CN103319456A - Dihydropyridine compounds, and compositions, preparation methods and applications thereof - Google Patents

Dihydropyridine compounds, and compositions, preparation methods and applications thereof Download PDF

Info

Publication number
CN103319456A
CN103319456A CN2012100816773A CN201210081677A CN103319456A CN 103319456 A CN103319456 A CN 103319456A CN 2012100816773 A CN2012100816773 A CN 2012100816773A CN 201210081677 A CN201210081677 A CN 201210081677A CN 103319456 A CN103319456 A CN 103319456A
Authority
CN
China
Prior art keywords
compound
cancer
general formula
application
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN2012100816773A
Other languages
Chinese (zh)
Other versions
CN103319456B (en
Inventor
程建军
秦继红
叶斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Huilun Jiangsu Pharmaceutical Co ltd
Shanghai Huilun Pharmaceutical Co ltd
Original Assignee
SHANGHAI HUILUN TECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SHANGHAI HUILUN TECHNOLOGY Co Ltd filed Critical SHANGHAI HUILUN TECHNOLOGY Co Ltd
Priority to CN201210081677.3A priority Critical patent/CN103319456B/en
Publication of CN103319456A publication Critical patent/CN103319456A/en
Application granted granted Critical
Publication of CN103319456B publication Critical patent/CN103319456B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dihydropyridine compounds are disclosed, and are compounds represented by the following general formula (I), wherein R1 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R2 is selected from hydrogen, alkyl, substituted alkyl or a heterocycle formed by R2 and R3; and R3 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or a heterocycle formed by R3 and R2. The invention also discloses preparation methods for the compounds represented by the general formula (I), and pharmaceutical compositions and applications of the compounds.

Description

Dihydropyridine compounds, its composition, preparation method and purposes
Technical field
The present invention relates to a kind of dihydropyridine compounds, its preparation method contains them as the pharmaceutical composition of activeconstituents, with and the purposes of the cancer of being correlated with in order to the treatment disease, particularly c-Met relevant with Tyrosylprotein kinase c-Met as medicine.
Background of invention
Cancer is the No.1 killer who threatens whole world human life's health.Although the progress of medical science makes human treatment for cancer have a lot of new means, cancer still is considered to still unsolved difficult medical problem at present.Cause the cause of disease of cancer a lot, in recent years, the development of the subjects such as molecular weight tumor, molecular pharmacology is progressively being illustrated the essence of tumour, and people recognize that gradually the essence of cell carcinogenesis is the cell infinite multiplication that the intracellular signal transduction pathway imbalance causes.As the of paramount importance member who participates in cell signaling, protein tyrosine kinase (protein tyrosine kinases, PTKs are called for short Tyrosylprotein kinase) is modal growth factor receptors, with the generation of tumour with develop closely related.The hyperactivity of Tyrosylprotein kinase causes its downstream signal pathway activation, thus cause cell transformation, propagation, to anti-apoptotic, promote cell survival, finally lead oncogenic formation.Therefore, the Development Trend of antitumor drug begins to turn to the medicine of transduceing for abnormal signal in the cell from traditional cell toxicity medicament in recent years, and there have successively related drugs to be applied to be clinical.Compare with traditional cell toxicant series antineoplastic medicament, this quasi-molecule targeting medicament curative effect is strong, toxic side effect is little, becomes gradually the focus of current antitumor drug research and development.
Tyrosylprotein kinase divides two kinds of receptor type tyrosine kinase and non-receptor type Tyrosylprotein kinases, receptor type tyrosine kinase has EGF-R ELISA (EGFR) family, vascular endothelial growth factor receptor (VEGFR) family, platelet derived growth factor receptor (PDGFR) family, fibroblast growth factor acceptor (FGFR) family etc., nonreceptor tyrosine kinase is Src kinases family, Jak for example, FAK etc. comprise again multiple hypotype in each kinases family.
Hepatic growth factor receptor c-Met is a kind of (Park et al., Proc.Natl.Acad.Sci.USA 84:6379-83,1987 of receptor type tyrosine kinase; Bottaro et al., Science 2S 1:802-4,1991), formed together with extracellular domain, transmembrane segment and tenuigenin tyrosine kinase domain by outside alpha subunit and the β subunit of high glycosylation.Its endogenic ligand is pHGF (hepatocyte growth factor, HGF) (Nature, 327:239-242 (1987); J.Cell Biol., 111:2097-2108 (1990)), ligand binding is induced the c-Met dimerization, generate the activated receptor of autophosphorylation, promote the signal transduction in downstream, multiple the replying of mediation in tumour cell comprises that increment, stimulation epithelial cell mobility, cell survival and the form of epithelial cell and endotheliocyte changes and promote intrusion etc.In addition, HGF regulates vasculogenesis, for the growth of tumour with spread extremely important.C-Met and part thereof crossing in kinds of tumors (comprising thyroid carcinoma, ovarian cancer, carcinoma of the pancreas etc.) expressed the effect that has also illustrated in its evolution in these tumours.At present, c-Met is as the action target spot of antitumor drug, its advantage progressively illustrated (Nature Reviews Cancer, 2012,12,89-103).
In the primary tumor and secondary tumors transfer that the c-Met receptor activation plays a key effect, the biological substance of target HGF or c-Met (ribozyme, antibody and sense-rna) can suppress the generation of tumour, and the selectivity micromolecular inhibitor of target c-Met is also predicted to have treatment potentiality.WO2009091374, WO2009149836, WO2011003604, WO2011042367, WO2011042368, CN200910247948.6 has all comprised optionally c-Met micromolecular inhibitor, Preparation Method And The Use in the patents such as CN201010175273.1.
Dihydropyridine compounds as tyrosine kinase inhibitor involved in the present invention as tyrosine kinase inhibitor, particularly c-Met inhibitor, never was in the news.
Summary of the invention
One of technical problem to be solved by this invention provides a kind of dihydropyridine compounds.
Two of technical problem to be solved by this invention provides the preparation method of above-mentioned dihydropyridine compounds.
Three of technical problem to be solved by this invention provides the composition that contains above-mentioned dihydropyridine compounds.
Four of technical problem to be solved by this invention provides the purposes of above-mentioned dihydropyridine compounds.
As the dihydropyridine compounds of first aspect present invention, for having the compound of following general formula (I):
Figure BDA0000146633410000031
Wherein,
R 1Be selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R 2Be selected from hydrogen, alkyl, substituted alkyl; Perhaps, R 2With R 3Form heterocycle;
R 3Be selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; Perhaps, R 3With R 2Form heterocycle.
More specifically, general formula of the present invention (I) compound is preferably certainly as shown in the formula (I-1) compound to (I-15):
Figure BDA0000146633410000041
The dihydropyridine compounds of described general formula (I) is any one in enantiomer, diastereomer, the conformer, or arbitrarily both, three or four mixture.
The dihydropyridine compounds of described general formula (I) comprises described compound pharmacy acceptable derivates.
The dihydropyridine compounds of general formula of the present invention (I) can exist with the form of pharmacy acceptable salt.
Pharmacy acceptable salt of the present invention is hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, mesylate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate, the malate of general formula (I) compound.
Preparation method as general formula (I) dihydropyridine compounds of second aspect present invention can carry out by method as described below (R wherein 1, R 2, R 3Described as defined above; " PG " (protecting groups) is the amido protecting group; such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.): take pimelinketone-4-ethyl formate (1) as raw material; at N; be converted into intermediate (2) under the effect of dinethylformamide dimethylacetal (DMF-DMA); this intermediate and hydrazine reaction, cyclisation are pyrazole compound (3).Ester group in the intermediate (3) is reduced with reductive agent (such as lithium aluminium hydride, sodium borohydride etc.), obtain intermediate (4).Then the amido of intermediate (4) pyrazoles is protected to get intermediate (II) with suitable protecting group (such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.); again with its alcoholic extract hydroxyl group with suitable condition (such as the Dess-Martin oxidation; the Swern oxidation) oxidation obtains aldehydes intermediate (III).Intermediate (III) and cyano group ketone compounds (A) condensation get intermediate (IV), and again with amido alkene nitrile raw material (B) condensation, then deprotection base under suitable condition namely gets compound (I).
Route 1:
Route 1In, R 1, R 2, R 3Described as defined above; Especially, R in the amido alkene nitrile raw material (B) 2With R 3Combinatorial optimization from following (B-1) to structure shown in (B-3):
Figure BDA0000146633410000061
R in general formula (I) 1With R 3Identical (replacing with Ra) and R 2During for hydrogen, its described compound also can be by the method shown in the following route 2 preparation (R wherein 1, R 2, R 3Described as defined above; " PG " (protecting groups) is the amido protecting group; such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.): take pimelinketone-4-ethyl formate (1) as raw material; at N; be converted into intermediate (2) under the effect of dinethylformamide dimethylacetal (DMF-DMA); this intermediate and hydrazine reaction, cyclisation are pyrazole compound (3).Ester group in the intermediate (3) is reduced with reductive agent (such as lithium aluminium hydride, sodium borohydride etc.), obtain intermediate (4).Then the amido of intermediate (4) pyrazoles is protected to get intermediate (II) with suitable protecting group (such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.); again with its alcoholic extract hydroxyl group with suitable condition (such as the Dess-Martin oxidation; the Swern oxidation) oxidation obtains aldehydes intermediate (III).Amino alkene nitrile raw material (C) condensation of this intermediate (III) and 2 equivalents, then deprotection base under suitable condition namely gets compound (I).
Route 2:
Figure BDA0000146633410000071
Above-mentioned protecting group is the amido protecting group.Described amido protecting group is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl.
Described under suitable condition deprotection base refers to: adopt organic solution or the trifluoracetic acid/methylene dichloride of hydrogenchloride to remove tertbutyloxycarbonyl; Adopt the method for catalytic hydrogenation to remove carbobenzoxy-(Cbz); Perhaps adopt trifluoracetic acid to remove methoxy-benzyl.
As the composition that contains dihydropyridine compounds of third aspect present invention, wherein said pharmaceutical composition comprises dihydropyridine compounds and the acceptable vehicle of pharmacy of the general formula (I) for the treatment of significant quantity.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable derivates and the acceptable vehicle of pharmacy of the dihydropyridine compounds of the general formula (I) for the treatment of significant quantity.
As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable salt and the acceptable vehicle of pharmacy of the dihydropyridine compounds of the general formula (I) for the treatment of significant quantity.
Described pharmaceutical composition is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, syrup, emulsion, ointment, ointment, suppository, injection.
As the application of fourth aspect present invention, wherein be the application of dihydropyridine compounds in preparation adjusting protein kinase catalytic activity goods of general formula (I).
As the application of fourth aspect present invention, wherein be the application of pharmacy acceptable derivates in preparation adjusting protein kinase catalytic activity goods of the dihydropyridine compounds of general formula (I).
As the application of fourth aspect present invention, wherein be the application of pharmaceutically useful salt in preparation adjusting protein kinase catalytic activity goods of the dihydropyridine compounds of general formula (I).
As the application of fourth aspect present invention, wherein be the application of pharmaceutical composition in the medicine of the preparation treatment disease relevant with protein kinase.
Described protein kinase is the c-Met receptor tyrosine kinase.
Described cancer is selected from cancer of the stomach, lung cancer, thyroid carcinoma, colorectal carcinoma, kidney, liver cancer, ovarian cancer, mammary cancer, prostate cancer, bladder cancer, head and neck cancer, carcinoma of the pancreas, carcinoma of gallbladder, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma.
The dihydropyridine compounds of general formula involved in the present invention (I) also can be used for the research of the signal transduction pathway that the research, Tyrosylprotein kinase of biology or pharmacology phenomenon participates in and for the comparative evaluation of new tyrosine kinase inhibitor.
Embodiment
The invention provides the dihydropyridine compounds shown in the general formula defined above (I), prepare these compounds method, use the pharmaceutical composition of these compounds and use the method for these compounds.
Below listed be definition to the various terms that are used for describing the compounds of this invention.These definition are applied at specification sheets employed term (unless in specific situation restriction being arranged in addition) everywhere, and no matter these terms use separately or as the part of macoradical more.
Unless otherwise defined, the employed term of the application " alkyl " (use separately or as the part of another group) refers to the univalent perssad that comprises 1 to 12 carbon atom that alkane is derivative.Preferred alkyl has 1 to 6 carbon atom.Alkyl is optional straight chain, side chain or the cyclic saturated hydrocarbon base that replaces.Exemplary alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.The substituting group of " substituted alkyl " is selected from following group: alkyl, halogen (such as fluorine, chlorine, bromine, iodine), alkoxyl group, amino/amido, haloalkyl (such as trichloromethyl, trifluoromethyl), aryl, aryloxy, alkylthio, hydroxyl, cyano group, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, carbamyl, urea or sulfydryl.
The employed term of the application " aryl " (use separately or as the part of another group) refers to monocyclic aromatic ring or polycyclic aromatic ring, such as the phenyl of phenyl, replacement etc. and group such as the naphthyl that condenses, phenanthryl etc.Thereby aryl comprises at least one ring with at least 6 atoms, comprises at the most five such rings (wherein comprising at the most 22 atoms), and has (conjugation) two keys alternately between adjacent carbon atom or the suitable heteroatoms.Preferred aryl comprises 6 to 14 carbon atoms in ring." substituted aryl " can be chosen wantonly to replace has one or more group, described group to include but not limited to halogen (such as fluorine, chlorine, bromine), alkyl (such as methyl, ethyl, propyl group), substituted alkyl (such as trifluoromethyl), cycloalkyl, alkoxyl group (such as methoxy or ethoxy), hydroxyl, carboxyl, amine formyl (C (=O) NR ' R "), alkoxy carbonyl (CO 2R), amino/amido, nitro, cyano group, thiazolinyl oxygen base, aryl, heteroaryl, alkylsulfonyl (SO 2R) etc., wherein, R, R ', R " are described alkyl.
The employed term of the application " heteroaryl " (use separately or as the part of another group) refers to replace and unsubstituted aromatics 5 or 6 yuan of monocyclic groups, 9 or 10 yuan of bicyclic radicals and 11 to 14 yuan of three cyclic groups, and these groups have at least one heteroatoms (O, S or N) at least one encircles.Each ring that comprises heteroatomic heteroaryl can comprise one or two Sauerstoffatoms or sulphur atom and/or one to four nitrogen-atoms, condition is four or still less for heteroatomic sum in each ring, and each ring has at least one carbon atom, the ring that condenses that forms above-mentioned bicyclic radicals and three cyclic groups can only comprise carbon atom, and can be saturated or fractional saturation.Nitrogen-atoms and sulphur atom can be oxidations, and nitrogen-atoms can be quaternary ammoniated.The heteroaryl of dicyclo or three rings must comprise the ring of at least one Wholly aromatic, but other ring that condenses or a plurality of ring can be aromatics or non-aromatic.Heteroaryl can be in arbitrarily any available nitrogen-atoms or the connection of carbon atom place of ring." substituted heteroaryl " ring system can comprise zero, one, two or three be selected from following substituting group: the alkyl of halogen, alkyl, replacement, thiazolinyl, piece base, aryl, nitro, cyano group, hydroxyl, alkoxyl group, alkylthio ,-CO 2H ,-C (=O) H ,-CO 2-alkyl ,-C (=O) alkyl, phenyl, benzyl, phenylethyl, phenyl oxygen base, thiophenyl, cycloalkyl, replacement cycloalkyl, Heterocyclylalkyl, heteroaryl ,-NR ' R " ,-C (=O) NR ' R " ,-CO 2NR ' R " ,-C (=O) NR ' R " ,-NR ' CO 2R " ,-NR ' C (=O) R " ,-SO 2NR ' R " and-NR ' SO 2R ", wherein R ' and R " independently be selected from separately alkyl and the cycloalkyl of hydrogen, alkyl, replacement, or R ' and R " form Heterocyclylalkyl or heteroaryl ring together.
The example of bicyclic heteroaryl comprises pyrryl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, di azoly, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazoles base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.
The example of bicyclic heteroaryl comprises indyl, benzothiazolyl, benzodioxole base, benzoxazolyl, benzothienyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, benzimidazolyl-, benzopyranyl, indolizine base, benzofuryl, chromone base, tonka bean camphor base, benzofuryl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl etc.
The example of tricyclic heteroaryl comprises carbazyl, benzindole base, phenanthroline base, acridyl, phenanthridinyl etc.
The heteroatoms that a carbon atom in the employed term of the application " heterocycle " (use separately or as the part of another group) finger ring is selected from O, S or N replaces and 3 extra carbon atoms cycloalkyl (non-aromatic) that can be replaced by described heteroatoms at the most.The employed term of the application " heterocyclic radical " (use separately or as the part of another group) refers to comprise the undersaturated monocycle ring system of stable saturated or part of 5 to 7 annular atomses (carbon atom and be selected from other atom of nitrogen, sulphur and/or oxygen).Heterocycle can be 5,6 or 7 yuan of monocycles, and comprises one, two or three heteroatoms that is selected from nitrogen, oxygen and/or sulphur.Heterocycle can be optional the replacement; this means that heterocycle can have one or more independently to be selected from following group in one or more commutable ring position replacement: alkyl, Heterocyclylalkyl, heteroaryl, alkoxyl group, nitro, monoalkyl amido, dialkyl amino, cyano group, halogen, haloalkyl, alkyloyl, ammonia/amido carbonyl, monoalkyl amido carbonyl, dialkyl amino carbonyl, alkylamidoalkyl, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl oxygen base and aryl, the optional replacement of described aryl has halogen, alkyl and alkoxyl group.The example of these Heterocyclylalkyls includes but not limited to: piperidines, morpholine, high morpholine, piperazine, parathiazan, tetramethyleneimine and azetidine.
The employed term of the application " alkoxyl group " (use separately or as the part of another group) refers to the alkyl that preferably has 1 to 6 carbon atom that connects by Sauerstoffatom, such as-OR, wherein R is described alkyl.
The employed term of the application " amino " (use separately or as the part of another group) refers to-NH 2" amido " can choose wantonly and replace one or two substituting groups are arranged (NR ' R "); wherein R ' and R " can be identical or different, such as alkyl, aryl, arylalkyl, thiazolinyl, alkynyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, alkyl, Heterocyclylalkyl alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, the basic alkyl of antelope, alkoxyalkyl, alkylthio, carbonyl or carboxyl.These substituting groups can further replace any one that has in the listed alkyl or aryl substituting group of carboxylic acid or the application.In some embodiments,, there are carboxyl or carbonyl amino the replacement, forms N-acyl group or N-carbamyl deriveding group.
The employed term of the application " haloalkyl " (use separately or as the part of another group) refers to the halogen atom that connects by alkyl, such as-CF 3
The employed term of the application " acyl group " (use separately or as the part of another group) refer to the alkyl that connects by carbonyl or-(=O) R, wherein R is described alkyl to C.
Please employed term " alkoxy carbonyl " in this (use separately or as the part of another group) refer to-C that (=O) OR, wherein R is described alkyl.
The employed term of the application " arylalkyl " or " aralkyl " (use separately or as the part of another group) refer to the aromatic ring (for example benzyl) that connects by alkyl described above.
The employed term of the application " aminoalkyl group " (use separately or as the part of another group) refers to amino (NR ' R ") of connecting by alkyl.
The employed term of the application " aryl-alkyl amino " (use separately or as the part of another group) refers to the aryl that connects by alkyl, and described alkyl connects by amino.
Term " heteroatoms " refers to independent O, S or the N that selects.It should be noted, the ungratified any heteroatom of valency all is considered to be connected with hydrogen atom, thereby satisfies valency.
Term " halogen " refers to independent fluorine, chlorine, the bromine or iodine of selecting.
The employed term of the application " cycloalkyl " (use separately or as the part of another tomb group) refers to 3 to 9 carbon atoms, is preferably the hydrocarbon ring of the complete saturated or fractional saturation of 3 to 7 carbon atoms.In addition, cycloalkyl can replace." cycloalkyl of replacement " refer to have once, two or three be selected from following substituent ring: the alkyl of halogen, alkyl, replacement (wherein substituting group such as above alkyl substituent define), thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), hydroxyl, alkoxyl group, alkylthio ,-CO 2H ,-C (=O) H ,-CO 2-alkyl ,-C (=O) alkyl, ketone group ,=N-OH ,=N-O-alkyl, aryl, heteroaryl, five or hexa-atomic ketal (namely 1,3-dioxane or 1,3-two uh alkane) ,-NR ' R " ,-C (=O) NR ' R " ,-CO 2NR ' R " ,-C (=O) NR ' R " ,-NR ' CO 2R " ,-NR ' C (=O) R " ,-SO 2NR ' R " and-NR ' SO 2The alkyl and the cycloalkyl that independently are selected from separately hydrogen, alkyl, replacement among the R ", wherein R ' and R ", or R ' and R ", form together Heterocyclylalkyl or heteroaryl ring.
Term " anticarcinogen " comprises any known medicine that can be used for treating cancer, comprising: (1) cytotoxic drug: chlormethine series pharmaceuticals, such as melphalan, endoxan; Platinum coordination complex is such as cis-platinum, carboplatin and oxaliplatin; (2) anti-metabolism antitumour drug: 5 FU 5 fluorouracil, capecitabine, methotrexate, Calciumlevofolinate, Raltitrexed, purine antagonist (for example 6-thioguanine and Ismipur); (3) hormones: the female alcohol of 17 alpha-acetylenes, stilboestrol, testosterone, prednisone, Fluoxymesterone, dromostanolone propionate, testolactone, Magace, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, Chlortrianisoestrol, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, toremifene; (4) tyrosine kinase inhibitor: the EGFR inhibitor comprises Gefitinib (Gefitinib), Erlotinib (Erlotinib), Cetuximab (Cetuximab), Trastuzumab (Herceptin) etc.; The VEGF inhibitor is such as VEGF antibody (Avastin (Avastin)) and micromolecular inhibitor such as Sunitinib, Vandetanib, Cediranib; Bcr-Abl inhibitor such as imatinib (Imatinib), Dasatinib (Dasatinib); Src inhibitor, MEK kinase inhibitor, mapk kinase inhibitor, PI3K kinase inhibitor, c-Met inhibitor, ALK inhibitor etc.; (5) act on the medicine of tubulin, such as vinca medicine, taxanes medicine, epothilones medicine such as ipsapirone (Ixabepilone) etc.; (6) topoisomerase I inhibitor is such as topotecan, irinotecan; (7) histon deacetylase (HDAC) (HDAC) inhibitor such as Vorinostat (Vorinostat); (8) proteasome inhibitor such as Velcade (Bortezomib); (9) anticarcinogen of other classifications such as aurora kinase (aurora kinase) inhibitor, biological response modifier, growth inhibitor, glu famine antagonist, angiogenesis inhibitor and anti-vascular medicine, matrix metallo-proteinase inhibitor etc.
" Mammals " comprises the mankind and domestic animal, such as cat, dog, pig, ox, sheep, goat, horse, rabbit etc.Preferably, for the purposes of the present invention, described Mammals is human.
" optional () " or " optional () " represent that the environment event of describing subsequently may exist or not exist, and described description comprises the situation that described event or environment occur and situation about not occuring.For example, the described aryl of " optional substituted aryl " expression may be substituted or not be substituted and described description comprises aryl and the unsubstituted aryl of replacement.
" pharmacy acceptable derivates " expression is during to recipient's administration, and salt, the acid amides of any nontoxic salt, ester, the ester of the active metabolite of compound of the present invention or its inhibition or resistates, salt or other derivatives of acid amides can directly or indirectly be provided.
" the acceptable vehicle of pharmacy " includes but not limited to be can be used for by state food and Drug Administration's approval conduct any assistant agent, carrier, vehicle, glidant, sweeting agent, dispersion agent, thinner, sanitas, suspending agent, stablizer, dyestuff/tinting material, odorant, tensio-active agent, wetting agent, isotonic agent, solvent or the emulsifying agent of the mankind or domestic animal.
" pharmacologically acceptable salts " comprises acid salt and base addition salt.
" the acceptable acid salt of pharmacy " refers to such salt, they have kept biological effect and the character of free alkali, can aspect biology or other, not produce adverse consequences, and be such as but not limited to hydrochloric acid with mineral acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid is such as but not limited to following acid: formic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2, the 2-dichloro acetic acid, hexanodioic acid, Lalgine, xitix, aspartic acid, phenylformic acid, paraacetaminobenzoic acid, dextrocamphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, sad, carbonic acid, styracin, citric acid, cyclohexane sulfamic acid, dodecyl sulphate, ethane-1, the 2-disulfonic acid, fumaric acid, tetrahydroxyadipic acid, gentisinic acid, glucoheptonic acid, glyconic acid, glucuronic acid, L-glutamic acid, pentanedioic acid, 2-oxo-pentanedioic acid, Phosphoric acid glycerol esters, oxyacetic acid, urobenzoic acid, isopropylformic acid, lactic acid, lactobionic acid, lauric acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, glactaric acid, naphthalene-2-sulfonic acid, naphthalene-1, the 5-disulfonic acid, the 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, vitamin B13, oxalic acid, the palm fibre eleostearic acid, pamoic acid, propionic acid, Pyrrolidonecarboxylic acid, pyruvic acid, Whitfield's ointment, 4-ASA, sebacic acid, stearic acid, fumaric acid, succsinic acid, tartrate, thiocyanic acid, the formation such as undecylenic acid.
" the acceptable base addition salt of pharmacy " refers to such salt, and they have kept biological effect and the character of free acid, can be not improper aspect biology or other.These salt are by mineral alkali or organic bases being added on the free acid and make.The salt that is derived from mineral alkali includes but not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salt etc.Preferred inorganic salt are ammonium, sodium, potassium, calcium and magnesium salts.The salt that is derived from organic bases includes but not limited to the salt of following substances: primary amine, secondary amine and tertiary amine, the amine that replaces, comprise naturally occurring replacement amine, cyclammonium and deacidite are such as ammonia, methylamine, dimethylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, Isopropylamine, diethanolamine, thanomin, DMAE, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming (hydrabamine), choline, trimethyl-glycine, Benethamine diacetale, quadrol, glycosamine, methylglucosamine, Theobromine, trolamine, Trometamol, purine, piperidines, piperazine, N-ethylpiperidine, versamid 900 etc.Preferred organic bases is Isopropylamine, diethylamine, thanomin, triethylamine, dicyclohexyl amine, choline and caffeine.
" pharmaceutical composition " refers to the preparation that compound of the present invention and the medium that biologically active cpds is delivered to the common acceptance among Mammals such as the mankind form.Such medium comprises all pharmaceutically acceptable carriers, thinner or the vehicle to this.
" treatment significant quantity " refers to when to the Mammals administration (preferred human), is enough to the amount of the compound of the present invention that relative disease or illness to Mammals (preferred human) be achieved as follows civilian defined treatment.The amount that consists of the compound of the present invention of " treatment significant quantity " can be according to for example activity of applied particular compound; The metabolic stability of described compound and effect duration; Patient's age, body weight, holistic health, sex and diet; Mode of administration and time; Discharge rate; Drug combination; The seriousness of specific illness or illness; And the individuality of experience treatment and changing, but it can be determined according to himself knowledge and the disclosure routinely by those of ordinary skills.
" treat " or " treatment " contained when being used for this paper having the Mammals of relative disease or illness, preferred human relative disease or the treatment of illness, and comprise:
(i) diseases or illness in the prevention Mammals, especially when such Mammals ill but also do not diagnose out when ill;
(ii) suppress disease or illness, namely stop its development;
(iii) alleviate disease or illness, cause that namely disease or illness disappear;
(iv) stable disease or illness.
When being used for this paper, term " disease " and " illness " can Alternates or can be different, reason is that specified disease or illness may not have known inducement (thereby also not working out the cause of disease), therefore also be not considered to disease and only as improper situation or syndrome, wherein the clinician has identified concrete syndrome more or less.
The compounds of this invention shown in this article and their structure also represent to comprise all isomer (for example enantiomer, diastereomer, rotamerism or conformational isomerism) form, they can according to be defined as for amino acid whose absolute stereo chemistry (R)-/(S)-or (D)-/(L)-or (R, R)-/(R, S)-/(S, S)-.The present invention represents the isomer that comprises that all these are possible, and their racemic, the enantiomorph enrichment and optional pure form.Optically-active (+) and (-), (R)-and (S)-and (R, R)-/(R, S)-/(S, S)-or (D)-and (L)-isomer can use that chirality is synthetic, the chiral separation preparation, perhaps can use routine techniques to split such as but not limited to the high performance liquid phase (HPLC) that uses chiral column.When compound as herein described comprised the two keys of thiazolinyl or other how much asymmetric centers, except as otherwise noted, described compound comprised E and Z geometrical isomer.Equally, also comprise all tautomeric forms.
" steric isomer " refers to be made of with identical chemical bonding but compound with different three-dimensional structures identical atom, and they are not interchangeable.The present invention is contained various steric isomers and composition thereof and is comprised " enantiomer " and " diastereomer ", and enantiomer refers to two kinds of steric isomers of the mirror image that its molecule each other can not be overlapping; Diastereomer refers to that molecule has two or more chiral centres, and intermolecular be the steric isomer of non-mirror.
" tautomer " refers to that proton moves to from an atom of molecule from original position on another position with a part.The present invention includes the tautomer of any described compound.
In addition, except as otherwise noted, compound of the present invention comprises that also the structure difference only is to exist the compound of one or more isotopic enrichment atoms.For example, have structure of the present invention, except replacing hydrogen with " deuterium " or " tritium ", perhaps use 18F-fluorine mark ( 18The F isotropic substance) replaces fluorine, perhaps use 11C-, 13C-, perhaps 14The carbon of C-enrichment ( 11C-, 13C-, perhaps 14The C-carbon markings; 11C-, 13C-, perhaps 14The C-isotropic substance) replace the compound of carbon atom to be in the scope of the present invention.Such compound can be used as analysis tool or the probe in the biological example mensuration, perhaps can be as the in-vivo diagnostic imaging tracer agent of disease, and the tracer agent of perhaps studying as pharmacodynamics, pharmacokinetics or acceptor.
The present invention also provides following methods: give the patient that (while or priority) needs this treatment by (I) compound of general formula as defined above and at least a other anticarcinogen combination that will treat significant quantity, treat proliferative disease (such as cancer) via regulating the c-Met kinases.In preferred embodiments, proliferative disease is cancer.
Particularly, general formula (I) compound can be used for treating kinds cancer, is specially those cancers that depend on the c-Met activation most.The c-Met activation can stimulate to regulate by gene amplification, sudden change (various mutations) and/or HGF, and wherein HGF is provided by tumour (autocrine) or host's (paracrine) tissue.Usually, compound of the present invention can be used for the treatment of following cancer:
(A) solid tumor comprises cancer of the stomach, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer), colorectal carcinoma, kidney, liver cancer, mammary cancer, ovarian cancer, cervical cancer, esophagus cancer, carcinoma of gallbladder, bladder cancer, carcinoma of the pancreas, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);
(B) the hematopoiesis tumour of lymph pedigree, comprise acute lymphoblastic leukemia (ALL), acute lymphoblast leukemia, B cell lymphoma, t cell lymphoma, Hodgkin lymphoma, non-Hodgkin′s woods bar knurl, hair cell lymphoma and Burkitt lymphoma (Burkett ' s lymphoma);
(C) the hematopoiesis tumour of marrow pedigree comprises acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;
(D) tumour of mesenchyme origin comprises fibrosarcoma and rhabdosarcoma;
(E) tumour of maincenter and peripheral nervous system comprises astrocytoma, neuroblastoma, neurospongioma and schwannoma;
(F) other tumour comprises melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma, follicular carcinoma of thyroid and Kaposi sarcoma.
General formula (I) compound also can be used for treating any lysis that is characterized as abnormal cell proliferation, the restenosis, inflammatory bowel, graft-rejection, endotoxin shock and the fungi infestation that for example occur after benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, angioplasty or the vascular surgery.
The level that the adjustable ganglion cell RNA of general formula (I) compound and DNA are synthetic.Therefore, these materials can be used for the treatment of virus infection (including but not limited to HIV, human papillomavirus, simplexvirus, poxvirus, Epstein-Barr virus, sindbis alphavirus and adenovirus).
General formula (I) compound can be used for the chemoprophylaxis of cancer.Chemoprophylaxis is defined as by blocking initial mutagenesis event or coming the development of anti-invasion cancer or suppress tumor recurrence by the precellular progress that cancerates that blocking-up has been damaged.
General formula (I) compound can be used for suppressing tumor-blood-vessel growth and transfer.
Compound of the present invention also can be used in combination with known anticarcinogen (include but not limited to mention in above-mentioned " anticarcinogen " those) or anticancer therapy (such as radiotherapy) (give or successively give).
In the described method, the protecting group that the functional group of midbody compound may need to be suited is protected hereinafter.Such functional group comprises hydroxyl, amino (the NH functional group that comprises heteroaryl) and carboxylic acid.The protecting group that is fit to that is used for hydroxyl comprises TMS, tertiary butyl dimethylsilyl, tert-butyl diphenyl silylation, THP trtrahydropyranyl, benzyl, to methoxy-benzyl etc.Be used for amino suitable protecting group and comprise tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, benzoyl etc.The suitable protecting group that is used for carboxylic acid comprises alkyl, aryl or alkyl aryl.Be used for heteroaryl such as the suitable protecting group such as the NH functional group of indoles or indazole ring comprise tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, benzoyl, to methoxy-benzyl, 2-TMS-ethoxyl methyl etc.
Protecting group can (also can be with reference to pertinent literature such as Greene T.W. according to method known to those skilled in the art; Protective Groups in Organic Synthesis; 1999, the 3rd edition, Wiley) add or removal with standard technique as herein described.Described protecting group also can be fluoropolymer resin such as Wang resin, Rink resin or 2-chlorine trityl chloride resin.
Simultaneously, although the protected derivative of some the compounds of this invention itself may not have pharmacological activity, they can be administered to Mammals, and then metabolism has the compounds of this invention of pharmacological activity with formation in vivo.Such derivative therefore be described to " prodrug ".All prodrugs of the compounds of this invention include within the scope of the invention.
The dihydropyridine compounds of some general formula of the present invention (I) can be prepared by the following method.(R wherein 1, R 2, R 3Described as defined above; " PG " (protecting groups) is the amido protecting group; such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.): take pimelinketone-4-ethyl formate (1) as raw material; at N; be converted into intermediate (2) under the effect of dinethylformamide dimethylacetal (DMF-DMA); this intermediate and hydrazine reaction, cyclisation are pyrazole compound (3).Ester group in the intermediate (3) is reduced with reductive agent (such as lithium aluminium hydride, sodium borohydride etc.), obtain intermediate (4).Then the amido of intermediate (4) pyrazoles is protected to get intermediate (II) with suitable protecting group (such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.); again with its alcoholic extract hydroxyl group with suitable condition (such as the Dess-Martin oxidation; the Swern oxidation) oxidation obtains aldehydes intermediate (III).Intermediate (III) and cyano group ketone compounds (A) condensation get intermediate (IV), and again with amido alkene nitrile raw material (B) condensation, then deprotection base under suitable condition namely gets compound (I).
Route 1:
Figure BDA0000146633410000221
Route 1In, R 1, R 2, R 3Described as defined above; Especially, R in the amido alkene nitrile raw material (B) 2With R 3Combinatorial optimization from following (B-1) to structure shown in (B-3):
Figure BDA0000146633410000222
R in general formula (I) 1With R 3Identical (replacing with Ra) and R 2During for hydrogen, its described compound also can be by the method shown in the following route 2 preparation (R wherein 1, R 2, R 3Described as defined above; " PG " (protecting groups) is the amido protecting group; such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.): take pimelinketone-4-ethyl formate (1) as raw material; at N; be converted into intermediate (2) under the effect of dinethylformamide dimethylacetal (DMF-DMA); this intermediate and hydrazine reaction, cyclisation are pyrazole compound (3).Ester group in the intermediate (3) is reduced with reductive agent (such as lithium aluminium hydride, sodium borohydride etc.), obtain intermediate (4).Then the amido of intermediate (4) pyrazoles is protected to get intermediate (II) with suitable protecting group (such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.); again with its alcoholic extract hydroxyl group with suitable condition (such as the Dess-Martin oxidation; the Swern oxidation) oxidation obtains aldehydes intermediate (III).Amino alkene nitrile raw material (C) condensation of this intermediate (III) and 2 equivalents, then deprotection base under suitable condition namely gets compound (I).
Route 2:
Figure BDA0000146633410000231
Wherein, following is the abbreviation of commonly using:
DMF:N, dinethylformamide;
DMSO: dimethyl sulfoxide (DMSO);
CDCl 3: deuterochloroform;
1H NMR: proton nmr spectra;
MS: mass spectrum;
S: unimodal
D: bimodal
T: triplet
Dd: doublet of doublet
Br: broad peak
M: multiplet
℃: degree centigrade
Mol: mole
TLC: tlc
Those skilled in the art can use suitable raw material, adopt similar method, prepare in the reaction scheme above with no specific disclosure of other compounds of the present invention.
By with suitable inorganic or organic bases or acid treatment, can be with according to the pharmacologically acceptable salts that above prepares all the compounds of this invention that exist with free alkali or sour form and change into them.Above the salt of the compound of preparation can change into by standard technique their free alkali or sour form.
All comprise its all crystal formations, amorphous forms, dehydrate, hydrate, solvate and salt compound of the present invention more.In addition, all compounds of the present invention that comprise ester group and amide group can change into corresponding acid by method known to those skilled in the art or by method described herein.Equally, the compounds of this invention that comprises hydroxy-acid group can be converted into corresponding ester and acid amides by method known to those skilled in the art.Also can carry out other replacements and replacement on the molecule by method known to those skilled in the art (such as hydrogenation, alkylation, with acyl chloride reaction etc.).
Prepare cyclodextrin inclusion compound of the present invention, the compound of the general formula (I) that defines in the summary of the invention above can be dissolved in the acceptable solvent of pharmacology for example in (but being not limited to) alcohol (preferred alcohol), ketone (for example acetone) or the ether (for example ether), and in 20 ℃ to 80 ℃ and alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin, the aqueous solution of preferred beta-cyclodextrin; Perhaps can be with the acid of the compound of the general formula (I) that defines in the summary of the invention above aqueous solution form and the cyclodextrin blend with its salt (for example sodium or sylvite), then with equivalent acid (for example HCl or H 2SO 4) solution blending, so that corresponding cyclodextrin inclusion compound to be provided.
This moment or after cooling, corresponding cyclodextrin inclusion compound crystal can crystallization.Perhaps when general formula (I) compound was oily and crystallization, by at room temperature stirring for a long time (for example 1 hour to 14 days), the aqueous solution that adds cyclodextrin was processed, and also can be converted into corresponding cyclodextrin inclusion compound.Then by filtering and drying, inclusion compound can be separated into solid or crystal.
Be used for cyclodextrin of the present invention commercially available (for example from Aldrich Chemical Co.), perhaps adopt known method preparation by those skilled in the art.Referring to for example Croft, the people such as A.P., " Synthesis of Chemically Modified Cyclodextrins ", Tetrahedron 1983,39,9,1417-1474.Suitable cyclodextrin comprises all kinds that prepare inclusion compound with the compound of listed formula (I) above.
By selecting an amount of cyclodextrin and water, can obtain the repeatably inclusion compound of active substance content according to stoichiometric composition.Inclusion compound can use for absorb water form or the moisture but form that more do not absorb water of drying.The typical mol ratio of the compound of cyclodextrin and general formula (I) is 2: 1 (cyclodextrin: compound).
Comprising general formula (I) compound can be to be suitable for oral form as the pharmaceutical composition of activeconstituents, such as being tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis or granule, syrup etc.The composition that can orally use can prepare according to any means for the preparation of pharmaceutical composition known in the art, and these compositions can comprise one or more material that is selected from sweeting agent, seasonings, tinting material and sanitas, in order to pharmaceutically attractive in appearance and agreeable to the taste preparation is provided.
Tablet comprises activeconstituents, and is mixed with nontoxic pharmaceutically acceptable vehicle or the carrier that is suitable for preparing tablet.These vehicle or carrier can be inert diluent, such as calcium carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example Celluloasun Microcrystallisatum, carmethose, W-Gum or alginic acid; Tackiness agent, for example starch, gelatin, polyvinylpyrrolidone or gum arabic; And lubricant, for example Magnesium Stearate, stearic acid or talcum powder.Tablet can be dressing not, maybe can come dressing by known technology, thereby cover the medicine taste that makes us unhappy, or postpone disintegration and absorption in gi tract, provides lasting effect thus within the long period.For example, can use water miscible taste to cover material (such as hydroxypropyl-methylcellulose gum or hydroxypropyl-Mierocrystalline cellulose) or time lag material (such as ethyl cellulose, cellulose acetate butyrate).
Capsule comprises hard-gelatin capsules, Gelseal.For example calcium carbonate, calcium phosphate or kaolin mix hard-gelatin capsules with inert solid diluent by activeconstituents; Gelseal is mixed with water-soluble carrier (such as polyoxyethylene glycol) or oily medium (for example peanut oil, whiteruss or sweet oil) by activeconstituents.
Aqueous suspension comprises active substance and is suitable for preparing the vehicle of aqueous suspension.These excipient are suspending agent, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl-cellulose, mosanom, polyvinylpyrrolidone and Arabic gum; Dispersant or wetting agent can be the condensation product (for example Myrj 45) of naturally occurring phosphatide (for example lecithin) or oxyalkylene and aliphatic acid or the condensation product of ethylene oxide and long-chain fatty alcohol (for example 17 oxygen ethene cetanols (heptadecaethylene-oxycetanol)) or ethylene oxide and from the condensation product (such as polyoxyethylene 80 sorbitan monooleate) of the derivative partial ester of aliphatic acid and hexitol or the ethylene oxide condensation product (for example polyethylene dehydrated sorbitol mono-fatty acid ester) with the partial ester that derives from aliphatic acid and the liquor-saturated mixture of hexitol.Aqueous suspension also can comprise one or more sanitass (for example ethyl p-hydroxybenzoate or n-propyl), one or more tinting material, one or more seasonings and one or more sweeting agent (such as sucrose, asccharin or aspartame).
The oiliness suspensoid can be prepared by activeconstituents being suspended in vegetables oil (for example peanut oil, sweet oil, sesame oil or cocounut oil) or the mineral oil (such as whiteruss).The oiliness suspensoid can comprise thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add sweeting agent (such as above listed those) and seasonings, thereby agreeable to the taste oral preparations is provided.These compositions can come anticorrosion by adding antioxidant (such as Butylated Hydroxyanisole or alpha-tocopherol).
Dispersible pulvis and granule comprise activeconstituents, and are mixed with dispersion agent or wetting agent, suspending agent and one or more sanitas.The example of suitable dispersion agent or wetting agent and suspending agent is above those that mentioned.Also can comprise other vehicle, for example sweeting agent, seasonings and tinting material.These compositions can come anticorrosion by adding antioxidant (such as xitix).Dispersible pulvis and granule can prepare aqueous suspension by adding water.
Syrup can be prepared with sweeting agent (for example glycerine, propylene glycol, sorbyl alcohol or sucrose).These preparations also can comprise negative catalyst, sanitas, seasonings, tinting material and antioxidant.
Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetables oil (for example sweet oil or peanut oil) or mineral oil (for example whiteruss) or their mixture.Suitable emulsifying agent can be naturally occurring phosphatide (for example soybean lecithin), from the derivative ester of lipid acid and hexitol mixture or the condensation product (for example Polysorbate 80) of partial ester (for example dehydrated sorbitol mono-fatty acid ester) and described partial ester and ethylene oxide.Emulsion also can comprise sweeting agent, seasonings, sanitas and antioxidant.
Pharmaceutical composition can be the form of the sterile injectable aqueous solution.Spendable accept carrier and solvent have water, Ringer's solution (Ringer ' s solution), etc. the sodium chloride solution and the glucose solution that ooze.
Sterile injectable preparation can be the sterile injectable water oil-packaging type micro-emulsion also, wherein activeconstituents is dissolved in the oil phase.For example, at first activeconstituents is dissolved in the mixture of soybean oil and Yelkin TTS.Then, resulting oil solution is imported in the mixture of water and glycerine and process, thereby form micro emulsion.
Injectable solution or micro emulsion can inject to import in patient's the blood flow by the part, or give in some way described solution or micro emulsion, thereby keep the circulation composition of constant the compounds of this invention.In order to keep this constant concentration, can use the continuous intravenous administration devices such as infusion pump.
Pharmaceutical composition can be for the sterile injectable water-based of intramuscular or subcutaneous administration or the form of oil-based suspension.This suspension can configure according to those suitable dispersion agents of having been mentioned more than the known utilization or wetting agent and suspending agent.Sterile injectable preparation also can be sterile injectable solution or the suspension of nontoxic pharmaceutically acceptable diluent or solvent, for example solution of 1,3 butylene glycol.In addition, aseptic fixed oil can be easily used as solvent or suspension medium.For this purpose, gentle fixed oil all can use arbitrarily, comprises synthetic direactive glyceride or two glyceryl ester.In addition, lipid acid (such as oleic acid) can use in the preparation injection.
General formula (I) compound also can give by the form of the suppository that is used for rectal administration.These compositions can prepare by hybrid medicine and suitable nonirritant excipient, and described vehicle is solid at normal temperature but is liquid in rectal temperature, therefore melts in rectum, thereby discharge medicine.These materials comprise the mixture of polyoxyethylene glycol of theobroma oil, glycogelatin, hydrogenated vegetable oil, different molecular weight and the fatty acid ester of polyoxyethylene glycol.
With regard to use the part, can prepare and use comprises ointment, ointment, jelly, solution or the suspensoid etc. of general formula (I) compound.
Compound of the present invention can give with form in the nose with carrier and doser in the suitable nose by the part, or with those skilled in the art well-known form through the skin skin patch by giving through the skin approach.Compound of the present invention also can be by using the form such as the suppository of following such matrix to give: the fatty vinegar of the mixture of the polyoxyethylene glycol of theobroma oil, glycogelatin, hydrogenated vegetable oil, different molecular weight and polyoxyethylene glycol.
When being administered to compound of the present invention in the human subject body, every per daily dose generally determined by the doctor of prescription, and described dosage changes with the severity of patient's age, body weight, sex and reaction and patient's symptom usually.Usually, be about 0.001mg/kg to 100mg/kg for the effective per daily dose of the patient of 70kg, be preferably 0.01mg/kg to 50mg/kg, more preferably 1mg/kg to 25mg/kg.
If be mixed with fixed dosage, the so the compounds of this invention of these combined prods uses in dosage range described above and other medical active agent treatment in the dosage range of its approval.When combination preparation was improper, general formula (I) compound also can successively give with known anticarcinogen or cytotoxicity medicine.The present invention is not subjected to the restriction of order of administration; General formula (I) compound can give before or after known anticarcinogen (multiple anticarcinogen) or the cytotoxicity medicine (various kinds of cell toxicity medicine) giving.
Compound of the present invention is the inhibitor of disease or the illness that c-Met mediates of c-Met mediation.Term " disease of c-Met mediation " and " illness of c-Met mediation " the expression effective any morbid state of known c-Met tool or other harmful illnesss.Term " disease of c-Met mediation " and " illness of c-Met mediation " also represent those diseases or illness by being eased with the c-Met inhibitor for treating.These diseases and illness include but not limited to cancer and other proliferative illness.
Therefore, described compound can be used for treating for example Mammals, especially following disease or the illness among the mankind: cancer of the stomach, lung cancer, esophagus cancer, carcinoma of the pancreas, kidney, colorectal carcinoma, thyroid carcinoma, the cancer of the brain, mammary cancer, prostate cancer and other solid tumor cancers; Atherosclerosis; The adjusting blood vessel occurs; Thrombosis and pulmonary fibrosis.
Compound involved in the present invention also can be used for the research of the signal transduction pathway that the research, Tyrosylprotein kinase of biology or pharmacology phenomenon participates in and for the comparative evaluation of new tyrosine kinase inhibitor.
The related compound of the application is including, but not limited to the given structure type of above-mentioned route 1 and route 2, and the personnel that know art technology can pass through suitable starting raw material, and method obtains like the application class.
Embodiment
The following concrete synthetic preparation example (for the preparation of compound of the present invention) that provides and biology embodiment (being used for proving the compounds of this invention purposes) are in order to help to put into practice the present invention, and they should not be considered to limit the scope of the invention.
Synthetic preparation example 1:2,6-dimethyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile
Figure BDA0000146633410000301
Step 1:
With pimelinketone-4-ethyl formate (20g, 0.12mol) join DMF dimethylacetal (DMF-DMA) (20mL) in, 100 ℃ of stirrings are spent the night.Concentrating under reduced pressure, resistates is directly used in next step.MS：[M+1]＝226；
Step 2:
Step 1 gained resistates is dissolved in the ethanol (50mL), then adds hydrazine hydrate (8.25g, 0.16mmol, 99%), and room temperature reaction stirred 4 hours, and is concentrated, gets product (12.5g, 54%) with purification by silica gel column chromatography.MS：[M+1]＝195；
Step 3:
Figure BDA0000146633410000313
Under the nitrogen protection, 4,5,6,7-tetrahydrochysene-1H-indazole-5-ethyl formate (2g, 10.3mmol) is dissolved in anhydrous THF (50mL), is cooled to 0 ℃, carefully adds lithium aluminum hydride (586mg, 15.45mmol) in batches, stirring at room 5 hours.Drip water (0.6mL) cancellation reaction, leave standstill a moment, filter, filtrate is with anhydrous sodium sulfate drying, concentrating under reduced pressure, the resistates purification by silica gel column chromatography, (4,5,6,7-tetrahydrochysene-1H-indazole-5-yl) methyl alcohol (0.43g, 27%), white solid.
Step 4:
Figure BDA0000146633410000321
Under the nitrogen protection, 4,5,6,7-tetrahydrochysene-1H-indazole-5-methyl alcohol (620mg, 4.07mmol) is dissolved in methylene dichloride (50mL), adds Dess-Martin oxygenant (3.46g, 8.14mmol), stirring at room 5 hours.Remove solvent under reduced pressure, add ethyl acetate in the resistates, stir, filter, filtrate concentrated 4,5,6,7-tetrahydrochysene-1H-indazole-5-formaldehyde crude product (370mg, 60% thick yield).
Step 5:
Figure BDA0000146633410000322
The amino propenyl cyanide of 4,5,6,7-tetrahydrochysene-1H-indazole-5-formaldehyde (320mg, 2.13mmol) and 3-(385mg, 4.69mmol) is dissolved in Glacial acetic acid (10mL) jointly, is heated to 95 ℃, stirs 15 minutes.Remove acetic acid under reduced pressure, resistates prepare TLC (methylene dichloride: methyl alcohol=10: 1) purifying, get 2,6-dimethyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (19mg, 3%) is white solid.ESI-MS：280[M+H]； 1HNMR(300MHz，DMSO)δ9.51(s，1H)，7.30(s，1H)，2.49-2.74(m，1H)，2.26-2.36(m，2H)，2.03(s，1H)，1.82-1.97(m，2H)，1.52-1.72(m，3H)。
Synthetic preparation example 2:2-ethyl-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3, the 5-dimethoxy nitrile
Figure BDA0000146633410000331
Step 1:
Figure BDA0000146633410000332
Under the nitrogen protection, anhydrous tetrahydro furan (125mL) places three-necked bottle, is cooled to-70 ℃, adds n-Butyl Lithium (hexane solution of 2.5M, 16mL, 40mmol), stirs and drips anhydrous acetonitrile (1.44g, 35mmol) a moment again.Finish and stirred 3 minutes, drip ethyl propionate (2.55g, 25mmol), keep temperature of reaction system to be no more than-66 ℃ during dropping.Complete reaction solution is warming up to-45 ℃ and stirred 2 hours.Drip 1N hydrochloric acid (60mL) cancellation, reaction solution is concentrated, and resistates is with extracted with diethyl ether, and extraction liquid merges, drying, and concentrated, remaining oily matter 3-oxo valeronitrile (2.224g, 92% thick yield) is directly used in next step reaction. 1HNMR(300MHz，CDCl 3)1.1(t，3H)，2.62(q，2H)，3.48(s，2H)。
Step 2:
(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl) methyl alcohol (5.1g, 34mmol) is dissolved in the anhydrous tetrahydro furan (100mL), adds triethylamine (3.4g, 34mmol) and DMAP (0.41g, 3.4mmol), stir and add (Boc) a moment 2O (7.2g, 34mmol), stirred overnight at room temperature.In system, add water, ethyl acetate extraction, extraction liquid merges, drying, concentrated, purification by silica gel column chromatography gets 5-(methylol)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (6.0g, 72%).MS：[M+1]＝253。
Step 3:
Figure BDA0000146633410000341
5-(methylol)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (3.0g, 11.9mmol) are dissolved in the dry methylene dichloride (50mL), add Dess-Martin oxygenant (10.5g, 24mmol), stirring at room 2 hours.Concentration of reaction solution, resistates adds acetic acid ethyl dissolution, and with saturated sodium bicarbonate aqueous solution washing, drying, concentrated, purification by silica gel column chromatography gets 5-formyl radical-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (1.8g, 61%).MS：[M+1]＝251。
Step 4:
Figure BDA0000146633410000342
5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (768mg, 3.072mmol) is dissolved in methylene dichloride (30mL) jointly with 3-oxo valeronitrile (597mg, 6.144mmol); add acetic acid (28mg; 0.461mmol) and piperidines (26mg, 0.307mmol), return stirring spends the night under the nitrogen protection.Reaction solution is cooled to room temperature, adds dehydrated alcohol (30mL), stirs after ten minutes and filters, filtrate is concentrated does, and the resistates column chromatography gets 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (291mg, 29%).LC-MS(ESI+)330[M+1] +。
Step 5:
Figure BDA0000146633410000351
With 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (120mg, 0.364mmol) and the amino propenyl cyanide of 3-(66mg, 0.801mmol) jointly be dissolved in the Glacial acetic acid (10mL), be heated to 100 and stirred 1 hour.Be cooled to room temperature, the reaction solution concentrating under reduced pressure is done, preparation TLC purifying (methylene dichloride: methyl alcohol=20: 1) get 2-ethyl-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (53mg, 49%).MS(ESI+)：294[M+1]； 1H?NMR(300MHz，DMSO-d 6)δ12.23(br，1H)，9.44(br，1H)，7.73(s，1H)，2.71(d，1H，J＝7.7Hz)，2.26-2.37(m，4H)，2.04(s，3H)，1.84-1.96(m，2H)，1.51-1.64(m，3H)，1.11(t，3H，J＝9.0Hz)。
Synthetic preparation example 3:
Step 1:
Figure BDA0000146633410000353
Under the nitrogen protection, dry tetrahydrofuran (100mL) places three-necked bottle, is cooled to-70 ℃, adds n-Butyl Lithium (hexane solution of 2.5M, 12.8mL, 32mmol).Drip anhydrous acetonitrile (1.15g, 28mmol), stir and drip 3 Methylbutanoic acid ethyl ester (2.6g, 20mmol) after 3 minutes, keep temperature of reaction system to be no more than-66 ℃ during dropping.Finish and be warming up to-45 ℃ of stirrings 2 hours.Drip 1N hydrochloric acid (40mL) cancellation, reaction solution is concentrated, adds extracted with diethyl ether in the resistates, and extraction liquid merges, drying, and concentrated, resistates oily matter is the own nitrile crude product of 5-methyl-3-oxygen (2.26g, 90% thick yield). 1H?NMR(300MHz，CDCl 3)0.93(d，6H，J＝6.9Hz)，2.15(m，1H)，2.46(d，2H，J＝6.6Hz)，3.44(s，2H)。
Step 2:
Figure BDA0000146633410000361
5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (1g, 3.995mmol) is dissolved in methylene dichloride (40mL) jointly with 5-methyl-own nitrile of 3-oxygen (750mg, 5.993mmol); add Glacial acetic acid (276mg; 4.594mmol) and piperidines (340mg, 3.995mmol), return stirring spends the night under the nitrogen protection.Reaction solution is cooled to room temperature, adds dehydrated alcohol (40mL), stirs after ten minutes and filters, filtrate is concentrated does, and the resistates column chromatography gets 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (284mg, 20%).MS(ESI+)：358[M+1] +。
Step 3:
Figure BDA0000146633410000362
With 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (150mg, 0.42mmol) and the amino propenyl cyanide of 3-(76mg, 0.923mmol) be dissolved in the Glacial acetic acid (10mL), be heated to 100 ℃ and stirred 1 hour.Be cooled to room temperature, concentrating under reduced pressure, preparation TLC purifying (methylene dichloride: methyl alcohol=20: 1), get 2-isobutyl--6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (40mg, 30%).MS(ESI+)：322[M+1] +； 1HNMR(300MHz，DMSO-d 6)δ9.41(br，1H)，7.28(s，1H)，2.67-2.74(m，1H)，2.13-2.49(m，4H)，2.04(s，3H)，1.85-2.02(m，2H)，1.51-1.69(m，2H)，1.21(d，1H，J＝4.8Hz)，0.91(d，6H，J＝4.8Hz)。
Synthetic preparation example 4:
Figure BDA0000146633410000371
Step 1:
Figure BDA0000146633410000372
Under the nitrogen protection, anhydrous tetrahydro furan (100mL) places three-necked bottle, is cooled to-74 ℃, adds n-Butyl Lithium (hexane solution of 2.5M, 16mL, 40mmol).Stir and drip anhydrous acetonitrile (1.437g, 35mmol) a moment, finish and stir 3 minutes dropping 4,4,4-trifluoroacetic acid ethyl esters (4.253g, 25mmol), keep temperature of reaction system to be no more than-69 ℃ in the process.Finish and be warming up to-45 ℃ of stirrings 2 hours, drip 1N hydrochloric acid (50mL) cancellation.Reaction solution is concentrated, adds extracted with diethyl ether in the resistates, and extraction liquid merges, drying, and concentrated, remaining oily matter thing is the own nitrile crude product of 6,6,6-, three fluoro-3-oxos (3.91g, 95% thick yield), is directly used in next step reaction. 1H?NMR(300MHz，CDCl 3)2.43-2.55(m，2H)，2.89(t，2H，J＝7.5Hz)，3.55(s，2H).
Step 2:
Figure BDA0000146633410000381
5-formyl radical-4; 5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg; 2mmol) with 6; 6,6-, the three fluoro-3-own nitriles of oxo (660mg, 4mmol) are dissolved in methylene dichloride (30mL) jointly; add Glacial acetic acid (138mg; 2.3mmol) and piperidines (170mg, 2mmol), return stirring spends the night under the nitrogen protection.Reaction solution is cooled to room temperature, add dehydrated alcohol (30mL), stir after ten minutes and filter, filtrate is concentrated does, and the resistates column chromatography gets 5-(2-cyano group-6,6,6-three fluoro-3-oxo-hexyls-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-t-butyl formate (180mg, 23%).MS(ESI+)：398[M+1] +.
Step 3:
5-(2-cyano group-6,6,6-three fluoro-3-oxo-hexyls-1-alkene-1-yl)-4,5, amino propenyl cyanide (the 82mg of 6,7-tetrahydrochysene-1H-indazole-t-butyl formate (180mg, 0.453mmol) and 3-, 0.997mmol) jointly be dissolved in the Glacial acetic acid (8mL), be heated to 100 ℃ and stirred 1 hour.Be cooled to room temperature, reaction solution is concentrated to be done, and resistates prepares TLC purifying (methylene dichloride: methyl alcohol=20: 1) get 2-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-6-(3,3,3-trifluoro propyl)-1,4-dihydropyridine-3,5-dimethoxy nitrile (46mg, 28%).MS(ESI+)：362[M+1] +； 1H?NMR(300MHz，DMSO-d 6)δ9.56(br，1H)，7.27(s，1H)，2.53-2.75(m，6H)，2.24-2.34(m，2H)，2.05(s，3H)，1.84-1.91(m，2H)，1.52-1.70(m，2H)。
Synthetic preparation example 5:2-(2-methoxy ethyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3, the 5-dimethoxy nitrile
Step 1:
Figure BDA0000146633410000392
Anhydrous tetrahydro furan (350ml) is cooled in-78 ℃, adds n-BuLi (31mL, 77mmol), drips acetonitrile (2.9g, 70mmol) behind the stirring several minutes, finishes and stirs 1 hour.Then drip 3-methoxy methyl propionate (5.9g, 50mmol), finish, temperature is increased to-45 ℃, stirs 2 hours.Drip 2N hydrochloric acid (160mL) cancellation, reaction solution slowly rises to room temperature, uses extracted with diethyl ether, and combining extraction liquid concentrates to get 5-methoxyl group-3-oxo valeronitrile (3.5g, 55%).
Step 2:
Figure BDA0000146633410000393
4,5,6,7-tetrahydrochysene-1H-indazole-5-formaldehyde (350mg, 2.3mmol) is dissolved in the methylene dichloride (5mL), adds 5-methoxyl group-3-oxo valeronitrile (292mg, 2.3mmol), piperidines (11mg, 0.13mmol), acetic acid (99mg, 1.643mmol) and 4A molecular sieve, finish and be heated to return stirring and spend the night.With reaction solution cooling, be concentrated into dried 5-methoxyl group-3-oxo-2-((4,5,6,7-tetrahydrochysene-1H-indazole-5-yl) methene) valeronitrile crude product (700mg), be directly used in next step.MS：[M+1]＝262。
Step 3:
Figure BDA0000146633410000401
Upper step gained 5-methoxyl group-3-oxo-2-((4,5,6,7-tetrahydrochysene-1H-indazole-5-yl) methene) valeronitrile (700mg, count 2.3mmol) and the amino propenyl cyanide (222mg of 3-, 2.7mmol) jointly be dissolved in the Glacial acetic acid (20mL), be heated to 100 ℃ and stirred 1 hour.Be cooled to room temperature, reaction solution is concentrated to be done, resistates column chromatography purification (methylene dichloride: methyl alcohol=20: 1) get crude product, through preparation TLC purifying, get 2-(2-methoxy ethyl)-6-methyl-4-(4 again, 5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (56mg, 7.5%).MS(ESI+)：324[M+1] +； 1H?NMR(300MHz，DMSO-d 6)δ9.46(br，1H)，7.25(s，1H)，3.39-3.32(m，2H)，3.30(s，3H)，2.75-2.53(m，4H)，2.34-2.24(m，2H)，2.14(s，3H)，2.01-1.94(m，2H)，1.62-1.45(m，2H)。
Synthetic preparation example 6:2-(4-fluorophenyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3, the 5-dimethoxy nitrile
Figure BDA0000146633410000411
Step 1:
Figure BDA0000146633410000412
5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg, 2.0mmol), 3-(4-fluorophenyl)-3-oxypropionitrile (326mg, 2.0mmol) are dissolved in methylene dichloride (15mL); add acetic acid (18mg; 0.3mmol) and piperidines (17mg, 0.2mmol), return stirring spends the night under the nitrogen protection.Reaction solution is cooled to room temperature, adds methylene dichloride (30mL) dilute reaction solution, filter, the concentrated 5-(2-cyano group-3-(4-fluorophenyl)-3-oxo third-1-alkene-1-yl)-4,5,6 that does to get of filtrate, 7-tetrahydrochysene-1H-indazole-1-t-butyl formate crude product is directly used in next step.
Step 2:
Figure BDA0000146633410000413
5-(2-cyano group-3-(4-fluorophenyl)-3-oxo third-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (790mg, 2.0mmol) and the amino propenyl cyanide (170mg of 3-, 2.0mmol) be dissolved in the acetic acid (15mL), be heated to 100 ℃ and stirred 1 hour, be cooled to room temperature, reaction solution is concentrated to be done, preparation TLC purifying (methylene dichloride: methyl alcohol=20: 1) get 2-(4-fluorophenyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-1,4-dihydropyridine-3,5-dimethoxy nitrile (100mg, 14%).MS：[M+1]＝260； 1H?NMR(300MHz，DMSO-d 6)δ12.25(s，1H)，9.82(s，1H)，7.64-7.62(m，2H)，7.40-7.32(m，3H)，3.41(br，1H)，2.75-2.42(m，4H)，2.12(s，3H)，2.05-1.95(m，1H)，1.85-1.63(m，2H)。
Synthetic preparation example 7:2-(4-p-methoxy-phenyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3, the 5-dimethoxy nitrile
Figure BDA0000146633410000421
Step 1:
Figure BDA0000146633410000422
Methyl p-methoxybenzoate (2.0g, 12mmol) is dissolved in the dry toluene (50mL), is cooled to 0 ℃, adds sodium hydrogen (1.2g, 30mmol).Stir and add acetonitrile (1.23g, 30mmol) after 10 minutes, slowly be warming up to 110 ℃, stirring is spent the night.After being cooled to room temperature, filter, filter residue is collected oven dry after with toluene wash, gets 1-cyano group-2-(4-p-methoxy-phenyl)-2-oxypropionitrile sodium salt (2.2g, 93%).
Step 2:
Figure BDA0000146633410000431
5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (600mg, 2.40mmol), 1-cyano group-2-(4-p-methoxy-phenyl)-2-oxypropionitrile sodium salt (510mg, 2.88mmol) are dissolved in the methylene dichloride (50mL); add acetic acid (173mg; 2.88mmol) and piperidines (245mg, 2.88mmol) in, return stirring spends the night under the nitrogen protection.Reaction solution is cooled to room temperature, add methylene dichloride (30mL) dilute reaction solution, filter, filtrate is concentrated does, resistates column chromatography (sherwood oil: ethyl acetate=7: 1) get 5-(2-cyano group-3-(4-p-methoxy-phenyl)-3-oxo third-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (550mg, 62%).
Step 3:
Figure BDA0000146633410000432
5-(2-cyano group-3-(4-p-methoxy-phenyl)-3-oxo third-1-alkene-1-yl)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (200mg; 0.49mmol) and the amino propenyl cyanide (96mg of 3-; 0.98mmol) be dissolved in the acetic acid (20mL), be heated to 100 ℃ under the nitrogen protection and stirred 1 hour.Be cooled to room temperature, reaction solution is concentrated to be done, preparation TLC purifying (methylene dichloride: methyl alcohol=20: 1) get 2-(4-p-methoxy-phenyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-1,4-dihydropyridine-3,5-dimethoxy nitrile (40mg, 17%).MS(ESI+)：372[M+1]+； 1H?NMR(300MHz，CDCl 3)δ9.74(s，1H)，8.30(s，1H)，7.52-7.49(m，2H)，7.32(s，1H)，7.06-7.04(m，2H)，3.80(s，3H)，3.36(br，1H)，2.74-2.58(m，4H)，2.12(s，3H)，1.98-1.95(m，1H)，1.80-1.61(m，2H)。
Synthetic preparation example 8:2-(pyridin-4-yl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-Isosorbide-5-Nitrae-dihydropyridine-3, the 5-dimethoxy nitrile
Figure BDA0000146633410000441
Step 1:
Figure BDA0000146633410000442
Iso methyl nicotinate (1.0g, 7.30mmol) is dissolved in toluene (30mL), is cooled to 0 ℃, carefully adds sodium hydrogen (60%, 0.58g, 14.6mmol) and stirs after 10 minutes.In mentioned solution, add acetonitrile (1.50g, 36.5mmol), slowly be warming up to 80 ℃, stirred 4 hours.After being cooled to room temperature, filter, filter residue is collected filter residue after with toluene wash, dry 1-cyano group-2-oxo-2-(pyridin-4-yl) ethane sodium salt (1.2g, 98%)
Step 2:
Figure BDA0000146633410000443
Under the nitrogen protection; 5-formyl radical-4; 5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (600mg; 2.40mmol) and 1-cyano group-2-oxo-2-(pyridin-4-yl) ethane sodium salt (421mg; 2.88mmol) be dissolved in methylene dichloride (50mL), add acetic acid (173mg, 2.88mmol) and piperidines (245mg; 2.88mmol), return stirring spends the night.Reaction solution is cooled to room temperature, add methylene dichloride (30mL) dilute reaction solution, filter, filtrate is concentrated does, resistates column chromatography (DCM: MEOH=100: 1) get compound 5-(2-cyano group-3-oxo-3-(pyridin-4-yl) third-1-alkene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg, 72% purity, 55% yield).MS(ESI+)：379[M+1]+。
Step 3:
Figure BDA0000146633410000451
5-(2-cyano group-3-oxo-3-(pyridin-4-yl) third-1-alkene-1-yl)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg; 1.32mmol) and the amino propenyl cyanide (163mg of 3-; 1.98mmol) be dissolved in the Glacial acetic acid (20mL), be heated to 100 ℃ under the nitrogen protection and stirred 1 hour.Be cooled to room temperature, reaction solution is concentrated dried, resistates prepares TLC (methylene dichloride: methyl alcohol=20: 1) separation and purification, get compound 2-(pyridin-4-yl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-1,4-dihydropyridine-3,5-dimethoxy nitrile (15mg, 3.3%).MS(ESI+)：343[M+1]+；1H?NMR(300MHz，DMSO-d 6)δ12.29(br，1H)，9.40(s，1H)，8.30(s，1H)，8.74-8.73(m，2H)，7.62-7.58(m，2H)，7.30(s，1H)，3.48(s，1H)，2.78-2.72(m，2H)，2.66-2.64(m，2H)，2.12(s，3H)，2.00-1.96(m，1H)，1.82-1.80(m，1H)，1.69-1.65(m，1H)。
Synthetic preparation example 9:6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-2,3,4,8-tetrahydrochysene-1H-quinolizine-7,9-dimethoxy nitrile
Figure BDA0000146633410000461
Step 1:
Piperidines 2-ketone (4.96g, 50mmol) is dissolved in methylene dichloride (200mL), adds MeOTf (10.2g, 62mmol), finishes stirring at room 18 hours.Add powdered sodium carbonate (20g) and water (8mL) in reaction solution, stirred 10 minutes, filter, filtrate is used anhydrous sodium sulfate drying, and is concentrated, resistates 6-methoxyl group-2,3,4, and 5-tetrahydropyridine (4.525g, 81%) is directly used in the next step.MS：[M+1]＝114。
Step 2:
Figure BDA0000146633410000463
Upper step gained 6-methoxyl group-2,3,4,5-tetrahydropyridine (4.525g, 40mmol) is dissolved in the anhydrous tetrahydro furan (150mL), adds the 2-cyanoacetic acid tert-butyl ester (5.98g, 42.3mmol), is heated to 70 ℃ of return stirrings and spends the night.Reaction solution is concentrated, resistates column chromatography (sherwood oil: ethyl acetate=10: 1) get 2-cyano group-2-(piperidines-2-thiazolinyl) tert.-butyl acetate (3.2g, 36%).MS：[M+1]＝223。
Step 3:
Figure BDA0000146633410000464
2-cyano group-2-(piperidines-2-thiazolinyl) tert.-butyl acetate (444mg, 2.0mmol) be dissolved in the 6M hydrochloric acid (5mL), be heated to 100 ℃ and stirred 15 minutes, be chilled to room temperature, concentrating under reduced pressure is done, and resistates 2-(piperidines-2-thiazolinyl) acetonitrile is directly used in the next step.
Step 4:
Figure BDA0000146633410000471
With compound 5-(2-cyano group-3-oxo but-1-ene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (630mg, 2.0mmol) and upper step gained 2-(piperidines-2-thiazolinyl) acetonitrile (244mg, 2.0mmol) be dissolved in the acetic acid (5mL), be heated to 100 ℃ and stirred 1 hour.Be cooled to room temperature, reaction solution is concentrated to be done, and the resistates purification by silica gel column chromatography gets 6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-2,3,4,8-tetrahydrochysene-1H-quinolizine-7,9-dimethoxy nitrile (150mg, 24%).MS：[M+1]＝319； 1H?NMR(300MHz，CDCl 3)δ7.42(s，1H)，3.62-3.55(m，1H)，3.46-3.42(m，1H)，3.27-3.23(m，1H)，2.93-2.59(m，5H)，2.40-2.23(m，1H)，2.26(s，3H)，2.03-1.69(m，7H)。
Method with reference to synthetic preparation example 9, respectively with " 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-yl)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate " in the preparation example 2 and the " 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-yl)-4; 5; 6 in the preparation example 3,7-tetrahydrochysene-1H-indazole-1-t-butyl formate " replacement " 5-(2-cyano group-3-oxo but-1-ene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate ", can obtain respectively the compound (I-10) and (I-11) in the following table:
Figure BDA0000146633410000481
Synthetic preparation example 12:6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-1,3,4, the 8-tetrahydropyridine is [2,1-c] [Isosorbide-5-Nitrae] oxazines-7 also, the 9-dimethoxy nitrile
Figure BDA0000146633410000482
Step 1:
Figure BDA0000146633410000483
Compound morpholine-3-ketone (303mg, 3mmol) is dissolved in methylene dichloride (20mL), adds MeOTf (610mg, 3.72mmol), stirring at room 18 hours.Add powdered sodium carbonate (5g), water (1mL), stir after 30 minutes and filter.Filtrate concentrates to get 5-methoxyl group-3 with anhydrous sodium sulfate drying, 6-dihydro-2H-1, and 4-oxazines crude product (261mg, 75%) is oily matter.
Step 2:
Figure BDA0000146633410000491
Compound 5-methoxyl group-3,6-dihydro-2H-1,4-oxazines (261mg, 2.27mmol) and the 2-cyanoacetic acid tert-butyl ester (461mg, 2.81mmol) are dissolved in anhydrous tetrahydro furan (10mL), and return stirring spends the night.Be cooled to room temperature, concentrating under reduced pressure, resistates column chromatography (sherwood oil: ethyl acetate=10: 1) get 2-cyano group-2-(morpholine-3-thiazolinyl) tert.-butyl acetate (106mg, 21%), be white solid.
Step 3:
Figure BDA0000146633410000492
2-cyano group-2-(morpholine-3-thiazolinyl) tert.-butyl acetate (163mg, 0.73mmol) is added in the 6N hydrochloric acid (5mL), be heated to 100 ℃ and stirred 15 minutes.Be chilled to room temperature, remove solvent under reduced pressure, resistates is 2-(morpholine-3-thiazolinyl) acetonitrile crude product, is directly used in next step.
Step 4:
Figure BDA0000146633410000501
With 5-(2-cyano group-3-oxo but-1-ene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (230mg, 0.73mmol) and upper step gained compound 2-(morpholine-3-thiazolinyl) acetonitrile crude product (90mg, 0.73mmol) be dissolved in the acetic acid (5mL), be heated to 100 ℃ and stirred 1 hour.Be cooled to room temperature, reaction solution is concentrated dried, and preparation plate TLC purifying (100% ethyl acetate is launched) gets 6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-yl)-1,3,4,8-tetrahydropyridine also [2,1-c] [Isosorbide-5-Nitrae] oxazines-7,9-dimethoxy nitrile (25mg, 11%).MS：[M+1]＝322； 1H?NMR(300MHz，CDCl 3)δ7.36(s，1H)，6.61(br，1H)，4.65(dd，J＝55.5Hz，15.9Hz，2H)，4.06-4.22(m，1H)，3.88-3.83(m，1H)，3.65-3.61(m，1H)3.48-3.44(m，1H)，3.33-3.30(m，1H)，2.92-2.83(m，1H)，2.70-2.62(m，2H)，2.48-2.39(m，1H)，2.29(s，3H)，2.05-1.82(m，2H)，1.79-1.63(m，1H)。
Copy the method for synthetic preparation example 12, with " 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-yl)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate " in the preparation example 2, " 5-(2-cyano group-6; 6,6-, three fluoro-3-oxo-hexyls-1-alkene-1-yl)-4,5; 6 in " 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-yl)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate " in the preparation example 3 and the preparation example 4,7-tetrahydrochysene-1H-indazole-t-butyl formate " replacement intermediate " 5-(2-cyano group-3-oxo but-1-ene-1-yl)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate ", can obtain respectively the compound (I-13) in the following table; (I-14) and (I-15):
Figure BDA0000146633410000502
Figure BDA0000146633410000511
Bioassay embodiment 1: compound is to the In-vitro Inhibitory Effect of c-Met enzyme
Utilize the method for Mobility Shift Assay, measure compound external to the effect of c-Met enzymeinhibition.
Experimental technique
1. prepare kinase buffer liquid and the stop buffer of 1.25x
1.1 do not contain MnCl 21.25 times of kinase buffer liquid
62.5mM?HEPES，pH?7.5
0.001875％Brij-35
12.5mM?MgCl2
2.5mMDTT
1.2 contain MnCl 21.25 times of kinase buffer liquid
62.5mM?HEPES，pH?7.5
0.001875％Brij-35
12.5mM?MgCl2
12.5mM?MnCl2
2.5mM?DTT
1.3 stop buffer
100mMHEPES，pH?7.5
0.015％Brij-35
0.2％Coating?Reagent#3
50mMEDTA
2. compound solution preparation
2.1 diluted chemical compound
The 50mM compound that adds 20 μ L in the EP pipe adds the 100%DMSO of 80 μ L, is made into the 10mM compound of 100 μ L.The 10mM compound that adds 30 μ L in another EP pipe adds the 100%DMSO of 70 μ L, is made into the 3mM compound of 100 μ L.
Add the 100%DMSO of 95 μ L and the 3mM compound of 5uL in second hole on 96 orifice plates, other holes add the 100%DMSO of 60 μ L.From the 2nd hole, get 30 μ L compounds and add in the 3rd hole, down do successively 3 times of dilutions, dilute altogether 10 concentration.The compound concentration scope is 150uM to 7.6nM.
2.2 transferase 45 times compound is to Sptting plate
Get 10 μ L to another piece 96 orifice plates from each hole of above-mentioned 96 orifice plates, add 90 μ L ultrapure waters.Therefore being the compound that is dissolved among the 10%DMSO in the second hole to the 11-holes, is 10%DMSO in the first hole and the 12 hole.
From above-mentioned 96 orifice plates, take out 5 μ L to 384 hole Sptting plates.Therefore, 5 times of compounds of 10%DMSO dissolving of 5 μ L and the 10%DMSO of 5 μ L are just arranged in the 384 hole Sptting plates.The EDTA that adds 5 μ L 250mM in the negative control hole.
3. kinase reaction
3.1 prepare 2.5 times of enzyme solution
Kinases is added 1.25 times of kinase buffer liquid, form 2.5 times of enzyme solution.
3.2 prepare 2.5 times substrate solution
Polypeptide and the ATP of FAM mark are added 1.25 times of kinase buffer liquid, form 2.5 times of substrate solutions.
3.3 in 384 orifice plates, add enzyme solution
5 times of compounds of the 10%DMSO of existing 5 μ L dissolving in the 384 hole Sptting plates.
2.5 times of enzyme solution that in 384 hole Sptting plates, add 10 μ L.
Hatched under the room temperature 10 minutes.
3.4 in 384 orifice plates, add substrate solution
2.5 times of substrate solutions that in 384 hole Sptting plates, add 10 μ L.
3.5 kinase reaction and termination
Hatched under 28 ℃ 1 hour.Add 25 μ L stop buffer termination reactions.
4.Caliper reading of data
The upper reading and converting rate of Caliper data.
5. inhibiting rate calculates
Copy conversion data from Caliper.Transformation efficiency is changed into the inhibiting rate data.Wherein max refers to the transformation efficiency of DMSO contrast, and min refers to the transformation efficiency without enzyme contrast alive.
Inhibiting rate=(max-conversion)/(max-min) * 100
Bioassay embodiment 1: experimental result
Figure BDA0000146633410000551
Remarks: "+" represents 100nM＜IC 50＜1uM; " ++ " represents 10nM＜IC 50＜100nM; " +++" represents IC 50＜10nM.
Bioassay embodiment 2: compound is to the restraining effect of stomach cancer cell MKN-45 propagation
Experimental technique
1. cell cultures
The used cell of this test is the MKN-45 cell, is incubated in the RPMI1640 substratum that contains 10% foetal calf serum.Cell cultures is in containing the substratum of following ingredients: RPMI1640 substratum, the foetal calf serum of 10% (v/v), 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates.Cell cultures is in 37 ℃ of 5%CO 2The nitrogen peroxide incubator in, the ratio of going down to posterity is 1: 2～1: 6.
2. compound preparation and dilution
Be pressed powder when compound is received, according to the quality that the client provides, the DMSO preparation that adds respective amount claims to become 9 concentration initial concentrations with the DMSO gradient dilution again by the storing solution of 10mM.In order to obtain the IC of compound 50, we have selected 9 test final concentrations (25000,8333,2778,926,309,103,34,11and 1.8nM) to test.Be diluted to final concentration with substratum, the ultimate density of DMSO is 0.25%.
3. experimental procedure
Test 3.1 cultivate the MKN-45 cell and be inoculated in 96 or 384 orifice plates.
3.2 approximately added test-compound after the cell inoculation in 24 hours, each compound is with tested 9 concentration (3 times of gradient dilutions), each point is tested two multiple holes.
3.3 cell is at 37 ℃, 5%CO 2Cultivated 5 days.
3.4 pass through the growing state of the detection method test cell of Celltiter Glo.
4. data analysis
Testing data is analyzed by XLFit software, draws half-inhibition concentration.
Bioassay embodiment 2: experimental result
Figure BDA0000146633410000581
Remarks: "+" represents 500nM＜IC50＜5uM; " ++ " represents 100nM＜IC50＜500nM; " +++" represents IC50＜100nM.

Claims (41)

1. dihydropyridine compounds, for having the compound of following general formula (I):
Figure FDA0000146633400000011
Wherein, R 1Be selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
R 2Be selected from hydrogen, alkyl, substituted alkyl or R 2With R 3Form heterocycle;
R 3Be selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 3With R 2Form heterocycle.
2. dihydropyridine compounds as claimed in claim 1, its formula of (I) compound is selected from the compound to (I-15) as shown in the formula (I-1):
Figure FDA0000146633400000021
3. dihydropyridine compounds as claimed in claim 1, the compound of its formula of (I) is any one in enantiomer, diastereomer, the conformer, or arbitrarily both, three or four mixture.
4. dihydropyridine compounds as claimed in claim 1, the compound of wherein said general formula (I) comprises described compound pharmacy acceptable derivates.
5. dihydropyridine compounds as claimed in claim 1, the compound of wherein said general formula (I) exists with the form of pharmacy acceptable salt.
6. dihydropyridine compounds as claimed in claim 5, the compound pharmacy acceptable salt of wherein said general formula (I) is hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, mesylate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or the malate of general formula (I) compound.
7. method for preparing dihydropyridine compounds claimed in claim 1, it is characterized in that, the compound of described general formula (I) is prepared from by the following method: take pimelinketone-4-ethyl formate (1) as raw material, at N, be converted into intermediate (2) under the effect of dinethylformamide dimethylacetal (DMF-DMA), this intermediate (2) and hydrazine reaction, cyclisation are pyrazole compound (3); Ester group in the pyrazole compound (3) is reduced with reductive agent, obtain intermediate (4); Then the amido of intermediate (4) pyrazoles is protected to get intermediate (II) with suitable protecting group, again with the alcoholic extract hydroxyl group of intermediate (II) with suitable condition oxidation, obtain aldehydes intermediate (III); Aldehydes intermediate (III) and cyano group ketone compounds (A) condensation; get intermediate (IV); intermediate (IV) again with amido alkene nitrile raw material (B) condensation, deprotection base under suitable condition then namely gets the compound (I) of general formula (I).Concrete route is as follows:
8. method as claimed in claim 7 is characterized in that, described reductive agent is lithium aluminium hydride, sodium borohydride.
9. method as claimed in claim 7 is characterized in that, described suitable protecting group is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl.
10. method as claimed in claim 7 is characterized in that, described suitable condition be oxidized to Dess-Martin oxidation, Swern oxidation.
11. method as claimed in claim 7 is characterized in that, described protecting group is the amido protecting group.
12. method as claimed in claim 7 is characterized in that, described amido protecting group is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl.
13. method as claimed in claim 12 is characterized in that, described under suitable condition deprotection base refers to: adopt organic solution or the trifluoracetic acid/methylene dichloride of hydrogenchloride to remove tertbutyloxycarbonyl; Adopt the method for catalytic hydrogenation to remove carbobenzoxy-(Cbz); Perhaps adopt trifluoracetic acid to remove methoxy-benzyl.
14. method as claimed in claim 7 is characterized in that, R in the described amido alkene nitrile raw material (B) 2With R 3Combination be selected from following (B-1) to structure shown in (B-3):
15. a method for preparing dihydropyridine compounds claimed in claim 1 is characterized in that, R in the compound of general formula (I) 1With R 3Identical and R 2During for hydrogen, the compound of its general formula (I) is compound (Ia); Compound (Ia) is prepared by following methods: take pimelinketone-4-ethyl formate (1) as raw material, at N, be converted into intermediate (2) under the effect of dinethylformamide dimethylacetal (DMF-DMA), this intermediate (2) and hydrazine reaction, cyclisation are pyrazole compound (3); Ester group in the pyrazole compound (3) is reduced with reductive agent, obtain intermediate (4); Then the amido of intermediate (4) pyrazoles is protected to get intermediate (II) with suitable protecting group; Again with the alcoholic extract hydroxyl group of intermediate (II) with suitable condition oxidation, obtain aldehydes intermediate (III); Amino alkene nitrile raw material (C) condensation of this aldehydes intermediate (III) and 2 equivalents, then deprotection base under suitable condition namely gets compound (Ia).Concrete route is as follows:
Figure FDA0000146633400000051
R wherein 1And R 3Replace with Ra.
16. method as claimed in claim 15 is characterized in that, described reductive agent is lithium aluminium hydride, sodium borohydride.
17. method as claimed in claim 15 is characterized in that, described protecting group is the amido protecting group.
18. method as claimed in claim 17 is characterized in that, described amido protecting group is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl.
19. method as claimed in claim 15 is characterized in that, described suitable condition be oxidized to Dess-Martin oxidation, Swern oxidation.
20. method as claimed in claim 18, it is characterized in that, described under suitable condition deprotection base refers to: described under suitable condition deprotection base refers to: adopt organic solution or the trifluoracetic acid/methylene dichloride of hydrogenchloride to remove tertbutyloxycarbonyl; Adopt the method for catalytic hydrogenation to remove carbobenzoxy-(Cbz); Perhaps adopt trifluoracetic acid to remove methoxy-benzyl.
21. contain the pharmaceutical composition of dihydropyridine compounds, wherein said pharmaceutical composition comprises compound and the acceptable vehicle of pharmacy of the general formula claimed in claim 1 (I) for the treatment of significant quantity.
22. pharmaceutical composition as claimed in claim 21, its pharmaceutical composition are made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, syrup, emulsion, ointment, ointment, suppository or injection.
23. a pharmaceutical composition, wherein said pharmaceutical composition comprise pharmacy acceptable derivates and the acceptable vehicle of pharmacy of the compound of the general formula claimed in claim 1 (I) for the treatment of significant quantity.
24. pharmaceutical composition as claimed in claim 23, its pharmaceutical composition are made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, syrup, emulsion, ointment, ointment, suppository or injection.
25. a pharmaceutical composition, wherein said pharmaceutical composition comprise pharmacy acceptable salt and the acceptable vehicle of pharmacy of the dihydropyridine compounds of the general formula claimed in claim 1 (I) for the treatment of significant quantity.
26. pharmaceutical composition as claimed in claim 25, its pharmaceutical composition are made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, syrup, emulsion, ointment, ointment, suppository or injection.
27. the application of a dihydropyridine compounds claimed in claim 1 wherein is the application of compound in preparation adjusting protein kinase catalytic activity goods of general formula (I).
28. the application of a dihydropyridine compounds claimed in claim 1 wherein is the application of pharmacy acceptable derivates in preparation adjusting protein kinase catalytic activity goods of the compound of general formula (I).
29. the application of a dihydropyridine compounds claimed in claim 1 wherein is the application of pharmaceutically useful salt in preparation adjusting protein kinase catalytic activity goods of the compound of general formula (I).
30. the application of a dihydropyridine compounds claimed in claim 1 wherein is the application of compound in the medicine of the preparation treatment disease relevant with protein kinase of general formula (I).
31. application as claimed in claim 30, wherein said protein kinase are the c-Met receptor tyrosine kinase.
32. application as claimed in claim 31, the wherein said disease relevant with protein kinase is cancer.
33. application as claimed in claim 32, wherein said cancer are selected from cancer of the stomach, lung cancer, thyroid carcinoma, colorectal carcinoma, kidney, liver cancer, ovarian cancer, mammary cancer, prostate cancer, bladder cancer, head and neck cancer, carcinoma of the pancreas, carcinoma of gallbladder, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma.
34. the application of a dihydropyridine compounds claimed in claim 1 wherein is the application of pharmacy acceptable derivates in the medicine of the preparation treatment disease relevant with protein kinase of the compound of general formula (I).
35. application as claimed in claim 34, wherein said protein kinase are the c-Met receptor tyrosine kinase.
36. application as claimed in claim 34, the wherein said disease relevant with protein kinase is cancer.
37. application as claimed in claim 35, wherein said cancer are selected from cancer of the stomach, lung cancer, thyroid carcinoma, colorectal carcinoma, kidney, liver cancer, ovarian cancer, mammary cancer, prostate cancer, bladder cancer, head and neck cancer, carcinoma of the pancreas, carcinoma of gallbladder, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma.
38. the application of a dihydropyridine compounds claimed in claim 1 wherein is the application of pharmaceutically useful salt in the medicine of the preparation treatment disease relevant with protein kinase of the compound of general formula (I).
39. application as claimed in claim 38, wherein said protein kinase are the c-Met receptor tyrosine kinase.
40. application as claimed in claim 38, the wherein said disease relevant with protein kinase is cancer.
41. application as claimed in claim 40, wherein said cancer are selected from cancer of the stomach, lung cancer, thyroid carcinoma, colorectal carcinoma, kidney, liver cancer, ovarian cancer, mammary cancer, prostate cancer, bladder cancer, head and neck cancer, carcinoma of the pancreas, carcinoma of gallbladder, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma.
CN201210081677.3A 2012-03-23 2012-03-23 Dihydropyridine compounds, and compositions, preparation methods and applications thereof Active CN103319456B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210081677.3A CN103319456B (en) 2012-03-23 2012-03-23 Dihydropyridine compounds, and compositions, preparation methods and applications thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210081677.3A CN103319456B (en) 2012-03-23 2012-03-23 Dihydropyridine compounds, and compositions, preparation methods and applications thereof

Publications (2)

Publication Number Publication Date
CN103319456A true CN103319456A (en) 2013-09-25
CN103319456B CN103319456B (en) 2015-05-13

Family

ID=49188547

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210081677.3A Active CN103319456B (en) 2012-03-23 2012-03-23 Dihydropyridine compounds, and compositions, preparation methods and applications thereof

Country Status (1)

Country Link
CN (1) CN103319456B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101558040A (en) * 2006-12-14 2009-10-14 拜耳先灵医药股份有限公司 Dihydropyridine derivatives useful as protein kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101558040A (en) * 2006-12-14 2009-10-14 拜耳先灵医药股份有限公司 Dihydropyridine derivatives useful as protein kinase inhibitors

Also Published As

Publication number Publication date
CN103319456B (en) 2015-05-13

Similar Documents

Publication Publication Date Title
CN102816175B (en) A kind of heterocycle pyridine compounds, its intermediate, preparation method and purposes
CN105899491B (en) For inhibiting the active 1- pyridazine-of SHP2/triazine -3- base-piperazine (- piperazine)/pyridine/pyrrolidin derivatives and combinations thereof
CN105916845B (en) N- heteroaryl compound and composition for inhibiting the active N- azaspiro cycloalkanes of SHP2 to replace
JP2022037083A (en) Compound and composition for inhibiting activity of shp2
CN110240596A (en) For treating the novel therapeutic agents of HBV infection
TWI361071B (en) Combinations for the treatment of diseases involving cell proliferation
CN108348529A (en) Hepatitis B virus conditioning agent
CN107787323A (en) For suppressing the compound and composition of SHP2 activity
CN105473588B (en) Compound and composition as mek inhibitor
KR20170095882A (en) Triazolopyrimidine compounds and uses thereof
ES2535212T3 (en) Carboxamido-4 - [(4-pyridyl) amino] -pyrimidines for the treatment of hepatitis C
CN108997225A (en) JAK2 and ALK2 inhibitor and its application method
CN101568529A (en) Heteroaryl-heteroaryl compounds as cdk inhibitors for the treatment of cancer, inflammation and viral infections
HUE032459T2 (en) Heterocyclic modulators of lipid synthesis
JP7148500B2 (en) Novel tetrahydronaphthyl urea derivatives
CN102574842A (en) Pyridinyl-imidazolone derivatives for inhibiting pi3 kinases
CN107531683B (en) USP7 inhibitor compounds and methods of use
CN108135871A (en) Block the amine naphthoquinone compound and medical composition of ubiquitination-proteasomal system of disease
CN104557871B (en) Arylmorpholine compounds with spiro substituents as well as preparation method and use thereof
CN108530444A (en) A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage
WO2016088813A1 (en) Novel diazabicyclo[2.2.2]octane derivative
KR20200041954A (en) Compounds, pharmaceutical compositions thereof, and uses and applications thereof
CN108366979A (en) Compound related with ubiquitination-proteasomal system and medical composition
AU2019214193B2 (en) Heterobicyclic carboxylic acids for treating cancer or inflammatory diseases
CN104557913A (en) Pyridopyrimidine compounds as well as preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20190514

Address after: Room 304-12, 665 Zhangjiang Road, Shanghai Free Trade Pilot Area, Pudong New Area, Shanghai 201210

Patentee after: Shanghai Huilun Pharmaceutical Technology Co.,Ltd.

Address before: Room 650-10, Building No. 2, 351 Guoshoujing Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai, 201203

Patentee before: SHANGHAI HUILUN LIFE SCIENCE & TECHNOLOGY Co.,Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20190816

Address after: Room 650-10, Building No. 2, 351 Guoshoujing Road, Shanghai Free Trade Pilot Area, 201203

Patentee after: SHANGHAI HUILUN LIFE SCIENCE & TECHNOLOGY Co.,Ltd.

Address before: Room 304-12, 665 Zhangjiang Road, Shanghai Free Trade Pilot Area, Pudong New Area, Shanghai 201210

Patentee before: Shanghai Huilun Pharmaceutical Technology Co.,Ltd.

TR01 Transfer of patent right
CP01 Change in the name or title of a patent holder

Address after: Room 650-10, Building No. 2, 351 Guoshoujing Road, Shanghai Free Trade Pilot Area, 201203

Patentee after: Shanghai Hui Bio Technology Co.,Ltd.

Address before: Room 650-10, Building No. 2, 351 Guoshoujing Road, Shanghai Free Trade Pilot Area, 201203

Patentee before: SHANGHAI HUILUN LIFE SCIENCE & TECHNOLOGY Co.,Ltd.

CP01 Change in the name or title of a patent holder
TR01 Transfer of patent right

Effective date of registration: 20211222

Address after: 201100 floor 10, building 5, No. 525, Yuanjiang Road, Minhang District, Shanghai

Patentee after: Shanghai Hui Bio Technology Co.,Ltd.

Patentee after: SHANGHAI HUILUN JIANGSU PHARMACEUTICAL Co.,Ltd.

Address before: Room 650-10, building 2, 351 GuoShouJing Road, Shanghai pilot Free Trade Zone, 201203

Patentee before: Shanghai Hui Bio Technology Co.,Ltd.

TR01 Transfer of patent right
CP03 Change of name, title or address

Address after: 200241 floor 10, building 5, No. 525, Yuanjiang Road, Minhang District, Shanghai

Patentee after: Shanghai Huilun Pharmaceutical Co.,Ltd.

Patentee after: SHANGHAI HUILUN JIANGSU PHARMACEUTICAL Co.,Ltd.

Address before: 201100 floor 10, building 5, No. 525, Yuanjiang Road, Minhang District, Shanghai

Patentee before: Shanghai Hui Bio Technology Co.,Ltd.

Patentee before: SHANGHAI HUILUN JIANGSU PHARMACEUTICAL Co.,Ltd.

CP03 Change of name, title or address