CN102153558A - Derivative of multi-target antitumor inhibitor 2-aminopyrrole-triazine and synthesis method thereof - Google Patents
Derivative of multi-target antitumor inhibitor 2-aminopyrrole-triazine and synthesis method thereof Download PDFInfo
- Publication number
- CN102153558A CN102153558A CN 201110043218 CN201110043218A CN102153558A CN 102153558 A CN102153558 A CN 102153558A CN 201110043218 CN201110043218 CN 201110043218 CN 201110043218 A CN201110043218 A CN 201110043218A CN 102153558 A CN102153558 A CN 102153558A
- Authority
- CN
- China
- Prior art keywords
- chloro
- triazine
- pyrrolo
- carboxylic acid
- amino
- 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
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a derivative of a multi-target antitumor inhibitor, namely 2-aminopyrrole-triazine and a synthesis method thereof, and relates to the technical field of the treatment of abnormal cells in mammals. The derivative is synthesized by taking ethyl isocyanoacetate as a starting point through a chemical synthesis method, and has the advantages of mature process, short production period, environment friendliness, low cost and the like. The product can be used as a heat shock protein (Hsp) 90 multi-target antitumor inhibitor, can inhibit Hsp90, and promote the degradation of Hsp90 effect proteins which play an important role in tumor growth signal pathways through ubiquitination, so that multiple targets of the tumor growth signal pathways are blocked and the growth of tumor is effectively prevented. The derivative has higher affinity with tumor cells, can selectively kill the tumor cells, and promote the degradation of primer proteins thereof through ubiquitin-proteasome pathways, so that the effects of tumor treatment and resistance of the targets are achieved, and the derivative has strong action and small side effect.
Description
Technical field
The present invention relates to treat the technical field of improper cell, particularly cancer cell in the mammalian body.
Background technology
(heat shock proteins is to be found by geneticist Ritossa in 1962 Hsps) to heat shock protein(HSP).This is that a class is at the conservative protein that also extensively is present in protokaryon and the eukaryote of organic evolution process camber.Hsp is a multigene family, and expression, function and the location of wherein heterogeneic product in cell all has different.Often distinguish this family member in this area, such as Hsp90, Hsp70 and Hsp27 etc. with molecular weight different.In addition, some heat shock protein(HSP) is classified with associated glycoprotein, such as GRP 94 and GRP 75.Hsps as molecular chaperones, participates in keeping the proteic proteic normal configuration that normally is folded to form in body, and plays an important role in the balance of and degraded synthetic at adjusting albumen and the albumen location.When cell was subjected to the various stimulation of environment, expression of heat shock increased in the cell, can protect momently fast cell antagonism endogenous stress attack, strengthen the repairing effect of cell and improve cell to stress tolerance degree.The generation of human a lot of diseases is relevant with proteic false folding.Therefore the medicine of developing the regulatory molecule companion becomes a kind of new thinking.Existing lot of documents show Hsps and tumour generation, the development closely related.Evidence suggests, in the different steps of tumour progression, the also corresponding change of the expression of Hsps in the tumour.And the severe environment around the easier adaptation of tumor cell ratio normal cell, this is obvious and the molecular chaperones role is closely related.Research in recent years thinks that Hsp90 has important effect in the survival course of tumour cell, and it is the important component part in a lot of oncogene paths; Heat shock protein 90 (Hsp90) has become antineoplastic novel targets, and the anti-tumor activity that some natural products had is just at this molecular target of Hsp90.Hsp90 and inhibitor thereof are the focus and the forward positions of present antitumor research.
The biological characteristics of Hsp90: Hsp90 is one of most active molecular chaperone protein in the cell, and the normal function performance of many signal transducers all depends on Hsp90.It when cell generation stress reaction, can with those owing to the protein-interacting that environmental stimulus changes self conformation, it is suitable folding and prevent the albumen non-specific aggregation to guarantee that albumen carries out, thereby keeps the normal activity of cell.Hsp90 also is an important buffering factor in the cell mutation process in addition, infers that it may can correct the false folding that mutain takes place equally.When cell was in the normal physiological situation, Hsp90 was an important attemperator equally.It is being regulated and control 40 kinds of proteic skies in the left and right sides and is asking that structure and these albumen of sudden change mainly can be divided three classes: the steroid hormone receptoroid at present; Serine/threonine or Tyrosylprotein kinase; Other albumen, such as mutant p53, telomerase hTERT subunit etc.All these albumen all are the important regulation proteins in cell physiological, the biochemical change procedure.Hsp90ct and Hsp9013 amphitypy are arranged in the endochylema, GRP94 is present in endoplasmic reticulum, (tumor necrosis factor receptorassociated protein1 TRAP1) then is present in the mitochondrial matrix Hsp75/ Tumor Necrosis Factor Receptors associated protein 1.Think that now these 4 members' the mode of action almost is consistent, but because they are originally different in intracellular location, so their institute's bonded albumen also has nothing in common with each other.For example Tyrosylprotein kinase ErbB2 acceptor is the single-minded downstream albumen of GRP94 (client protein), and I type Tumor Necrosis Factor Receptors (type I tumour necrosis factor receptor.TNFR1) and retinoblastoma protein R (retinoblastoma protein) then are the downstream effects albumen of TRAP1.Link to each other forms c one end of Hsp90 monomer and one 55 kDa terminal by the N one of 25 conservative kDa by a joining region (TRAP1 does not contain this district).These two ends can combine with substrate polypeptide such as downstream albumen or other coefficient molecular chaperoneses.In addition, the N end also has a special ATP-binding site, and the similar of the structure in this site and Topo II 13 is that a new Nucleotide is in conjunction with the territory.
Hsp90 plays a role and depends on the existence of ATP, and the ATP/ADP combining site is being born the effect in comformational switch district, regulates the assembling of the polymolecular partner complexes of its participation.When Hsp90 was in ADP in conjunction with conformation, Hsp90 formed mixture so that combine with Hsp70 with p60HOP.Because the action protein of Hsp90 is common and the combination of Hsp70/Hsp40 mixture elder generation, and then combine with Hsp90.After ATP replaces ADP, the Hsp90 occurred conformation changes, p60HOP and Hsp70/Hsp4O mixture are released, at this moment other is assisted molecular chaperones, comprise p23, some immunophilin or p50cdc37 combination with it makes action protein stable, and is in and can combines (if action protein is a steroid receptor) maybe can react to the stimulation conformational state of (for example action protein is some protein kinases) with part.Certainly this conversion is dynamic, a two-way process.When ATP is hydrolyzed to ADP, the conformation of Hsp90 changes once more, so corresponding conversion takes place the auxilliary molecular chaperones of its institute's bonded once more, institute's bonded action protein is released and is degraded under the effect of proteasome ".
At the beginning of the 2O century 9O age, Srivastava confirm from tumour cell, to carry heat shock protein(HSP) can cause the host to produce very strong immune response, this may be because this heat shock protein(HSP) can be used as the molecular chaperones of some tumour antigens.Ciocca etc. find again that in 1992 the breast cancer cell of high expression level Hsps has the tolerance effect to some chemotherapeutics.It may be more necessary proteic molecular chaperoneses in the growth of tumour cell that these results point out Hsps.Because Hsp90 has a lot of downstream effects albumen, can participate in regulating different signal transduction pathways, so its mechanism of action in tumor development also becomes very complicated.Mostly for the research of Hsp90 effect is to find by the inhibitor that uses it.A large amount of experiments proves also that at different cell strains it is also different that Hsp90 is suppressed its action effect of back, and this has different genetic background with different tumour cells and biological property is relevant.But in general, the antitumor action of Hsp90 inhibitor spectrum is very widely.
1992, Whitesell etc. found that benzoquinones ansamycins (benzoquinone ansamycins) microbiotic in vitro and in vivo can both show strong anti-tumor activity, and this effect is difficult to explanation with known restraining effect to some Tyrosylprotein kinases.Such microbiotic of further investigation discovery especially GA can combine with Hsp90 single-mindedly, hinders Hsp90 and v-Src albumen and connects, thereby cause this albumen instability, suppresses the kinase whose activity of v.Src.The discovery of such inhibitor makes Hsp90 become a stem-winding novel targets of oncotherapy.The Hsp90 inhibitor that has has at present entered clinical experimental stage.
Geldanamycin (GA) is found the earliest Hsp90 inhibitor, its biological function that is found feasible research Hsp90, and the effect of albumen in cancer development that research relies on Hsp90 becomes possibility.GA belongs to benzoquinones ansamycins microbiotic.This class microbiotic is structurally all pacified husky bridge by a benzoquinones part with a big ring of planarity and is linked to each other.It is a natural product, is the earliest to separate the seventies in 20th century to obtain from actinomycete meat soup, but finds just that up to the eighties in 20th century this compound has anti-tumor activity.It can reverse transfection v-the fibroblastic of Src proto-oncogene cancerate, in experiment in vitro and animal body, also confirmed its anti-tumor activity in succession.Initial this compounds is considered to the inhibitor of Tyrosylprotein kinase.Yet along with going deep into of research, the performance of finding its antitumor action mainly depends on by proteoclastic approach and makes those oncogene proteins, protein kinase inactivation, rather than directly suppresses kinase whose catalytic activity.The main mechanism that immunoprecipitation and avidity experiment disclose GA is to realize by the combination with Hsp90.Though GA has shown better antitumor activity, its serious hepatotoxicity is restricted its clinical application, yet action target spot of its uniqueness and biological activity still cause medicine scholar and biologist's attention.Present its more instrument medicine as biological function in research Hsp90 body, and be that the lead compound of the medicine of action target spot is studied with Hsp90 as exploitation.
Because the vital role of Hsp90 in keeping the proteic normal configuration of kinds of tumors, function and stability, it has been considered to a novel targets of oncotherapy.The extensive distribution of Hsp90 in healthy tissues in addition also is provided with obstacle for it becomes the oncotherapy target spot.Experiment in vivo and vitro finds that the Hsp90 in tumor tissues source is higher 100 times than the Hsp90 in healthy tissues source with the avidity of 17-AAG recently.Kamal etc. think this be since the Hsp90 in the tumor tissues usually and other albumen form activated many partner complexes, and the activity of ATP enzyme is also than the Hsp90 height in the healthy tissues, and Hsp90 exists with inactive form in healthy tissues.Therefore the excavation of this treatment target spot might provide the novel method of special, effective a, few side effects for oncotherapy.The searching of Hsp90 inhibitor is just becoming research focus at present.Benzoquinones Ansamycin compounds has entered clinical study as first-generation Hsp9O inhibitor, also has the natural product of some different structures also can demonstrate restraining effect to Hsp90 in addition.But existing inhibitor all has stronger toxic side effect, has limited its clinical application.Can establish suitable dosage regimen in addition, also be the conditionality factor of this compounds performance antitumous effect.Therefore it is good to seek anti-Hsp90 biological activity, and the micromolecular compound that toxic side effect is little has become the direction of present research.The example that these heat shock protein 90s suppress compound comprises the description that those patent applications of having announced are interior, and these patents comprise WO2006/071789, WO2006/008503, WO2006/090094, WO2005/021552.
Summary of the invention
The object of the invention is to propose a kind of host molecule structure and derivative, active strong thereof of micromolecular compound, heat shock protein 90 (Hsp90) inhibitor that low toxicity and side effect are little---the derivative of the antitumor inhibitor 2-of many target spots ammonia pyrroles-triazine.
Chemical molecular formula of the present invention is:
Wherein,
R1a is hydrogen base, C
1-C
6Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
6-C
14Aryl, C
2-C
9Heteroaryl, C
2-C
9Different cycloalkyl or C
3-C
8Cycloalkyl in optional functional group;
R1b is hydrogen base, C
1-C
6Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
6-C
14Aryl, C
2-C
9Heteroaryl, C
2-C
9Different cycloalkyl or C
3-C
8Cycloalkyl in optional functional group;
R2 is chlorine, fluorine, C
1-C
3Alkyl or 1 to 6 fluorine replace C
1-C
3Alkyl;
R3 is chlorine, fluorine, C
1-C
3Alkyl or 1 to 6 fluorine replace C
1-C
3Alkyl;
R4 is-(C
1-C
6Thiazolinyl)-OH ,-O-(C
1-C
6Alkyl) ,-(C
1-C
6Thiazolinyl)-O-(C
1-C
6Alkyl) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(C
6-C
10-aryl) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(C
3-C
10-cycloalkyl) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(5-10 heterocycle) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(3-10 heterocycle) ,-(C
1-C
6Thiazolinyl)
p -O-(C
2-C
6Thiazolinyl) ,-O-(C
2-C
6Thiazolinyl)-(3-10 heterocycle) ,-O-(C
2-C
6Alkyl)-(3-10 heterocycle) or C
1-C
8In the alkoxyl group to any one functional group.
2-aminophenyl pyrrolo-of the present invention [2,1-f]-1,2, the derivative of 4-triazine carboxylic amine are the derivatives of the antitumor inhibitor 2-of many target spots ammonia pyrroles-triazine, (press the rule of sFDA, the antitumor inhibitor of these many target spots belongs to a class new medicine).Can be applicable to as the antineoplastic inhibitor of heat shock protein class target spot more than 90, can suppress Hsp90, impel the Hsp90 effect protein that in the tumor growth signal path, plays an important role by the ubiquitin degraded, thereby a plurality of target spots of blocking-up tumor proliferation growth signals path effectively stop growth of tumor.Compound of the present invention and its esters can promote its substrate protein by the degraded of uiquitin-protease enzyme body path, thereby bring into play its antineoplastic effect.The present invention has clear and definite anti-tumor activity as inhibitor of heat shock protein 90, and with tumour cell higher avidity, optionally killing tumor cell is arranged.The specificity of target treatment determined that the therapeutic action of target drug is strong, and side effect is little.
Another purpose of the present invention is to provide the synthetic method of the compound with above molecular characterization.
Synthesis step is as follows:
1) 1H-pyrroles-2,4 dicarboxylic acid of synthetic diethyl ester:
With isocyano acid B ester and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene is dissolved in the tetrahydrofuran (THF) earlier, forms solution, adds formaldehyde again in solution, and with reaction mixture stirring reaction under 50 ± 0.5 ℃ of environment; After question response finishes, reaction mixture is cooled to normal temperature, wash reaction mixture with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate again, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain 1H-pyrroles-2,4 dicarboxylic acid of diethyl ester;
2) the amino diethyl-1H of synthetic 1--pyrroles-2,4 dicarboxylic acid:
1H-pyrroles-2 with diethyl ester, 4 dicarboxylic acid, ammonium chloride, methyl trioctylphosphine ammonium chloride, aqueous sodium hydroxide solution mix the formation solvent with methyl tertiary butyl ether, in solvent, add dense ammonium, and then add Javelle water, again with the reaction mixture that forms stirring reaction at ambient temperature; After reaction is finished, reaction mixture is filtered, get filtrate and wash with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain the amino diethyl-1H of 1--pyrroles-2,4 dicarboxylic acid;
3) [1,2,4] triazine-6-carboxylic acid of synthetic diethylamino-4-4-hydroxyl pyrrolo-[2,1-f]:
Amino diethyl-the 1H of 1--pyrroles-2,4 dicarboxylic acid and chloromethane amidine hydrochloride are mixed stirring reaction with methyl-sulphoxide under 150 ± 0.5 ℃ of envrionment conditionss; After reaction mixture is cooled to normal temperature, wash reaction mixture with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid, use the recrystallization method purifying at last, obtain purifying diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
4) [1,2,4] triazine-6-carboxylic acid of synthetic ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f]:
[1,2,4] triazine-6-carboxylic acid of diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] mixed with dimethyl formamide, thionyl chloride, methylene dichloride carry out back flow reaction; After reaction mixture is cooled to normal temperature, wash reaction mixture with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] the thick product of [1,2,4] triazine-6-carboxylic acid; Use the recrystallization method purifying again, obtain [1,2,4] triazine-6-carboxylic acid of ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] of purifying;
5) synthetic ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid:
With ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid and phosphorus oxychloride stirring reaction under 100 ± 0.5 ℃ of conditions makes the color of reaction mixture become after the even brown insulation 30 minutes; Then reaction mixture is cooled to 0 ℃ rapidly, adjust the pH value to 7.2 of reaction mixture then with NaOH solution, filter back extracting waste suspended substance, clean with ethyl acetate, get filtering filtrate and scoop up with salt solution and get organic layer, again through dehydrating and vacuum concentration, obtain ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid crude product; Carry out purifying with silicagel column at last, obtain ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid of purifying;
6) [1,2,4] triazine-6-carboxylic acid of synthetic ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f]:
With aqueous sodium carbonate and ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, (3,5-two chloro-2-(hydroxyl boron) phenol) (7) and 1,4 dioxanes mix, and with adding tetrakis triphenylphosphine palladium behind the nitrogen purging again, stirring reaction under 80 ± 0.5 ℃ of conditions; Question response finishes postcooling to room temperature, and then adds entry and form water mixture, with the water mixture ethyl acetate extraction, comes together with saturated sodium-chloride water solution and to wash organic layer after the extraction; Through dehydrating and vacuum concentration, obtain the thick product of [1,2,4] triazine-6-carboxylic acid of ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] then; At last with ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid carries out purifying with silicagel column, obtains the ethyl 4-(2 of purifying, 4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
7) [1,2,4] triazine-6-carboxylic acid of synthetic diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f]:
With [1,2, the 4] triazine-6-carboxylic acid of the dioxan solution of 4M hydrochloric acid and ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] and methyl alcohol stirring reaction at room temperature; Extract reaction solution after vacuum-evaporation and neutralize with saturated sodium carbonate solution again, use ethyl acetate extraction again; Wash organic layer after the extraction with saturated sodium-chloride water solution collection,, obtain the thick product of [1,2,4] triazine-6-carboxylic acid of diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] then through dehydrating and vacuum concentration; At last with diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid carries out purifying with silicagel column, obtains the diethylamino-4-(2 of purifying, 4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
8) [1,2, the 4] triazine-6-carboxylic acid of synthetic diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f]:
With [1,2,4] triazine-6-carboxylic acid of salt of wormwood and 1-(2-chloroethyl)-1H-pyrazoles (10), diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f], dimethyl formamide 120 ± 0.5
oStirring reaction under the C condition; Question response finishes postcooling to room temperature, adds entry and ethyl acetate to reaction mixture again, and restir 30 minutes obtains water mixture; Water intaking mixture ethyl acetate extraction, wash organic layer after the extraction with saturated sodium-chloride water solution collection, then through dehydrating and vacuum concentration, obtain diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-thick product of 6-carboxylic acid; At last with diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-thick product of 6-carboxylic acid carries out purifying with silicagel column, obtains the diethylamino-4-{ 2 of purifying, 4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
9) [1,2,4] triazine-6-carboxylic acid of Synthetic 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f]:
With [1,2, the 4] triazine-6-carboxylic acid of aqueous sodium hydroxide solution and diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f], ethanol stirring reaction at room temperature; Question response finishes the back and adds aqueous hydrochloric acid, obtains the pH value and be 7.0 ± 1 mixture; With the mixture ethyl acetate extraction, wash organic layer after the extraction with saturated sodium-chloride water solution collection, then through dehydrating and vacuum concentration, obtain 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
10) Synthetic 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[[1,2,4] triazine-6-methane amide of 2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f]:
With 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, cyclopropylamine, triethylamine, dimethyl formamide stirring reaction at room temperature; Question response finishes the back ethyl acetate extraction, wash organic layer after the extraction with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection, then through dehydrating and vacuum concentration, obtain 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f] the thick product of [1,2,4] triazine-6-methane amide; At last with 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f] [1,2,4] the thick product of triazine-6-methane amide carries out purifying with silicagel column, obtains the 2-amino-N-cyclopropyl-4-(2 of purifying, 4-two chloro-6-[2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f] [1,2,4] triazine-6-methane amide.
In addition, of the present invention 3, the synthesis step of 5-two chloro-2-(hydroxyl boron) phenol is:
1) synthetic two iodo-, 3,5-chlorophenesic acid:
Will be to 3, the 5-chlorophenesic acid is mixed the back and is added sodium hydride aqueous solution react under 0 ℃ and nitrogen atmosphere with dry toluene; Reaction mixture is warmed up to room temperature and stirred 30 minutes, the suspension that forms is cooled back 0 ℃, add iodine then and further react; Getting last reaction mixture stirs and is placed on 0 ℃ to the environment of room temperature after at least 24 hours, quench with aqueous hydrochloric acid successively and separate, quench with ethyl acetate and get, separate, quench with saturated sodium-chloride water solution and wash with ethyl acetate layer, the organic layer that getting quenches again after washing is through dehydrating and vacuum concentration, obtain the thick product of two iodo-, 3,5-chlorophenesic acid; Again the thick product of two iodo-, 3,5-chlorophenesic acid is carried out purifying with silicagel column, obtain two iodo-, 3, the 5-chlorophenesic acid of purifying;
2) synthesize 1,5-two chloro-3-(methoxy ethoxy)-2-iodobenzene:
With two iodo-, 3,5-chlorophenesic acid, chlorine methyl ethyl ether, cesium carbonate and dimethyl formamide stirring reaction at room temperature; Post reaction mixture is washed in water and salt shrend successively, and the organic layer that getting quenches after washing obtains 1, the 5-two chloro-3-thick product of (methoxy ethoxy)-2-iodobenzene through dehydrating and vacuum concentration; With 1,5-two chloro-3-thick product of (methoxy ethoxy)-2-iodobenzene carries out purifying with silicagel column, obtains 1 of purifying again, 5-two chloro-3-(methoxy ethoxy)-2-iodobenzene;
3) Synthetic 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane:
With 1,5-two chloro-3-(methoxy ethoxy)-2-iodobenzene and 4,4,5,5-methyl-[1,3,2] dioxy boron lane and triethylamine use nitrogen purging after 30 minutes in dioxan solution, again palladium and biphenyl-2-Ji-dicyclohexylphosphontetrafluoroborate are joined in the reaction mixture, reaction mixture stirring reaction to reaction under 80 ℃ of conditions is finished; After the question response mixture cooling, successively quench with saturated ammonium chloride solution, water and saturated sodium-chloride water solution and to wash reaction mixture; The organic layer that getting quenches after washing is obtained 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3, the thick product in 2-dioxy boron lane through dehydrating and vacuum concentration; Again with 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3, the thick product in 2-dioxy boron lane carries out purifying with silicagel column, obtain 2 of purifying-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane;
4) synthesize 3,5-two chloro-2-(hydroxyl boron) phenol:
With 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane and anhydrous methylene chloride mix the back and add boron tribromide react under 0 ℃ and nitrogen atmosphere; Question response is poured reaction mixture in the water into after finishing, and adds aqueous sodium hydroxide solution again, pH value to 10 ± 1 of conditioned reaction mixture; Through separating, remove organic layer; With the pH value to 3 that the adjustment of 1NHCl solution separates the water layer solution obtain, use ethyl acetate extraction again, come together with saturated sodium-chloride water solution and wash organic layer after the extraction, through dehydrating and vacuum concentration, obtain 3 then, 5-two chloro-2-(hydroxyl boron) phenol.
Synthetic method of the present invention has successfully been used area of computer aided medicine small molecules designing technique, for the topic design of anticancer section and research and development and successfully synthesized some brand-new and active very high small molecules, have synthesis technique maturation, with short production cycle, environmentally friendly, superiority such as cost is low.
Embodiment
One, synthetic method:
The raw material that the present invention uses all comes from market sale.
Below " DMF " be dimethyl formamide, " DMAP " is dimethyl aminopyridine, " TBME " is methyl tertiary butyl ether, " Me " is meant methyl, and " TEA " is triethylamine, and " i-PrOH " is Virahol, " DMSO " is dimethyl sulfone, " DCM " is methylene dichloride, and " TLC " is tlc, and " MTBE " is methyl tertiary butyl ether.
Following reactions steps has illustrated a kind of synthetic route of the present invention:
The concrete operations explanation of each reactions steps:
1, the synthetic method of the 1H-pyrroles of compound diethyl ester-2,4 dicarboxylic acid (2):
Earlier with (4.56 grams, 40mmol) isocyano acid B ester (1) and (9.2 grams, 60mmol) 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) is dissolved in the tetrahydrofuran (THF) of 200 ml, form solution, in solution, add the p type formaldehyde of 80mmol again, and reaction mixture is placed stirring reaction under 50 ± 0.5 ℃ of environment; Through 5 hours, question response is cooled to normal temperature with reaction mixture after finishing, wash reaction mixture with 100ml saturated sodium bicarbonate aqueous solution and twice collection of 100ml saturated sodium-chloride water solution respectively with the 500ml ethyl acetate again, then the ethyl acetate organic layer that merges is dehydrated with sodium sulfate, again through vacuum concentration, collect 3.0 grams, yield is the 1H-pyrroles-2 of 36% diethyl ester, the thick product of 4 dicarboxylic acid (2), thick product is the faint yellow solid shape, need not to be further purified and can be directly and be used for next step reaction.
1H?NMR?(400MHz,?DMSO-D
6).ppm?1.52-1.58?(t,6H)，?1.891.98?(m,?6H)，?2.45-2.55?(m,?4H)?，4.32?(br,s,1H)，?5.23(s,?1H)?，7.09(s,?1H)?，8.23?(s,?1H)。
2, the amino diethyl-1H of compound 1--pyrroles-2,4 dicarboxylic acid (3) is synthetic:
With (3.0 grams, 14.3mmol) 1H-pyrroles-2 of diethyl ester, 4 dicarboxylic acid (2), (2.3 grams, 42.9mmol) ammonium chloride, (6.9 grams, 17.16mmol) methyl trioctylphosphine ammonium chloride and (14.3 milliliters, 28.6mmol) 2N aqueous sodium hydroxide solution mix with the 200ml methyl tertiary butyl ether, form solvent, in solvent, add the dense ammonium of 40ml, and then add the 30ml Javelle water, again the reaction mixture that forms was stirred 6 hours at ambient temperature.After reaction is finished, reaction mixture is filtered, remove solid salt, get filtrate and wash twice with 100ml saturated sodium bicarbonate aqueous solution and 100ml saturated sodium-chloride water solution collection respectively, then the ethyl acetate organic layer that merges is dehydrated with sodium sulfate, again through vacuum concentration with the 500ml ethyl acetate, collect the amino diethyl-1H of the 2.4 gram 1--pyrroles-2 who is the faint yellow solid shape, the thick product of 4 dicarboxylic acid (3), yield is 75%, need not to be further purified and can be directly and be used for next step reaction.
1H?NMR?(400MHz,?DMSO-D
6).ppm?1.52-1.58?(t,6H)，?2.45-2.55?(m,?4H)，?4.45?(br,s,2H)，?7.24?(s,?1H)，?8.34?(s,?1H)。
3, [1,2, the 4] triazines-6-carboxylic acid (4) of compound diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] is synthetic:
Will (2.4 grams, 10.7mmol) the amino diethyl-1H of 1--pyrroles-2,4 dicarboxylic acid (3) and (19.7 grams, 171.2mmol) chloromethane amidine hydrochloride drops in methyl-sulphoxide (DMSO) solvent of 200ml 150 ℃ of stirrings 1 hour.Reaction finishes postcooling to normal temperature, wash reaction mixture twice with 100ml saturated sodium bicarbonate aqueous solution and 100ml saturated sodium-chloride water solution collection respectively with the 500ml ethyl acetate again, merge the ethyl acetate organic layer after collection is washed, dehydrate with sodium sulfate, again through vacuum concentration, obtain diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid (4) carries out purifying with recrystallization method again and collects 1.45 gram diethylamino-4-4-hydroxyl pyrrolo-es [2 that are the pale powder shape, 1-f] [1,2,4] triazine-6-carboxylic acid (4), yield is 61%.
1H?NMR?(400MHz,?DMSO-D
6).?ppm?1.52-1.58?(t,3H)，?2.45-2.55?(m,?2H)，?6.53?(br,s,2H)，?7.12(s,?1H)，?8.35(s,?1H)，?10.23(s,?1H)。
4, [1,2, the 4] triazines-6-carboxylic acid (5) of compound ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] is synthetic:
With (1.45 grams, 6.6mmol) diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (4), 6ml dimethyl formamide, (1.01ml, 3.2mmol) thionyl chloride and dichloromethane solution carried out back flow reaction 3 hours.Reaction mixture, wash reaction mixture with 100ml saturated sodium bicarbonate aqueous solution and twice collection of 100ml saturated sodium-chloride water solution respectively with the 500ml ethyl acetate again, getting the ethyl acetate organic layer that merges after collection is washed dehydrates with sodium sulfate, again through vacuum concentration, obtain ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] the thick product of [1,2,4] triazine-6-carboxylic acid (5).With recrystallization method thick product (5) is carried out purifying again, collect be the pale powder shape 1.8 the gram ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-es [2,1-f] [1,2,4] triazine-6-carboxylic acid (5), yield is 91%.
1H?NMR?(400MHz,?DMSO-D
6).ppm?1.28（d,?J=5.81Hz,?6H），1.52-1.58?(t,3H)，?2.45-2.55?(m,?2H)，?4.56-4.89(m,?1H)，?6.53?(br,s,2H)?7.12(s,?1H)，?8.35(s,?1H)，?10.23(s,?1H)。
5, compound ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazines-6-carboxylic acid (6) is synthetic:
With (1.8 grams, 6.5mmol) ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (5) and (31ml, 332mmol) phosphorus oxychloride stirred 30 minutes energetically at 100 ℃, and the color of question response mixture has become even brown and continued then to heat extra 30 minutes.Then reaction mixture is placed ice or pond to be cooled to 0 ℃ rapidly, use the NaOH aqueous solution titration of 2N then, adjust the pH value to 7.2 of reaction mixture.Consequent white suspension, filter then, clean with the 600ml ethyl acetate, filtrate is scooped up with salt solution and is got, and organic layer dehydrates with sodium sulfate, again through vacuum concentration, obtain ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] the thick product of [1,2,4] triazine-6-carboxylic acid (6); Recycle silicon glue post carries out purifying (with ethyl acetate/normal hexane to thick product (6), the 0-30% solvent), the product of collecting purifying is 1.2 gram (4.23mmol) ethyls, 4-chloro-, 2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-es [2 that are the faint yellow solid shape, 1-f] [1,2,4] triazine-6-carboxylic acid (6), yield is 65%.
1H?NMR?(400MHz,?DMSO-D
6).ppm?1.28（d,?J=5.81Hz,?6H），1.52-1.58?(t,3H)，?2.45-2.55?(m,?2H)，?4.56-4.89(m,?1H)，?6.53?(br,s,2H)，?7.12(s,?1H)?8.35(s,?1H)。
6, compound 3, the synthetic route of 5-two chloro-2-(hydroxyl boron) phenol (7 is F):
6.1 compound two iodo-3,5-chlorophenesic acid (2) is synthetic:
To (70 grams, 0.43mol) to 3, the 5-chlorophenesic acid is mixed the back at 1 liter dry toluene and add (51.5 grams, 1.29mol) sodium hydride under 0 ℃ and nitrogen atmosphere.Reaction mixture is risen to room temperature, and stirred 30 minutes, consequent suspension is cooled back 0 ℃, slowly add (253.8 grams, 91.5mol) iodine then.Get last reaction mixture stirring and be placed on 0 ℃ to the environment of room temperature, after at least 24 hours, quench with 1 liter 1N hydrochloric acid soln successively and separate reaction mixture, quench with 1 liter of ethyl acetate and to get, separate, quench with 100 ml saturated sodium-chloride water solutions then and wash with ethyl acetate layer, the organic layer that getting quenches after washing dehydrates with sodium sulfate, through vacuum concentration, obtain two iodo-, 3,5-chlorophenesic acid crude product again.Again two iodo-, 3,5-chlorophenesic acid crude product is carried out purifying (with ethyl acetate/normal hexane, the 0-20% solvent) with silicagel column, the product of collecting purifying is that 85 grams, yield are two iodo-, 3,5-chlorophenesic acid (2) of 68%, and solid state is white in color.
6.2 compound 1,5-two chloro-3-(methoxy ethoxy)-2-iodobenzene (3) synthetic:
Will (67 grams, 0.23mol) two iodo-, 3,5-chlorophenesic acid (2), (31.8 grams, 0.29mol) chlorine methyl ethyl ether and (63.7 grams, 0.2mol) cesium carbonate mixes with 600 ml dimethyl formamides and also stirred at ambient temperature 2 hours.After question response finishes, with the 500ml ethyl acetate and successively and x3 water of 100 ml and 100ml saturated sodium-chloride water solution quench and wash, the organic layer that getting quenches after washing dehydrates with sodium sulfate, again through vacuum concentration, obtain 1,5-two chloro-3-(methoxy ethoxy)-2-iodobenzene crude product.Recycle silicon glue post carries out purifying (with ethyl acetate/normal hexane, the 0-50% solvent) to crude product, and the product of collecting purifying is 80 grams 1 that are the yellow solid shape, 5-two chloro-3-(methoxy ethoxy)-2-iodobenzene (3), and yield is 99%.
6.3 compound 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane (4) synthetic:
With (77 grams, 0.22mol) 1,5-two chloro-3-(methoxy ethoxy)-2-iodobenzene (3), (57 grams, 0.44mol) 4,4,5,5-methyl-[1,3,2] dioxy boron lane and (92ml, 0.66mol) triethylamine puts in the 500 ml dioxan solution, uses nitrogen purging again 30 minutes, then will (2.7 grams, 0.011mol) palladium and (8.5 grams, 0.22mol) biphenyl-2-Ji-dicyclohexylphosphontetrafluoroborate joins in the reaction mixture, and reaction mixture is being warming up to 80 ℃, stirred 1.5 hours.After cooling down, reaction mixture is successively quenched with 100ml saturated ammonium chloride solution, 100ml water and 100ml saturated sodium-chloride water solution with the 500ml ethyl acetate and is washed.The organic layer that getting quenches after washing dehydrates with sodium sulfate, and through vacuum concentration, obtains 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane crude product.Recycle silicon glue post carries out purifying (with ethyl acetate/normal hexane to crude product, the 0-50% solvent), the product of collecting purifying is to be 2-[2 of brown solid shape, 35 grams, 4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane (4), yield are 45%.
6.4 compound 3,5-two chloro-2-(hydroxyl boron) phenol (F) synthetic:
With (35 grams, 0.1mol) 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane (4) and 200ml anhydrous methylene chloride mix stirring, slowly add (125 grams, 0.5mol) boron tribromide under 0 ℃ of envrionment conditions and nitrogen atmosphere, behind the restir 20 minutes, reaction mixture is poured in the water, and the pH value that adds 100ml 3N sodium hydroxide solution adjustment reaction mixture then is about 10, removes organic layer through separating then.500 ml 1NHCl solution are joined in the isolating water layer, make the pH value of isolating water layer mixed solution be about 3, use 500 milliliters of isolating water layer mixed solutions of ethyl acetate extraction 3 times more respectively.Merge the organic layer after extracting, wash twice with 500 ml and saturated sodium-chloride water solution collection respectively, dehydrate with sodium sulfate then, again through vacuum concentration, collect 40 grams 3 of the solid state that is white in color, 5-two chloro-2-(hydroxyl boron) phenol (F), yield is 80%, need not to be further purified and can be directly and be used for next step reaction.
1H?NMR?(400MHz,?MeOD).ppm?6.875-6.878(d,?1H),?6.727-6.737?(d,?1H)。
7, [1,2, the 4] triazines-6-carboxylic acid (8) of compound ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] is synthetic:
With (1.84 grams, 16.92mmol) yellow soda ash, 33ml water, (1.2 grams, 4.23mmol) ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (6) (1.2 grams, 5.8mmol) (3,5-two chloro-2-(hydroxyl boron) phenol) (F) and 70ml1, after the 4 dioxane hybrid reactions, reaction solution added for several times with nitrogen purging again (490 milligrams, 0.423mmol) tetrakis triphenylphosphine palladium is in reaction mixture.Reaction mixture was stirred 12 hours under 80 ℃ of conditions.Add 100ml water behind the cool to room temperature again, this water mixture is used the 500ml ethyl acetate extraction respectively 2 times.Merge the organic layer after extracting, come together with the 100ml saturated sodium-chloride water solution and to wash, dehydrate with sodium sulfate then, again through vacuum concentration, collect ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid, again crude product is carried out purifying (with ethyl acetate/normal hexane, the 0-50% solvent) with silicagel column, the product of collecting purifying is for being light gray solid (1.34 grams, 3.17mmol) ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (8), yield is 75%.
1H?NMR?(400MHz,?DMSO-D
6).ppm?1.28（d,?J=5.81Hz,?6H），1.52-1.58?(t,3H)，?2.45-2.55?(m,2H)，?4.56-4.89(m,1H)，?6.53?(br,s,2H)，?6.95(d,J=1.77Hz,?1H)，?7.08-7.21?(m,1H)，?7.32(s,?1H)，?8.35(s,?1H),10.67(s,?1H)。
8, [1,2, the 4] triazines-6-carboxylic acid (9) of compound diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] is synthetic:
With (12 ml, 48mmol) the dioxan solution of 4M hydrochloric acid, (1.34 grams, 3.17mmol) ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (8) and 10 ml methanol mixed and at room temperature stirring reaction 12 hours.Reaction solution neutralizes with saturated sodium carbonate solution after vacuum-evaporation again, obtains water mixture.Water mixture is used 500 ml ethyl acetate extractions 2 times respectively, the organic layer that merges after extracting is washed with 100ml and saturated sodium-chloride water solution collection, dehydrate with sodium sulfate then, collect diethylamino-4-(2 through vacuum concentration again, 4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] the thick product of [1,2,4] triazine-6-carboxylic acid.Crude product is carried out purifying (with ethyl acetate/normal hexane with silicagel column, the 0-50% solvent), the product of collecting purifying is for being light gray solid, (1.01 grams, 2.69mmol) diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) [1,2 of pyrrolo-[2,1-f], 4] triazine-6-carboxylic acid (9), yield is 85%.
1H?NMR?(400MHz,?DMSO-D
6).ppm?1.52-1.58?(t,3H)，?2.45-2.55?(m,2H)，6.53?(br,s,2H)，?6.95(d,J=1.77Hz,?1H)，?7.08-7.21?(m,1H)，?7.32(s,?1H)，?8.35(s,?1H),10.67(s,?1H)。
9, [1,2, the 4] triazine-6-carboxylic acid (11) of compound diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] is synthetic:
With (1.12 grams, 8.07mmol) salt of wormwood, (1.05 the gram, 8.07mmol) 1-(2-chloroethyl)-1H-pyrazoles (10), (1.01 the gram, 2.69mmol) diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] [1,2,4] triazines-6-carboxylic acid (9) and 70 ml dimethyl formamides 120
oMix stirring reaction under the C condition, to be cooled after room temperature through 12 hours, add 100ml water and 500ml ethyl acetate to reaction mixture, and stirred 30 minutes, form water mixture.This water mixture is used the ethyl acetate extraction 2 times of 500ml respectively, merge the organic layer after extracting, wash with 100ml and saturated sodium-chloride water solution collection, dehydrate with sodium sulfate then,, collect diethylamino-4-{ 2 again through vacuum concentration, 4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-thick product of 6-carboxylic acid.Again crude product is carried out purifying (with ethyl acetate/normal hexane with silicagel column, the 0-50% solvent), the product of collecting purifying is (0.741 gram that is the faint yellow solid shape, 1.64mmol) diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (11), yield is 61%.
1H?NMR?(400MHz,?DMSO-D
6).ppm?1.52-1.58?(t,3H)，?2.45-2.55?(m,2H),3.29-3.59（m,1H）,?3.77(d,J=22.8Hz,1H),4.20-4.28(m,?1H),?4.29-4.35(m,?2H),?6.53?(br,s,2H)，?6.95(d,J=1.77Hz,?1H)，7.01(s,?1H),7.04(s,?1H),?7.08-7.21?(m,1H)，?7.32(s,?1H)，?8.35(s,?1H)。
10, [1,2, the 4] triazines-6-carboxylic acid (12) of compound 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] is synthetic:
With (4 ml, 8.2mmol) the 2N aqueous sodium hydroxide solution, (0.741 the gram, 1.64mmol) diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (11) and 20ml ethanol mix and stirring reaction 12 hours at room temperature.Add 2N aqueous hydrochloric acid solution then, make the pH value of the mixture of reaction be about 7.0.Again respectively with the mixture of 500 ml ethyl acetate extractions reactions 2 times.Merge the organic layer after extracting, come together with 100ml and saturated sodium-chloride water solution and to wash, dehydrate with sodium sulfate again, again through vacuum concentration, collect and be light gray solid, (0.554 gram, 1.28mmol) 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (12), yield is 78%, need not to be further purified and can be directly and be used for next step reaction.
1H?NMR?(400MHz,?DMSO-D
6).ppm?3.29-3.59（m,1H）,?3.77(d,J=22.8Hz,1H),4.20-4.28(m,?1H),?4.29-4.35(m,?2H),?6.53?(br,s,2H)，?6.95(d,J=1.77Hz,?1H)，7.01(s,?1H),7.04(s,?1H),?7.08-7.21?(m,1H)，?7.32(s,?1H)，?8.35(s,?1H)，10.67（s，1H）。
11, compound 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[[1,2, the 4] triazines-6-methane amide (13) of 2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f] synthetic:
With (490 milligrams, 2.56mmol) 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC HCl), (0.554 the gram, 1.28mmol) 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid (12), (146 milligrams, 2.56mmol) cyclopropylamine, (0.53 ml, 3.84mmol) triethylamine and 10 ml dimethyl formamides mix and stirring reaction 12 hours at room temperature.After question response finished, reaction mixture was used 500 ml ethyl acetate extractions 2 times respectively.Merge the organic layer after extracting, come together with 100ml saturated sodium bicarbonate aqueous solution and 100ml and saturated sodium-chloride water solution and to wash, dehydrate with sodium sulfate then, again through vacuum concentration, collect 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[[1 of 2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f], 2,4] the thick product of triazine-6-methane amide.Crude product is carried out purifying (with ethyl acetate/normal hexane with silicagel column, the 0-50% solvent), the product of collecting purifying is for being light pale solid, (490 milligrams, 1.04mmol) 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[[1,2 of 2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f], 4] triazine-6-methane amide (13), yield is 81%.
1H?NMR?(400MHz,?DMSO-D
6).ppm?0.33-0.44(m,?2H),0.46-0.59(m,2H),?0.80-0.91(m,1H),3.29-3.59（m,1H）,?3.77(d,J=22.8Hz,1H),4.20-4.28(m,?1H),?4.29-4.35(m,?2H),?6.23(d,?J=2.78Hz,?1H),6.53?(br,s,2H)，?6.95(d,J=1.77Hz,?1H)，7.01(s,?1H),7.04(s,?1H),?7.08-7.21?(m,1H)，?7.32(s,?1H)，?8.35(s,?1H)。
Two, adopt all right synthetic compound 14-17 of above-described similar synthetic method, its molecular structural formula and analytical data see the following form:
Three, the biochemical analysis of heat shock protein 90:
The evaluated biological activity of The compounds of this invention uses flicker to detect the biological activity of heat shock protein 90 in conjunction with experiment near (SPA) competition.No matter be total length or N-end heat shock protein 90, wherein be loaded with its C-end and yttrium silicate glimmered pearl in conjunction with the label of copper by it in conjunction with 6 click labels.Tritium propyl group geldanamycin, its structure is as follows to be a natural inhibitor derivative.It comprises the Ge Erde (pGA) that tritium is handled propyl group amine group that tritium handles and is added on No. 17 positions, and the combination of heat shock protein 90 also makes its band bead eyes isotropic substance.17-N-propyl group amine-Ge Erde can by U.S. Patent number be 4261,989 described in writing come synthetic and as with reference to file.Second tritium handle compound, also can use in this experiment as follows, and as a specified compd A.
In the following formula, " T " indicates the position of the hydrogen atom mark of tritium processing in the structure of compd A.This compound has K
d: the biological activity of 40nM and can synthesizing as follows.Compd A synthesizes from parent compound.N-allyl group-2-(5-chloro-, 2,4-dihydroxy-benzene formyl) isoindoline-1-methane amide is pressed following synthetic explanation:
(2.5 milliliters of allyl amines, 5.0mmol, in the 2M tetrahydrofuran solution) join reaction solution mixture tertiary butyl carboxylamine (R, S) 1, (263 milligrams of 3-dihydros-2H-isoindole carboxylic acid, 1.0mmol), diisopropyl ethyl amine (0.9 milliliter, 5.0mmol) and 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester; 2-(7-azepine benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (420 milligrams, 1.1mmol) 5.In 0 milliliter the dimethyl formamide and under nitrogen atmosphere, and at room temperature stirred 12 hours.This mixture extracts with ethyl acetate (500 milliliters of x2), the organic layer that merges is to come together to wash then with saturated sodium bicarbonate aqueous solution (100 milliliters) and bittern (100 milliliters) to use (sodium sulfate) to dehydrate then to collect thick product through vacuum concentration, crude product carries out purifying (with ethyl acetate/normal hexane with silicagel column, the 0-50% solvent) product of collection purifying is the tertiary butyl-1-[(allyl amino) carbonyl]-1,3-dihydro-2H-isoindole-2-carboxylic acid (321 milligrams, quantitative output).
The 4M hydrochloric acid soln in dioxan (3.0 milliliters, 12mmol) join the reaction mixture tertiary butyl-1-[(allyl amino) carbonyl]-1,3-dihydro-2H-isoindole-2-carboxylic acid (1.0mmol) is in 5.0 milliliters of methylene dichloride and 40
o(at room temperature stirred again 12 hours in about 4 hours under the C.This mixture collects that oily product N-allyl group isoindoline-1-methane amide need not to be further purified and can be directly and be used for next step reaction through vacuum concentration.
N-allyl group isoindoline-1-methane amide (1.0mmol) joins reaction solution mixture pentachloro--2,4-two (methoxymethoxy) phenylformic acid (can by the patent No. be described in WO2006/1175669 writes come synthetic and as with reference to file) (340 milligrams, 1.2mmol), (2.2 milliliters of 4-methylmorpholines, 20.0mmol), (460 milligrams of 1-ethyls-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC HCl), 2.4mmol) and (330 milligrams of 1-hydroxy benzo triazoles, 2.4mmol) in 12 milliliters the dimethyl formamide and under nitrogen atmosphere, and at room temperature stirred 12 hours.Add water (50 milliliters) stopped reaction in the reaction mixture; this mixture extracts with ethyl acetate (500 milliliters of x2); the organic layer that merges is to come together to wash then with saturated sodium bicarbonate aqueous solution (100 milliliters) and bittern (100 milliliters) to use (sodium sulfate) to dehydrate then to collect thick product through vacuum concentration; crude product carries out purifying (with ethyl acetate/normal hexane with silicagel column; the 50-60% solvent) the required intermediates of collection purifying are (423 milligrams; 92% earning rate) N-allyl group-2-[5-chloro-2,4-two (methoxymethyl) benzoyl] isoindoline-1-methane amide.
4M hydrochloric acid soln in dioxan (3.0 milliliters; 12mmol) join reaction mixture N-allyl group-2-[5-chloro-2; 4-two (methoxymethyl) benzoyls] isoindoline-1-methane amide (392 milligrams 0.85mmol) were also at room temperature stirred 12 hours in 5.0 milliliters of methylene dichloride.Adding saturated sodium bicarbonate aqueous solution then is neutralized to the pH value and is about 7.0.This mixture extracts with ethyl acetate (500 milliliters of x2), the organic layer that merges is to come together with bittern (100 milliliters) to wash then that to use (sodium sulfate) to dehydrate then the finished product of collecting needs through vacuum concentration be (221 milligrams of parent compounds, 70% earning rate) isoindoline-1-methane amide solid that is white in color N-allyl group-2-(5-chloro-2,4-dihydroxy-benzene formyl).
1H?NMR?(400MHz,?DMSO-D
6).ppm?3.57（d,J=79.33Hz,2H）,4.65-4.93(m,1H),4.97-5.19(m,1H),5.42-5.60(m,1H),5.68-5.95(m,1H),6.40-6.71(m,1H),6.92(s,1H),7.15-7.67(m,4H),8.28(s,1H),10.06(s,1H),10.40(s,1H)。Anal.Calcd.forC
19H
17ClN
2O
4:?C,61.21;H,4.60;N,7.51,Found:C,61.02;H,4.62;N,7.36?。
In case prepared parent compound, the preparation of compd A is just used the standard hydrogenation preparation method and is used tritium gas.Test signal send the isotropic substance excitement flicker this will create a measurable signal that sends flicker.When competitive compound added in the mixture of test, Ge Erde (pGA) that the constraint tritium of their competitions is handled or compd A were to ATP-binding site N-end heat shock protein 90 terminal.When compound was replaced Ge Erde (pGA) or tagged compound A, signal reduced (beta-particle is no longer with approaching with pearl).The signal of this minimizing be used for quantizing to a certain extent your moral (pGA) of inhibitor/compound dative or the cut-throat competition between the compd A.
For
3The survey inspection of H-pGA (being appointed as G1) and compd A (being appointed as G2) SPA, (the peaceful Corning#3604 of section) carried out in the combination of heat shock protein 90 in the flat white dish in 96 holes.For G1, comprise 30nM heat shock protein 90 and 200nM in the typical reaction solution
3The binding buffer liquid of H-pGA (100mM substratum, pH7.5 and 150mM Repone K).For G2, comprise 5nM heat shock protein 90 and 50nM compd A in the typical reaction solution.For G1,
3H-pGA at first be diluted to 33% label and not mark pGA its be synthesized that to give final concentration with purifying be 200nM.For G2, the compd A of mark and nonlabelled compound A dilution provide a mark: no label ratio is that its final concentration of 1:2 is 50nM.Inhibitor join heat shock protein 90/
3H-pGA(or heat shock protein 90/compd A) in the solution of 11 kinds of different concns as the mensuration of the activity (Ki) of enzyme.The concentration range of inhibitor is 100uM or can be with suitable concentration range for solid sample, can be with the concentration range of 10uM for the target compound storehouse, and liquid sample can be with the concentration range of 10mM.In order determine to suppress active per-cent, compound will 1 and 10uM test.Sample concentration in dimethyl sulphoxide solution is 4%.Copper label-Ysi pearl (Amersham#RPNQ5096) is used for being diluted in binding buffer liquid and is added to then that to give ultimate density in every dish hole be the every hole of 100ug/.After model is sealed, cover cover lid, and at room temperature shook 30 minutes with aluminium foil.The model inner integument allowed clear fixed 30 minutes to use the instrument of the topcount NXT of Hewlett-Packard to count then.This process has also adopted medium-sized throughput capacity and has used the instrument of Beckman Biomek FX to test.Sample test in duplicate and with two independent dates to guarantee the mensuration of the activity of enzyme (Ki) accurately.
For the mensuration of the activity (Ki) of enzyme, use GraphPad Prim software and with the correct actual cpm ' s of cpm ' s(background subtraction) and the concentration of inhibitor draw.These data are to be fit to general IC
50Equation, Y=YI/ (1+[X]/IC
50), wherein YI=Y-intercept and [X] they are competition part/inhibitor.Its IC
50Be used to the Ki that calculates at that time and passed through the Cheng-Prusoss equation:
Wherein, Cl=is cold ligand concentration (variable), hI=be heat ligand concentration (200nM or 50nM) and Kd{hI}=240nM (for
3H-pGA) or 40nM(for compd A).Following its IC of error calculation method
50Error/IC
50Value=relative error, fraction error: * Ki value/Ki error.
In some cases, inhibitor so closely combines with heat shock protein 90 free inhibitor molecules to be shown annotate and loses the enzyme inhibitor complex that forms thus, and therefore above-mentioned equation no longer includes value.This is normally as viewed IC
50For approximately identical with the concentration of heat shock protein 90.For the inhibitor of combining closely, will be suitable for following formula:
EL and EL are the mixtures that there is and lacks inhibitor in radioligand-heat shock protein 90, EL/EL
oBe illustrated in inhibitor and have fractional signal, I
o, E
oAnd L
oBe respectively inhibitor, the concentration of heat shock protein 90 and radioligand.Ki is the inhibition constant part of part, K
LIt is the affinity constant between enzyme (heat shock protein 90) and the part.
Following table is that the Ki of compound 13-17 detects data:
| Compound # | (G2) the active Ki (nM) of enzyme | Half inhibiting rate Akt Lum:IC 50（uM） |
| 13 | 50.65 | 0.55 |
| 14 | 100.75 | 2.44 |
| 15 | 10.32 | 0.051 |
| 16 | 25.82 | 0.61 |
| 17 | 210.75 | 4.55 |
The active Ki and the half inhibiting rate Akt Lum:IC of the enzyme of compound 13-17 in the last table
50Detect obvious this compound of data and have certain anti-tumor bioactivity, when compound of the present invention and its esters and ATP-binding site N-end heat shock protein 90 terminal closely fashionable, can suppress heat shock protein 90 (Hsp90), impel the Hsp90 effect protein that in the tumor growth signal path, plays an important role by the ubiquitin degraded, thereby a plurality of target spots of blocking-up tumor proliferation growth signals path effectively stop growth of tumor.The active Ki of enzyme and half inhibiting rate Akt Lum:IC
50Numerical value show that the biological activity of this compound is strong more more for a short time, with tumour cell higher avidity, optionally killing tumor cell are arranged.
Heat shock protein 90 (Hsp90) participates in regulation and control, keeps the conformation and the function of multiple protein in the cell as molecular chaperones, to help cell normal growth under stress environmental stimulus.A lot of oncogene proteins are the action target spot of Hsp90, and the function that therefore suppresses Hsp90 will promote the degraded of these oncogene proteins to help cancer therapy.
The anti-tumor activity that compound of the present invention and its esters biochemical analysis and the experiment in vivo and vitro by heat shock protein 90 confirmed the Hsp90 inhibitor, the performance of the antitumor action that is characterized as them of compound 13 to 17 of the present invention mainly depends on by proteoclastic approach and makes those oncogene proteins, protein kinase inactivation, rather than directly suppresses kinase whose catalytic activity.The main mechanism that immunoprecipitation and avidity experiment disclose compound of the present invention is to realize by the combination with Hsp90.X one ray crystalline diffraction and Biochemistry Experiment result show that compound of the present invention can compete the ATP-binding site of Hsp90, suppress the endogenous of Hsp90 and the activity of ATP enzyme.Experiment in vitro confirms: compound of the present invention can make tumour cell enter stationary phase, also can bring out cell generation apoptosis.Compound of the present invention is held combination by the N with Hsp90, suppresses endogenic atpase activity.Compound effects of the present invention is in the N of Hsp90 end ATP/ADP binding site.It is the micromolecular compound that the consequence devised according to x one ray crystalline diffraction obtains.Can degrade the equally action protein of a lot of Hsp90 of compound of the present invention.
Four, the note of relational language:
" pharmaceutically acceptable preparation " refers to the combination of compound or physiology/pharmacy acceptable salt and the carrier and the auxiliary material of this invention.Use known artistic technical ability and usual procedure and carry out the preparation of reagent combination.For example, compound of the present invention can be formulated common auxiliary material diluent or carrier and form tablet, capsule, or the like.These auxiliary material diluent or carriers comprise following content: filler and weighting agent such as starch, sugar, N.F,USP MANNITOL, and silica derivative; As carboxymethyl cellulose and other derivatived cellulose tackiness agents, alginate, gelatin, polyvinylpyrrolidone, wetting Agent for Printing Inks such as glycerine; Disintegrating agent such as polyvidone, Starch Sodium oxyacetic acid, Xylo-Mucine, agar, lime carbonate, sodium bicarbonate; Retardant such as paraffin absorb accelerator such as quarternary ammonium salt compound; Tensio-active agent such as hexadecanol, Zerol; Absorption carrier such as kaolin, wilkinite; Lubricating oil such as talcum powder, calcium stearate, magnesium and solid polyethylene glycol.Last preparation may be a pill, tablet, and pulvis, lozenge, capsule, or aseptic packaging powder, this depends on the type of the use of auxiliary material.In addition, it is special pharmaceutically acceptable preparation.
" heat shock protein 90-amount of suppression " be meant The compounds of this invention quantity or physiology/pharmacy acceptable salt need suppress in vivo the heat shock protein 90 enzyme activity as Mammals, or external.The required amount of this compound causes this inhibition can determine to need not to test described and those the known ordinary skills of using method.
" activity of heat shock protein 90 inhibitory enzyme " mean by The compounds of this invention and contacting of enzyme reduce the heat shock protein 90 enzyme at external or intravital functional activity as in the Mammals and the mankind.
" treatment significant quantity " is meant that the quantity of compound of the present invention or physiology/pharmacy acceptable salt is administered into Mammals to the required enough results of treatment of this treatment.It is so-called that " " be meant that some amount is enough to regulate or suppress the activity of heat shock protein 90 enzyme, it makes the situation of disease reduce or alleviate by the activity of the heat shock protein 90 enzyme of mediation to the treatment significant quantity.
" control " in " treatment " and be meant any heat shock protein 90 mediation to Mammals, particularly Human diseases treatment.Comprising: the disease that 1) prevents or the generation of situation, 2) adjusting or inhibition disease or situation, promptly stop its development, 3) palliate a disease or situation, promptly cause disease or the situation or 4 cause of restoring) alleviate and/or palliate a disease or situation, cause the disease or the situation of these symptoms, reaction for example reduces inflammation.About cancer, this means that just the influence of a people's life-span and cancer will increase or the symptom of one or more diseases can reduce.
Speaking of treatment for cancer, what the treatment significant quantity referred to has one of following effect at least: the size that 1) reduces tumour; 2) suppress (that is, slow down to a certain extent, preferably stop) metastases; 3) suppress (that is, slow down to a certain extent, preferably stop) growth of tumor to a certain extent; 4) alleviate to a certain extent (or best, eliminate) the one or more symptoms relevant with cancer.
" compound " refers to any above-claimed cpd, also comprises the description that those are general or the compound of introduction.The solvate that also refers to pharmacy acceptable salt or these compounds.
" growth of undesired cell " except as otherwise noted, is the growth of phalangeal cell, and it is a normal regulation mechanism (for example, the loss of inhibition contact) independently, comprises normal cell growth abnormity and paracytic growth.This includes, but not limited to growth failure: this includes but not limited to tumour cell, supernormal growth: the tyrosine-kinase expression of enzymes of tumor cell proliferation the receptor tyrosine kinase of sudden change or overexpression; In other optimum and malignant proliferation disease cells Tyrosylprotein kinase activate take place unusual; The receptor tyrosine kinase of any tumor cell proliferation; The paraplasm serine/threonine kinase of any tumour activates and takes place; The activation of other the unusual serine/threonine kinases in the optimum and malignant cell proliferative disease takes place; An optimum and pernicious activated RAS oncogene expression; Tumour cell, optimum and pernicious, wherein RAS albumen is to cause activating carcinogenic in another kind of transgenation; The other diseases optimum and malignant cell is bred, wherein the activation of RAS takes place unusual.The example of this benign proliferative diseases is a psoriasis, benign prostate hyperplasia, Human papilloma virus HPV (HPV)." growth of undesired cell " also refers to, comprises the misgrowth of cell, and be optimum and pernicious, produces from the farnesyl-protein transferase activity.
The application of " paracytic growth " and " super hyperplasia disease " is to exchange use.
" three-dimensional arrangement " refers to have the chemical structure of identical compound, but the space of arranging for different atoms or functional group.
" enantiomorph " refers to that the compound of two steric isomers is not surpass each other to apply mirror image.
" racemization " or " racemic mixture " refer to the mixing of a certain specific compound enantiomorph 1:1.
" diastereomer ", on the other hand, two or more center of asymmetries that isomer between being meant is formed can not reflect that image is to each other relation.
" medicament combination " refers to the described mixture of one or more compounds, or physiology/pharmacy acceptable salt, solvate, hydrate, or prodrug and with other chemical ingredientss, as or physiology/pharmaceutically acceptable carrier and auxiliary material.The purpose of medicine composition is in order to promote a compound to be entered as mammiferous organism, comprises the mankind.
The cancer cell that the present invention is used to handle abnormal cell growth includes but not limited to: mesothelioma, liver and gall (liver and biliary tract), first phase or the second stage of central nerve neuroma, first phase or the second stage of cerebral tumor, lung cancer (nonsmall-cell lung cancer and nonsmall-cell lung cancer), osteocarcinoma, cancer of pancreas, skin carcinoma, head or neck cancer, skin or intraocular melanochrome tumour, ovary, colon, the rectum cancer, anal regions cancer, cancer of the stomach, gi tract (stomach, large intestine, duodenum) cancer, mammary cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, uterine cervix, vagina, carcinoma vulvae, Hodgkin's disease, esophagus, intestinal tumor, the cancer of endocrine system, Tiroidina, parathyroid gland, adrenal carcinoma, soft tissue sarcoma's cancer, urethra, penile cancer, prostate cancer, carcinoma of testis, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder, kidney, ureter, carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, central nerve neuroma, primary central nervous system lymphoma, non-Hodgkin lymphoma, the spinal column axis tumour, brain stem glioma, pituitary adenoma, adrenal cortex, the courage bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or by the combination of one or more above-mentioned cancers.
The cancer cell that the present invention is used to handle abnormal cell growth comprises: a benign proliferative diseases but be not limited to psoriatic, benign prostatic hyperplasia.
In embodiment of the invention cancer is that first-selection is selected from lung cancer (nonsmall-cell lung cancer and nonsmall-cell lung cancer), head or neck, ovarian cancer, colorectal carcinoma, the rectum cancer, anal regions, cancer of the stomach, mammary cancer, kidney or carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, central nerve neuroma, primary central nervous system lymphoma, non-Hodgkin lymphoma, spinal column axis tumour or by the combination of one or more above-mentioned cancers.
In another the preferred embodiments of the present invention cancer is to be selected from lung cancer (nonsmall-cell lung cancer and nonsmall-cell lung cancer), head or neck, ovarian cancer, colorectal carcinoma, the rectum cancer, anal regions, cancer of the stomach, mammary cancer, kidney or carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, central nerve neuroma, primary central nervous system lymphoma, non-Hodgkin lymphoma, spinal column axis tumour or by the combination of one or more above-mentioned cancers.
In a preferred embodiment, cancer of the present invention is to be selected from lung cancer (nonsmall-cell lung cancer and nonsmall-cell lung cancer), head or neck, ovarian cancer, colorectal carcinoma, the rectum cancer, anal regions cancer or by the combination of one or more above-mentioned cancers.
Claims (3)
1. the derivative of the antitumor inhibitor 2-of many target spots ammonia pyrroles-triazine, its molecular formula is as follows:
In the following formula,
R1a is hydrogen base, C
1-C
6Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
6-C
14Aryl, C
2-C
9Heteroaryl, C
2-C
9Different cycloalkyl or C
3-C
8Cycloalkyl in optional functional group;
R1b is hydrogen base, C
1-C
6Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
6-C
14Aryl, C
2-C
9Heteroaryl, C
2-C
9Different cycloalkyl or C
3-C
8Cycloalkyl in optional functional group;
R2 is chlorine, fluorine, C
1-C
3Alkyl or 1 to 6 fluorine replace C
1-C
3Alkyl;
R3 is chlorine, fluorine, C
1-C
3Alkyl or 1 to 6 fluorine replace C
1-C
3Alkyl;
R4 is-(C
1-C
6Thiazolinyl)-OH ,-O-(C
1-C
6Alkyl) ,-(C
1-C
6Thiazolinyl)-O-(C
1-C
6Alkyl) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(C
6-C
10-aryl) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(C
3-C
10-cycloalkyl) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(5-10 heterocycle) ,-(C
1-C
6Thiazolinyl)
p -O-(C
1-C
6Thiazolinyl)
p -(3-10 heterocycle) ,-(C
1-C
6Thiazolinyl)
p -O-(C
2-C
6Thiazolinyl) ,-O-(C
2-C
6Thiazolinyl)-(3-10 heterocycle) ,-O-(C
2-C
6Alkyl)-(3-10 heterocycle) or C
1-C
8In the alkoxyl group to any one functional group.
2. the synthetic method of the derivative of the antitumor inhibitor 2-of a many according to claim 1 target spots ammonia pyrroles-triazine is characterized in that may further comprise the steps:
1) 1H-pyrroles-2,4 dicarboxylic acid of synthetic diethyl ester:
With isocyano acid B ester and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene is dissolved in the tetrahydrofuran (THF) earlier, forms solution, adds formaldehyde again in solution, and with reaction mixture stirring reaction under 50 ± 0.5 ℃ of environment; After question response finishes, reaction mixture is cooled to normal temperature, wash reaction mixture with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate again, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain 1H-pyrroles-2,4 dicarboxylic acid of diethyl ester;
2) the amino diethyl-1H of synthetic 1--pyrroles-2,4 dicarboxylic acid:
1H-pyrroles-2 with diethyl ester, 4 dicarboxylic acid, ammonium chloride, methyl trioctylphosphine ammonium chloride, aqueous sodium hydroxide solution mix the formation solvent with methyl tertiary butyl ether, in solvent, add dense ammonium, and then add Javelle water, again with the reaction mixture that forms stirring reaction at ambient temperature; After reaction is finished, reaction mixture is filtered, get filtrate and wash with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain the amino diethyl-1H of 1--pyrroles-2,4 dicarboxylic acid;
3) [1,2,4] triazine-6-carboxylic acid of synthetic diethylamino-4-4-hydroxyl pyrrolo-[2,1-f]:
Amino diethyl-the 1H of 1--pyrroles-2,4 dicarboxylic acid and chloromethane amidine hydrochloride are mixed stirring reaction with methyl-sulphoxide under 150 ± 0.5 ℃ of envrionment conditionss; After reaction mixture is cooled to normal temperature, wash reaction mixture with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid, use the recrystallization method purifying at last, obtain purifying diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
4) [1,2,4] triazine-6-carboxylic acid of synthetic ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f]:
[1,2,4] triazine-6-carboxylic acid of diethylamino-4-4-hydroxyl pyrrolo-[2,1-f] mixed with dimethyl formamide, thionyl chloride, methylene dichloride carry out back flow reaction; After reaction mixture is cooled to normal temperature, wash reaction mixture with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection respectively with ethyl acetate, merge the ethyl acetate organic layer after collection is washed, through dehydrate, vacuum concentration, obtain ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] the thick product of [1,2,4] triazine-6-carboxylic acid; Use the recrystallization method purifying again, obtain [1,2,4] triazine-6-carboxylic acid of ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] of purifying;
5) synthetic ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid:
With ethyl-2-{ (five)-[(dimethylamino) methylene radical] amino }-4-hydroxyl pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid and phosphorus oxychloride stirring reaction under 100 ± 0.5 ℃ of conditions makes the color of reaction mixture become after the even brown insulation 30 minutes; Then reaction mixture is cooled to 0 ℃ rapidly, adjust the pH value to 7.2 of reaction mixture then with NaOH solution, filter back extracting waste suspended substance, clean with ethyl acetate, get filtering filtrate and scoop up with salt solution and get organic layer, again through dehydrating and vacuum concentration, obtain ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid crude product; Carry out purifying with silicagel column at last, obtain ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid of purifying;
6) [1,2,4] triazine-6-carboxylic acid of synthetic ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f]:
With aqueous sodium carbonate and ethyl 4-chloro-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, (3,5-two chloro-2-(hydroxyl boron) phenol) (7) and 1,4 dioxanes mix, and with adding tetrakis triphenylphosphine palladium behind the nitrogen purging again, stirring reaction under 80 ± 0.5 ℃ of conditions; Question response finishes postcooling to room temperature, and then adds entry and form water mixture, with the water mixture ethyl acetate extraction, comes together with saturated sodium-chloride water solution and to wash organic layer after the extraction; Through dehydrating and vacuum concentration, obtain the thick product of [1,2,4] triazine-6-carboxylic acid of ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] then; At last with ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid carries out purifying with silicagel column, obtains the ethyl 4-(2 of purifying, 4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
7) [1,2,4] triazine-6-carboxylic acid of synthetic diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f]:
With [1,2, the 4] triazine-6-carboxylic acid of the dioxan solution of 4M hydrochloric acid and ethyl 4-(2,4-two chloro-6-hydroxy phenyl)-2-{ (five)-[(dimethylamino) methylene radical] amino } pyrrolo-[2,1-f] and methyl alcohol stirring reaction at room temperature; Extract reaction solution after vacuum-evaporation and neutralize with saturated sodium carbonate solution again, use ethyl acetate extraction again; Wash organic layer after the extraction with saturated sodium-chloride water solution collection,, obtain the thick product of [1,2,4] triazine-6-carboxylic acid of diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] then through dehydrating and vacuum concentration; At last with diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] [1,2,4] the thick product of triazine-6-carboxylic acid carries out purifying with silicagel column, obtains the diethylamino-4-(2 of purifying, 4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
8) [1,2, the 4] triazine-6-carboxylic acid of synthetic diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f]:
With [1,2,4] triazine-6-carboxylic acid of salt of wormwood and 1-(2-chloroethyl)-1H-pyrazoles (10), diethylamino-4-(2,4-two chloro-6-hydroxy phenyl) pyrrolo-[2,1-f], dimethyl formamide 120 ± 0.5
oStirring reaction under the C condition; Question response finishes postcooling to room temperature, adds entry and ethyl acetate to reaction mixture again, and restir 30 minutes obtains water mixture; Water intaking mixture ethyl acetate extraction, wash organic layer after the extraction with saturated sodium-chloride water solution collection, then through dehydrating and vacuum concentration, obtain diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-thick product of 6-carboxylic acid; At last with diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-thick product of 6-carboxylic acid carries out purifying with silicagel column, obtains the diethylamino-4-{ 2 of purifying, 4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
9) [1,2,4] triazine-6-carboxylic acid of Synthetic 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f]:
With [1,2, the 4] triazine-6-carboxylic acid of aqueous sodium hydroxide solution and diethylamino-4-{ 2,4-two chloro-6-[2-(hydrogen-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f], ethanol stirring reaction at room temperature; Question response finishes the back and adds aqueous hydrochloric acid, obtains the pH value and be 7.0 ± 1 mixture; With the mixture ethyl acetate extraction, wash organic layer after the extraction with saturated sodium-chloride water solution collection, then through dehydrating and vacuum concentration, obtain 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid;
10) Synthetic 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[[1,2,4] triazine-6-methane amide of 2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f]:
With 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 2-amino-4-{ 2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) oxyethyl group] phenyl } pyrrolo-[2,1-f] [1,2,4] triazine-6-carboxylic acid, cyclopropylamine, triethylamine, dimethyl formamide stirring reaction at room temperature; Question response finishes the back ethyl acetate extraction, wash organic layer after the extraction with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution collection, then through dehydrating and vacuum concentration, obtain 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f] the thick product of [1,2,4] triazine-6-methane amide; At last with 2-amino-N-cyclopropyl-4-(2,4-two chloro-6-[2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f] [1,2,4] the thick product of triazine-6-methane amide carries out purifying with silicagel column, obtains the 2-amino-N-cyclopropyl-4-(2 of purifying, 4-two chloro-6-[2-(1H-pyrazoles-1-yl) ethoxyl phenenyl) pyrrolo-es [2,1-f] [1,2,4] triazine-6-methane amide.
3. according to the derivative synthesizing process of the antitumor inhibitor 2-of the described many target spots of claim 2 ammonia pyrroles-triazine, it is characterized in that describedly 3, the synthesis step of 5-two chloro-2-(hydroxyl boron) phenol is:
1) synthetic two iodo-, 3,5-chlorophenesic acid:
Will be to 3, the 5-chlorophenesic acid is mixed the back and is added sodium hydride aqueous solution react under 0 ℃ and nitrogen atmosphere with dry toluene; Reaction mixture is warmed up to room temperature and stirred 30 minutes, the suspension that forms is cooled back 0 ℃, add iodine then and further react; Getting last reaction mixture stirs and is placed on 0 ℃ to the environment of room temperature after at least 24 hours, quench with aqueous hydrochloric acid successively and separate, quench with ethyl acetate and get, separate, quench with saturated sodium-chloride water solution and wash with ethyl acetate layer, the organic layer that getting quenches again after washing is through dehydrating and vacuum concentration, obtain the thick product of two iodo-, 3,5-chlorophenesic acid; Again the thick product of two iodo-, 3,5-chlorophenesic acid is carried out purifying with silicagel column, obtain two iodo-, 3, the 5-chlorophenesic acid of purifying;
2) synthesize 1,5-two chloro-3-(methoxy ethoxy)-2-iodobenzene:
With two iodo-, 3,5-chlorophenesic acid, chlorine methyl ethyl ether, cesium carbonate and dimethyl formamide stirring reaction at room temperature; Post reaction mixture is washed in water and salt shrend successively, and the organic layer that getting quenches after washing obtains 1, the 5-two chloro-3-thick product of (methoxy ethoxy)-2-iodobenzene through dehydrating and vacuum concentration; With 1,5-two chloro-3-thick product of (methoxy ethoxy)-2-iodobenzene carries out purifying with silicagel column, obtains 1 of purifying again, 5-two chloro-3-(methoxy ethoxy)-2-iodobenzene;
3) Synthetic 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane:
With 1,5-two chloro-3-(methoxy ethoxy)-2-iodobenzene and 4,4,5,5-methyl-[1,3,2] dioxy boron lane and triethylamine use nitrogen purging after 30 minutes in dioxan solution, again palladium and biphenyl-2-Ji-dicyclohexylphosphontetrafluoroborate are joined in the reaction mixture, reaction mixture stirring reaction to reaction under 80 ℃ of conditions is finished; After the question response mixture cooling, successively quench with saturated ammonium chloride solution, water and salt solution and to wash reaction mixture; The organic layer that getting quenches after washing is obtained 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3, the thick product in 2-dioxy boron lane through dehydrating and vacuum concentration; Again with 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3, the thick product in 2-dioxy boron lane carries out purifying with silicagel column, obtain 2 of purifying-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane;
4) synthesize 3,5-two chloro-2-(hydroxyl boron) phenol:
With 2-[2,4-two chloro-6-(methoxy ethoxy) phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxy boron lane and anhydrous methylene chloride mix the back and add boron tribromide react under 0 ℃ and nitrogen atmosphere; Question response is poured reaction mixture in the water into after finishing, and adds aqueous sodium hydroxide solution again, pH value to 10 ± 1 of conditioned reaction mixture; Through separating, remove organic layer; With the pH value to 3 that the adjustment of 1NHCl solution separates the water layer solution obtain, use ethyl acetate extraction again, come together with saturated sodium-chloride water solution and wash organic layer after the extraction, through dehydrating and vacuum concentration, obtain 3 then, 5-two chloro-2-(hydroxyl boron) phenol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100432181A CN102153558B (en) | 2011-02-23 | 2011-02-23 | Derivative of multi-target antitumor inhibitor 2-aminopyrrole-triazine and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100432181A CN102153558B (en) | 2011-02-23 | 2011-02-23 | Derivative of multi-target antitumor inhibitor 2-aminopyrrole-triazine and synthesis method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102153558A true CN102153558A (en) | 2011-08-17 |
| CN102153558B CN102153558B (en) | 2012-11-21 |
Family
ID=44435268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100432181A Expired - Fee Related CN102153558B (en) | 2011-02-23 | 2011-02-23 | Derivative of multi-target antitumor inhibitor 2-aminopyrrole-triazine and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102153558B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204857A (en) * | 2013-05-08 | 2013-07-17 | 兰州聚成生物科技有限公司 | Synthesis method of 4-chlorine-2-(methylmercapto)-7H-pyrrolo [2, 3-D] pyrimidine |
| CN104003990A (en) * | 2013-02-21 | 2014-08-27 | 江苏先声药物研究有限公司 | Heterocyclic amine Hedgehog signal path inhibitor |
| CN105130992A (en) * | 2015-07-16 | 2015-12-09 | 苏州大学 | Nitrogen-containing heterocyclic compound having kinase inhibiting activity, preparation method and application |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024042494A1 (en) * | 2022-08-25 | 2024-02-29 | Molecure Sa | Substituted pyrrolotriazines |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043912A2 (en) * | 2002-11-06 | 2004-05-27 | Bristol-Myers Squibb Company | Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors |
| WO2005066176A1 (en) * | 2003-12-29 | 2005-07-21 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds as kinase inhibitors |
| CN1882589A (en) * | 2003-09-18 | 2006-12-20 | 康福玛医药公司 | Novel heterocyclic compounds as HSP90-inhibitors |
| CN101395158A (en) * | 2006-03-07 | 2009-03-25 | 百时美施贵宝公司 | Pyrrolotriazine aniline prodrug compounds useful as kinase inhibitors |
| WO2010018481A1 (en) * | 2008-08-13 | 2010-02-18 | Pfizer Inc. | 2-amino pyrimidine compounds as potent hsp-90 inhibitors |
-
2011
- 2011-02-23 CN CN2011100432181A patent/CN102153558B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043912A2 (en) * | 2002-11-06 | 2004-05-27 | Bristol-Myers Squibb Company | Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors |
| CN1882589A (en) * | 2003-09-18 | 2006-12-20 | 康福玛医药公司 | Novel heterocyclic compounds as HSP90-inhibitors |
| WO2005066176A1 (en) * | 2003-12-29 | 2005-07-21 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds as kinase inhibitors |
| CN101395158A (en) * | 2006-03-07 | 2009-03-25 | 百时美施贵宝公司 | Pyrrolotriazine aniline prodrug compounds useful as kinase inhibitors |
| WO2010018481A1 (en) * | 2008-08-13 | 2010-02-18 | Pfizer Inc. | 2-amino pyrimidine compounds as potent hsp-90 inhibitors |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104003990A (en) * | 2013-02-21 | 2014-08-27 | 江苏先声药物研究有限公司 | Heterocyclic amine Hedgehog signal path inhibitor |
| CN104003990B (en) * | 2013-02-21 | 2017-09-15 | 江苏先声药业有限公司 | Heterocyclic amine Hedgehog signal pathway inhibitors |
| CN103204857A (en) * | 2013-05-08 | 2013-07-17 | 兰州聚成生物科技有限公司 | Synthesis method of 4-chlorine-2-(methylmercapto)-7H-pyrrolo [2, 3-D] pyrimidine |
| CN105130992A (en) * | 2015-07-16 | 2015-12-09 | 苏州大学 | Nitrogen-containing heterocyclic compound having kinase inhibiting activity, preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102153558B (en) | 2012-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI791511B (en) | apoptosis inducer | |
| CN104470921B (en) | Thiophene miazines derivate, preparation method therefor, and medical application thereof | |
| CN103570725B (en) | Piperazidinoltriazole compound as well as preparation method and application thereof | |
| TWI675840B (en) | Fused pyrimidine compound or salt thereof | |
| CN107200749B (en) | DNA-PK inhibitor | |
| CN104603130B (en) | The salt form of mankind's histone methyltransferase EZH2 inhibitor | |
| CN109071552A (en) | The degradation and application method that cell cycle protein dependent kinase 4/6 (CDK4/6) passes through the conjugation of CDK4/6 inhibitor and E3 ligase ligand | |
| CN104093398B (en) | 7 (6 (2 hydroxy propane, 2 base) 3 base of pyridine) 1 ((trans) 4 methoxycyclohexyl) 3,4 dihydro pyrazines simultaneously [2,3 B] pyrazine 2 (1H) ketone, the pharmaceutical composition of its solid form and its using method | |
| CN110177788A (en) | Compound as BCL-2 selectivity inducer of apoptosis | |
| TWI736578B (en) | Certain protein kinase inhibitors | |
| CN109153675A (en) | The degradation and application method that cell cycle protein dependent kinase 9 (CDK9) passes through the conjugation of CDK9 inhibitor and E3 ligase ligand | |
| EA009920B1 (en) | Pyrimidothiophene compounds | |
| EA016301B1 (en) | Pyrrolopyrimidine compounds and their uses | |
| CN111971287B (en) | Macrocyclic compounds as TRK kinase inhibitors | |
| CN103874494A (en) | Combination therapies for treating hematologic malignancies using pyridopyrimidinone inhibitors of pi3k/mtor with bendamustine and/or rituximab | |
| JP2010503653A (en) | Pyrido (2,3-D) pyrimidinone compounds and their use as PI3 inhibitors | |
| EA024252B1 (en) | Phosphoinositide 3-kinase inhibitors with a zinc binding moiety | |
| CN101228171A (en) | Macrolide conjugates of pyrrolizine and indolizine compounds as inhibitors of 5-lipooxygenase and cyclooxygenase | |
| CN105732615A (en) | CDK kinase inhibitor | |
| TW202028209A (en) | Substituted imidazo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine compounds as ret kinase inhibitors | |
| CN110167941A (en) | Substituted fused heteroaryl compounds are as kinase inhibitor and its application | |
| US20240166617A1 (en) | Phosphoinositide 3 kinase beta inhibitors and compositions and methods thereof | |
| CN102153558B (en) | Derivative of multi-target antitumor inhibitor 2-aminopyrrole-triazine and synthesis method thereof | |
| CN113518779B (en) | Thieno heterocyclic derivative, preparation method and medical application thereof | |
| CN109456331A (en) | A kind of substituted pyrazolo [1,5-a] pyrimidine compound and its pharmaceutical composition and purposes |
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 | ||
| ASS | Succession or assignment of patent right |
Owner name: QINGDAO JIANUOHUA PHARMACEUTICAL TECHNOLOGY CO., L Free format text: FORMER OWNER: YANGZHOU YONGJI MEDICAL NEW TECHNOLOGY CO.,LTD. Effective date: 20140627 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 225600 YANGZHOU, JIANGSU PROVINCE TO: 266400 QINGDAO, SHANDONG PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20140627 Address after: 266400, No. 1003, King Hai Road, Jiaonan, Shandong, Qingdao Patentee after: Qingdao Jia Jia Novartis Medical Technology Co., Ltd. Address before: 225600 building A6, science and Technology Pioneering zone, Changjiang Road, Gaoyou Economic Development Zone, Jiangsu, Yangzhou Patentee before: Yangzhou Yongji Medical New Technology Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20121121 Termination date: 20190223 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |