CN102344443A - Open-loop maleimide compound utilizing click chemosynthesis and application in treating diseases thereof - Google Patents
Open-loop maleimide compound utilizing click chemosynthesis and application in treating diseases thereof Download PDFInfo
- Publication number
- CN102344443A CN102344443A CN2011101977369A CN201110197736A CN102344443A CN 102344443 A CN102344443 A CN 102344443A CN 2011101977369 A CN2011101977369 A CN 2011101977369A CN 201110197736 A CN201110197736 A CN 201110197736A CN 102344443 A CN102344443 A CN 102344443A
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- alkynyl
- assorted
- alkyl
- 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.)
- Pending
Links
Images
Abstract
The invention relates to an open-loop maleimide derivative utilizing click chemosynthesis and having kinase inhibitory activity. The structural general formula of the open-loop maleimide derivative is shown in A. In the formula, R1 and R2 can be a hydrogen atom, alkyl, a naphthenic base, heterocyclic alkyl, heterocyclic alkyl, alkenyl, cyclohexenyl, heterocyclic alkenyl, heterocyclic alkenyl, chain alkynyl, heterocyclic alkynyl, heterocyclic alkenyl, aryl, heterocyclic aryl or glycosyl, wherein R3 is the hydrogen atom or methyl. The open-loop maleimide derivative comprises a compound obtained through performing substitution derivatization or bridging derivatization on the R1 and/or the R2 alternately and repeatedly, and also comprises a compound obtained through performing single-bond linked derivatization on the R1 and the R2. The compounds can be applied to preparing drugs for treating neurodegenerative diseases and cancers.
Description
[technical field]: the invention belongs to the biological medicine technology field, relate to a kind of open loop maleimide compounds that utilizes the click-reaction preparation, synthesis method and their application in preparation treatment tumour or nerve degenerative diseases medicine.
[background technology]: open loop maleimide compounds usually has kinase inhibiting activity.As: gift comes the Ruboxistaurin of company's research and development to belong to the macrocyclic derivatives of bisindole maleimide, is the specific inhibitor of protein kinase C (PKC) β 1 and beta 2 subunit type.This medicine has been used for the treatment of diabetic subject's microvascular complication.
[summary of the invention]:
The implication of related term is following among the present invention:
Alkyl: be meant straight chain or have the aliphatic hydrocarbon group of side chain; Preferentially be chosen as C
1-C
14Alkyl; More preferably be chosen as C
1-C
10Alkyl; The prepreerence C that is chosen as
1-C
6Embodiment is including, but not limited to methyl, ethyl, n-propyl, 2-propyl group, normal-butyl, isobutyl-, tertiary butyl, hexyl etc.
Cycloalkyl: the carbocyclic ring that is meant monocycle, condensed ring or the volution of saturated or fractional saturation.The ring of forming with 3-9 carbon atom is preferential the selection.Instance includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
Assorted alkyl: be meant straight chain or contain the group of branched-chain alkyl, and in main chain, contain one or more S of being selected from least, the heteroatoms of O and N.The preferential chain of selecting to contain 2-14 atom.Assorted alkyl includes but not limited to: ethers, thioether class, alkyl esters, second or trialkyl amines, alkyl sulfinic acid etc.
Heterocyclylalkyl: be meant that containing one at least is selected from N, S, the heteroatomic cycloalkyl of O.Preferably contain 1-3 heteroatoms.Preferred ring is 3-14 person's ring, and more preferably the ring of Xuan Zeing is 4-7 person's ring.Heterocyclylalkyl includes, but are not limited to: pyrrolidyl, pyrrolin base, Pyrrolidine base, pyrazoline base, piperidyl, morpholine tetrahydrofuran base, tetrahydrochysene thio-furan base, THP trtrahydropyranyl etc.
Alkenyl: be meant the aliphatic hydrocarbon group that contains a carbon-to-carbon double bond at least during as a group a part of, can be used as straight chain and also can have side chain.Preferential selection has C
2-C
14Thiazolinyl.C
1-C
12Then better; That the most preferentially select is C
2-C
6Thiazolinyl.This group can contain a plurality of pairs of keys and its conformation can respectively do for oneself E or Z in its main chain.The example of alkenyl group includes, but are not limited to: vinyl, propenyl etc.
Cycloalkenyl group: be meant that some at least carbon-carbon single bonds are replaced by a carbon-carbon double bond in the cycloalkyl.
Assorted thiazolinyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon-carbon double bond in the assorted alkyl.
Heterocycloalkenyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon-carbon double bond in the Heterocyclylalkyl.
Alkynyl group: be meant the aliphatic hydrocarbon group that contains a carbon-to-carbon triple bond at least during as a group a part of, can be used as straight chain and also can have side chain.Preferential selection has C
2-C
14Alkynyl.C
1-C
12Then better; That the most preferentially select is C
2-C
6Alkynyl.This group can contain a plurality of pairs of keys and its conformation can respectively do for oneself E or Z in its main chain.The example of alkynyl group includes, but are not limited to: ethynyl, proyl etc.
Cycloalkynyl radical: be meant that some at least carbon-carbon single bonds are replaced by a carbon carbon triple bond in the cycloalkyl.
Assorted alkynyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon carbon triple bond in the assorted alkyl.
The heterocycle alkynyl: be meant that some at least carbon-carbon single bonds are replaced by a carbon carbon triple bond in the Heterocyclylalkyl.
Aryl: the part as a group or a group is meant: the monocycle or the condensed ring of (1) aromaticity: preferential aromaticity carbocyclic ring (annular atoms is the atoll texture of carbon) of selecting to have 5-12 carbon atom.The instance of aryl includes, but are not limited to: phenyl, naphthyl; (2) can the saturated carbocyclic ring in connection portion, for example: phenyl and C
5-7Cycloalkyl or C
5-7Cycloalkenyl groups system condenses mutually and forms a ring texture.Instance includes, but are not limited to: tetralyl, indenyl or hydrogen indenyl etc.Aromatic yl group can be replaced by one or more substituting groups.
Heteroaryl: be meant the many aromatic heterocyclics of monocycle property or condensed.The preferential selection contained one or more N of being selected from, and O is or/and the heteroatoms 5-7 person aromatic nucleus of S.Typical heteroaryl substituting group comprises instance, but is not limited to: furyl, thienyl, pyrroles, pyrazoles, triazole, thiazole, pyridine, pyrimidine, pyrazine, indoles, benzoglyoxaline etc.
Glycosyl: be meant glucose, semi-lactosi, seminose, deoxyglucose, deoxidation semi-lactosi, deoxidation seminose, glucosamine, galn, epichitosamine etc.
Halogen: fluorine, chlorine, bromine and iodine.
Acyl group: be meant [R-CO-] group, R is an alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl.The instance of acyl group is including, but not limited to ethanoyl, propionyl, isobutyryl, benzoyl etc.
Substituted imido: be meant that (hydrogen atom NH-) is substituted the group that obtains after group replaces, and (NR-), R is an alkyl to imino-, cycloalkyl, assorted alkyl, Heterocyclylalkyl; Alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group; Cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl.The instance of acyl group is including, but not limited to ethanoyl, propionyl, isobutyryl, benzoyl etc.R also comprises the substituting group that at least one singly-bound is obtained by the bridge joint derivatize in the above-mentioned substituted radical.
Substituted radical: including, but not limited to alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,=O ,=S ,-CF
3,-OCF
3, carboxyl (COOH), sulfonic group (SO
3H), cyanic acid (CN), hydroxyl (OH), amino (NH
2), nitro (NO
2).
Replace derivatize: one or more hydrogen atoms of parent compound are by " substituted radical " substituted process.
The bridge joint group: be meant that (A-), they can insert among a certain singly-bound X-Y substituting group with two connection site, form the new texture of X-A-Y.The bridge joint group is including, but not limited to thioether group (S-), ether (O-), imino-(HN-), substituted imido (NR-), carbonyl ((CO)-), alkylsulfonyl ((SO
2)-), sulfinyl ((SO)-).
The bridge joint derivatize: some substituting groups are meant by the bridge joint derivatize, are inserted into the process that " bridge joint group " obtains recruit's structure through some or a plurality of singly-bounds.The singly-bound that is inserted into the bridge joint group can be positioned at substituting group, or is positioned at other segmental junction of this substituting group and molecule.
Kinase inhibitor: the IC50 value of inhibition of histone deacetylase is 1mM or lower compound.
The invention discloses one type of open loop maleimide compounds, disclosed content comprises: the structure of compound, preparation method and application.Compound involved in the present invention is that with the difference of the maleimide compounds of having reported open loop maleimide compounds disclosed by the invention contains one 1, the substituted triazole ring of 4-.Maleimide compounds disclosed by the invention has good kinase inhibiting activity, and these compounds can be applied to prepare the medicine of treatment cancer or nerve degenerative diseases.Compound of the present invention has the compound of following general structure A:
In the formula, R
1And R
2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, or glycosyl; R
3Be hydrogen atom or methyl.
The present invention also comprises: to R
1And/or R
2The compound that alternately repeatedly replaces derivatize and bridge joint derivatize and obtain.
Replace derivatize R
1And/or R
2The time preferred substituents comprise: alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, halogen ,-CF
3,-OCF
3, carboxyl (COOH), sulfonic group (SO
3H), cyanic acid (CN), hydroxyl (OH), amino (NH
2), or nitro (NO
2);
Bridge joint derivatize R
1And/or R
2The time preferred bridge joint group comprise: thioether group (S-), ether (O-), imino-(HN-), carbonyl ((CO)-), alkylsulfonyl ((SO
2)-), or sulfinyl ((SO)-);
The present invention also comprises: with R
1And/or R
2Through the continuous derivative that obtains of singly-bound.
According to the described structure of general structure A, the compound that it can be for reference is including, but not limited to molecule as follows:
The present invention also provides a kind of pharmaceutical composition, and said composition comprises the above-mentioned suppressor factor of claim or its salt, and pharmaceutically acceptable carrier.
The present invention also provides the purposes of above-mentioned suppressor factor in the medicine of preparation treatment and nerve degenerative diseases or cancer.
The present invention also provides the preceding drug compound of above-mentioned suppressor factor; The various isomeric form of preceding drug compound; The medicinal activity metabolite of suppressor factor; Metabolite is at pharmacy acceptable salt, and wherein isomeric form comprises the E/Z isomer of non-mirror image isomer, mirror image isomer, tautomer, two keys.
The present invention also provides corresponding pharmacy acceptable salt of above compound institute and prodrug, and medicinal activity metabolite and these metabolites are at pharmacy acceptable salt.The present invention also provides the hydrate forms of all kinds of SOLVENTS form, particularly related compound of above all compounds.And above all compounds through with pharmaceutically acceptable dispersion agent or the carrier substance resulting mixture that combines, including, but not limited to liposome, nano particle, high molecular polymer, micro emulsion etc.The prodrugs of above all compounds also is provided, and prodrug is meant that the mode by means of internal metabolism is converted into corresponding drug molecule with it in body.
A kind of based on the corresponding pharmacy acceptable salt of above-claimed cpd or preceding drug compound institute, and medicinal activity metabolite and these metabolites are at pharmacy acceptable salt.Described pharmacy acceptable salt is meant that drug molecule can keep or partly keep original biological activity, and is applicable to some salt of medicinal use.
These salts comprise three kinds of forms:
The one, (these acid are including, but not limited to formic acid, acetate, propionic acid, succsinic acid for above-described compound or preceding drug compound and certain acid; Glycolic acid, gluconic acid, lactic acid, oxysuccinic acid; Tartrate, glycine, arginine, Hydrocerol A; FUMARIC ACID TECH GRADE, FUMARIC ACID TECH GRADE, alkylsulphonic acid, aryl sulfonic acid; Hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid; Propanedioic acid, Whitfield's ointment, gentisinic acid etc.) the formed salt of pairing negatively charged ion;
Another kind is the formed salt of above-described compound or preceding drug compound and certain positively charged ion (these positively charged ions including, but not limited to ammonium, quaternary ammonium group positively charged ion, lithium ion, sodium ion, potassium ion, magnesium ion, calcium ion, aluminum ion, zine ion etc.);
The third is the formed salt of positively charged ion that the protonated back of above-described compound or preceding drug compound and organic amine forms, and these organic amines are including, but not limited to choline, terepthaloyl moietie amine, morpholine etc.
Steric isomer:
The present invention also comprises the various isomeric form of all compounds that above-described parent drug molecule or preceding drug compound and salt thereof are represented.Comprise non-mirror image isomer, mirror image isomer, tautomer, the E/Z isomer of two keys.Any chemist with certain basis is all separable to go out above-mentioned optical purity or the pure compound of stereoisomerism.
The present invention also comprise the compound that above-described parent drug molecule or preceding drug compound and salt thereof are represented possible raceme or/and the mirror image isomerism thing or/and the mixture of non-mirror image isomerism thing.
A kind of pharmaceutical composition, it comprises: above each described parent drug molecule or preceding drug compound and pharmaceutically acceptable carrier.
The isotope atom substitution compound:
The present invention also comprises the isotropic substance substitution compound of above-described parent drug molecule.
The medical use of above-claimed cpd
The present invention includes above each described parent drug molecule, preceding drug compound, salt, steric isomer or composition as but be not limited to the acetylation of histone enzyme inhibitors; Separately; Perhaps with other medicines; Thinner; Vehicle and/or other medicines carrier are united use, are used as preparing the application of the medicine of treating relative disease.These diseases existing many known relate to or part is regulated by kinase activity.These illnesss include but not limited to proliferative disorders (like cancer) and neurodegenerative disease.
More than the NSC 630176 of each described parent drug molecule, preceding drug compound, salt, steric isomer or composition can pass through stomach and intestine administration (oral or rectal administration); Or parenteral introduction is (including, but not limited to subcutaneous; Muscle, approach such as in intravenously and the skin).
The solid dosage of clothes administration is including, but not limited to capsule, lozenge, tablet, powder, particle and microcapsule.The NSC 630176 that contains above each described parent drug molecule, preceding drug compound, salt, steric isomer or composition and at least a inertia and pharmaceutically acceptable vehicle or supporting agent mix.These vehicle and supporting agent comprise Trisodium Citrate or Lin Suanergai, and/or: 1) weighting agent (as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and Whitfield's ointment); 2) wedding agent (as, carboxymethyl cellulose, alginate, gelatin polyvinylpyrrolidone, sucrose and gum arabic); 3) disintegrating agent (as, agar glue, lime carbonate, potato or cassava starch, alginic acid, some silicate and yellow soda ash); 4) dissolving delayed-action activator (like, paraffin); 5) absorb accelerator (like, quaternary ammonium compound); 6) wetting agent (as, hexadecanol, glyceryl monostearate); 7) sorbent material (as, talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol).Solid dosage can be prepared into has coating or shell.
The liquid formulation of oral administration except active compound, also including, but not limited to pharmaceutically acceptable inert diluent (as, water or other solvent); Stablizer and emulsifying agent (as, ethyl alcohol, ethyl-carbonate; Ethyl acetate, phenylformic acid alcohol, phenylamino benzoic acid methyl esters; Ucar 35,1,3 butylene glycol; Dimethyl formamide, Oleum Gossypii semen, peanut oil; Semen Maydis oil, germ oil, sweet oil; Viscotrol C, sesame oil, glycerine; Tetrahydrofuran (THF) alcohol, the fatty acid ester of polyoxyethylene glycol and sorbitol anhydride etc.), suspension agent (as; Ethoxyquin iso stearyl alcohols, polyoxyethylene sorbitol acid anhydride ester etc.), wetting agent; Sweeting agent, spices and deodorant tune etc.
Be used for the preferred composition that rectum or vagina give and include but are not limited to suppository; Suppository can be mixed with suitable non-irritating excipient or carrier and got by above each described parent drug molecule, preceding drug compound, salt, steric isomer or composition.
The formulation that is used for topical is including, but not limited to powder, paster, spray, ointment and inhalation.More than each described parent drug molecule, preceding drug compound, salt, steric isomer or composition under aseptic condition, mix and get with pharmaceutically acceptable carrier and required any assistant agent.These assistant agents include but not limited to any sanitas, buffer reagent and/or mixture etc.
Non-enteron aisle injecting drug use prescription is including, but not limited to pharmaceutically aseptic aqua of acceptable or non-aqueous solvent, dispersion agent, suspension agent or emulsifying agent and use before just be made into the powder injection of injectable aseptic aqueous solution.
The preferential measures range of selecting is per kilogram of body weight about 0.01-300 milligram every day; Preferred measures range is per kilogram of body weight about 0.2-80 milligram every day.Also can select suitable metering repeatedly to divide the agent administration every day.
Advantage of the present invention and positively effect:
The present invention is the open loop maleimide compounds of novel structure, has the kinase whose biologic activity of target.
Description of drawings
Fig. 1 is 2, the synthetic route chart of 3-dichloromaleic anhydride (1)
Fig. 2 is 2, the synthetic route chart of 3-two chloro-N-methyl maleimides (2)
Fig. 3 is the 2-chloro-3-(synthetic route chart of 1H-indoles-3-)-N-methyl maleimide (3)
Fig. 4 is 3-(1H-indoles-3-)-1 methyl-4-((trimethyl silicon based) ethynyl)-1H-pyrroles-2, the synthetic route chart of 5-diketone (4)
Fig. 5 is 3-(1H-indoles-3-)-4 (1-(2,3,4,6-four oxygen ethanoyl-β-D-galactosyl)-1H-1,2, the synthetic route chart of 3-triazole-4-)-N-methyl maleimide (A-I-1)
Fig. 6 is 3-(1H-indoles-3-)-4 (1-(β-D-galactosyl)-1H-1,2, the synthetic route chart of 3-triazole-4-)-N-methyl maleimide (A-II-1)
Fig. 7 is 3-(1H-indoles-3-)-4 (1-(β-D-galactosyl)-1H-1,2, the synthetic route chart of maleimide (A-III-1) of 3-triazole-4-)
[embodiment]:
Related compound of the present invention and uses thereof is described through concrete embodiment with the preparation method.Those skilled in the art can use for reference links such as content appropriate change raw material of the present invention, processing condition and realize corresponding other purpose; Its relevant change does not all break away from content of the present invention; All similar replacements and change will become apparent to those skilled in the art that all to be regarded as and comprise within the scope of the present invention.
2,3-dichloromaleic anhydride (1) synthetic
9.81 gram (0.10mmol) maleic anhydrides are placed the 250mL three-necked bottle, add the 100mL thionyl chloride, the ice-water bath cooling slowly drips 16.50mL (0.20mmol) pyridine, after dripping, is warming up to 75 ℃, is incubated 5 minutes.After being cooled to room temperature, revolve the steaming precipitation, remove thionyl chloride, residuum dissolves with toluene, filters, and collects filtrating, and precipitation gets thick product 2,3-dichloromaleic anhydride 13.22 grams, yield 79.7%.
2,3-two chloro-N-methyl maleimides (2) synthetic
With 8.71g (52.00mmol) 2, the 3-dichloromaleic anhydride places the 100mL round-bottomed flask, adds the 25mL Glacial acetic acid, the ice-water bath cooling; Drip the aqueous methylamine solution of 8mL (about 25%), dropwise, remove ice-water bath; Reflux 300 minutes is cooled to room temperature, adds 30mL water; In 4 ℃ of following standing over night, solid is separated out, and filters; Washing, dry yellow thick product, distillation purify 4.0 grams 2; 3-two chloro-N-methyl maleimides (1), yield 42.7%, fusing point 82-84 ℃.
1H?NMR(400Hz，DMSO-d
6，δ：ppm)2.953(s，3H)。
13C?NMR(100Hz，DMSO-d
6，δ：ppm)24.747，132.369，163.198。
2-chloro-3-(1H-indoles-3-)-N-methyl maleimide (3) synthetic
655mg (5.50mmol) indoles is placed the 100mL there-necked flask; Add the 20mL tetrahydrofuran (THF); Slow Dropwise 5 .5mL (tetrahydrofuran solution of 1.0mol/L) ethylmagnesium bromide; Be heated to 60 ℃; After about 1 hour, drip 2,3-two chloro-N-methyl maleimide 1.0g (5.50mmol) tetrahydrofuran solution 20mL; Be warming up to 65 ℃, be incubated 1 hour.Be cooled to room temperature, reaction solution is poured in the frozen water, use ethyl acetate extraction, organic phase is used saturated aqueous ammonium chloride, water washing successively, uses anhydrous sodium sulfate drying, the decompression precipitation, and column chromatography gets yellow solid 752mg, yield 52.0%.
1H?NMR(400MHz，DMSO-d
6，δ：ppm)12.12(1H，s)，8.06(1H，d，J＝2.8Hz)，7.90(1H，d，J＝8.0Hz)，?7.51(1H，d，J＝8.0Hz)，7.23(1H，t，J＝7.2Hz)，7.16(1H，t，J＝7.8Hz)，3.02(3H，s)。
Implement row 4
3-(1H-indoles-3-)-1-methyl-4-((trimethyl silicon based) ethynyl)-1H-pyrroles-2,5-diketone (4) synthetic
(1H-indoles-3-)-N-methyl maleimide 2 is dissolved in the mixing solutions of 40mL triethylamine and 10mL tetrahydrofuran (THF) with 450mg (1.73mmol) 2-chloro-3-; Add 110mg (0.09mmol) four triphenyl phosphorus palladiums and 326mg (0.17mmol) cuprous iodide; Feed argon gas; In reaction solution, add 0.5mL (3.5mmol) trimethylsilyl acetylene; Stirring at room is spent the night.Reaction solution is poured in the 70mL saturated aqueous ammonium chloride, and (3 * 20mL) extract, and organic phase is used saturated aqueous common salt and water washing successively, uses anhydrous sodium sulfate drying, and the decompression precipitation gets red solid 411mg, yield 75% with ether.
1HNMR(400MHz，DMSO-d6，δ：ppm)12.30(1H，s)，8.33(1H，s)，8.31(1H，s)，7.52(1H，d，J＝8.0Hz)，7.26(1H，t，J＝8.0Hz)，7.16(1H，t，J＝8.0Hz)，2.97(3H，s)，0.24(9H，s)。HRMS(ESI，m/z)：calcd?for?C
18H
18N
2O
2Si(M+Na)
+，345.1030；found，345.1030。
Implement row 5
3-(1H-indoles-3-)-4-(1-(2,3,4,6-four oxygen ethanoyl-β-D-galactosyl)-1H-1,2,3-triazole-4-)-N-methyl maleimide (A-I-1) synthetic
With 100mg (0.31mmol) 3-(1H-indoles-3-)-1-methyl-4-((trimethyl silicon based) ethynyl)-1H-pyrroles-2; 5-diketone 3 is dissolved in the mixing solutions of 10mL tetrahydrofuran (THF) and 10mL methyl alcohol; Add 0.31mL (tetrahydrofuran solution of 1.0mol/L) tetrabutyl ammonium fluoride; Stirring at room; It is complete that TLC detects raw material reaction; Add 116mg (0.31mmol) 2 successively; 3; 4; 6-is tetra-acetylated-β-D-galactosyl nitrine, and 155mg (0.62mmol) sodium ascorbate, 31mg (0.06mmol) Salzburg vitriol; Stirring at room is spent the night.Reaction solution is poured in the frozen water, used ethyl acetate extraction, anhydrous sodium sulfate drying revolves the steaming precipitation, and column chromatography gets compd A-I-1,60mg, yield 31%.
1H?NMR(400Hz，CD
3Cl，δ：ppm)8.96(1H，s)，8.59(1H，s)，8.09(1H，d，J＝3.2Hz)，7.34(1H，d，J＝8.0Hz)，7.18(1H，t，J＝8.0Hz)，7.08(1H，d，J＝7.6Hz)，7.03(1H，t，J＝7.6Hz)，5.86(1H，d，J＝9.2Hz)，5.61(1H，t，J＝9.6Hz)，5.57(1H，d，J＝3.2Hz)，5.27(1H，dd，J＝10.4Hz，J＝3.2Hz)，4.17-4.26(3H，m)，3.19(3H，s)，3.26(3H，s)，2.06(3H，s)，2.03(3H，s)，1.92(3H，s)。HRMS(ESI，m/z)：calcd?forC
29H
29N
5O
11Na(M+Na)
+，646.1751；found，646.1756.
With similar approach synthetic compound, see table 1 and see table 2.
The yield of table 1 compd A-I
The 1H NMR data of table 2 compd A-I
* the NMR solvent of compound is CDCl
3, the NMR solvent of other compounds is DMSO-d
6All compounds are all confirmed through HRMS.
Implement row 6
3-(1H-indoles-3-)-4-(1-(β-D-galactosyl)-1H-1,2,3-triazole-4-)-N-methyl maleimide (A-II-1) synthetic
(1H-indoles-3-)-(1-(2,3,4 for 4-with 20mg (0.03mmol) 3-; 6-four oxygen ethanoyl-β-D-semi-lactosi)-and 1H-1,2,3-triazole-4-)-N-methyl maleimide A-I-1 is dissolved in the 4mL methanol solution; The sodium methylate that adds catalytic amount, stirring at room, TLC detects; After reactant disappears, regulate the pH value to neutral with acidic resins, filter; Precipitation; Get red solid A-II-1,14mg, yield 100%.
1H?NMR(400MHz，CD
3OD，δ：ppm)8.49(1H，s)8.05(1H，s)7.31(1H，d，J＝8.0Hz)7.03(1H，t，J＝7.6Hz)6.81(1H，t，J＝7.6Hz)6.69(1H，d，J＝8.0Hz)5.52(1H，s，J＝8.8Hz)4.08(1H，t，J＝9.6Hz)3.89(1H，d，J＝4.2Hz)3.58-3.78(4H，m)3.02?(3H，s)。HRMS(MALDI，m/z)：calcd?for?C
20H
18N
4O
8Na(M+Na)
+，478.1331；found，478.1333。With similar approach synthetic compound See Figure and table 3.
Table 3. compd A-II's
1The HNMR data
Embodiment 7
3-(the 1H-indoles-3-)-4-(1-(β-D-galactosyl)-1H-1,2, the 3-triazole-4-) maleimide (A-III-1) is synthetic
At 100mg (0.16mmol) 3-(1H-indoles-3-)-4-(1-(β-D-galactosyl)-1H-1; 2; In the suspension liquid that 3-triazole-4-)-N-methyl maleimide A-II-1 and 50mL water are formed; Add 89mg (1.60mmol) sodium hydroxide and 10mL tetrahydrofuran (THF); Stirring at room 2 hours, the hydrochloric acid of dropping 2mol/L is adjusted to pH=1; Continue stirring at room, spend the night.Revolve the steaming precipitation, wash residue with tetrahydrofuran (THF), filter, collect filtrating, precipitation gets midbody compound M.This midbody compound M is dissolved among the 5mL DMF, adds the 2.0g ammonium acetate, be heated to 140 ℃, after about 1 hour, stop heating, be cooled to room temperature, precipitation, column chromatography get red solid A-III-1,34mg, yield 33.5%.
1H?NMR(400MHz，CD
3OD，δ：ppm)3.597-3.714(3H，m)，3.760(1H，t，J＝6.0Hz)，3.894(1H，d，J＝2.8Hz)，4.078(1H，t，J＝9.2Hz)，5.525(1H，d，J＝9.2Hz)，6.688(1H，d，J＝8.0Hz)，6.816(1H，t，J＝7.6Hz)，7.029(1H，t，J＝7.6Hz)，7.322(1H，d，J＝8.4Hz)，8.019(1H，s)，8.466(1H，s)。HRMS(ESI，m/z)：calcd?for?C
20H
18N
5O
7(M-H)
-，440.1210；found，440.1212。
With similar approach synthetic compound, see table 4 and see table 5.
The yield of table 4. compd A-III
Table 5. compd A-III's
1The HNMR data
* the NMR solvent of compound is acetone-d
6, the NMR solvent of other compounds is DMSO-d
6All compounds are all confirmed through HRMS.
Implement row 8
The anti-tumor activity experiment of part of compounds
1, collect the logarithmic phase cell, the adjustment concentration of cell suspension, the every hole of 96 orifice plates adds 100ul, and bed board makes cell to be measured transfer density to the 1000-10000 hole;
2, at 5%CO
2Under the atmosphere, hatch for about 37 ℃, be paved with the hole to cell monolayer at the bottom of (96 hole flat underside), add the medicine of concentration gradient, general 5-8 gradient, every hole 100uL, every gradient is provided with 3 and answers holes;
3, at 5%CO
2Under the atmosphere, hatched 24-72 hour for about 37 ℃, inverted microscope is observed down;
4, every hole adds 20uL MTT solution (5mg/mL, i.e. 0.5%MTT), continues to cultivate 4h.If medicine and MTT can react, discard nutrient solution after can be earlier centrifugal, carefully with PBS after 2-3 time, adding contains the nutrient solution of MTT again;
5, stop cultivating, centrifugal, carefully discard nutrient solution in the hole;
6, every hole adds the 150uL methyl-sulphoxide, puts vulgar vibration 10min on the shaking table, and crystallization is fully dissolved.Measure it in the OD of 570nm place value with microplate reader.
7, draw dose-effect curve, and calculate IC
50Value.
It is following to calculate IC50 value formula:
IC50＝lg-1[Xm-i(∑P-0.5)]
The average OD value of the average OD value/control wells of growth inhibition ratio P=1-experimental port of each drug level; Xm: the logarithmic value of the peak concentration of design; I: the logarithmic value of each concentration multiple proportions; ∑ P: each organizes the growth inhibition ratio sum; 0.5: empirical constant.Above-claimed cpd is as shown in table 6 to IC50 (uM) value of Neuro-2a (mouse brain neuroma cell), SH-SY5Y (human neuroblastoma cell) and A549 (human lung adenocarcinoma cell):
Table 6 cell inhibitory activity
Implement row 9
With GSK-3b is the kinase activity test analysis of example:
1) final 22.5uL enzyme is lived and is comprised in the test reaction liquid: 1nM people source GSK-3b (Upstate Biotechnology Inc.), 50mM 3-(N-morphine quinoline) propanesulfonic acid (pH 7.0); 0.2mM EDTA; The 10mM magnesium acetate; 7.5mM mercaptoethanol; The glycerine of 5% (w/v); The Tween-20 of 0.01% (w/v); The DMSO of 10% (v/v); The GS-2 peptide substrate of 28uM (Upstate Biotechnology Inc., YRRAAVPPSPSLSRHSSPHQSEDEEE); 10uM ATP (0.34u Ci[
33P-γ-ATP]), and the inhibitor molecules of proper concn.
2) room temperature reaction added and contains 2.5% (v/v) H after 30 minutes
3PO
421mM ATP.
3) sample is contained the P81 screen plate by enrichment (P81-Unifiler plate Whatman), and with 50mM phosphoric acid buffer flushing, reads numerical value with scintillometer then to 96 holes.
The partial synthesis compound is as shown in table 7 to the IC50 value of GSK-3 β (glycogen synthase kinase), ZAP-70 (recombinant human ZETA chain accessory protein kinases), CLK2 (dual specificity protein kinases) and VEGFR (vascular endothelial growth factor receptor):
Table 7. compd A-III-7 is active to the inhibition of protein kinase
Claims (9)
1. one kind is utilized click chemistry synthetic kinase inhibitor, and this suppressor factor is the compound with following general structure A:
In the formula, R
1And R
2Be hydrogen, alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl, the assorted alkynyl of ring, aryl, heteroaryl, or glycosyl; R
3Be hydrogen atom or methyl.
2. compound according to claim 1 is at R
1Or R
2In at least one singly-bound in the middle of can insert the bridge joint group, the bridge joint group is selected from thioether group (S-), ether (O-), imino-(NH-), substituted imido (NR-), carbonyl, alkylsulfonyl, or sulfinyl.
3. according to claim 1 and 2 described compounds, R
1Or R
2In at least one hydrogen atom can be substituted base institute and substitute, substituting group comprises: alkyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, alkenyl, cycloalkenyl group, assorted thiazolinyl, heterocycloalkenyl, alkynyl group, cycloalkynyl radical, assorted alkynyl encircles the alkynyl of mixing, aryl, heteroaryl, halogen ,-CF
3,-OCF
3, carboxyl, sulfonic group, cyanic acid, hydroxyl, amino, or nitro.
4. the present invention also comprises through to the described compound of claim 1, alternately repeatedly carries out bridge joint and inserts with the hydrogen atom replacement and connect the compound that derivatize obtains.
5. suppressor factor according to claim 3, this suppressor factor are the compound that is selected from following structure:
6. the preceding drug compound of each described compound of claim 1-5; The various isomeric form of preceding drug compound; And medicinal activity metabolite; Metabolite is at pharmacy acceptable salt, and wherein isomeric form comprises the E/Z isomer of non-mirror image isomer, mirror image isomer, tautomer, two keys.
7. each described compound isotope atom substituent of claim 1-6.
8. pharmaceutical composition, said composition comprises each described compound or its salt of claim 1-7, and pharmaceutically acceptable carrier.
9. each described compound of claim 1-8 is in preparation treatment and cytodifferentiation or breed the purposes in the medicine of relevant disease or nerve degenerative diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101977369A CN102344443A (en) | 2011-07-15 | 2011-07-15 | Open-loop maleimide compound utilizing click chemosynthesis and application in treating diseases thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101977369A CN102344443A (en) | 2011-07-15 | 2011-07-15 | Open-loop maleimide compound utilizing click chemosynthesis and application in treating diseases thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102344443A true CN102344443A (en) | 2012-02-08 |
Family
ID=45543554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101977369A Pending CN102344443A (en) | 2011-07-15 | 2011-07-15 | Open-loop maleimide compound utilizing click chemosynthesis and application in treating diseases thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102344443A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527241A (en) * | 2021-07-30 | 2021-10-22 | 中化学科学技术研究有限公司 | Preparation method, preparation device and intermediate of 4-chlorophthalic anhydride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1320123A (en) * | 1998-07-30 | 2001-10-31 | 日本烟草产业株式会社 | Disubstituted maleimide compounds and medicinal utilization thereof |
| US20050004201A1 (en) * | 2003-06-13 | 2005-01-06 | Han-Cheng Zhang | Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors |
-
2011
- 2011-07-15 CN CN2011101977369A patent/CN102344443A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1320123A (en) * | 1998-07-30 | 2001-10-31 | 日本烟草产业株式会社 | Disubstituted maleimide compounds and medicinal utilization thereof |
| US20050004201A1 (en) * | 2003-06-13 | 2005-01-06 | Han-Cheng Zhang | Substituted indazolyl(indolyl)maleimide derivatives as kinase inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527241A (en) * | 2021-07-30 | 2021-10-22 | 中化学科学技术研究有限公司 | Preparation method, preparation device and intermediate of 4-chlorophthalic anhydride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021129820A1 (en) | Spiro ring-containing quinazoline compound | |
| JP6035423B2 (en) | Novel condensed pyrimidine compound or salt thereof | |
| WO2021190467A1 (en) | Spiro ring-containing quinazoline compound | |
| CN110036007B (en) | Pyridine compound | |
| TW200526639A (en) | Pyrazole derivatives and uses thereof | |
| CN102741253A (en) | Pi3k (delta) selective inhibitors | |
| KR20180042368A (en) | A condensed pyrimidine compound or a salt thereof | |
| CN102503959B (en) | Tricyclic compounds and preparation method thereof, and medicinal composition containing compounds and application thereof | |
| CN110382499A (en) | FGFR inhibitor and its application | |
| CN101679426A (en) | 9-(pyrazol-3-yl)-9h-purine-2-amine and 3-(pyraz0l-3-yl)-3h-imidaz0[4,5-b]pyridin-5-amine derivatives and their use for the treatment of cancer | |
| KR20170045748A (en) | Compositions and methods for treating proliferation disorders | |
| CN107759600A (en) | Crystallization as the Pyrrolopyrimidine compounds of JAK inhibitor | |
| TWI760005B (en) | Fluorinated heterocyclic derivatives with macrocyclic structure and uses thereof | |
| KR20120113760A (en) | Purified pyrroloquinolinyl-pyrrolidine-2,5-dione compositions and methods for preparing and using same | |
| CN104837844A (en) | Pyrazole substituted imidazopyrzines as casein kinase 1D/E inhibitors | |
| CN113518779B (en) | Thieno heterocyclic derivative, preparation method and medical application thereof | |
| WO2020224626A9 (en) | Compound used as kinase inhibitor and application thereof | |
| WO2016023330A1 (en) | Quinazoline derivative | |
| CN109988151B (en) | Acetylene compound, preparation method and application thereof | |
| CN113366008A (en) | CD73 inhibitor, preparation method and application thereof | |
| WO2020172906A1 (en) | New-type pan-raf kinase inhibitor and use thereof | |
| CN114605391B (en) | Quinoxaline derivative, preparation method and application thereof | |
| CN102344443A (en) | Open-loop maleimide compound utilizing click chemosynthesis and application in treating diseases thereof | |
| CN101857594B (en) | Tetrahydropyridoindole compounds, and preparation method and application thereof | |
| CN110407839B (en) | Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120208 |