGF causes Receptor dimerization and experiences the self-phosphorylation of tyrosine residues and mutual phosphorylation, and this can improve the kinase activity of acceptor and promote that the downstream effect factor is by activating raising of SH2 protein binding domain.Comprise PI-3 kinases, the multi-signal molecule of Phospholipase C-γ, src and GAP (the GTP (guanosine triphosphate) acid ras GTPase activating protein ras-GTP for p21-ras) and the PDGFR of activation and form mixture.By activating PI-3 kinases, PDGF activates Rho cellular pathways thus causes cell movement and migration, and causes by activating GAP the mitotic division activated by p21-ras and MAPK signal pathway.
In adult, the Main Function of PDGF promotes and improves the speed of wound healing and keep the homeostasis of blood vessel.In thrombocyte, found the PDGF of high density, it is a kind of effective chemokine for inoblast, smooth muscle cell, neutrophilic granulocyte and scavenger cell.Except its effect in wound healing, PDGF helps the homeostasis keeping blood vessel.In new vessel growth course, PDGF raises pericyte required for blood vessel structure integrity and smooth muscle cell.PDGF is considered in tumor angiogenesis, play similar effect.As a part for its role in vasculogenesis, PDGF controls the hydrodynamicpressure of tissue space to the perviousness of adjustment blood vessel interactional between phoirocyte and extracellular matrix by it.Suppress the activity of PDGFR can reduce the pressure of tissue space and promote cytotoxin to flow into tumour and improve the antitumor efficacy of these materials.
PDGF can directly stimulate the PDGFR on mesenchymal cell or tumour cell by paracrine or autocrine or be amplified by the signal of acceptor or promoted tumor growth through recombination activation acceptor.The PDGF of process LAN can make the cell type of the melanoma cells of people and keratinocyte these two kinds not PDGF-B expression acceptor can transform the direct effect that interstitial is formed and induction of vascular generates by PDGF.Tumour PDGF-B expression but the paracrine that not also been observed this mesenchyma stroma of tumors in the tumour such as the colorectal carcinoma of expressed receptor, lung cancer, breast cancer and prostate cancer stimulate wherein.The autocrine stimulation to growth of tumour cell has been reported, wherein major part tumor cells expression PDGF part by analysis and acceptor in spongioblastoma, soft-tissue tumor, ovarian cancer, prostate cancer, carcinoma of the pancreas and lung cancer.The receptor activation of non-ligand-dependent type finds less, but has been reported in chronic myelomonocytic leukemia (CMML), and wherein a chromosome translocation forms fusion rotein between class Ets transcription factor TEL and pdgf receptor.In addition, in gastrointestinal stromal tumor, had been found that the activated mutant activated with c-Kit in irrelevant PDGFR.Mesenchyma stroma of tumors can be disturbed to grow for PDGFR inhibitor and Tumor suppression grows and shifts and do not have excessive side effect.
Vascular endothelial growth factor (VEGF is also referred to as Vascular Permeability Factor VPF) is the another kind of main regulatory factors occurred with disease medium vessels new life and the blood vessel of the dependence of some vasculogenesis in fetal development.VEGF represents due to selectivity RNA montage with the former isomer family of mitogenesis that homodimer form exists.VEGF isomer is high special for vascular endothelial cell.
Vegf expression is by cytokine profiles and the growth factor-induced such as anoxic and such as interleukin-11, interleukin 6, Urogastron and transforming growth factor.Report at present, one or more in VEGF and VEGF family member and following three kinds of transmembranous receptor tyrosine kinases combine: vegf receptor 1 (also referred to as flt-1 (class fms Tyrosylprotein kinase 1)), VEGFR-2 (also referred to as containing Kinase insert Domain acceptor (KDR), the mouse analogue of KDR is called tire liver kinases 1 (flk-1)) and VEGFR-3 (also referred to as flt-4).Verified, VEGFR-2 and flt-1 has different signal transduction character.Therefore, VEGFR-2 experiences the strong tyrosine phosphorylation of ligand-dependent in intact cell, and flt-1 shows weak response.Therefore, believe that being combined with VEGFR-2 is key request for the biological answer-reply of the FR VEGF mediation of induction.
VEGF in vivo blood vessel plays central role in occurring, and causes angiogenesis and Vascular permeability.The vegf expression not adding adjustment causes various diseases, it is characterized in that abnormal angiogenesis and/or hypertonicity effect.Believe that some material can provide effective control to abnormal angiogenesis and/or hypertonicity effect to the adjustment of the signal transduction cascade that VEGF mediates.Anti-tumor cell in tumor hypoxia region is reacted by stimulating VEGF to produce, and this causes the activation of reticent endotheliocyte to stimulate new vascularization.In addition, the VEGF in the tumor region not having angiogenesis produces can promote ras signal transduction pathway.In situ hybridization research shows, the remarkable rise of VEGF mRNA in the various human tumors comprising lung cancer, thyroid carcinoma, breast cancer, gastroenteric tumor, kidney and tumor of bladder, ovarian cancer, cervical cancer and vascular tumor and several intracranial tumors.Neutrality VEGFR-2 monoclonal antibody is proved to be effective in blocking-up neonate tumour blood vessel.
The process LAN (such as under extreme oxygen deficiency condition) of VEGF can cause angiogenesis in eyeball, causes blood vessel excessive proliferation, finally causes blind.In the multiple retinopathy comprising diabetic retinopathy, ischemic retinal vein inaccessible and retinopathy of prematurity and age related macular degeneration, observed such cascade reaction.
In rheumatic arthritis (RA), the generation of angiogenesis factor can mediate vascular screen interior to growth.In the synovia of RA patient, there is high-caliber immunoreactivity VEGF, and in the synovia of other form sacroiliitis or degenerative joint disease patient VEGF low SI.Verified in anti-rat collagen induction type arthritis model, angiogenesis inhibitor AGM-170 hinders the neovascularization in joint.
Form to subepidermal blister the raising also showing vegf expression in relevant herpes diseases in psoriatic and such as bullous pemphigoid, erythema multiforme and dermatitis herpetiformis etc.
Vascular endothelial growth factor (VEGF, VEGF-C, VEGF-D) and acceptor (VEGFR2, VEGFR3) thereof are not only tumor-blood-vessel growth and are the key regulators that lymphatic vessel generates.VEGF, VEGF-C and VEGF-D are main frequent with the horizontal expression fully improved during tumor growth in most of tumour.The stimulation of the oncogene of vegf expression by anoxic, cytokine, such as ras or the deactivation by tumor suppressor gene.
The biologic activity of VEGF is by being mediated with the combination of its acceptor.The main lymphatic endothelial cells in normal adult tissue of VEGFR3 (also referred to as flt-4) is expressed.New lymphatic vessel is formed and needs VEGFR3 function, but the already present lymphatic vessel of maintenance is not then needed.VEGFR3 raises.Recently, the ligand VEGF-C of VEGFR3 and VEGF-D are confirmed as the regulatory factor that in Mammals, lymphatic vessel generates.The lymphatic vessel generation that the lymphatic vessel that tumour is correlated with generates factor induction may promote that new vessel growth enters tumour, and this enters the passage of systemic circulation for tumour cell provides.Invade vasculolymphatic cell and can enter blood circulation by thoracic duct.Tumour expression study has allowed to express the clinical pathology factor (such as nodus lymphoideus transferring rate, lymphatic vessel invade, Secondary cases shift and disease free survival phase) directly related with same primary tumo(u)r diffusibility to VEGF-C, VEGF-D and VEGFR3 and has directly compared.In many cases, these researchs describe the statistics dependency between lymphatic vessel generation factor expression and primary noumenal tumour transfer ability.
For VEGF in malignant cell produces, it seems that anoxic be a kind of important stimulating factor.Concerning anoxic, response produced for tumour cell and induces VEGF, needing the kinase whose activation of p38MAP.Except participating in except vasculogenesis by regulating VEGF to secrete, p38MAP kinases promotes the migration of malignant cell intrusion and different tumor type by regulating collagenase activities and urokinase Plasminogen Activator to express.
The suppression of the former activated protein kinase of mitogenesis (MAPK) p38 is proved to be and in test tube and/or body, the T suppression cell factor can forms (such as TNF, IL-1, IL-6, IL-8) and protease-producing (such as MMP-1, MMP-3).The former activated protein kinase p38 of mitogenesis participates in IL-1 and TNF signal pathway.
Tumour necrosis factor (TNF) has produced and/or has linked up to the various diseases comprising rheumatoid arthritis by clinical study.In addition, in multiple inflammatory and/or immunomodulatory class disease, the TNF of excessive levels has been found.These diseases comprise acute rheumatic fever, bone resorption, postmenopausal osteoporosis, pyemia, septic shock, endotoxic shock, systemic inflammatory reaction disease, asthma etc.TNF is also relevant to infectious diseases, and these diseases comprise the helicobacter pylori infection etc. in pulmonary tuberculosis, stomach ulcer process.
Numerous disease is considered to active by excessive or unwanted matrix destruction metalloprotease (MMP) or is mediated by the proportional imbalance of the tissue depressant (TMP) of MMP and metalloprotease.Degenerative cartilage disappearance after the coronary artery thrombosis that these diseases comprise osteoarthritis, rheumatic arthritis, septic arthritis, metastases, periodontopathy, cornea come off, albuminuria, atherosclerotic plaque break to be caused, aortic aneurysm, infertile, EBD, traumatic joint injury, the osteoporosis of MMP activity mediation, jawbone joint disease and neural demyelinating disease.
Owing to suppressing p38 to cause the suppression that TNF is formed and MMP is formed, believe and suppress mitogenesis former activated protein kinase p38 can provide the means comprising the above-mentioned disease of osteoporosis and inflammatory disease for the treatment of such as rheumatoid arthritis and COPD.
For VEGF in malignant cell produces, it seems that anoxic be a kind of important stimulating factor.Concerning anoxic, response produced for tumour cell and induces VEGF, needing the kinase whose activation of p38MAP.Except participating in except vasculogenesis by regulating VEGF to secrete, p38MAP kinases promotes the migration of malignant cell intrusion and different tumor type by regulating collagenase activities and urokinase Plasminogen Activator to express.Therefore, also wish that suppressing p38 kinases to invade relevant signal cascade by interference to vasculogenesis and malignant cell affects tumor growth.
The serine-threonine kinase inhibitor have some urea and/or tyrosine kinase inhibitor activity are described.Especially the treatment being used for cancer, vasculogenesis disease, inflammatory diseases as the activeconstituents of pharmaceutical composition using some urea has been confirmed.
This area still expects there is effective antitumour medicine, and such as it can be used for situation mentioned above.And the useful preparation method of this series antineoplastic medicament.
Formula (I) compound 4-[4-({ [the chloro-3-of 4-(trifluoromethyl) phenyl] carbamyl } amino)-3-fluorophenoxy]-N-picoline-2-methane amide, namely 4-[4-({ [4-chloro-3-(trifluoromethyl) phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide is open in WO2005009961:
The monohydrate of formula (I) compound and Rui Gefeini (Regorafenib), with trade(brand)name Stivarga listing, are used for the treatment of excess proliferative disease, such as cancer, tumour, lymphoma, sarcoma and leukemia.The molecular formula of Rui Gefeini is C 21h 15clF 4n 4o 3h 2o, molecular weight is 500.83.
The Rui Gefeini of monohydrate form mentions in WO2008043446.In addition, the salt of formula (I) compound, such as its hydrochloride, mesylate and phenylbenzimidazole sulfonic acid salt are mentioned in WO2005009961, and can by being formed with corresponding acid treatment formula (I) compound.Formula (I) compound is described for overmedication proliferative disease, such as cancer, tumour, lymphoma, sarcoma and leukemia.
WO2005009961 describes the method for a kind of preparation formula (I) compound, and it is illustrated in scheme below:
In a first step, by the potassium tert.-butoxide process of 4-amino-3-fluorophenol, and add the solution of the chloro-N-methyl of 4--2-pyridine carboxamides in N,N-dimethylacetamide, to form 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acids methyl nitrosourea;
After extraction by its final isocyanic acid (the chloro-3-of 4-(trifluoromethyl) phenyl) solution-treated of ester in toluene, to form 4{4-[3-(the chloro-3-trifluoromethyl of 4-)-urea groups]-3-fluorophenoxy }-pyridine-2-carboxylic acids methyl nitrosourea, it is formula (I) compound.
Although method disclosed in prior art itself can be effective to preparation formula (I) compound, its monohydrate, hydrochloride, mesylate and phenylbenzimidazole sulfonic acid salt, such as the factor of purity, product yield, method efficiency, security and economy is very important for the method for plant-scale medicament production.
Summary of the invention
The object of this invention is to provide the method for the technical scale (more than kilogram levels) of a kind of preparation formula (I) compound and salt and monohydrate, it meets the standard applied aborning and provides the improvement of purity, environmental compatibility, industrial applicibility, secure context and volume yield aspect.Especially, for the preparation of medicine, purity and secure context need to be considered.This purpose is achieved by the present invention.Formula of the present invention (I) compound is the omega-carboxyaryl diphenyl urea with the fluoro-4-of the 2-be combined with urea (2-(N-methylcarbamoyl)-4-pyridyloxy) phenylene group; it is the kinase whose effective inhibitor of raf kinases, VEGFR kinases, p38 kinases and PDGFR, and described kinases is all for the osteoporosis treating and prevent to comprise cancer, inflammatory diseases, excess proliferative disease and the interested molecular target of vasculogenesis disease.
The preparation of formula of the present invention (I) compound is shown in scheme below.
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 first aspect present invention provides a kind of Medicinal crude drug, it is formula of the present invention (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, wherein comprise trace as 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 for the weight of formula (I) compound, the content of formula (X) compound is less than 0.2%, such as be less than 0.15%, such as be less than 0.1%, such as, be less than 0.05%.
Have been surprisingly found that, for the Medicinal crude drug that formula (X) compound (relative to formula (I) compound) content is less than 0.2%, it has significantly more excellent stability, and such as preparation activeconstituents in Long-term Storage process of its bulk drug or interpolation auxiliary material can maintain higher level significantly.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, it is prepared by a method comprising the following steps and obtains:
(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 the acid treatment of gained formula (I) compound to form the pharmaceutical salts of formula (I) compound; Then, optionally,
(3) make the process of step (2) gained pharmaceutical salts alkaline aqueous solution to be settled out the monohydrate of formula (I) compound.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein in step (3), make the monohydrate of formula (I) compound precipitate at the temperature of 35 DEG C to 45 DEG C.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein also comprise step (4), that is: make the monohydrate drying under reduced pressure of step (3) gained formula (I) compound to form the step of formula (I) compound.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, formula (I) compound wherein comprising dissolving and the solution of material be settled out from the salt of formula (I) compound are the independent solution of reaction mixture or formula (I) compound prepared after isolate formula (I) compound from reaction mixture.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding proton material and acid precursor in reaction mixture.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein said proton material is alcohol and described acid precursor is chloride of acid.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate; wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding alcohol and chloride of acid in reaction mixture.
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 chloride of acid is Acetyl Chloride 98Min..
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein carry out, in the process that formula (IV) compound and formula (V) compound react, being also added with paraffinic acid with formula (IV) compound in step (1).In one embodiment, the mol ratio of formula (IV) compound and paraffinic acid is 1:0.1 ~ 0.2.In one embodiment, paraffinic acid is glacial acetic acid.Have been surprisingly found that, in condensation reaction, add the generation that appropriate paraffinic acid contributes to reduction formula (X) compound.
Formula (IV) compound is known.Certainly it also prepares by following methods.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, its Chinese style (IV) compound is prepared by following steps:
Make formula (III) compound
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and forms 4 to 7 yuan of cycloalkyl rings together with the carbon atom be connected with them
React in the presence of base with following formula (II) compound,
Add acid subsequently 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 uses and generates by making 4-amino-3-fluorophenol and formula (VI) compound react in the solution of the organic solvent be applicable to
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and the carbon atom be connected with them forms 4 to 7 yuan of cycloalkyl rings together.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, its Chinese style (II) compound uses in the solution of the organic solvent be applicable to, and described solution is by preparing with the hydrochloride of formula (II) compound with in alkali.
Formula (I) compound or pharmaceutically acceptable salt thereof according to a first aspect of the present invention or monohydrate, wherein by formula (II) compound dissolution be applicable to organic solvent in, with the acid treatment by adding proton material and acid precursor in-situ generation, be precipitated as the salt of formula (II) compound, and the aqueous solution neutralization by adding alkali.
Further, second aspect present invention provides the method prepared with 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
Obtain formula (I) compound; Then, optionally,
(2) make the acid treatment of gained formula (I) compound to form the pharmaceutical salts of formula (I) compound; Then, optionally,
(3) make the process of step (2) gained pharmaceutical salts alkaline aqueous solution 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 Medicinal crude drug.Or second aspect present invention provides the method preparing Medicinal crude drug, this Medicinal crude drug its be formula of the present invention (I) compound or pharmaceutically acceptable salt thereof or monohydrate.
Method according to a second aspect of the present invention, in formula (I) compound or pharmaceutically acceptable salt thereof obtained by it or monohydrate, comprise trace as impurity with following formula (X) compound
Method according to a second aspect of the present invention, in formula (I) compound or pharmaceutically acceptable salt thereof obtained by it or monohydrate, for the weight of formula (I) compound, the content of formula (X) compound is less than 0.2%, such as be less than 0.15%, such as be less than 0.1%, such as, be less than 0.05%.
Method according to a second aspect of the present invention, wherein in step (3), makes the monohydrate of formula (I) compound precipitate at the temperature of 35 DEG C to 45 DEG C.
Method according to a second aspect of the present invention, wherein also comprises step (4), that is: make the monohydrate drying under reduced pressure of step (3) gained formula (I) compound to form the step of formula (I) compound.
Method according to a second aspect of the present invention, formula (I) compound wherein comprising dissolving and the solution of material be settled out from the salt of formula (I) compound are the independent solution of reaction mixture or formula (I) compound prepared after isolate formula (I) compound from reaction mixture.
Method according to a second aspect of the present invention, wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding proton material and acid precursor in reaction mixture.
Method according to a second aspect of the present invention, wherein said proton material is alcohol and described acid precursor is chloride of acid.
Method according to a second aspect of the present invention, wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding alcohol and chloride of acid in reaction mixture.
Method according to a second aspect of the present invention, wherein said alcohol is methyl alcohol or ethanol and described chloride of acid is Acetyl Chloride 98Min..
Method according to a second aspect of the present invention, wherein carries out, in the process that formula (IV) compound and formula (V) compound react, being also added with paraffinic acid with formula (IV) compound in step (1).In one embodiment, the mol ratio of formula (IV) compound and paraffinic acid is 1:0.1 ~ 0.2.In one embodiment, paraffinic acid is glacial acetic acid.
Method according to a second aspect of the present invention, its Chinese style (IV) compound is prepared by following steps:
Make formula (III) compound
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and forms 4 to 7 yuan of cycloalkyl rings together with the carbon atom be connected with them
React in the presence of base with following formula (II) compound,
Add acid subsequently with production (IV) compound.
Method according to a second aspect of the present invention, its Chinese style (III) compound uses and generates by making 4-amino-3-fluorophenol and formula (VI) compound react in the solution of the organic solvent be applicable to
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and the carbon atom be connected with them forms 4 to 7 yuan of cycloalkyl rings together.
Method according to a second aspect of the present invention, its Chinese style (II) compound uses in the solution of the organic solvent be applicable to, and described solution is by preparing with the hydrochloride of formula (II) compound with in alkali.
Method according to a second aspect of the present invention, wherein by formula (II) compound dissolution be applicable to organic solvent in, with the acid treatment by adding proton material and acid precursor in-situ generation, be precipitated as the salt of formula (II) compound, and the aqueous solution neutralization by adding alkali.
Further, third aspect present invention provides a kind of pharmaceutical composition, wherein comprises Medicinal crude drug described in the arbitrary embodiment of first aspect present invention, and the acceptable auxiliary material of pharmacy.
Or further, third aspect present invention provides a kind of pharmaceutical composition, wherein contained (I) compound or pharmaceutically acceptable salt thereof or monohydrate, and the acceptable auxiliary material of pharmacy.
Pharmaceutical composition according to a third aspect of the present invention, wherein comprise trace as impurity with following formula (X) compound
Pharmaceutical composition according to a third aspect of the present invention, wherein for the weight of formula (I) compound, the content of formula (X) compound is less than 0.2%, such as, be less than 0.15%, such as, be less than 0.1%, such as, be less than 0.05%.
According to either side of the present invention, no matter be described Medicinal crude drug or pharmaceutical composition, wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0001% ~ 0.2%, be such as 0.0001% ~ 0.15%, being such as 0.0001% ~ 0.1%, such as, is 0.0001% ~ 0.05%.According to either side of the present invention, no matter be described Medicinal crude drug or pharmaceutical composition, wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0005% ~ 0.2%, be such as 0.0005% ~ 0.15%, being such as 0.0005% ~ 0.1%, such as, is 0.0005% ~ 0.05%.According to either side of the present invention, no matter be 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%, be such as 0.001% ~ 0.15%, being such as 0.001% ~ 0.1%, such as, is 0.001% ~ 0.05%.The present inventor has been found that it is quite difficult technically that the content of formula (X) compound is dropped to 0.0001%, can cause the productive rate of target compound sharply to decline.Therefore formula (X) compounds content is useful accepting (i.e. lower limit) to controlled (i.e. the upper limit).
Arbitrary technical characteristic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
In the present invention, if not otherwise indicated, the % related to is w/w percentage ratio.
The present invention comprises the method for a kind of preparation formula (I) compound, its salt or monohydrate, and the method is passed through in the reactive mixture by formula (IV) compound (it is 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides)
With formula (V) compound (it is isocyanic acid (the chloro-3-trifluoromethyl-phenyl of 4-) ester) process,
Then by dissolve the acid treatment of formula (I) compound with formed formula (I) compound salt (its from containing dissolve formula (I) compound solution be precipitated out), then optionally by the salt of formula (I) compound with alkaline aqueous solution process with the monohydrate of precipitation (I) compound, and optionally by this monohydrate drying under reduced pressure, until form formula (I) compound.
Carrying out, in the process that formula (IV) compound and formula (V) compound react, being also added with paraffinic acid with formula (IV) compound.In one embodiment, the mol ratio of formula (IV) compound and paraffinic acid is 1:0.1 ~ 0.2.In one embodiment, paraffinic acid is glacial acetic acid.
The salt of formula (I) compound can be prepared by following steps: in the reactive mixture by formula (IV) compounds having formula (V) compound treatment, then by dissolve the acid treatment of formula (I) compound to form the salt of formula (I) compound, its from containing dissolve formula (I) compound solution be precipitated out.
The monohydrate of formula (I) compound can be prepared by following steps: in the reactive mixture by formula (IV) compounds having formula (V) compound treatment, then by dissolve the acid treatment of formula (I) compound with formed formula (I) compound salt (its from containing dissolve formula (I) compound solution be precipitated out), then the preferred temperature at 35 DEG C to 45 DEG C, most preferably 38 DEG C to 42 DEG C by the salt alkaline aqueous solution process of formula (I) compound 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 dissolve the acid treatment of formula (I) compound with formed formula (I) compound salt (its from containing dissolve formula (I) compound solution be precipitated out), then by the salt of formula (I) compound with alkaline aqueous solution process with the monohydrate of precipitation (I) compound, and preferably the temperature of 85 DEG C to 120 DEG C, and preferably at the pressure lower than 30mbar by this monohydrate drying under reduced pressure, until form formula (I) compound.
According to above-described method, can reaction mixture be preferably containing formula (I) compound dissolved and the solution of material that is settled out from the salt of formula (I) compound, or can be the independent solution containing formula (I) compound.This independent solution can be isolate from reaction mixture formula (I) compound (such as by according to the standard be described in such as WO2005009961 post-treating method and by formula (I) compound dissolution in be applicable to organic solvent in) after prepare.
In the preferred embodiment of the method for preparation formula as described above (I) compound, its monohydrate or salt, described acid produces in the solution containing formula (I) compound dissolved on the spot by adding proton material and acid precursor in reaction mixture.
In the preferred embodiment of the method for preparation formula (I) compound, its monohydrate or salt, described acid produces after formula (I) compound generates in the reactive mixture on the spot by adding alcohol and acid precursor in reaction mixture.
In the most preferred embodiment of the method for preparation formula (I) compound, its monohydrate or salt, described acid produces after formula (I) compound generates in the reactive mixture on the spot by adding alcohol and chloride of acid (preferred Acetyl Chloride 98Min.) in reaction mixture.
In the method for preparation formula (I) compound, its monohydrate or salt, the reaction of formula (IV) compound and formula (V) compound is in the organic solvent be applicable to (such as in tetrahydrofuran (THF)), higher than 15 DEG C and lower than the temperature of 70 DEG C (preferably the temperature of 15 DEG C to 60 DEG C, more preferably at 15 DEG C to 50 DEG C, most preferably in room temperature) occur.Preferably first formula (IV) compound is added in applicable organic solvent (such as in tetrahydrofuran (THF)), and with formula (V) compound 30 to 300 minutes, preferably 60 to 150 minutes, most preferably 80 to 100 minutes, preferred dissolution or be suspended in applicable organic solvent (such as toluene), described solvent can be different from the first organic solvent be applicable to.After forming formula (I) compound, acid is added in reaction mixture.Preferred described acid is passed through at such as 5 to 60 minutes; preferably add proton material (such as water and/or alcohol, preferred alcohols) and acid precursor (preferred chloride of acid) (thus in-situ generation acid accordingly) in 10 to 30 minutes to produce on the spot in the reactive mixture.Preferably first add proton material.The salt of formula (I) compound can be separated by precipitating.
In order to the monohydrate of preparation formula (I) compound, alkaline aqueous solution (preferably using the mixture of organic solvent and alkaline aqueous solution) is used by the salt of formula (I) compound to process further.The monohydrate of formula (I) compound can be separated by precipitating, and preferably the temperature of 35 DEG C to 45 DEG C, most preferably carries out to 42 DEG C at 38 DEG C.
In order to preparation formula (I) compound, the monohydrate of formula (I) compound is dry, preferably 85 DEG C to 120 DEG C temperature and at reduced pressure conditions, more preferably carry out under lower than the pressure of 30mbar.
The suitable acid forming acid salt in the method for preparation formula (I) compound, its monohydrate or salt includes but not limited to mineral acid, carboxylic acid and sulfonic acid, such as hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, fumaric acid, toxilic acid and phenylformic acid.Preferred hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid and naphthalene disulfonic acid, more preferably hydrochloric acid, Phenylsulfonic acid, toluenesulphonic acids or methylsulfonic acid, most preferably hydrochloric acid.
The salt (it is pharmacy acceptable salt) of formula (I) compound includes but not limited to the acid salt of mineral acid, carboxylic acid and sulfonic acid, such as hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, fumaric acid, toxilic acid and benzoic salt.The salt of preferred hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid and naphthalene disulfonic acid, the more preferably salt of hydrochloric acid, Phenylsulfonic acid, toluenesulphonic acids or methylsulfonic acid, most preferably hydrochloride.
According to the present invention, alcohol is the organic substance carrying at least one oh group.Alcohol includes but not limited to methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, Pentyl alcohol, glycerine or its mixture.Preferably methyl alcohol, ethanol and Virahol are used as the alcohol in present method.
In order to prepare acid on the spot, applicable acid precursor includes but not limited to organic acyl halide, preferred acyl halide, such as chloride of acid and acid bromide, more preferably Acetyl Chloride 98Min., acetyl bromide, propionyl chloride or propionyl bromide, most preferably Acetyl Chloride 98Min..
Preferred above-described method, wherein prepares acid in the absence of water on the spot.
In the method for preparation formula (I) compound, its monohydrate or salt, suitable organic solvent includes but not limited to tetrahydrofuran (THF), toluene, ethyl acetate, diox, methyl tertiary butyl ether, glycol dimethyl ether, the mixture of methyl-sulphoxide, dimethyl formamide, 1-Methyl-2-Pyrrolidone or above-mentioned solvent.More preferably tetrahydrofuran (THF), toluene and composition thereof is used.
In the method for the monohydrate of preparation formula (I) compound, suitable alkaline aqueous solution includes but not limited to the aqueous solution of alkali metal hydroxide, alkaline earth metal hydroxides, alkali metal alcoholates, alkaline-earth alkoxides, organic amine and ammonia, the aqueous solution of preferred sodium hydroxide and potassium hydroxide, the more preferably aqueous solution of sodium hydroxide.Alkaline aqueous solution can with organic solvent, such as acetone, ethyl acetate, tetrahydrofuran (THF) mixing, preferably mix with acetone.
The present invention comprises the method for a kind of preparation formula (IV) compound equally, and the method is by making formula (III) compound
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 be connected and, 4 to 7 yuan of cycloalkyl rings are formed together with the carbon atom that they connect
React in the presence of base with formula (II) compound (it is the chloro-N-methyl of 4--2-pyridine carboxamides),
Add acid subsequently with production (IV) compound.
In the preferred embodiment of the method for preparation formula (IV) compound, formula (III) compound uses and is formed by making 4-amino-3-fluorophenol and formula (VI) compound react in the solution of the organic solvent be applicable to
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, 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 that they connect.
In the further preferred embodiment of the method for preparation formula (IV) compound, formula (II) compound uses in the solution of the organic solvent be applicable to, described solution is by with alkali, preferably use sodium hydroxide, more preferably to use in the aqueous solution of sodium hydroxide and prepared by the hydrochloride of formula (II) compound.
In the method for preparation formula (IV) compound, 4-amino-3-fluorophenol and formula (VI) compound at 20 ° to the temperature being up to reflux temperature, preferably at 50 DEG C to the temperature being up to reflux temperature, most preferably react under the reflux temperature of formula (VI) compound, described formula (VI) compound can excessive use as solvent.Optionally, other different solvent can be added, such as toluene, ethyl acetate, hexanaphthene or its mixture.Can by the optional removing of component distillation at reduced pressure conditions volatile reaction component.Formula (III) compound formed can be applicable to organic solvent solution in (preferably in 1-Methyl-2-Pyrrolidone solution) use, and use in the presence of base the chloro-N-methyl of 4--2-pyridine carboxamides (preferably be applicable to organic solvent solution in use, more preferably use in 1-Methyl-2-Pyrrolidone solution) process.Reaction mixture is heated to 50 DEG C to the temperature being up to 150 DEG C, preferably 80 DEG C to the temperature being up to 120 DEG C.After 1 to 5h, preferably after 2 to 4h, temperature is adjusted to 50 DEG C to being up to 90 DEG C, preferably 70 DEG C to being up to 90 DEG C, and add acid (being preferable over the acetic acid in water).After cooling, be preferably cooled to the temperature of 0 DEG C to 10 DEG C, and optionally use the crystal of formula (IV) compound to sow, can precipitate and separate formula (IV) compound be passed through.
Preferred formula (VI) compound, wherein R1 with R2 be connected independently selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl or R1 with R2 and, form 4 to 7 yuan of cycloalkyl rings together with the carbon atom that they connect.More preferably formula (VI) compound is selected from 4-methyl-2 pentanone, 3-methyl-2-butanone, 2-butanone, 2 pentanone, dipropyl ketone, 2,4-dimethyl-propione and pimelinketone.
In the method for preparation formula (IV) compound, suitable organic solvent includes but not limited to the mixture of 1-Methyl-2-Pyrrolidone, dimethyl formamide, N,N-dimethylacetamide, methyl-sulphoxide, tetramethylene sulfone or mentioned solvent.Preferred use 1-Methyl-2-Pyrrolidone and/or dimethyl formamide.
The alkali be applicable in the method for preparation formula (IV) compound is alkali metal hydroxide and alkali metal alcoholates.Preferred potassium tert.-butoxide.Potassium tert.-butoxide preferably uses in the solution, more preferably uses in tetrahydrofuran solution.
In order to provide formula (II) compound of high-purity forms, be dissolved in applicable organic solvent, with the acid treatment by adding proton material and acid precursor in-situ generation, be precipitated as the salt (hydrochloride of preferred formula (II) compound) of formula (II) compound, and the aqueous solution neutralization by adding alkali.
In order to this object; chloro-for initial compounds 4-N-methyl-2-pyridine carboxamides is dissolved in applicable organic solvent (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 (preferred chloride of acid) such as in 5 to 60 minutes; preferably in 10 to 30 minutes, thus in-situ generation acid accordingly) process.Preferably first add proton material.The salt of the chloro-N-methyl of 4--2-pyridine carboxamides, the hydrochloride of the chloro-N-methyl of preferred 4--2-pyridine carboxamides can pass through precipitate and separate.The salt of the purifying of chloro-for such 4-N-methyl-2-pyridine carboxamides is dissolved in applicable organic solvent (preferably in toluene), and the aqueous solution (aqueous solution of the preferred sodium hydroxide) neutralization by adding alkali.After separation of phases, optionally concentrating under reduced pressure organic phase, and adding applicable organic solvent (preferred 1-Methyl-2-Pyrrolidone) to prepare a kind of solution, it can be directly used in preparation formula (IV) compound (as described above).
In the method preparing 4-chloro-N-methyl-2-pyridine carboxamides, suitable organic solvent includes but not limited to the mixture of tetrahydrofuran (THF), toluene, ethyl acetate, diox, methyl tertiary butyl ether, glycol dimethyl ether, methyl-sulphoxide, dimethyl formamide, 1-Methyl-2-Pyrrolidone or mentioned solvent.More preferably tetrahydrofuran (THF), toluene and composition thereof is used.
According to the present invention, alcohol is the organic substance carrying at least one oh group.Alcohol includes but not limited to methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, Pentyl alcohol, glycerine or its mixture.Preferably methyl alcohol, ethanol and Virahol are used as the alcohol in the inventive method.
In order to prepare acid on the spot, applicable precursor includes but not limited to organic acyl halide, preferred acyl halide, such as chloride of acid and acid bromide, more preferably Acetyl Chloride 98Min., acetyl bromide, propionyl chloride or propionyl bromide, most preferably Acetyl Chloride 98Min..
Preferably prepare described acid on the spot in the absence of water.
Alternative mode is, formula (II) compound and hydrochloride thereof can according to being described in the people such as WO2005009961 or Bankston (Organic Process Research & Development, 2002,6,777-781) in method prepare.. formula (V) compound (it is isocyanic acid (the chloro-3-trifluoromethyl-phenyl of 4-) ester) can according to the method preparation be described in WO2000042012.
Pharmaceutical composition according to a third aspect of the present invention, it is the dosage forms such as tablet, capsule, granule, powder.
Pharmaceutical composition according to a third aspect of the present invention, comprising: active pharmaceutical compounds, thinner, disintegrating agent, tackiness agent, lubricant; Described active pharmaceutical compounds is 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 thinner includes but not limited to: secondary calcium phosphate, kaolin, dextrin, lactose, N.F,USP MANNITOL, sucrose, Microcrystalline Cellulose, powdered cellulose, precipitated calcium carbonate, sorbyl alcohol and starch and derivative (such as W-Gum, potato starch, amylum pregelatinisatum, modified starch, pregelatinized Starch etc.), erythritol, Xylitol, fructose etc. and their combination.
Pharmaceutical composition according to a third aspect of the present invention, the active pharmaceutical compounds wherein comprised counts 40 weight parts with formula (I) compound, and the amount of described thinner is 50 ~ 500 weight parts; The amount of such as described thinner is 50 ~ 400 weight parts; The amount of such as described thinner is 50 ~ 300 weight parts; The amount of such as described thinner is 50 ~ 200 weight parts.
Pharmaceutical composition according to a third aspect of the present invention, wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, croscarmellose sodium etc. and their combination.
Pharmaceutical composition according to a third aspect of the present invention, the active pharmaceutical compounds wherein comprised counts 40 weight parts with formula (I) compound, and the amount of described disintegrating agent is 50 ~ 500 weight parts; Such as 50 ~ 400 weight parts; Such as 50 ~ 300 weight parts; Such as 50 ~ 200 weight parts.
Pharmaceutical composition according to a third aspect of the present invention, wherein said tackiness agent such as, such as but not limited to hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone (molecular weight is the PVP of 5000 ~ 50000, PVP K15, PVP K17, PVP K25, PVP K30 etc.), polyvinyl alcohol, gum arabic, Lalgine, sodium alginate, gelatin etc. and their combination.Preferredly comprise hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone or polyvinyl alcohol.
Pharmaceutical composition according to a third aspect of the present invention, the active pharmaceutical compounds wherein comprised counts 40 weight parts with formula (I) compound, and the amount of described tackiness agent is 50 ~ 500 weight parts; Such as 50 ~ 400 weight parts; Such as 100 ~ 300 weight parts; Such as 100 ~ 200 weight parts.Tackiness agent can be added by dry method, and adopts typical compressing dry granulation to prepare tablet; Tackiness agent can be added by dry method, and adopts water or aqueous ethanol to be that wetting agent carries out wet granulation to whole material and then prepares tablet; Tackiness agent can also use water or aqueous ethanol wiring solution-forming as binder solution, then carries out wet granulation with this binder solution and then prepares tablet; Tackiness agent can also be dissolved in suitable solvent (such as ethanol and/or acetone) together with active medicine, more spray-dried for this solution technique is added in thinner and/or disintegrating agent.These different types of tackiness agent feed postition all well known to a person skilled in the art, and are that appearance is facile.
Pharmaceutical composition according to a third aspect of the present invention, wherein said lubricant also can be described as glidant in this area, is usually referred to as lubricant.Lubricant includes but not limited to: Magnesium Stearate, stearic acid, calcium stearate, Zinic stearas, Liquid Paraffin, polyoxyethylene glycol, silicon-dioxide, colloid silica, micropowder silica gel, 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 comprised counts 40 weight parts with formula (I) compound, and the amount of described lubricant is 1 ~ 50 weight part; The amount of such as described lubricant is 1 ~ 25 weight part; The amount of such as described lubricant is 1 ~ 20 weight part; The amount of such as described lubricant is 1 ~ 10 weight part; The amount of such as described lubricant is 2 ~ 8 weight parts.
Pharmaceutical composition according to a third aspect of the present invention, the pharmacologically acceptable salts of wherein said formula (I) compound comprises traditional nontoxic salt, such as, by salt that method well known in the art obtains from inorganic or organic acid.The such as vitriol of formula (I) compound, phosphoric acid salt, fluoroform sulphonate, tosilate, 1-naphthalene sulfonic aicd salt, trifluoroacetate, malate, fumarate, benzoate, salicylate, phenylacetate, acetate, adipate, alginate, ascorbate salt, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cinnamate, cipionate, two gluconate, dodecyl sulfate, isethionic acid, fumarate, glucose enanthate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyethanesulfonic acid salt, itaconate, lactic acid salt, maleate, mandelate, methane sulfonates, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, embonate, pectate, persulphate, 3-phenpropionate, picrate, pivalate, propionic salt, succinate, sulfonate, tartrate, thiocyanate-, toluenesulphonic acids and undecylate are at interior acid salt.
Pharmaceutical composition according to a third aspect of the present invention, the solvate of wherein said formula (I) compound or pharmaceutically acceptable salt thereof can be its any acceptable solvate thereof.The such as hydrate of formula (I) compound, the such as monohydrate etc. of formula (I) compound.
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 of example formula (I) compound as is known, etc.
Pharmaceutical composition according to a third aspect of the present invention, it is prepared by the preparation process of routine.
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-coat.
Pharmaceutical composition according to a third aspect of the present invention, wherein said clothing layer accounts for 1 ~ 5% of tablet total weight amount, and such as 1 ~ 4%, such as 2 ~ 3%.
Pharmaceutical composition according to a third aspect of the present invention, the main film forming material of the coating material of wherein said clothing layer is selected from: ethyl cellulose, Vltra tears and methacrylic acid-alkyl acrylate copolymer; Further, the main film forming material of coating material is Vltra tears, such as, be its aqueous dispersion; Further, coating material is it is Vltra tears aqueous dispersion; Further, coating material is selected from with
Pharmaceutical composition according to a third aspect of the present invention, the main film forming material of the coating material of wherein said clothing layer is polyvinyl alcohol.In one embodiment, they can prepare according to the conventional amount used of this area with water before to tablet coating temporarily, can also easily buy from market.Such as, can buy from the happy Kanggong department of card, such as film-coating premixing is filled a prescription, such as powder pin again such as, can buy from Ai Leyi medical material company, such as series product, such as a kind of typical coating material composition comprises: tinting material (such as red iron oxide and/or iron oxide yellow or other), phosphatide (such as fabaceous lecithin), polyoxyethylene glycol (such as PEG3350), polyvinyl alcohol, talcum powder, titanium dioxide etc.Such as from the pink colour that the happy Kanggong department of card buys polyvinyl alcohol (accounting for 44% of mixture total weight amount) wherein containing partial hydrolysis, PEG3350 (accounting for 12.4% of mixture total weight amount), fabaceous lecithin, ferric oxide (red iron oxide and iron oxide yellow), talcum powder, titanium dioxide.
the purposes of the present composition
The invention provides the pharmaceutical composition that can regulate and relate to kinase whose one or more signal transduction pathway of raf, VEGFR, PDGFR, p38 and/or flt-3.Raf is the important signaling molecule of regulation and control of many important cell processes participating in comprising Growth of Cells, cell survival and intrusion.It is Ras/raf/MEK/ERK approach member.This approach is present in most of tumour cell.VEGFR, PDGFR and flt-3 are the acceptor molecules of cross-film, can trigger Ras/raf/MEK/ERK Cell signal transduction pathway when it is subject to suitable ligand stimulation, cause intracellular level to join reaction.These acceptor molecules all have tyrosine kinase activity.
VEGFR acceptor stimulates by vascular endothelial growth factor (VEGF), and is the important control point in endothelial cell development and function point analysis.PDGF beta receptor regulates cell proliferation and survival in the various kinds of cell type comprising mesenchymal cell.Flt-3 is the acceptor of FL part.Its similar in c-kit, and regulates the growth of multipotency hematopoietic cell, thus affects the growth of T cell, B cell and dendritic cell.
Any gene or the isomer that comprise raf, VEGFR, PDGFR, p38 and/or flt-3 of wild-type and saltant type can regulate according to the present invention.Raf or raf-l kinases is serine/threonine kinase family, and it comprises at least 3 family members (a-raf, b-raf and c-raf or raf-1).C-raf and b-raf is the preferred target spot of pharmaceutical composition of the present invention.In the kinds of tumors comprising melanoma, authenticated the activated mutant (such as V599E mutant) of b-raf, and pharmaceutical composition as described herein may be used for suppressing it active.
Term " adjustment " refers to the functionally active changing described approach (or its component) compared with normal activity when not existing with described pharmaceutical composition.This effect comprises the adjustment in any quantity or degree, and this comprises raising, activation, enhancing, increase, promotion, stimulation, reduction, obstruction, suppression, minimizing, reduction, antagonism etc.
Pharmaceutical composition of the present invention also can regulate following one or more process, and these processes include but not limited to that such as Growth of Cells (comprising such as differentiation, cell survival and/or propagation), growth of tumour cell (comprising such as differentiation, cell survival and/or propagation), tumor regression, endothelial cell growth (comprising such as differentiation, cell survival and/or propagation), vasculogenesis (angiogenic growth), lymphatic vessel generate (lymphatic growth) and/or hemopoietic function (growth of such as T cell and B cell, dendritic cell growth etc.).
Although do not wish the constraint being subject to any mechanism of action or mechanism, have been found that pharmaceutical composition of the present invention has the ability regulating kinase activity.But method of the present invention is not limited to any concrete mechanism or how described pharmaceutical composition realizes its therapeutic action.Term " kinase activity " refers to the catalytic activity on the amino-acid residue (such as Serine, Threonine or tyrosine) wherein transferred to from Triphosaden (ATP) by a γ phosphate radical protein substrate.Pharmaceutical composition can regulate kinase activity, such as, compete kinase whose ATP-binding site by direct and ATP and suppressing its activity, affecting its activity (such as by destroying the three-dimensional structure with biologic activity) etc. by producing conformational change in the structure of enzyme.
Use common detection methods can carry out conventional determining to kinase activity.Kinase assays generally includes kinases, substrate, damping fluid and detection system component.Typical kinase assay comprises protein kinase and peptide substrate and the ATP as P-ATP and reacts with the end product producing phosphorylation (phosphorylated protein such as when using peptide substrate).Any appropriate means can be used to detect final product.When using radioactivity ATP, use affinity membrane or gel electrophoresis radiolabeled phosphorylated protein can be separated with unreacted γ-32P-ATP, and use radioautograph develop on gel or use scintillometer to detect subsequently.Also Non-radioactive methods can be used.The antibody (such as antiphosphotyrosine antibody) identifying phosphorylated substrate can be used.Such as, can there is ATP and kinase buffer liquid with substrate and hatch under the condition of substrate described in the acidifying of described kinases available phosphorus in kinases.Can separate reacted mixture (such as passing through electrophoresis), and subsequently can the phosphorylation (such as by using the immunoblotting of antiphosphotyrosine antibody) of detection substrate.Described antibody can with detectable marker mark (enzyme of such as such as HRP, avidin or vitamin H, chemical illuminating reagent etc.).Other method can adopt the separation of ELISA, affinity membrane, fluorescence polarization method, luminescence method etc.
Another kind of method outside radioactive form is time resolved fluorescence resonant energy transfer (TR-FRET).Described method conveniently kinase reaction, wherein substrate (poly-(GluTyr) of biological example elementization) is by protein phosphatase phosphorylation under ATP existent condition.Final product can detect with the phospho-specif iotac antibodies of europium chelating (anti-Tyrosine O-phosphate or phosphoserine/Threonine) and the streptavidin-APC be combined with biotinylated substrate subsequently.Above-mentioned two components in conjunction with time spatially close, and produce the fluorescence reading of homogeneous form to the transmission ofenergy of acceptor (SA-APC) from phospho-specif iotac antibodies.
Pharmaceutical composition of the present invention may be used for treating and/or preventing any disease or illness that the one or more cellular signal transduction pathways that relate to raf, VEGFR, PDGFR, p38 and/or flt-3 mediate.Term " treatment " uses according to its conventional meaning, such as, process for the symptom of resisting, alleviating, reducing, removing, improving disease or dysfunction etc. object patient or look after.Described pharmaceutical composition also can for preventing and/or treating the disease that mediated by described signaling molecule and/or illness is described.Term " mediation " represents that such as described signaling molecule is a part for approach abnormal or not normal in described disease and/or illness.
Treatable disease and illness comprise any above and disease mentioned below and:
Comprise the raf relative disease of such as cell generation disorders, cancer, tumour etc.;
Comprise the VEGFR-2 relative disease of such as cancer, tumor growth, inflammatory disease, rheumatic arthritis, retinopathy, psoriatic, renal glomerulus ephrosis, asthma, chronic bronchitis, arteriosclerosis, transplant rejection, the illness relating to vasculogenesis etc.;
Draw together such as cancer, keratopathy, cornea redness, corneal transplantation, lymph gland hyperplasia, the illness relating to lymphatic vessel generation etc. VEGFR-3 relative disease;
Comprise the PDGFR-ss related diseases of disease or the illness being such as characterised in that cell proliferation, cell matrix formation, cell movement and/or extracellular matrix are formed.Concrete example comprises such as tumour, malignant tumour, cancer, cancer metastasis, chronic lymphocytic leukemia, inflammation, ephrosis, diabetic nephropathy, mesangium hyperplastic glomerular ephrosis, fibrotic conditions, arteriosclerosis, heart lobe restenosis, hypertension related arteriosclerosis, venous bypass graft arteriosclerosis, scleroderma, interstitial lung disease, synovia disease, sacroiliitis, leukemia, lymphoma etc.;
Comprise such as immune correlated disease, blood cell disease, relate to the Flt-3 relative disease of illness, cancer, anaemia, HIV, acquired immunodeficiency disease etc. that hematopoietic cell (such as T cell, B cell, dendritic cell) is grown;
Comprise the p38 relative disease of inflammatory disease, immunoregulatory disorder and other produce to abnormal cytokine (particularly TNF α) or the MMP activity of exception is relevant other diseases.These diseases include but not limited to rheumatic arthritis, chronic obstructive pulmonary disease (COPD), osteoporosis, Crohn's disease and psoriatic.
In addition, pharmaceutical composition of the present invention may be used for treating such as following illness and disease: glomerular sclerosis, interstitial nephritis, interstitial pulmonary fibrosis, arteriosclerosis, wound scar and scleroderma.
Pharmaceutical composition of the present invention also has therapeutic activity widely in order to treatment or the progress of preventing various disease, these diseases such as inflammatory disorders, coronary restenosis, tumor-associated vessels generates, arteriosclerosis, autoimmune disease, inflammation, some relevant ephrosis is bred to renal glomerulus or mesangial cell, and the illness in eye relevant to retinal vessel proliferation, psoriatic, liver cirrhosis, diabetes, arteriosclerosis, restenosis, vascular graft restenosis, in-stent restenosis, vasculogenesis, illness in eye, lung fiber is sick, bronchiolitis obliterans, renal glomerulus ephrosis, rheumatic arthritis.
The present invention is also for one or more people following and/or other mammiferous illnesss provide treatment, prevention, regulate etc.: the retinopathy comprising diabetic retinopathy, ischemic retinal vein obturation, retinopathy of prematurity and age related macular degeneration, rheumatic arthritis, psoriatic, or form relevant bullous disease to subcutaneous bubble and (comprise bullous pemphigoid, erythema multiforme or dermatitis herpetiformis), rheumatic fever, bone resorption, post-menopausal osteoporosis, pyemia, Gram-negative pyemia, septic shock, endotoxin shock, Toxin shock syndrom, Systemic inflammatory syndrome, inflammatory bowel (Crohn's disease and ulcerative colitis), Herxheimer reaction, asthma, adult respiratory distress waits group, Acute Lung fibrotic disease, sarcoidosis of lung, supersensitivity respiratory disease, silicosis, coal miner pneumoconiosis, alveolar damage, liver failure, hepatopathy in acute inflammation, severe alcoholic hepatitis, malaria (Plasmodium falciparum malaria and brain malaria), non insulin dependent diabetes (NEDDM), congestive heart failure, damage after heart trouble, arteriosclerosis, alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelination in multiple sclerosis and few dendritic cell disappearance), terminal cancer, malignant lymphoma, pancreatitis, in infection, wound healing weakens, inflammation and cancer, myelodysplastic syndrome, systemic lupus erythematous, cholehepatocirrhosis, bowel necrosis, toxicity after radiational injury/give monoclonal antibody, host-transplant reaction (ischemia reperfusion injury and kidney, liver, heart and skin allograft rejection), lung allograft rejection (bronchitis obliterans), total hip displacement complication, and be selected from pulmonary tuberculosis, helicobacter pylori infection in gastric ulcer disease, the summer Graves disease that Ku Shi Trypanosoma cruzi infection causes, the shiga-like toxin effect that coli-infection causes, the enterotoxin A effect that staphylococcal infections causes, the infectious diseases of meningococcal infection, and lyme disease spirochete, Leptospira, the huge virus of cell, influenza virus, the infection that theiler's encephalomyelitis virus and human immunodeficiency virus (HIV) cause, papilloma, bud shape neurospongioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, colorectal carcinoma, thyroid carcinoma, carcinoma of the pancreas, cancer of the stomach, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease, Hugh Burkitt is sick, sacroiliitis, rheumatic arthritis, diabetic retinopathy, vasculogenesis, restenosis, in-stent restenosis, vascular graft restenosis, pulmonary fibrosis, liver cirrhosis, arteriosclerosis, renal glomerulus ephrosis, diabetic nephropathy, transplant rejection, psoriatic, diabetes, wound healing, inflammation, and neurodegenerative disease, excessive immune is sick, vascular tumor, angiogenesis of cardiac muscle, crown and brain collateral is formed, ischemic, keratopathy, iridopathy, neovascular glaucoma, premature labor maculopathy retinopathy, wound healing, Helicobacter pylori ulcers relative disease, fracture, endometriosis, diabetic symptom, cat scratch fever, Tiroidina is loose, asthma or burnt degree edema, wound, chronic lung disease, apoplexy, polyp, tumour, synovitis, chronic and allergic inflammation, ovary height stimulates syndrome, lung and brain edema, keloid, cystic fibrosis, sclerosis, carpal tunnel syndrome, adult respiratory distress syndrome, ascites, illness in eye, cardiovascular diseases, Ke-Fu (POEMS) syndrome, Crohn's disease, renal glomerulus ephrosis, osteoarthritis, multiple sclerosis, transplant rejection, Lyme arthritis, pyemia, Feng's angiomatosis retinae et cerebelli syndrome, pemphigoid, Paget's disease, multicystic kidney disease, sarcoidosis, thyroiditis, hyperviscosity syndrome, Osier-Weber-Rendir is sick, chmnic. obstructive's tuberculosis, radiation, anoxic, preeclampsia, menorrhagia, endometriosis, herpes simplex infection, ischemic retinopathies, corneal vessels generates, zoster, human immunodeficiency virus, parapoxvirus, protozoon, toxoplasmosis and relevant the oozing out and oedema of tumour.
Pharmaceutical composition of the present invention can have more than one described activity and therefore can for many barss transduction pathway.Therefore, these pharmaceutical compositions can realize usually can only when using different pharmaceutical combination of compositions just obtainable treatment and preventive effect.Such as, be particularly useful by use single medicine composition to suppress new conduit to be formed cell proliferation exception that (being such as connected with VEGFR-2 with VEGFR-3 function) (such as blood vessel and/or lymphatic vessel) and cell proliferation (being such as connected with raf with PDGFR β function) promotes by new vascularization at Therapeutic cancer and other.Therefore, the invention particularly relates to the pharmaceutical composition at least with inhibition of cell proliferation and angiogenesis inhibitor (i.e. inhibiting angiogenesis) activity.The disease can benefiting from vessel growth and cell inhibitory effect to any according to the present invention or illness are treated.Due to its field of activity can be defined more accurately, single medicine composition is used also to be favourable.
Pharmaceutical composition of the present invention can be treated any tumour, and these tumours include but not limited in raf, ras and/or flt-3 and have the tumour of one or more sudden change in any upstream of signal pathway of participating in or downstream member.As discussed previously, tumour can be carried out treating with pharmaceutical composition of the present invention and not consider the mechanism corresponding to it.Can treat the tumour of any organ, this includes but not limited to such as colorectal carcinoma, carcinoma of the pancreas, breast cancer, prostate cancer, osteocarcinoma, liver cancer, kidney, lung cancer, carcinoma of testis, skin carcinoma, cancer of the stomach, colorectal carcinoma, renal cell carcinoma, hepatocellular carcinoma, melanoma etc.
The example of breast cancer includes but not limited to infitrating ductal carcinoma, infiltrating lobular carcinoma, ductal carcinoma in situ and LCIS.
The example of respiratory cancer includes but not limited to minicell and nonsmall-cell lung cancer and bronchial adenoma and pleuropulinonary blastoma.
The example of the cancer of the brain includes but not limited to brain stem and hypophtalmic glioma, cerebellum and cerebral astrocytoma, medulloblastoma, ependymoma and neural outer embryoma and pine nut adenoma.
Genital orgnas,male's tumour includes but not limited to prostate cancer and carcinoma of testis.Tumors of female reproductive organ includes but not limited to carcinoma of endometrium, cervical cancer, ovarian cancer, carcinoma of vagina and carcinoma vulvae and sarcoma of uterus.
Digestive tract tumor includes but not limited to anus cancer, colorectal carcinoma, colorectal carcinoma, esophagus cancer, carcinoma of gallbladder, cancer of the stomach, the rectum cancer, carcinoma of small intestine and salivary-gland carcinoma.
Urethral system tumour includes but not limited to bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter and urethral carcinoma.
Cancer eye includes but not limited to intraocular melanoma and retinoblastoma.
The example of liver cancer includes but not limited to hepatocellular carcinoma (having or do not have the hepatocellular carcinoma of fibrolamellar form), cholangiocellular carcinoma and mixed type liver cell cholangiocellular carcinoma.
Skin carcinoma includes but not limited to squamous cytoma, Kaposi sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanoma skin carcinoma.
Head and neck cancer includes but not limited to laryngocarcinoma, hypopharyngeal cancer, nasopharyngeal carcinoma and/or oropharynx cancer and lip and oral carcinoma.
Lymphoma includes but not limited to AIDS associated lymphoma, non-Hodgkin lymphoma, cutaneous T cell lymphoma, Hodgkin's disease and central nervous system lymphoma.
Sarcoma includes but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and rhabdosarcoma.
Leukemia includes but not limited to acute myeloid leukemia, Acute Lymphoblastic Leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia and hairy cell leukemia.
Except inhibition tumor cell propagation, pharmaceutical composition of the present invention also can cause tumor regression, the reduction of the reduction of such as tumor size or tumour distribution range in vivo.
Embodiment
The following examples provided only for task of explanation instead of for, should not be interpreted as limiting the present invention by any way yet.The spectrograph of Bruker is used to compose at room temperature record 1H-NMR.Deuterated dimethyl sulfoxide is used as solvent, and described solvent comprises tetramethylsilane as interior mark (if not mentioning in addition).This is composed with the spectrograph record MS of Applied Biosystems to use water.Give relative signal intensity (representing with the per-cent based on main peak).Favour spectrum HP1100 is used to carry out HPLC.The conditions accompanying determined working Examples separately provides.
embodiment 1:4-{4-[({ [the chloro-3-of 4-(trifluoromethyl)-phenyl] is amino } carbonyl) is amino]-3-fluorophenoxy }-N-picoline-2-carboxylic acid amides, the preparation of its hydrochloride and its monohydrate
stage 1:
The chloro-N-methvl-pyridinium of 4--2-carboxamide hydrochloride:
Chloro-for the 4-of 420g N-picoline-2-carboxylic acid amides (preparing according to the WO2006/034796) solution in toluene (about 30%w/w) and 48.8g ethanol are added in reaction flask.67.2g Acetyl Chloride 98Min. is added under stirring is no more than the condition of the degree of 30 DEG C with the temperature reaching reaction mixture.After at room temperature stirring 1.5h further, product is leached, with toluene (212g) washing also drying under reduced pressure (30 DEG C, 80mbar).In this way, the chloro-N-methvl-pyridinium of 156.3g (quantitative yield) 4--2-carboxamide hydrochloride is obtained.Fusing point 173.7-174.5 DEG C.
1H-NMR(500MHz，DMSO-d 6)：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: stationary phase: Nucleodur Gravity C18 (150mm is long, 3mm ID, 3.0 μm of particle diameters); Mobile phase A: the o-phosphoric acid of 1.15g Secondary ammonium phosphate+0.68mL (85% solution) in water/lL water; Mobile phase B: acetonitrile; UV detects: at 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 time of 80%B; Purity: >98% (Rt=17.8min.).
stage 2:
4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides
method 2a:
The chloro-N-methvl-pyridinium of the 4--2-carboxamide hydrochloride of 41.4g and the 100g toluene as solvent is added in the reaction flask with agitator.After adding 68.4g water and 19.6g aqueous sodium hydroxide solution (45%w/w), reaction mixture is stirred 30 minutes.Two-phase laminated flow is discarded water layer.Organic layer concentrated through vacuum distilling and toluene 1-Methyl-2-Pyrrolidone (70g) is replaced, obtaining the solution of the chloro-N-methvl-pyridinium of 4--2-carboxylic acid amides in 1-Methyl-2-Pyrrolidone.
4-amino-3-the fluorophenol of 26.7g and the 4-methyl-2 pentanone of 100g is added in second reaction flask with agitator.By being heated to backflow and additionally stirring 1 hour, through component distillation except anhydrating.Then excessive 4-methyl-2 pentanone removed through vacuum distilling and use 1-Methyl-2-Pyrrolidone (70g) to replace with the solution of preparation containing the group with imine moiety of with good grounds formula (III).The solution of the chloro-N-methvl-pyridinium of 4--2-carboxylic acid amides in 1-Methyl-2-Pyrrolidone is added in gained reaction mixture.Reaction mixture is heated to about 100 DEG C.Drip (in about 70 minutes) 123.2g potassium tert.-butoxide solution in tetrahydrofuran (THF) (20%w/w), simultaneously through distillation removing tetrahydrofuran (THF).Thereafter, reaction mixture is stirred extra 3 hours to complete reaction at 100 DEG C.Being adjusted to after 80 DEG C, add 350ml toluene, 392ml water and 8g acetic acid.Mixture is stirred 10 minutes at 80 DEG C, is cooled to 50 DEG C and sows with the crystal of 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides.Being cooled to after 0 DEG C, suspension is stirred about 30 minutes.Product is leached, with methanol/water (1:3v/v, 144ml) washing also drying under reduced pressure (30 DEG C, 80mbar).In this way, obtaining 40.4g (78% of theoretical value) 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides, is brown crystal.
Fusing point 140.8-141.4 DEG C
1H-NMR(100MHz，DMSO-d 6)：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: stationary phase: Agilent Zorbax SB-AQ (150mm is long, 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: at 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 time of 80%B; Purity: >97% (Rt=9.22min.).
method 2b:
The chloro-N-methvl-pyridinium of the 4--2-carboxamide hydrochloride of 41.4g and the 100g toluene as solvent is added in the reaction flask with agitator.After adding 68.4g water and 19.6g aqueous sodium hydroxide solution (45%w/w), reaction mixture is stirred 30 minutes.Two-phase laminated flow is discarded water layer.Organic layer concentrated through vacuum distilling and toluene 1-Methyl-2-Pyrrolidone (70g) is replaced, obtaining the solution of the chloro-N-methvl-pyridinium of 4--2-carboxylic acid amides in 1-Methyl-2-Pyrrolidone.
4-amino-3-the fluorophenol of 26.7g and the 3-methyl-2-butanone of 100g is added in second reaction flask with agitator.By being heated to backflow and additionally stirring 3 hours, through component distillation except anhydrating.Then excessive 3-methyl-2-butanone removed through vacuum distilling and use 1-Methyl-2-Pyrrolidone (70g) to replace with the solution of preparation containing the group with imine moiety of with good grounds formula (III).The solution of the chloro-N-methvl-pyridinium of 4--2-carboxylic acid amides in 1-Methyl-2-Pyrrolidone is added in gained reaction mixture.Reaction mixture is heated to about 100 DEG C.Drip the solution of 123.2g potassium tert.-butoxide in tetrahydrofuran (THF) (20%w/w) (in about 3 hours), simultaneously through distillation removing tetrahydrofuran (THF).Thereafter, reaction mixture is stirred extra 2.5 hours to complete reaction at 100 DEG C.Being adjusted to after 80 DEG C, add 350ml toluene, 392ml water and 8g acetic acid.Mixture is stirred 10 minutes at 80 DEG C, is cooled to 50 DEG C and sows with the crystal of 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides.Being cooled to after 0 DEG C, suspension is stirred about 30 minutes.Product is leached, with methanol/water (1:3v/v, 144ml) washing also drying under reduced pressure (30 DEG C, 80mbar).In this way, obtaining 44.6g (84% of theoretical value) 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides, is light-brown crystals.Fusing point 141.9-142.6 DEG C.
1H-NMR(400MHz，DMSO-d 6)：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: stationary phase: Agilent Zorbax SB-AQ (150mm is long, 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: at 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 time of 80%B; Purity: >99% (Rt=9.16min.).
method 2c:
The chloro-N-methvl-pyridinium of the 4--2-carboxamide hydrochloride of 41.4g and the 100g toluene as solvent is added in the reaction flask with agitator.After adding 68.4g water and 19.6g aqueous sodium hydroxide solution (45%w/w), reaction mixture is stirred 30 minutes.Two-phase laminated flow is discarded water layer.Organic layer concentrated through vacuum distilling and toluene 1-Methyl-2-Pyrrolidone (70g) is replaced, obtaining the solution of the chloro-N-methvl-pyridinium of 4--2-carboxylic acid amides in 1-Methyl-2-Pyrrolidone.
4-amino-3-the fluorophenol of 26.7g, 73g hexanaphthene and 20.6g pimelinketone is added in second reaction flask with agitator.By being heated to backflow and additionally stirring 3 hours, through component distillation except anhydrating.Then solvent hexanaphthene and excessive pimelinketone removed through vacuum distilling and use 1-Methyl-2-Pyrrolidone (70g) to replace with the solution of preparation containing the group with imine moiety of with good grounds formula (III).The solution of the chloro-N-methvl-pyridinium of 4--2-carboxylic acid amides in 1-Methyl-2-Pyrrolidone is added in gained reaction mixture.Reaction mixture is heated to about 100 DEG C.Drip (in about 40 minutes) 126g potassium tert.-butoxide solution in tetrahydrofuran (THF) (20%w/w), simultaneously through distillation removing tetrahydrofuran (THF).Thereafter, reaction mixture is stirred extra 3 hours to complete reaction at 100 DEG C.After 80 DEG C of being adjusted to, add 350ml toluene, 392ml water and 8g acetic acid.Mixture is stirred 10 minutes at 80 DEG C, is cooled to 50 DEG C and sows with the crystal of 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides.Being cooled to after 3 DEG C, suspension is stirred about 30 minutes.Product is leached, with methanol/water (1:3v/v, 144ml) washing also drying under reduced pressure (30 DEG C, 80mbar).In this way, obtaining 40.1g (76% of theoretical value) 4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides, is light-brown crystals.
Fusing point 141.4 DEG C
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: stationary phase: Agilent Zorbax SB-AQ (150mm is long, 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: at 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 time of 80%B; Purity: >98% (Rt=9.14min.).
stage 3: preparation 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl)-phenyl] is amino } carbonyl) is amino]-3-fluorophenoxy }-N-picoline-2-carboxylic acid amides monohydrate (monohydrate)
4-(4-amino-3-fluorophenoxy)-N-picoline-2-carboxylic acid amides (i.e. formula (IV) compound), glacial acetic acid (mol ratio of formula (IV) compound and glacial acetic acid is 1:0.15) and the 180g tetrahydrofuran (THF) as solvent that the stage 2 method 2a of 20.0g is obtained is added in the reaction flask with agitator.In about 90 minutes, the solution of 18.7g isocyanic acid (the chloro-3-trifluoromethyl-phenyl of 4-) ester and 21.1g toluene is dripped in room temperature.By gained solution stirring 3 hours to complete reaction.Then 30g tetrahydrofuran (THF) and 7.8g methyl alcohol are added in reaction mixture.Then in 15 minutes, 9.0g Acetyl Chloride 98Min. is dropped in reaction mixture.After extra stirring about 2 hours, suspension is filtered and solid tetrahydrofuran (THF) (18.2g) and acetone (136.4g) are washed.Solid is added in the mixture of acetone (268.6g), water (55.8g) and aqueous sodium hydroxide solution (8.2g, 45%w/w) at 40 DEG C.Mixture is stirred extra 30 minutes.So by with 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl)-phenyl] is amino } carbonyl) is amino]-3-fluorophenoxy } the crystal sowing of-N-picoline-2-carboxylic acid amides monohydrate causes crystallization.Being cooled to after 20 DEG C, add 31.6g water.Suspension is cooled to about 3 DEG C and stir 30 minutes.Product is leached, washs and drying under reduced pressure (30 DEG C, 80mbar) with the cold mixture of acetone (106g) and water (44g).In this way, obtain 31.6g (83% of theoretical value) 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl)-phenyl] is amino } carbonyl) is amino]-3-fluorophenoxy }-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 the content of formula (I) compounds content (i.e. purity) in various forms bulk drug or its preparation and related impurities.[HPLC-A method] is as follows:
Stationary phase: Eclipse XDB-C8 (150mm is long, 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: at 232nm; Oven temperature: 43 DEG C, volume injected: 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 time of 80%B;
By external standard method with the content of calculated by peak area raw material or composition Chinese style (I) compound;
By external standard method with calculated by peak area raw material or composition Chinese style (X) the Compound Phase relative content for formula (I) compound;
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% (namely formula (I) compound monohydrate accounts for the content of bulk drug gross weight) in the Medicinal crude drug of formula (I) compound monohydrate that obtains of above stage 3;
After measured, Medicinal crude drug Chinese style (X) Compound Phase of formula (I) compound monohydrate that obtains of above stage 3 is 0.063% (its content relative to bulk drug gross weight is 0.0631%) for the relative content of formula (I) compound monohydrate.
Supplementary test 1: 4-(4-amino-3-the fluorophenoxy)-N-picoline-2-carboxylic acid amides (i.e. formula (IV) compound) that operational phase 2 method 2b is obtained, other starting material use with same batch of stage 3, with reference to the method in above " stage 3 ", obtain formula (I) compound monohydrate (yield 83%); After measured, this Medicinal crude drug purity 99.94%, formula (X) compound relative content is 0.007%.
Supplementary test 2: 4-(4-amino-3-the fluorophenoxy)-N-picoline-2-carboxylic acid amides (i.e. formula (IV) compound) that operational phase 2 method 2c is obtained, other starting material use with same batch of stage 3, with reference to the method in above " stage 3 ", obtain formula (I) compound monohydrate (yield 81%); After measured, this Medicinal crude drug purity 99.93%, formula (X) compound relative content is 0.016%.
Supplementary test 3: use and stage 3 starting material of same batch, with reference to the method in above " stage 3 ", the consumption of the glacial acetic acid that different is only adds is: the mol ratio of formula (IV) compound and glacial acetic acid is 1:0.2, obtains formula (I) compound monohydrate (yield 86%); After measured, this Medicinal crude drug purity 99.86%, formula (X) compound relative content is 0.036%.
Supplementary test 4: use and stage 3 starting material of same batch, with reference to the method in above " stage 3 ", the consumption of the glacial acetic acid that different is only adds is: the mol ratio of formula (IV) compound and glacial acetic acid is 1:0.1, obtains formula (I) compound monohydrate (yield 85%); After measured, this Medicinal crude drug purity 99.86%, formula (X) compound relative content is 0.168%.
Supplementary test 5: use and stage 3 starting material of same batch, with reference to the method in above " stage 3 ", the consumption of the glacial acetic acid that different is only adds is: the mol ratio of formula (IV) compound and glacial acetic acid is 1:0.5 or 1:1, obtains formula (I) compound monohydrate (yield is respectively 75% and 63%); After measured, this Medicinal crude drug purity 99.89%, formula (X) compound relative content is 0.108% and 0.094.Show effectively to improve product purity when increasing glacial acetic acid consumption, but significant detrimentally affect can be produced to the yield of product.
Supplementary test 6: use and stage 3 starting material of same batch, with reference to the method in above " stage 3 ", different is only do not add glacial acetic acid, obtains formula (I) compound monohydrate (yield 84%); After measured, this Medicinal crude drug purity 99.23%, formula (X) compound relative content is 0.47%;
Supplementary test 7: with reference to the method for above " supplementary test 1 ", different is only do not add glacial acetic acid, obtains formula (I) compound monohydrate (yield 82%); After measured, this Medicinal crude drug purity 99.16%, formula (X) compound relative content is 0.63%;
Supplementary test 8: with reference to the method for above " supplementary test 2 ", different is only do not add glacial acetic acid, obtains formula (I) compound monohydrate (yield 83%); After measured, this Medicinal crude drug purity 99.24%, formula (X) compound relative content is 0.44%;
Supplementary test 9: use and stage 3 starting material of same batch, with reference to the method in above " stage 3 ", different is only change glacial acetic acid into formic acid, obtains formula (I) compound monohydrate (yield 86%); After measured, this Medicinal crude drug purity 99.23%, formula (X) compound relative content is 0.39%.
Supplementary test 10: use and stage 3 starting material of same batch, with reference to the method in above " stage 3 ", different is only that the methyl alcohol forming acid with Acetyl Chloride 98Min. reaction in－situ uses ethanol instead, obtains formula (I) compound monohydrate (yield 76%); After measured, this Medicinal crude drug purity 99.79%, formula (X) compound relative content is 0.057%.
stage 4: preparation 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl)-phenyl] is amino } carbonyl) is amino]-3-fluorophenoxy }-N-picoline-2-carboxylic acid amides (anhydride)
4-{4-[({ [the chloro-3-of 4-(trifluoromethyl)-phenyl] is amino } carbonyl) is amino]-3-fluorophenoxy by obtained for 10.2g stage 4 }-N-picoline-2-carboxylic acid amides monohydrate is 90 DEG C of drying under reduced pressure (21mbar) 3 hours, in this way, obtain 4-{4-[({ [the chloro-3-of 4-(trifluoromethyl)-phenyl] is amino } carbonyl)-the amino]-3-fluorophenoxy of 9.8g }-N-picoline-2-carboxylic acid amides is white crystal.Fusing point 187.3-188.1 DEG C.
1h-NMR (400MHz, methyl alcohol-d 4): 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 obtains of above stage 4;
After measured, Medicinal crude drug Chinese style (X) Compound Phase of formula (I) compound anhydride that obtains of above stage 4 is 0.054% (it is 0.0541% relative to the content of material Chinese style (I) compound anhydride gross weight) for the relative content of formula (I) compound anhydride.
Supplementary test example 11: with reference to the method in above " stage 4 ", the different products using 1 to the supplementary test of supplementary test example above example 10 gained various formula (I) compound monohydrate instead is raw material, obtains the anhydride of 10 batch (I) compound; Measure through [HPLC-A method], they respectively monohydrate raw material used with it at purity and formula (X) compound relative content all without obviously changing, purity difference is no more than 0.1%, and formula (X) Compound Phase is no more than 0.003% to content difference.
embodiment 2: the study on the stability of bulk drug
Respectively formula (I) the compound monohydrate of the various different purity prepared in above embodiment 1, its each stage and each supplementary test example and the medicinal aluminum plastic composite membrane of formula (I) compound anhydride medicinal raw material are packed, put in 45 DEG C of thermostat containers and place 4 months to carry out high-temperature treatment.Measure each bulk drug 0 month time and April time purity and formula (X) compound relative content, and the purity of more every batch sample and the changing value of formula (X) compound relative content respectively, characterize this change with purity changing value and relative content percent change respectively.The calculating formula of two parameter is as follows:
Purity changing value=0 month purity-April purity
Relative content percent change=[(relative content in April-0 month relative content) ÷ 0 month relative content] × 100%
Result shows:
The purity of whole bulk drug when April and the purity of this batch of bulk drug 0 month time have no significant change, purity changing value is all in 0.2 percentage ranges, the such as Medicinal crude drug of stage 3 gained formula (I) compound monohydrate, purity 99.82% when its 0 month, purity 99.67% during April, purity changing value is only 0.15%, shows to say from the angle changing of principal constituent not occur significantly reducing; But, the relative content percent change of formula (X) compound but presents the relevant variation tendency of relative content to itself in bulk drug, specifically: for formula (X) compound relative content lower than 0.2% whole Medicinal crude drug, their relative content percent change is all lower than 13%, and the relative content percent change of the Medicinal crude drug of such as stage 3 gained formula (I) compound monohydrate its Chinese style (X) compound after high-temperature treatment April is 8.7%; But whole Medicinal crude drug that formula (X) compound relative content is greater than 0.2%, they in the relative content percent change of its Chinese style (X) compound after high-temperature treatment April all in 52 ~ 183% scopes, and its formula of bulk drug (X) Compound Phase that the relative content of formula (X) compound is higher is larger to content percentage ratio, formula (X) Compound Phase of such as supplementary test 8 product is 146% to content percentage ratio.
embodiment 3: the pharmaceutical composition preparing tablet form
With reference to step formula a), b), c) and the method for making of 19 pages of embodiments 1 of WO2014039677A1, formula (I) the compound monohydrate using foregoing embodiments 1 of the present invention to prepare respectively or the Medicinal crude drug of formula (I) compound anhydride are activeconstituents, prepare coated tablet (every sheet contained (I) compound 40mg).
Each for gained tablet is packed with aluminum plastic composite membrane respectively, puts in 45 DEG C of thermostat containers and place 4 months to carry out high-temperature treatment.With reference to the method in above embodiment 2, measure each tablet 0 month time and April time formula (I) compounds content and formula (X) Compound Phase to (in formula (I) compound) content, and formula (I) the compound residues content of more every batch sample and the changing value of formula (X) compound relative content respectively, with formula (I) compound residues content and formula (X) Compound Phase, this change is characterized to content percentage ratio respectively.The calculating formula of two parameter is as follows:
Formula (I) compound residues content=(content ÷ in April 0 month relative content) × 100%
Relative content percent change=[(relative content in April-0 month relative content) ÷ 0 month relative content] × 100%
Result shows: all the formula of tablet when April (I) compound residues content is all greater than 95%, all in 95% ~ 99% scope, show to say that each tablet is without obvious stability difference from the angle changing of activeconstituents, the tablet that such as stage 3 gained formula (I) compound monohydrate Medicinal crude drug is made, its, up-to-date style (I) compound residues content was 97.8% in April; But, the relative content percent change of formula (X) compound, but its variation tendency in bulk drug is similar to, present the variation tendency relevant to itself relative content in tablets, specifically: for formula (X) compound relative content lower than 0.2% whole tablets of making of bulk drug, their relative content percent change is all lower than 15%, and the relative content percent change of the tablet made of such as stage 3 gained formula (I) compound monohydrate Medicinal crude drug its Chinese style (X) compound after high-temperature treatment April is 9.7%; But whole tablets that the bulk drug that formula (X) compound relative content is greater than 0.2% is made, they in the relative content percent change of its Chinese style (X) compound after high-temperature treatment April all in 64 ~ 197% scopes, and its formula of tablet (X) Compound Phase that the relative content of formula (X) compound is higher is larger to content percentage ratio, formula (X) Compound Phase of such as supplementary test 9 product is 133% to content percentage ratio.
By present pre-ferred embodiments, spirit of the present invention is elaborated above.It will be appreciated by those skilled in the art that every above embodiment is done according to the technology of the present invention essence any amendment, equivalent variations and modification, all drop in protection scope of the present invention.

Claims (10)

1. with following formula (I) compound or pharmaceutically acceptable salt thereof or monohydrate:
2. formula according to claim 1 (I) compound or pharmaceutically acceptable salt thereof or monohydrate, is characterized in that:
It is Medicinal crude drug;
Wherein comprise trace as impurity with following formula (X) compound:
Wherein for the weight of formula (I) compound, the content of formula (X) compound is less than 0.2%, such as, be less than 0.15%, such as, be less than 0.1%, such as, be less than 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0001% ~ 0.2%, such as, be 0.0001% ~ 0.15%, such as, be 0.0001% ~ 0.1%, such as, be 0.0001% ~ 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0005% ~ 0.2%, such as, be 0.0005% ~ 0.15%, such as, be 0.0005% ~ 0.1%, such as, be 0.0005% ~ 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.001% ~ 0.2%, such as, be 0.001% ~ 0.15%, such as, be 0.001% ~ 0.1%, such as, be 0.001% ~ 0.05%;
And/or
It is prepared by a method comprising the following steps and obtains:
(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 the acid treatment of gained formula (I) compound to form the pharmaceutical salts of formula (I) compound; Then, optionally,
(3) make the process of step (2) gained pharmaceutical salts alkaline aqueous solution to be settled out the monohydrate of formula (I) compound.
3., according to formula (I) compound or pharmaceutically acceptable salt thereof or the monohydrate of claim 1 or 2, it is characterized in that:
Wherein in step (3), at the temperature of 35 DEG C to 45 DEG C, the monohydrate of formula (I) compound is made to precipitate;
Wherein also comprise step (4), that is: make the monohydrate drying under reduced pressure of step (3) gained formula (I) compound to form the step of formula (I) compound;
Formula (I) compound wherein comprising dissolving and the solution of material be settled out from the salt of formula (I) compound are the independent solution of reaction mixture or formula (I) compound prepared after isolate formula (I) compound from reaction mixture;
Wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding proton material and acid precursor in reaction mixture;
Wherein said proton material is alcohol and described acid precursor is chloride of acid;
Wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding alcohol and chloride of acid in reaction mixture;
Wherein said alcohol is methyl alcohol or ethanol and described chloride of acid is Acetyl Chloride 98Min.;
Wherein carry out, in the process that formula (IV) compound and formula (V) compound react, being also added with paraffinic acid with formula (IV) compound in step (1);
Its Chinese style (IV) compound is prepared by following steps:
Make formula (III) compound
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and forms 4 to 7 yuan of cycloalkyl rings together with the carbon atom be connected with them
React in the presence of base with following formula (II) compound,
Add acid subsequently with production (IV) compound.
4., according to formula (I) compound or pharmaceutically acceptable salt thereof or the monohydrate of claim 1-3, it is characterized in that:
Its Chinese style (III) compound uses and generates by making 4-amino-3-fluorophenol and formula (VI) compound react in the solution of the organic solvent be applicable to
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and the carbon atom be connected with them forms 4 to 7 yuan of cycloalkyl rings together;
Its Chinese style (II) compound uses in the solution of the organic solvent be applicable to, and described solution is by preparing with the hydrochloride of formula (II) compound with in alkali;
Wherein by formula (II) compound dissolution in the organic solvent be applicable to, with the acid treatment by adding proton material and acid precursor in-situ generation, be precipitated as the salt of formula (II) compound, and by the neutralization of the aqueous solution that adds alkali.
5. prepare the method with 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
Obtain formula (I) compound; Then, optionally,
(2) make the acid treatment of gained formula (I) compound to form the pharmaceutical salts of formula (I) compound; Then, optionally,
(3) make the process of step (2) gained pharmaceutical salts alkaline aqueous solution to be settled out the monohydrate of formula (I) compound.
6. method according to claim 5, is characterized in that:
Wherein said formula (I) compound or pharmaceutically acceptable salt thereof or monohydrate are Medicinal crude drug;
In formula (I) compound or pharmaceutically acceptable salt thereof obtained by it or monohydrate, comprise trace as impurity with following formula (X) compound
In formula (I) compound or pharmaceutically acceptable salt thereof obtained by it or monohydrate, for the weight of formula (I) compound, the content of formula (X) compound is less than 0.2%, such as, be less than 0.15%, such as be less than 0.1%, such as, be less than 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0001% ~ 0.2%, such as, be 0.0001% ~ 0.15%, such as, be 0.0001% ~ 0.1%, such as, be 0.0001% ~ 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0005% ~ 0.2%, such as, be 0.0005% ~ 0.15%, such as, be 0.0005% ~ 0.1%, such as, be 0.0005% ~ 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.001% ~ 0.2%, such as, be 0.001% ~ 0.15%, such as, be 0.001% ~ 0.1%, such as, be 0.001% ~ 0.05%;
Wherein in step (3), at the temperature of 35 DEG C to 45 DEG C, the monohydrate of formula (I) compound is made to precipitate;
Wherein also comprise step (4), that is: make the monohydrate drying under reduced pressure of step (3) gained formula (I) compound to form the step of formula (I) compound;
Formula (I) compound wherein comprising dissolving and the solution of material be settled out from the salt of formula (I) compound are the independent solution of reaction mixture or formula (I) compound prepared after isolate formula (I) compound from reaction mixture;
Wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding proton material and acid precursor in reaction mixture;
Wherein said proton material is alcohol and described acid precursor is chloride of acid;
Wherein said acid adds like this: after forming formula (I) compound, produces (i.e. in-situ preparation) on the spot in the reactive mixture by adding alcohol and chloride of acid in reaction mixture;
Wherein said alcohol is methyl alcohol or ethanol and described chloride of acid is Acetyl Chloride 98Min.;
Wherein carry out, in the process that formula (IV) compound and formula (V) compound react, being also added with paraffinic acid with formula (IV) compound in step (1);
The mol ratio of formula (IV) compound and paraffinic acid is 1:0.1 ~ 0.2; And/or
Paraffinic acid is glacial acetic acid.
7. method according to claim 5, is characterized in that:
Its Chinese style (IV) compound is prepared by following steps:
Make formula (III) compound
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and forms 4 to 7 yuan of cycloalkyl rings together with the carbon atom be connected with them
React in the presence of base with following formula (II) compound,
Add acid subsequently with production (IV) compound;
Its Chinese style (III) compound uses and generates by making 4-amino-3-fluorophenol and formula (VI) compound react in the solution of the organic solvent be applicable to
Wherein R1 and R2 is independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl, or R1 with R2 is connected and the carbon atom be connected with them forms 4 to 7 yuan of cycloalkyl rings together;
Its Chinese style (II) compound uses in the solution of the organic solvent be applicable to, and described solution is by preparing with the hydrochloride of formula (II) compound with in alkali; And/or
Wherein by formula (II) compound dissolution in the organic solvent be applicable to, with the acid treatment by adding proton material and acid precursor in-situ generation, be precipitated as the salt of formula (II) compound, and by the neutralization of the aqueous solution that adds alkali.
8. a pharmaceutical composition, wherein comprises formula (I) compound or pharmaceutically acceptable salt thereof or the monohydrate of any one of claim 1-4, and the acceptable auxiliary material of pharmacy; Or, wherein contained (I) compound or pharmaceutically acceptable salt thereof or monohydrate, and the acceptable auxiliary material of pharmacy.
9. pharmaceutical composition according to claim 8, is characterized in that:
Wherein comprise trace as impurity with following formula (X) compound
Wherein for the weight of formula (I) compound, the content of formula (X) compound is less than 0.2%, such as, be less than 0.15%, such as, be less than 0.1%, such as, be less than 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0001% ~ 0.2%, such as, be 0.0001% ~ 0.15%, such as, be 0.0001% ~ 0.1%, such as, be 0.0001% ~ 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.0005% ~ 0.2%, such as, be 0.0005% ~ 0.15%, such as, be 0.0005% ~ 0.1%, such as, be 0.0005% ~ 0.05%;
Wherein for the weight of formula (I) compound, the content of formula (X) compound is 0.001% ~ 0.2%, such as, be 0.001% ~ 0.15%, such as, be 0.001% ~ 0.1%, such as, be 0.001% ~ 0.05%.
10. according to Claim 8-9 pharmaceutical composition, it is characterized in that:
It is the dosage forms such as tablet, capsule, granule, powder;
Comprising: active pharmaceutical compounds, thinner, disintegrating agent, tackiness agent, lubricant; Described active pharmaceutical compounds is with following formula (I) compound or its salt, monohydrate:
Wherein said thinner includes but not limited to: secondary calcium phosphate, kaolin, dextrin, lactose, N.F,USP MANNITOL, sucrose, Microcrystalline Cellulose, powdered cellulose, precipitated calcium carbonate, sorbyl alcohol and starch and derivative (such as W-Gum, potato starch, amylum pregelatinisatum, modified starch, pregelatinized Starch etc.), erythritol, Xylitol, fructose etc. and their combination;
The active pharmaceutical compounds wherein comprised counts 40 weight parts with formula (I) compound, and the amount of described thinner is 50 ~ 500 weight parts; The amount of such as described thinner is 50 ~ 400 weight parts; The amount of such as described thinner is 50 ~ 300 weight parts; The amount of such as described thinner is 50 ~ 200 weight parts;
Wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, croscarmellose sodium etc. and their combination;
The active pharmaceutical compounds wherein comprised counts 40 weight parts with formula (I) compound, and the amount of described disintegrating agent is 50 ~ 500 weight parts; Such as 50 ~ 400 weight parts; Such as 50 ~ 300 weight parts; Such as 50 ~ 200 weight parts;
Wherein said tackiness agent such as, such as but not limited to hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone (molecular weight is the PVP of 5000 ~ 50000, PVP K15, PVP K17, PVP K25, PVP K30 etc.), polyvinyl alcohol, gum arabic, Lalgine, sodium alginate, gelatin etc. and their combination;
The active pharmaceutical compounds wherein comprised counts 40 weight parts with formula (I) compound, and the amount of described tackiness agent is 50 ~ 500 weight parts; Such as 50 ~ 400 weight parts; Such as 100 ~ 300 weight parts; Such as 100 ~ 200 weight parts;
Wherein said lubricant is selected from: Magnesium Stearate, stearic acid, calcium stearate, Zinic stearas, Liquid Paraffin, polyoxyethylene glycol, silicon-dioxide, colloid silica, micropowder silica gel, talcum powder, starch, hydrogenated vegetable oil etc. or its combination;
The active pharmaceutical compounds wherein comprised counts 40 weight parts with formula (I) compound, and the amount of described lubricant is 1 ~ 50 weight part; The amount of such as described lubricant is 1 ~ 25 weight part; The amount of such as described lubricant is 1 ~ 20 weight part; The amount of such as described lubricant is 1 ~ 10 weight part; The amount of such as described lubricant is 2 ~ 8 weight parts.
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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
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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
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CN112159351A (en) * 2020-09-21 2021-01-01 广州南鑫药业有限公司 Preparation method of multi-target antitumor drug
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
WO2022057164A1 (en) * 2020-09-21 2022-03-24 广州南鑫药业有限公司 Preparation method for multi-target anti-tumor drug
CN114315710A (en) * 2022-01-07 2022-04-12 江苏豪森药业集团有限公司 Method for preparing or purifying regorafenib
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

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