CN101696183A - (Z)-2-phenyl-3-(pyrrol-2-yl)-acrylonitrile derivative as well as salts, composition, preparation method and application thereof - Google Patents
(Z)-2-phenyl-3-(pyrrol-2-yl)-acrylonitrile derivative as well as salts, composition, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a new tyrosine kinase inhibitor, in particular to a (Z)-2-phenyl-3-(pyrrol-2-yl)-acrylonitrile derivative shown as a general formula (I) or pharmacologically acceptable salts, preparation method and application thereof in treating or preventing related diseases in organisms and protein kinase. The invention also provides a pharmaceutical composition containing a compound shown as the general formula (I) or/and pharmacologically acceptable salts thereof.
Description
Technical field
The present invention relates to a class vinyl cyanide derived compounds and their acceptable salt, composition and their preparation method and uses on pharmacology.
Background technology
Protein tyrosine kinase be a class can catalysis phosphate on the ATP transfer on the proteinic tyrosine residues of many important adjustings, make it that phosphorylation take place and regulate these and regulate proteic function.Difference according to the structure of protein tyrosine kinase can be divided into receptor type and non-receptor type.Receptor type tyrosine kinase by the extracellular domain that contains ligand-binding site point, single stride film hydrophobic alpha helical region, contain the active cell intracellular domain of tyrosine protein kinase (RTK) and form, their part be regulate the cell growth in the organism, grow, differentiation and dead somatomedin; And the non-receptor type protein tyrosine kinase only has the active cell intracellular domain composition of tyrosine protein kinase (RTK).
Protein tyrosine kinase plays crucial effect in regulating important biomolecule processes such as cells whose development, growth, differentiation, death.A large amount of studies show that, the generation development of the imbalance of protein tyrosine kinase function and numerous disease, especially malignant tumour is in close relations.In malignant tumour, unusual main three aspects, the one, the high expression level of receptor tyrosine kinase and their part-somatomedin of showing of protein tyrosine kinase; The 2nd, the sudden change of Tyrosylprotein kinase or disappearance; The 3rd, Tyrosylprotein kinase and a kind of paraprotein are in conjunction with the persistence activation that causes it.These are tumour cell paraplasm, unusual differentiation, persistence growth unusually and do not produce one of major reason of apoptosis.Therefore, with the Tyrosylprotein kinase be target spot to come efficient, special, the hypotoxic antitumour drug of Development of New Generation be field the most popular in the antitumor research and development of more than ten years in the past, also obtained many challenging achievements.
United States Patent (USP) 5521184 finds that a class aminopyrimidine derivative all has the obvious suppression effect to the BCR/abl in the protein tyrosine kinase, PDGFR and c-kit, and preferred compounds imatinib (imatinib) wherein successfully has been used for the clinical treatment chronic myelocytic leukemia and can't have used the gastrointestinal stromal tumor of excision; United States Patent (USP) 5457105 has been invented a class quinazoline compounds, has inhibition EGF-R ELISA (epidermalgrowth factor receptor, EGFR) effect of Tyrosylprotein kinase, preferred compounds Gefitinib (gefitinib) wherein successfully is used for the treatment of lung cancer in non-cellule type; United States Patent (USP) 5747498 has been invented an other class and has been had the quinazoline compounds that suppresses the EGFR Tyrosylprotein kinase, and preferred compounds erlotinib (erlotinib) wherein also successfully is used for the treatment of lung cancer in non-cellule type.United States Patent (USP) 7235576 has been invented a class aryl urea compounds, for the multiple protein Tyrosylprotein kinase, comprise PDGFR, VEGFR, Kit and Raf etc. are inhibited, and preferred compounds Xarelto (sorafenib) wherein successfully is used for the treatment of advanced liver cancer and kidney.United States Patent (USP) 6573293 has been invented an other class and has been had the multiple protein Tyrosylprotein kinase is had inhibiting micromolecular compound, they belong to the dihydroindole ketone, and preferred compounds Sutent (sunitinib) wherein is by the clinical kidney and gastrointestinal stromal tumor in late period that is used for the treatment of.
Summary of the invention
The present invention's technical problem at first to be solved provides the new tyrosine kinase inhibitor of a class, and they are for having acceptable salt on (Z)-2-phenyl-3-(pyrroles-2-yl)-acrylonitrile derivative as general formula (I) or its pharmacology:
Wherein:
R1, R5 select from following groups independently :-H, halogen, alkyl, cycloalkyl, aromatic base, assorted aromatic base, heterolipid cyclic group, hydroxyl, alkoxyl group ,-C (O) NR
10R
11,-NR
15R
16The R of ,-(CO)
17,-(CH
2)
rR
18
R2 selects from following groups :-H, halogen, alkyl, trihalogenmethyl, hydroxyl, alkoxyl group, cyano group, aromatic base, assorted aromatic base ,-NR
15R
16,-NR
15C (O) R
16,-C (O) R
16,-S (O)
2NR
15R
16
R3 selects from following groups :-H, halogen, alkyl, trihalogenmethyl, hydroxyl, alkoxyl group, aromatic base, assorted aromatic base ,-(CO) R
17,-NR
15R
16,-NR
15S (O)
2R
16,-S (O)
2N R
15R
16,-N R
15R
16,-NR
15C (O) R
16,-SO
2R
19,-SO
2R
19In R
19Can from following groups, select: alkyl, replacement and unsubstituted aromatic base, replacement and unsubstituted aralkyl, replace and unsubstituted assorted aromatic base, replace and unsubstituted heteroaralkyl;
R4 selects from following groups :-H, halogen, alkyl, hydroxyl, alkoxyl group ,-NR
15R
16
R6, R8 select from following group :-H, alkyl, replacement and unsubstituted aromatic base, replacement and unsubstituted assorted aromatic base;
R7 is C (O) R
12, C (O) R
12In R
12Be-NR
13(CH
2)
nR
14,-NR
13(CH
2)
nR
14In R
13Be-H or unsubstituted low alkyl group-NR
13(CH
2)
nR
14In R
14Be-NR
15R
16Or-N
+(O) R
15R
16, n is 2 or 3;
R9 selects from following group :-H, alkyl, cycloalkyl, the aromatic base that does not replace or replace, the assorted aromatic base that does not replace or replace, and R9 and R8 can be in conjunction with forming cycloalkanes, heterocyclic group;
R10 and R11 select from following group independently :-H, alkyl, aromatic base;
R15 and R16 select from following group independently :-H, alkyl and the low alkyl group that is replaced by hydroxyl, aminoalkyl group, cyano group alkyl, cycloalkyl, aromatic base and assorted aromatic base; R15 and R16 can be in conjunction with forming heterocyclic group;
R17 selects from following group :-H, hydroxyl, alkoxyl group, aryloxy;
R18 selects from following group: hydroxyl ,-C (O) R
17,-N R
15R
16With-C (O) N R
15R
16
R is 1,2,3, perhaps 4.
Acceptable salt can play the effect of modulin Tyrosylprotein kinase on above-claimed cpd and its pharmacology, acts on thus and produces the relevant illness of the protein tyrosine kinase for example treatment and the preventive effect of malignant tumour.
Preferred The compounds of this invention is an acceptable salt on general formula (I) compound or its pharmacology, wherein:
R1, R5 are-H;
R2 is-Cl-F ,-Br, perhaps cyano group;
R3 is-Cl-F ,-Br, perhaps cyano group;
R4 is-H;
R6 is low alkyl group;
R7 is-C (O) R
12, R here
12Be-N R
13(CH
2)
nR
14, R here
13Be-H or unsubstituted low alkyl group; N is 2 or 3; R
14Be-N R
15R
16, R here
15And R
16It is independently unsubstituted low alkyl group;
R8 is low alkyl group;
R9 is-H.
The further preferred compound of the present invention is an acceptable salt on formula (I) compound or its pharmacology, wherein: R7 is preferably from following group (but being not limited to): N-(2-dimethylaminoethyl) amido carbonyl, N-methyl amido carbonyl, N-(3-dimethylaminopropyl) amido carbonyl, N-(2-diethylamino ethyl) amido carbonyl, N-(2-ethylamino ethyl) amido carbonyl, N-(3-ethylamino propyl group) amido carbonyl or N-(3-diethylamino propyl group) amido carbonyl.
The concrete preferred compound of the present invention is an acceptable salt on general formula (I) compound or its pharmacology, it is characterized in that it is (but being not limited to):
5-[(Z)-and 2-itrile group-2-(2-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-bromophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-trifluoromethyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-trifluoromethyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-Dimethoxyphenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(4-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(4-trifluoromethyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-bromophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-3,5-dimethylphenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-methyl-4-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-methoxyl group-4-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(4-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2,4 dichloro benzene base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2, the 3-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-fluoro-4-Phenylsulfonic acid base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(2,4 dichloro benzene base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(2, the 3-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate.
The term that uses among the present invention " alkyl " refers to the aliphatic saturated hydrocarbon that comprises straight chain and branched group.Described alkyl preferably has 1-20 carbon atom, and more preferably medium sized alkyl with 1-10 carbon atom most preferably is the low alkyl group of 1-4 carbon atom.Described alkyl can be replacement or unsubstituted.When being substituted; substituting group is preferably one or more following groups that are selected from separately: cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, amino, alkoxyl group, aryloxy, thiocarbonyl, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, C-carboxyl, O-carboxyl, nitro, silyl.
" cycloalkyl " refer to all be carbon monocycle or thick with ring (promptly having a ring of adjacency pair carbon atom mutually) group, wherein one or more rings do not have fully the Pi-electronic system that connects.The example of cycloalkyl (being not limited to) is cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Cycloalkyl can be replacement or unsubstituted.When being substituted, substituting group is preferably one or more following groups that are selected from separately: alkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, cyano group, halo, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, O-formamyl, N-formamyl, C-amido, N-amido, nitro, amino.
" aromatic base " refer to promising carbon monocycle or thick and the ring the polynary ring with the Pi-electronic system that is connected fully (being its ring that has phase adjacency pair carbon atom) group.Aromatic base can be replacement or unsubstituted.When being substituted; substituting group is preferably one or more following groups that are selected from, and comprising: halo, trihalomethyl group, alkyl, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, formamyl, O-thiocarbamoyl, N-sulfo-amino acyl group, C-amido, N-amido, sulfinyl, alkylsulfonyl, amino.
" assorted aromatic base " refers to monocycle or thick and ring (promptly having the ring of adjacency pair atom mutually) group, and it has on encircling and one or morely is selected from the atom of nitrogen, oxygen and sulphur and has the Pi-electronic system that is connected fully in addition.The example (being not limited to) of assorted aromatic base is pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyridine, pyrimidine, quinoline, isoquinoline 99.9, purine or carbazole.Heteroaryl can be replacement or unsubstituted.When being substituted; substituting group is preferably one or more following groups that are selected from, and comprising: alkyl-cycloalkyl, halo, trihalomethyl group, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, cyano group, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxyl, O-carboxyl, sulfinyl, alkylsulfonyl, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, amino.
" heterolipid cyclic group " refers to has one or more monocycle or thick and rings that are selected from the atom of nitrogen, oxygen and sulphur on ring.Described ring also can contain one or more pairs of keys.Yet described ring does not have the Pi-electronic system that connects fully.The heterolipid ring can be replacement or unsubstituted.When being substituted; substituting group is preferably one or more following groups that are selected from, and comprises alkyl, cycloalkyl, halo, trihalomethyl group, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, cyano group, nitro, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, sulfinyl, alkylsulfonyl, C-amido, N-amido, amino.
" alkoxyl group " refer to R wherein be straight or branched alkyl as defined herein-the OR group.The straight or branched alkoxyl group of wherein preferred 1～6 carbon atom is as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.More preferably the straight or branched alkoxyl group of 1～4 carbon atom of tool, most preferably methoxy or ethoxy.
" hydroxyl " refers to-the OH group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" trihalogenmethyl " refer to X wherein for halo group as defined herein-CX
3Group.
" cyano group " refers to-C ≡ N group.
As mentioned above, compound of the present invention also can exist with the form of acceptable salt on the pharmacology, i.e. acceptable salt on the pharmacology of (Z)-2-phenyl-3-of general formula (I) (pyrroles-2-yl)-acrylonitrile derivative.Pharmacy acceptable salt class form comprises acceptable acidity/anion salt or basic/cationic salts on the pharmacology.Representative organic or inorganic acid comprises (being not limited only to this certainly) hydrochloric acid, Hydrogen bromide, hydrofluoric acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetate, propionic acid, oxyacetic acid, lactic acid, succsinic acid, toxilic acid, tartrate, citric acid, M-nitro benzoic acid, amygdalic acid, methylsulfonic acid, hydroxyethylsulfonic acid, Phenylsulfonic acid, oxalic acid, palmitinic acid, 2-naphthene sulfonic acid, tosic acid, ethylenimine base sulfonic acid, Whitfield's ointment, saccharinic acid, trifluoroacetic acid.Pharmaceutically acceptable basic/cationic salts class comprises (being not limited only to this certainly) aluminium, calcium, chloroprocaine, choline, diethanolamine, quadrol, lithium, magnesium, Jia ， Na and zinc.
The present invention also comprises the prodrug that compound constituted of invention.So-called prodrug be meant some other known or do not have disclosed compound and active compound described in the invention in conjunction with after reach than the purpose that is easier to administration, can be converted into after in it enters body described in the invention active compound arranged and play function.
Another technical problem to be solved of the present invention provides a kind of pharmaceutical composition, and it has the function and the effect of above-claimed cpd at least.For this reason the present invention by the following technical solutions, it contains:
General formula (I) compound or its pharmacological-acceptable salt,
Acceptable assistant agent on the optional pharmacology,
Perhaps, described pharmaceutical composition also contains optional one or more known drug compounds that contains.
Another technical problem to be solved of the present invention provides preparation and has the method for (Z)-2-phenyl-3-(pyrroles-2-the yl)-acrylonitrile derivative as above-mentioned general formula (I).Condensation under alkaline condition obtains general formula (I) compound by general formula (II) compound and general formula (III) compound for it,
This method can illustrate by following representational embodiment.Preparation method involved in the present invention can obtain essential raw material by standard organic chemistry method, or obtains essential raw material by the similar approach of the method set forth in the general organic chemistry.
Described be reflected to be preferably under the alkaline condition under the existence that is reflected at following suitable alkali carry out: can be organic amine alkali, as pyridine, triethylamine, N-methylmorpholine, 4-dimethylaminopyridine; Or be the carbonate or the oxyhydroxide of basic metal or alkaline-earth metal, as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide, potassium hydroxide; Perhaps, be basic metal or alkaline-earth metal amide, as sodium amide or two (three silyls) ammonification sodium.
Preparation has the reaction of (Z)-2-phenyl-3-(pyrroles-2-the yl)-acrylonitrile derivative as above-mentioned general formula (I) can react in the presence of following The suitable solvent or thinner, and solvent or thinner comprise that alkanol or ester or alcohol are as methyl alcohol, ethanol, Virahol or ethyl acetate; Halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin; Ether such as tetrahydrofuran (THF) or 1, the 4-dioxane; Aromatic solvent such as toluene; Or dipolar nature aprotonic solvent such as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone, dimethyl sulfoxide (DMSO).
Temperature of reaction of the present invention is generally 10～150 ℃, is preferably in 20～120 ℃ of scopes to react, and most preferably is 30～90 ℃.
Acceptable salt can adopt the preparation of following method on the pharmacology of (Z)-2-phenyl-3-of above-mentioned general formula of the present invention (I) (pyrroles-2-yl)-acrylonitrile derivative: behind (Z)-2-phenyl-3-(pyrroles-2-the yl)-acrylonitrile derivative of preparation general formula (I), and then prepare additive salt with suitable acid.
The pharmaceutical preparation that another technical problem to be solved of the present invention provides acceptable assistant agent preparation on acceptable salt on above-mentioned arbitrary compound or its pharmacology and the optional pharmacology is in treatment or prevention organism and the application in the protein kinase related disorder.
An important biomolecule effect of compound described in the invention be can the modulin Tyrosylprotein kinase activity.The protein tyrosine kinase here is meant receptor protein road propylhomoserin kinases (RTKs), non-acceptor or " cell " Tyrosylprotein kinase (CTKs).Regulation and control are meant that compound described in the invention can make the catalytic activity of RTKs and CTKs change, and especially suppresses the catalytic activity of RTKs and CTKs.
Be subjected to the receptor protein kinase of The compounds of this invention regulation and control to include but is not limited to VEGFR, EGFR, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR alpha, PDGFR beta, KIT (CD117), CSF1R, C-kit, C-fms, Flk-lR, Flk4, KDR/Flk-L Flt-l, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R, wherein preferably VEGFR, PDGFRs and c-KIT, wherein the receptor tyrosine kinase of preferred regulation and control is PDGFRs, VEGFRs and c-KIT.
Be subjected to the nonreceptor tyrosine kinase of The compounds of this invention regulation and control to be selected from (but being not limited to) Src, Frk, Btk, Csk, Abl, ZAp70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
Compound described in the invention can prove with some experiment in vitro methods that those skilled in the art know the regulation and control of Tyrosylprotein kinase, can also measure the IC50 of these compounds in this way and reaches the purpose of preferred compound.The Tyrosylprotein kinase that is used for these experimental techniques can extract from cell, also can obtain by vivoexpression with engineered method.
The method that the biological effect that compound described in the invention produces after to tyrosine kinase regulatory can be known with the researchist, for example cell in vitro is cultivated and is observed.One of method wherein is to observe that compound effects described in the invention suppresses the growth of tumour cell behind tumour cell and/or the apoptosis effect of the cell that causes.
Compound described in the invention can be verified in the animal model of disease the therapeutic action of tyrosine kinase related disorder.One of typical example be with the heteroplastic transplantation model of tumour with people's tumour transplatation to animal for example in the mouse, the compound of the present invention of taking dose therapeutically effective to animal reaches certain hour then, and the tumour that can observe the back animal of taking medicine can stop growth, volume-diminished or disappearance (comparing with control group).
The optimizing compound that obtains after the optimization according to biology that compound described in the invention is carried out and pharmacological experiment is 5-[(Z)-2-itrile group-2-(3, the 4-dichlorophenyl)-and vinyl]-2, acceptable salt on 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides and its pharmacology is called compound following No. 8 with this preferred compound.
Because it is closely related that Tyrosylprotein kinase function out of control, especially function are crossed the generation development of strong and numerous disease, so compound described in the invention can be used for treating many diseases relevant with Tyrosylprotein kinase to the regulation and control of Tyrosylprotein kinase.The most important thing is malignant tumour in these diseases, comprise the malignant tumour that is derived from various epithelial cancers, derives from mesoblastemic pernicious sarcoma, derives from the leukemia of blood system and derive from lymphoid malignant lymphoma and derive from sexual cell, specifically include but is not limited to lung cancer, liver cancer, kidney, cancer of the stomach, large bowel cancer, prostate cancer, mammary cancer, esophagus cancer, carcinoma of the pancreas, ovarian cancer, cervical cancer, leukemia, lymphoma, brain tumor, thyroid carcinoma, genitourinary cancer and pernicious sarcoma.
These diseases also include (but are not limited to) metabolic disease (for example diabetes), autoimmune disorder, diseases associated with inflammation, excess proliferative disease, cardiovascular and cerebrovascular diseases and bone and joint diseases.
Another aspect of the present invention is, compound described here or its salt or prodrug can be united with other chemotherapeutic agent and be used for the treatment of disease discussed above and imbalance to obtain better effect.Typical illustration is the purpose that the compound described of the present invention and known antitumor drug combined utilization can obtain better to treat tumour.These known antitumor drugs include but is not limited to cytotoxic drug, hormone medicine, biological species antitumour drug, monoclonal antibodies medicine and up-to-date molecular targeted property medicine.
In order to reach the purpose of the above-mentioned disease of treatment, acceptable salt needs and suitable carriers, vehicle and the mixing of other assistant agent on compound described in the invention or its pharmacology, according to selected medication, with conventional formulation method for example mix, dissolving, granulation, dressing, grinding, emulsification, parcel, embedding or cryodesiccated method be prepared into suitable formulation.
For injection, The compounds of this invention can be dissolved in damping fluid suitable on the physiology such as HankShi solution, Ringer's solution or normal saline buffer solution are mixed with aqueous solution preparation, also can be dispersed in suitable liquid vehicle and for example form suspension, liposome or emulsion in oiliness or the water miscible medium.To saturating film administration, can in preparation, use the permeate agent that is suitable for passing barrier.It is known that such permeate agent is generally those skilled in the art.
For oral preparations, by active compound is mixed with pharmaceutically acceptable carrier known in the art, vehicle and assistant agent, can be mixed with tablet, pill, capsule, solution, gelifying agent, syrup, slurry agent, suspensoid etc. with formulation method well known to those skilled in the art.Vehicle wherein and weighting agent can be carbohydrates, comprising lactose, sucrose, mannitol or Sorbitol Powder, cellulose preparation such as W-Gum, wheat starch, Starch rice and yam starch, also can be other material for example gelatin, methylcellulose gum, HYDROXY PROPYL METHYLCELLULOSE, Suo Jia base Xian Wei Su Na and/or polyvinylpyrrolidone (PVP).If desired, also can add disintegrating agent such as cross-linked polyvinylpyrrolidone, agar or alginic acid or Zao Suan Na.
Tablet can be made coated tablet by packaging technique with suitable coating material.Coating material can use dense sugar soln and optional from gum arabic, talcum powder, polyvinylpyrrolidone, carbopol glue, polyoxyethylene glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture and harmless pigment or dyestuff composition.Oral preparations commonly used also comprise with gel form hard capsule and with the soft capsule of gelatin and softening agent such as glycerine or Sorbitol Powder composition.Activeconstituents needs and weighting agent such as lactose, tackiness agent such as starch and/or lubricant such as talcum powder or the sharp and optional stablizer mixing of stearic acid in the hard capsule.In soft capsule the active compound solubilized or be suspended in appropriate liquid such as fatty oil, whiteruss or liquid macrogol in, also stablizer can be joined in these preparations.
To inhalation, use pressurization filling or spraying gun and suitable propellent for example (to be not limited to) Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane or carbonic acid gas, transmit the compound of purposes of the present invention with the form of aerosol spray.
Compound of the present invention can also be made slow releasing capsule or other sustained release preparation with the sustained release preparation technology and be used for long term administration.
In order to reach the purpose of treatment, can take different medications according to the feature of above-mentioned different preparations.These medications include but is not limited to oral, rectum,, see through mucous membrane or enterally administering; Perhaps in intramuscular, subcutaneous, the marrow, in the sheath, directly in the ventricle, in vein, artery, the vitreum, in intraperitoneal, the nose or intraocular injection.The optimization approach of administration is oral and non-enteron aisle.
The method of administration can also adopt the part but not the mode of whole body gives described compound, and for example the compound with liquid preparation is injected directly in the solid tumor.In addition, can also for example give medicine with the targeted drug transfer system with the liposome of tumor specific antibody bag quilt.These liposomes will optionally be transported to tumor tissues with medicine.
The drug regimen of activeconstituents of the present invention also comprises effective therapeutic dose, just refers to reach effective prevention, alleviation or improves disease symptoms or the amount of certain compound energy of prolongation curee's survival rate.The research of medicine effective dose and calculating are well-known to those skilled in the art.Conventional method is to calculate according to the data of experiment in vitro and animal pharmacodynamics.The scope of effective dose is greatly about between every day 0.001 milligram to 300 milligrams of the pers kilogram of body weight, and relatively more commonly used is every day, per kilogram of body weight was 0.01 milligram to 100 milligrams, more suitably is 0.1 milligram to 30 milligrams of per kilogram of body weight every day.
Embodiment
First part's compound part
The representative compound that following examples are chosen for the present invention synthetic do not constitute about synthetic method of the present invention or in the restriction of the compound that the present invention includes.
Embodiment 1
5-[(Z)-and 2-itrile group-2-(3-fluorophenyl)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides
With 5-formyl radical-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylamino-ethyl) acid amides
(1)(1.33g, 5.0mmol), between fluorophenyl acetonitrile (0.85g, 6.7mmol) and Virahol (30mL) add in the three-necked bottle, after the stirring and dissolving, be added dropwise to 4N sodium hydroxide solution (10mL), the system stirred overnight at room temperature, concentrating under reduced pressure removes and to desolvate, and enriched material is with ethyl acetate (100mL) dilution, respectively water (2 * 50mL) and saturated aqueous common salt (50mL) wash, organic layer with anhydrous sodium sulfate drying after, evaporated under reduced pressure, enriched material is handled with ethyl acetate-normal hexane, filters and separates out solid, 80 ℃ of dry 4h, promptly get yellow solid target compound 5-[(Z)-2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (1.2g, 62.8%)
m.p.156.7～157.8℃
1H-NMR(500MHz，DMSO-d6)δ10.93(s，1H)，7.73(s，1H)，7.69(d，1H)，7.50(m，2H)，7.40(m，1H)，7.18(t，1H)，3.27(m，2H)，2.52(m，6H)，2.41(s，3H)，2.28(s，3H)，0.97(t，6H)
(1)J.Med.Chem.1999，42，5120
Embodiment 2
5-[(Z)-and 2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides
With embodiment 1 operation, prepare yellow solid target compound 5-[(Z with chlorobenzene acetonitrile between corresponding)-2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (1.51g, 75.7%)
m.p.143.2～145.3℃
1H-NMR(500MHz，DMSO-d6)δ10.89(s，1H)，7.76(s，1H)，7.72(s，1H)，7.62(d，1H)，7.47(dd，1H)，7.439(d，1H)，7.37(t，1H)，3.26(m，2H)，2.50(m，6H)，2.41(s，3H)，2.28(s，3H)，0.97(t，6H).
Embodiment 3
5-[(Z)-and 2-itrile group-2-(3-bromophenyl)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides
With embodiment 1 operation, prepare yellow solid target compound 5-[(Z with bromobenzylcyanide between corresponding)-2-itrile group-2-(3-bromophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (1.47g, 66.3%)
m.p.143.4～144.8℃
1H-NMR(500MHz，DMSO-d6)δ10.89(s，1H)，7.88(s，1H)，7.71(s，1H)，7.66(d，1H)，7.53(d，1H)，7.41(dd，1H)，7.36(t，1H)，3.26(m，2H)，2.50(m，6H)，2.40(s，3H)，2.27(s，3H)，0.97(t，6H).
Embodiment 4
5-[(Z)-and 2-itrile group-2-(3-fluorophenyl)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate
With 5-[(Z)-2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (0.63g, 1.63mmol) and methyl alcohol (100mL) join in the three-necked bottle, add (2S)-hydroxy-butanedioic acid (0.236g again, 1.76mmol), stirring at room 0.5h, dissolving back concentrating under reduced pressure removes and desolvates, add acetonitrile (25.0mL) in the enriched material, behind the reflux 0.5h, stirring is cooled to room temperature, places refrigerator (5 ℃) cold analysis again, filters precipitate, 60 ℃ of decompression oven dry (4h), promptly get light tan solids 5-[(Z)-2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate (0.66g, 78.4%).
m.p.95.4～99.8℃
1H-NMR(500MHz，DMSO-d6)δppm?1.18(t，J＝7.10Hz，6H)，2.30(s，3H)，2.38(dd，J＝5.5Hz，1H)，2.44(s，3H)，2.57(dd，J＝8.0Hz，1H)，3.03(m，6H)，3.50(br，2H)，4.04(dd，J＝6.0Hz，1H)，7.18(br，1H)，7.50(s，1H)，7.58(d，J＝10.5Hz，1H)，7.71(m，2H)，10.98(s，1H)
Embodiment 5
5-[(Z)-and 2-itrile group-2-(2, the 3-dichlorophenyl)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides
With embodiment 1 operation, with corresponding 2, the 3-dichloro benzyl cyanide prepares the yellow solid target compound
5-[(Z)-and 2-itrile group-2-(2, the 3-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (1.36g, 62.8%).
Embodiment 6
5-[(Z)-and 2-itrile group-2-(2,4 dichloro benzene base)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides
With embodiment 1 operation, prepare the yellow solid target compound with corresponding 2,4 dichloro benzene acetonitrile
5-[(Z)-and 2-itrile group-2-(2,4 dichloro benzene base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (1.21g, 55.9%).
Embodiment 7
5-[(Z)-and 2-itrile group-2-(3-fluoro-4-Phenylsulfonic acid base)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides
With 5-[(Z)-2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (0.63g, 1.63mmol) and the vitriol oil (5.0mL) join in the three-necked bottle, stirring at room reaction 20h, reaction system is poured in a certain amount of water, filter precipitate, 100 ℃ of oven dry (4h), promptly get yellow solid 5-[(Z)-2-itrile group-2-(3-fluoro-4-Phenylsulfonic acid base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (0.69g, 91.2%).
MS?m/z?463[m+1]
Embodiment 8
5-[(Z)-and 2-itrile group-2-(3, the 4-dichlorophenyl)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides
With embodiment 1 operation, with corresponding 3, the 4-dichloro benzyl cyanide prepares the yellow solid target compound
5-[(Z)-and 2-itrile group-2-(3, the 4-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (1.36g, 62.8%).
m.p.157.0～159.3℃
1H-NMR(500MHz，DMSO-d6)δ10.89(s，1H)，7.96(s，1H)，7.74(s，1H)，7.69(d，1H)，7.64(d，1H)，7.37(t，1H)，3.27(m，2H)，2.51(m，6H)，2.40(s，3H)，2.28(s，3H)，0.97(t，6H).
Embodiment 9
5-[(Z)-and 2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate
With 5-[(Z)-2-itrile group-2--(3-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (0.72,1.8mmol) and methyl alcohol (100mL) join in the three-necked bottle, add (2S)-hydroxy-butanedioic acid (0.265g again, 1.98mmol), stirring at room 0.5h, dissolving back concentrating under reduced pressure removes and desolvates, add acetonitrile (25.0mL) in the enriched material, behind the reflux 0.5h, stirring is cooled to room temperature, places refrigerator (5 ℃) cold analysis again, filters precipitate, 60 ℃ of decompression oven dry (4h), promptly get light tan solids 5-[(Z)-2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate (0.63g, 65.7%).
1H-NMR(500MHz，DMSO-d6)δppm?1.14(t，J＝7.00Hz，6H)，2.30(s，3H)，2.35(dd，J＝5.5Hz，1H)，2.43(s，3H)，2.54(dd，J＝8.0Hz，1H)，2.96(m，6H)，3.47(br，2H，2x?OH)，4.00(m，1H)，7.38(d，J＝8.0，1H)，7.47(m，1H)，7.62(d，J＝8.0Hz，1H)，7.67(br，1H)，7.73(s，1H)，7.76(s，1H)，10.97(s，1H)
Embodiment 10
5-[(Z)-and 2-itrile group-2-(3, the 4-dichlorophenyl)-vinyl]-2, the preparation of 4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate
With 5-[(Z)-2-itrile group-2-(3, the 4-dichlorophenyl)-and vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides (0.35g, 0.81mmol) and methyl alcohol (30mL) join in the three-necked bottle, add (2S)-hydroxy-butanedioic acid (0.12g again, 0.89mmol), stirring at room 0.5h, dissolving back concentrating under reduced pressure removes and desolvates, and adds acetonitrile (5.0mL) in the enriched material, behind the reflux 0.5h, stirring is cooled to room temperature, place refrigerator (5 ℃) cold analysis again, filter precipitate, 60 ℃ of decompression oven dry (4h), promptly get yellow solid 5-[(Z)-2-itrile group-2-(3, the 4-dichlorophenyl)-and vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate (0.4g, 87.0%).
1H-NMR(500MHz，DMSO-d6)δppm?1.13(t，J＝7.00Hz，6H)，2.29(s，3H)，2.36(dd，J＝5.5Hz，1H)，2.42(s，3H)，2.54(m，1H)，2.93(m，6H)，3.45(br，2H)，4.02(dd，J＝5.50Hz，1H)，7.63(m，2H)，7.70(d，J＝8.5Hz，1H)，7.77(s，1H)，7.97(m，2H)，10.99(s，1H)
Second section biology and pharmacodynamics
Embodiment 11
Compound suppresses experiment external to tyrosine kinase activity
The effect of acceptable salt pair Tyrosylprotein kinase can detect with the test kit of standard on compound described in the invention or its pharmacology, for example the Universal Tyrosine Kinase Assay Kit of TaKaRa Bio Inc..Its principle is to observe the effect of compound to different Tyrosylprotein kinase catalytic tyrosine substrate phosphorylations, below be detection compound to the inhibiting concrete operations step of protein tyrosine kinase in the tumour cell, compound also can use the same method to for example different classes of receptor tyrosine kinase of specific Tyrosylprotein kinase and measure:
1. the preparation of Tyrosylprotein kinase sample
1) in the 10cm plate, cultivates Hep2 laryngeal cancer cell 1-5X10
6Cell is removed substratum, and it is inferior to give a baby a bath on the third day after its birth with PBS;
2) add 1ml and extract damping fluid, with the careful collecting cell of cell scraper, 10000xg is centrifugal 10 minutes under 4 degree, leaves and takes supernatant as sample.
2. detect:
1) sample is done suitable dilution with the kinase reaction damping fluid, adds the compound of different concns simultaneously;
2) each reacting hole adds standard substance and the dilute sample of 40ul;
3) every hole adds the 40mM ATP one 2Na solution of 10ul, abundant mixing, 37 degree reactions 30 minutes;
4) abandon reaction solution, fully wash 4 times with washings;
5) every hole adds the lock solution of 100ul, 37 degree reactions 30 minutes;
6) abandon confining liquid, every hole adds the 50ul enzyme labelled antibody, 37 degree reactions 30 minutes;
7) abandon antibody response liquid, fully wash 4 times with washings;
8) every hole adds the 100ul substrate solution, 37 degree reactions 15 minutes;
9) every hole adds the 100ul reaction terminating liquid;
10) detect 450mM OD value, drawing standard curve, the IC50 that the computerized compound suppresses the Tyrosylprotein kinase sample.
Record IC50 value that synthetic compound suppresses Tyrosylprotein kinase between 6-600nM with this law, the IC50 of wherein preferred No. 8 compounds is 6nM.
Embodiment 12
Compound external to the tumor cell proliferation inhibition effect
It is as follows that preferred compound of the present invention can be measured the concrete operations step in the technology of external use cell cultures to the tumor cell proliferation inhibition effect:
1. on 96 well culture plates, add a certain amount of tumour cell (every hole adds the quantity of cell decides according to the speed of cell growth, generally between 2000 to 200000);
2. cell cultures changed nutrient solution into 1640 substratum that contain 0.5%FBS, overnight incubation after 4 hours;
3. abandon supernatant liquor, every hole adds the RPMI-1640 of 180ul serum-free, and then adds the compound of the different concns that 20ul prepares in advance; After 1 hour, every hole adds FBS again, and to make its final concentration be 0.5%, continues to cultivate 24 hours;
4. every hole adds 20ul MTT, hatches 4 hours; Abandon supernatant liquor, every hole adds 200ul DMSO solution, and mixing is surveyed absorbancy at 570nm.
5. can calculate the IC50 of this compound according to the absorbance value of different concns compound.
After measured, the IC50 value that compound of the present invention suppresses tumor cell proliferation is between 1.92-25.6uM, wherein preferred No. 8 compounds are 1.97uM to the IC50 concentration of Hep2 laryngeal cancer cell propagation, and the IC50 that the SW620 colorectal cancer cells is bred is 1.92uM.
Embodiment 13
Preferred No. 8 compounds are in animal body to the inhibition effect experiment of tumor growth
Preferred No. 8 compounds of the present invention can carry out at the heteroplastic transplantation model of nude mice with the human tumor cell the pharmacodynamic experiment of tumor growth, and concrete operations are as follows:
1. human body Hep2 laryngocarcinoma tumour cell is implanted the back flank of nude mice, every animal is implanted 5x10
6Cell, every group of 8 animals;
2. implanting rising on the same day to animal oral No. 8 compounds every day once of cell, dosage is respectively per kilogram of body weight 25mg every day, 50mg, and 100mg took 21 days continuously;
3. measured the size of control group and administration group tumour every three days, calculate tumor size with the wide x height of long x
4. calculate No. 8 compounds according to the size of administration group and control group gross tumor volume the inhibiting rate experimental result of tumor growth is found that No. 8 compounds inhibiting rate to the Hep2 tumor growth after 21 days is 85.6%, significant difference is arranged through t check and control group.
Claims (15)
1. have acceptable salt on (Z)-2-phenyl-3-(pyrroles-2-yl)-acrylonitrile derivative as general formula (I) or its pharmacology:
Wherein:
R1, R5 select from following groups independently :-H, halogen, alkyl, cycloalkyl, aromatic base, assorted aromatic base, heterolipid cyclic group, hydroxyl, alkoxyl group ,-C (O) NR
10R
11,-NR
15R
16The R of ,-(CO)
17,-(CH
2)
rR
18
R2 selects from following groups :-H, halogen, alkyl, trihalogenmethyl, hydroxyl, alkoxyl group, cyano group, aromatic base, assorted aromatic base ,-NR
15R
16,-NR
15C (O) R
16,-C (O) R
16,-S (O)
2NR
15R
16
R3 selects from following groups :-H, halogen, alkyl, trihalogenmethyl, hydroxyl, alkoxyl group, aromatic base, assorted aromatic base ,-(CO) R
17,-NR
15R
16,-NR
15S (O)
2R
16,-S (O)
2NR
15R
16,-NR
15R
16,-NR
15C (O) R
16,-SO
2R
19,-SO
2R
19In R
19Can from following groups, select: alkyl, replacement and unsubstituted aromatic base, replacement and unsubstituted aralkyl, replace and unsubstituted assorted aromatic base, replace and unsubstituted heteroaralkyl;
R4 selects from following groups :-H, halogen, alkyl, hydroxyl, alkoxyl group ,-NR
15R
16
R6, R8 select from following group :-H, alkyl, replacement and unsubstituted aromatic base, replacement and unsubstituted assorted aromatic base;
R7 is C (O) R
12, C (O) R
12In R
12Be-NR
13(CH
2)
nR
14,-NR
13(CH
2)
nR
14In R
13Be-H or unsubstituted low alkyl group-NR
13(CH
2)
nR
14In R
14Be-NR
15R
16Or-N
+(O) R
15R
16, n is 2 or 3;
R9 selects from following group :-H, alkyl, cycloalkyl, the aromatic base that does not replace or replace, the assorted aromatic base that does not replace or replace, and R9 and R8 can be in conjunction with forming cycloalkanes, heterocyclic group;
R10 and R11 select from following group independently :-H, alkyl, aromatic base;
R15 and R16 select from following group independently :-H, alkyl and the low alkyl group that is replaced by hydroxyl, aminoalkyl group, cyano group alkyl, cycloalkyl, aromatic base and assorted aromatic base; R15 and R16 can be in conjunction with forming heterocyclic group;
R17 selects from following group :-H, hydroxyl, alkoxyl group, aryloxy;
R18 selects from following group: hydroxyl ,-C (O) R17 ,-NR
15R
16With-C (O) NR
15R
16
R is 1,2,3, perhaps 4.
2. acceptable salt on compound as claimed in claim 1 or its pharmacology is characterized in that:
R1, R5 are-H;
R2 is-Cl ,-F ,-Br or cyano group;
R3 is-Cl ,-F ,-Br or cyano group;
R4 is-H;
R6 is low alkyl group;
R7 is-C (O) R
12, C (O) R
12In R
12Be-NR
13(CH
2)
nR
14,-NR
13(CH
2)
nR
14In R
13Be-H or unsubstituted low alkyl group-NR
13(CH
2)
nR
14In R
14Be-NR
15R
16,-NR
15R
16Be independently unsubstituted low alkyl group, n is 2 or 3;
R8 is low alkyl group;
R9 is-H.
3. acceptable salt on compound as claimed in claim 1 or its pharmacology, it is characterized in that: R7 is selected from: N-(2-dimethylaminoethyl) amido carbonyl, N-methyl amido carbonyl, N-(3-dimethylaminopropyl) amido carbonyl, N-(2-diethylamino ethyl) amido carbonyl, N-(2-ethylamino ethyl) amido carbonyl, N-(3-ethylamino propyl group) amido carbonyl or N-(3-diethylamino propyl group) amido carbonyl.
4. acceptable salt on compound as claimed in claim 1 or its pharmacology is characterized in that it is:
5-[(Z)-and 2-itrile group-2-(2-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-bromophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-trifluoromethyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-trifluoromethyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(4-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(4-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(4-trifluoromethyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-bromophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-3,5-dimethylphenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-methyl-4-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-methoxyl group-4-aminomethyl phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-Dimethoxyphenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-p-methoxy-phenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2,4 dichloro benzene base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(2, the 3-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-fluoro-4-Phenylsulfonic acid base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides,
Or 5-[(Z)-and 2-itrile group-2-(3-fluorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(3-chloro-phenyl-)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(3, the 4-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(2,4 dichloro benzene base)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate,
Or 5-[(Z)-and 2-itrile group-2-(2, the 3-dichlorophenyl)-vinyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides-(2S)-malate.
5. prepare the contained method with any one compound of general formula (I) of claim 1～4, condensation under alkaline condition obtains general formula (I) compound by general formula (II) compound and general formula (III) compound.
6. pharmaceutical composition is characterized in that it contains:
General formula (I) compound or its pharmacological-acceptable salt,
Acceptable assistant agent on the optional pharmacology,
Perhaps, described pharmaceutical composition also contains optional one or more known drug compounds that contains.
7. pharmaceutical composition is characterized in that it contains:
Acceptable salt on the pharmacology of any one compound in any one compound or claim 2 and the claim 4 in claim 2 and the claim 4,
Acceptable assistant agent on the optional pharmacology.
Perhaps, described pharmaceutical composition also contains optional one or more known drug compounds that contains.
On the described arbitrary compound of claim 1, claim 2 and claim 4 or its pharmacology on acceptable salt and the optional pharmacology pharmaceutical preparation of acceptable assistant agent preparation in treatment or prevention organism and the application in the protein kinase related disorder.
9. application as claimed in claim 8, wherein said protein kinase related disorder are selected from the relevant disease of receptor tyrosine kinase.
10. application as claimed in claim 8, wherein said protein kinase related disorder are selected from the relevant disease of EGF-R ELISA, the disease that platelet derived growth factor receptor is relevant, the disease disease relevant with C-KIT that IGF-1 is relevant.
11. purposes as claimed in claim 8, wherein said protein kinase related disorder is selected from innocent tumour.
12. purposes as claimed in claim 8, wherein said protein kinase related disorder is selected from malignant tumour, and described malignant tumour comprises that all derive from epithelial cancer, derive from mesoblastemic pernicious sarcoma, derive from the leukemia of blood system, the malignant tumour that derives from lymphoid malignant lymphoma and derive from sexual cell.
13. purposes as claimed in claim 8, wherein said protein kinase related disorder is selected from lung cancer, liver cancer, kidney, cancer of the stomach, large bowel cancer, prostate cancer, mammary cancer, esophagus cancer, carcinoma of the pancreas, ovarian cancer, cervical cancer, leukemia, lymphoma, brain tumor, thyroid carcinoma, genitourinary cancer and pernicious sarcoma.
14. purposes as claimed in claim 8, wherein said protein kinase related disorder is selected from metabolic disease, autoimmune disorder, diseases associated with inflammation, excess proliferative disease, cardiovascular and cerebrovascular diseases and bone and joint diseases.
15. as the arbitrary described purposes of claim 8 to 14, it is characterized in that the organism of getting involved of described illness is a Mammals, particularly human.
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| CN2009101544280A CN101696183B (en) | 2009-10-27 | 2009-10-27 | (Z)-2-phenyl-3-(pyrrol-2-yl)-acrylonitrile derivative as well as salts, composition, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319392A (en) * | 2013-07-10 | 2013-09-25 | 张家港市华昌药业有限公司 | Preparation method of sunitinib intermediate |
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| US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
| EP1864972A4 (en) * | 2005-03-30 | 2009-11-11 | Yakult Honsha Kk | Bcrp/abcg2 inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319392A (en) * | 2013-07-10 | 2013-09-25 | 张家港市华昌药业有限公司 | Preparation method of sunitinib intermediate |
| CN103319392B (en) * | 2013-07-10 | 2015-10-28 | 张家港市华昌药业有限公司 | A kind of preparation method of sutent intermediate |
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