CN103819476B - Pyrrolidone pyrazole compound and the purposes as medicine thereof - Google Patents
Pyrrolidone pyrazole compound and the purposes as medicine thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A—HUMAN NECESSITIES
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Abstract
The invention belongs to pharmaceutical technology field.The invention provides a kind of pyrrolidone compound, including its optical isomer, racemic modification, cis-trans-isomer and combination in any or its pharmaceutical salts, structure is as shown in formula I.The compound of the present invention can be as p53 MDM2/X protein-interacting micromolecular inhibitor.The compound of the present invention can be used for preparing antitumor drug or anti-inflammatory drug.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, be pyrrolidone pyrazole compound and conduct thereof
The purposes of medicine, the particularly application in preparing antitumor drug.
Background technology
P53 albumen is a kind of cancer suppressor protein, and its inactivation occurs closely related with the cancer of 50%～60%.Its
Reason is probably the transcriptional activation domain connection of p53 cancer suppressor protein has cell carcinoma albumen, as far back as mice
In the double minute chromosome gene amplification of cell line find a gene (murine double minute2,
MDM2), the many places tissue Mus and people's (homologous genes is HDM2) has expression (Michael S C, et al.
Regulation of p53stability and activity in response to genotoxic stress[J].Mvta
Res,2000,462:179-188.)。
The discovery of p53 antioncogene in recent years has greatly facilitated Tumorigenesis and antitumor drug
Research, substantial amounts of research proves: the p53 albumen of coding is repaired and induction at cell cycle regulating, DNA
The aspects such as apoptosis are respectively provided with key effect, and the afunction sudden change of p53 gene occurs in cancer patient,
It is the main cause mushroomed out causing tumor cell, upper in China of recombinant human adenovirus p 53 injection
City has absolutely proved that p53 is effective antitumour drug target so that the antitumor with p53 as action target spot
Drug research becomes a focus.Molecular biology research shows MDM2 (Murine present in cell
Double Minute2) albumen is one of negative regulator main for p53, p53 can activate MDM2 and transcribe,
MDM2 can suppress the most again p53 activity, is formed and is automatically adjusted feedback loop, to keep under normal circumstances
P53 and MDM2 is all in low-level state.In tumor cell, the unconventionality expression of MDM2 can cause p53
The fast degradation because of its ubiquitination, thus have impact on p53 suppression (U.M.Moll, O. to tumor cell
Petrenko.The MDM2-p53Interaction.Molecular Cancer Research.2003,
1:1001-1008).The crystal structure of p53-MDM2 complex illustrates the binding mode of p53 Yu MDM2,
The key aminoacid Phe of p5319、Trp23And Leu26The active chamber formation three inserting MDM2 is hydrophobic
Property active force (P.H.Kussie, S.Gorina, V.Marechal, and et al.Structure of the MDM2
oncoprotein bound to the p53tumor suppressor transactivation domain.Science.
1996,274:948-953).This discovery makes to be combined into the antitumor drug research of target with p53-MDM2
Become a major domain in recent years, the research of micromolecular inhibitor in early days be concentrated mainly on polypeptide and
Analog, the octapeptide AP and natural product ring nonapeptide chlorofusin of synthesis has the inhibitory activity of excellence,
But owing to the Premeabilisation of cells ability of peptides causes the unsatisfactory (C. of anti-tumor activity
Garcia-Echeverria,P.Chene and M.JJ Blommers.Discovery of potent antagonists
of the interaction between human double minute2and tumor suppressor p53.
Journal Medicinal Chemistry.2000,43:3205-3208)。
The most non-peptide micromolecular p53-MDM2 binding inhibitors becomes the focus of antitumor drug research,
Researcher uses virtual high flux screening successively to obtain the micromolecular inhibitor of various structures type both at home and abroad, main
(wherein nutlin-3 is frequently as mdm2 inhibitor positive control for cis-imidazolines class (Nutlins) to be included
Medicine), Spiroindolinone class (Spiro-oxindoles), 1,4-Benzodiazepine-2,5-diones
(Benzodiazepinediones) three big structure types, wherein the compound R O5045337 of Roche company
It is currently in I phase clinical (Melissa Millard, Divya Pathania, Fedora Grande, Shili Xu, and
Nouri Neamati*.Small-Molecule Inhibitors of p53-MDM2Interaction:the
2006-2010Update.Current Pharmaceutical Design,2011,17,536-559).These little point
Sub-inhibitor the most relatively peptides all shows preferably anti-tumor activity.
Summary of the invention
It is an object of the invention to provide a kind of new non-peptide micromolecular p53-MDM2 binding inhibitors,
It is specially pyrrolidone pyrazole compound.Another object of the present invention provides pyrrolidone pyrazole compound
Purposes in preparing antitumor drug, this compounds can improve p53-MDM2 protein-interacting to be pressed down
System activity.Present invention also offers pyrrolidone the pyrazoles purposes in preparing anti-inflammatory drug.
The present invention is by obtaining little point of brand new to the transformation of the virtual screening integrated structure of business database
Sub-inhibitor.
The concrete technical scheme of the present invention is as follows:
As a first aspect of the present invention, a kind of pyrrolidone compound, including optical isomer, raceme
Body, cis-trans-isomer and combination in any or its pharmaceutical salts, structure such as formula I；
Wherein, R1Be hydrogen, low alkyl group, lower alkoxy, low-grade alkenyl, cycloalkyl, triazole ring, aryl,
Heteroaryl, saturated or part unsaturated heterocycle, aralkyl or heteroaryl alkyl；
Preferably R1It is aryl, heteroaryl, saturated or part unsaturated heterocycle, aralkyl or heteroaryl alkyl；
More preferably, R1Be phenyl, to fluorophenyl, rubigan, p-bromophenyl, to iodophenyl, p-nitrophenyl,
P-hydroxybenzene, p-methoxyphenyl, p-methylphenyl, adjacent fluorophenyl, Chloro-O-Phenyl, o-bromophenyl,
Adjacent iodophenyl, O-Nitrophenylfluorone, o-hydroxy-phenyl, o-methoxyphenyl, a fluorophenyl, a chlorphenyl,
Between bromophenyl, an iodophenyl, m-nitro base, a hydroxy phenyl, m-methoxyphenyl, Dichlorobenzene base；
R2Be hydrogen, low alkyl group, lower alkoxy, low-grade alkenyl, cycloalkyl, triazole ring, aryl,
Heteroaryl, saturated or part unsaturated heterocycle, aralkyl or heteroaryl alkyl；
Preferably R2It is aryl, heteroaryl, saturated or part unsaturated heterocycle, aralkyl or heteroaryl alkyl,；
More preferably, R2Be phenyl, to fluorophenyl, rubigan, p-bromophenyl, to iodophenyl, p-nitrophenyl,
P-hydroxybenzene, p-methoxyphenyl, p-methylphenyl, to tert-butyl-phenyl, naphthyl, adjacent fluorophenyl,
Chloro-O-Phenyl, o-bromophenyl, adjacent iodophenyl, O-Nitrophenylfluorone, o-hydroxy-phenyl, o-methoxyphenyl,
Between fluorophenyl, a chlorphenyl, a bromophenyl, an iodophenyl, m-nitro base, a hydroxy phenyl, a first
Phenyl, 3,5-dimethylphenyl, Dichlorobenzene base, thienyl, furyl, pyridine radicals, adjacent chloropyridine base；
R3It is hydrogen, hydroxyl, amino, optionally substituted amido, low alkyl group, halogen, class halogen, rudimentary
Para-orientation or two replacements between alkoxyl, low-grade alkenyl, nitro, hydroxyl imide alkyl, triazole ring, neighbour
Aryl, para-orientation or dibasic saturated or portion between para-orientation or disubstituted heteroaryl, neighbour between neighbour
Divide unsaturated heterocycle；
Preferably R3It is between low alkyl group, halogen, class halogen, neighbour between para-orientation or disubstituted aryl, neighbour
Para-orientation or two replacements are saturated or part unsaturated heterocycle between para-orientation or two substituted heteroaryls, neighbour；More
Goodly, R3It is chlorine, bromine, imidazole radicals, pyridine radicals；
R4It is hydrogen, low alkyl group, halogen, class halogen, low-grade halogenated alkyl, lower alkoxy, lower alkanols
Thiazolinyl, cycloalkyl, nitro, azido, carboxyl or alkoxy carbonyl, hydroxyl, fluorine replace lower alkoxy,
Hydroxy-substituted lower alkyl, carboxyl or ester group replace low alkyl group, amide groups, rudimentary amido alkyl, hydroxyl
Base imines alkyl, aryl, heteroaryl, saturated or part unsaturated heterocycle, aralkyl or heteroaryl alkyl,
-NHRa, wherein RaBe para-orientation or disubstituted aryl between hydrogen, low alkyl group, lower halogenated alkane, neighbour,
Between para-orientation or di-substituted aryl amido between neighbour, saturated or part unsaturated heterocycle, neighbour, para-orientation or two takes
For aralkyl or heteroaryl alkyl；
Preferably R4It is hydrogen, low alkyl group, lower alkoxy, low-grade alkenyl, cycloalkyl, hydroxyl replacement
Low alkyl group, carboxyl or ester group replace low alkyl group, aryl, heteroaryl, saturated or part unsaturated heterocycle,
Aralkyl or heteroaryl alkyl；More preferably, R4Be hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl,
Isobutyl group, n-pentyl, n-hexyl, n-heptyl, n-octyl, the tert-butyl group, pi-allyl, propinyl, ring fourth
Base, cyclopenta, cyclohexyl, benzyl, to luorobenzyl, adjacent luorobenzyl, a luorobenzyl, ethyl acetate base,
Ethyl propionate base, ethyl n-butyrate. base, acetate, propionyloxy, butanoic acid base；
N is the integer between 1 to 6；Preferably n is the integer between 1 to 3；
X is oxygen or sulphur atom independently；
Described low alkyl group is containing 1 to 8 carbon atom straight chain or branched alkyl；Lower alkoxy be containing 1 to
8 carbon atom straight chains or branched alkoxy；Low-grade halogenated alkyl is substituted rudimentary containing 1 to 3 halogen atom
Alkyl.
In this article, relevant with alkyl and alkoxyl term " rudimentary " refers to the straight chain containing 1 to 8 carbon atom
Or side chain saturated fat hydrocarbyl group, such as, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group,
Methyl mercapto, ethylmercapto group, methoxyl group and ethyoxyl, the term " rudimentary " relevant with term alkenyl or alkynyl group
Refer to containing 2 to 8 carbon atoms and the group of one or more double or triple bonds, such as: vinyl, pi-allyl,
Isoolefine propyl group, pentenyl, hexenyl, acrylic, acetenyl, propinyl and butynyl.Term alkyl halide
Base is containing 1 to 3 substituted low alkyl group of halogen atom.Term cycloalkyl refers to the ring containing 3 to 7 carbon,
Such as, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.Term aryl refers to mono-, di-or tricyctic hydrocarbon compound,
At least one of which ring is aromatic rings, and each ring contains most 7 carbon atoms, such as, phenyl, naphthyl, anthracene
Base, xenyl or indenyl.Term halogen refers to chlorine, bromine, iodine or fluorine.Term class halogen refers to cyano group, trifluoro
Methyl, trifluoromethoxy.
Formula I compound is selected from following compound:
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles-6 (1H)-
Ketone,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-methyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-normal-butyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-pi-allyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-propargyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-cyclohexyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-octyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-isopropyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-cyclobutyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-heptyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-cyclopenta-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-pro-pyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-ethyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-pentyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-hexyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-isobutyl group-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-(2-(tetrahydrochysene-2H-pyrans)-2-ethoxy)-3-phenyl
-4,5-pyrrolin [3,4-c] pyrazoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-(2-ethoxy)-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-neighbour's luorobenzyl-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-the bromophenyl)-1-tert-butyl group-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
2-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) ethyl acetate,
4-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) ethyl n-butyrate.,
3-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) ethyl propionate,
4-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) butanoic acid,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
3-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) propanoic acid,
(+)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
(-)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
(+)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin
[3,4-c] pyrazoles-6 (1H)-one, or
(-)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin
[3,4-c] pyrazoles-6 (1H)-one.
5 of the pyrrole ring of the compounds of this invention contain an asymmetric c atom, have two kinds of configurations of R and S.
Its racemic modification can obtain single optical pure compound by chirality preparative separation.The present invention includes these mappings
Body configuration and their various combinations, and racemic compound.
As a second aspect of the present invention, some compound of the present invention can conventionally be prepared as medicinal
The form of salt.Including its acylate and inorganic acid salt: mineral acid include, but is not limited to hydrochloric acid, sulphuric acid,
Phosphoric acid, diphosphonic acid, hydrobromic acid, nitric acid etc., organic acid includes, but is not limited to acetic acid, maleic acid, richness
Horse acid, tartaric acid, succinic acid, lactic acid, p-methyl benzenesulfonic acid, salicylic acid, oxalic acid etc..
The compound of the present invention may be used to lower section method and prepares:
The first step, by various 2-hydroxy-4-phenyl-4-oxo-2-butylene acid methyl ester, corresponding aldehyde with corresponding
Amine in 1,4-dioxane, carry out three component reaction obtain the basic parent nucleus of pyrrolidone；
Second step, by obtaining pyrrolidone pyrazoles parent nucleus with hydrazine cyclization；
3rd step, obtains substituted pyrrolidone pyrazole compound by substitution reaction.
A second aspect of the present invention, is to provide any of the above-described compound, including optical isomer, racemic modification,
Cis-trans-isomer and combination in any or its pharmaceutical salts, the use in preparing antitumor drug or anti-inflammatory drug
On the way.
Further, described purposes is as p53-MDM2/X protein-interacting micromolecular inhibitor
Medicinal usage.
Studying through anti tumor activity in vitro, the compound of the present invention has good anti-tumor activity, and they can
For treating tumor, including esophagus, stomach, intestinal, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland,
Uterus, endometrium, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone, connective tissue,
The cancer that the position such as skin, eye, brain and central nervous system occurs, and thyroid carcinoma, leukemia, suddenly
King's evil, lymphoma and myeloma etc..
The compounds of this invention can be used on the medicine aspect of preparation suppression p53-MDM2 protein-interacting.
The compounds of this invention and its esters have good anti-tumor activity, and multiple compounds are higher than positive control
Medicine nutlin-3, therefore the compounds of this invention and its esters may be used for preparing antitumor drug.
The compounds of this invention and its esters have good anti-inflammatory activity, therefore the compounds of this invention and its esters
May be used for preparing anti-inflammatory drug.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following example are only used
In illustrating rather than for limiting the scope of the present invention.
The experimental technique of unreceipted actual conditions in the following example, generally according to normal condition, such as " molecule
Clone: laboratory manual " (New York:Cold Spring Harbor Laboratory Press, 1989)
Described in condition or manufacturer provide condition carry out.
The preparation of embodiment 1:2-hydroxy-4-phenyl-4-oxo-2-butylene acid methyl ester
29.2g (0.2mol) ethyl oxalate, 12.0g (0.1mol) 1-Phenylethanone. mixed liquor are slowly dropped into 2
In the Feldalat NM/methanol solution of mol/L, solution slowly becomes yellow, has solid to separate out.Dripping and finish, machinery stirs
Mixing down, 70 DEG C are heated 2-3 hour, stop heating, are cooled to room temperature, are poured into by reactant liquor in 2L water,
Insoluble matter is filtered after fully dissolving.Filtrate regulates pH to 3-4 with concentrated hydrochloric acid, stirs 1-2 little under ice-water bath
Time, separating out a large amount of faint yellow solid, sucking filtration, clean with clear water and obtain faint yellow solid, lyophilization obtains pure
Product 15.0g, yield 72.8%.
1H NMR(300MHz,DMSO-d6)δ:14.83(bar,1H),8.06(d,2H,J=7.5Hz),
7.70(t,1H,J=7.1Hz),7.57(d,2H,J=7.5Hz),7.11(s,1H),3.85(s,3H).ESI-MS
(m/z):207.29[M+1]+.
The preparation of embodiment 2:2-(3-(1H-imidazoles) propyl group) iso-indoles-1,3-diketone
The sodium hydride of 2.0g60% and 2.7g imidazoles are put in 25mL eggplant-shape bottle, adds 50mL DMF
By 5.4g2-(3-bromopropyl) iso-indoles-1 after 40 DEG C of stirrings 1.5 hours, 3-diketone adds in reaction bulb, stirring
Within 30 minutes, post-heating is to 80 DEG C, and overnight, TLC display reaction is complete in reaction, and stopped reaction adds water, second
Acetoacetic ester extracts, and anhydrous sodium sulfate is dried organic facies.Combiflash companion separates (CH2Cl2: CH3OH=
100:1) obtain white solid 1.18g, yield 24.7%.
1H NMR(300MHz,DMSO-d6)δ:7.86(m,4H),7.62(s,1H),7.18(s,1H),
6.86(s,1H),4.00(t,2H,J=7.1Hz),3.53(t,1H,J=6.8Hz),2.01(m,2H).
ESI-MS(m/z):255.27[M+1]+.
The preparation of embodiment 3:3-(1H-imidazoles) propylamine
The hydrazine hydrate of 1.0g2-(3-(1H-imidazoles) propyl group) iso-indoles-1,3-diketone with 0.50g80% is added 60
In mL ethanol, it is heated to reflux 12 hours, cooling, filters the white solid of precipitation, then filtrate is concentrated
To 20mL, add the hydrochloric acid 10mL of 4mol/L, be then heated to 50 DEG C 30 minutes, filter precipitation
White solid, filtrate is cooled to 0 DEG C, adds KOH solid to pH value of solution 10-12, have solid to separate out,
Be dissolved in water separate out solid after with dichloromethane extract, be dried organic facies, be evaporated and obtain colourless liquid 220
Mg, yield 44.8%.
1H NMR(300MHz,DMSO-d6)δ:7.48(s,1H),7.05(s,1H),6.92(s,1H),
4.00(t,2H,J=6.9Hz),2.70(t,1H,J=6.8Hz),1.90(m,2H).ESI-MS(m/z):
126.35[M+1]+.
Embodiment 4:1-(3-(1H-imidazoles) propyl group)-4-benzoyl-5-(4-bromophenyl)-3-hydroxyl-1H-pyrroles
-2 (5H)-one
1.80g p-bromobenzaldehyde is added 10mL1,4-dioxane with 1.25g3-(1H-imidazoles) propylamine
In, the 2-hydroxy-4-phenyl-4-after being stirred at room temperature 30 minutes, 2.06g 5mL1,4-dioxane dissolved
Oxo-2-butylene acid methyl ester is slowly dropped in reaction bulb, and a small amount of solid that has slowly separates out, and drips and finishes, and room temperature is anti-
Answer 24 hours.Reactant liquor becomes thick, has a large amount of solid to produce after dilute, and sucking filtration obtains yellowish
Color solid, obtains white solid 2.40g, yield 64.5% by recrystallizing methanol.
1H NMR(300MHz,DMSO-d6)δ:8.20(s,1H),7.70(d,2H,J=6.9Hz),
7.46(m,3H),7.36(m,3H),7.30(m,2H),7.15(s,1H),5.46(s,1H),3.95(m,
2H),3.51(m,1H),2.61(m,1H),1.83(m,2H).ESI-MS(m/z):468.92[M+
1]+.
Embodiment 5:5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one
The product of 0.5g embodiment 4 is mixed with 0.69g80% hydrazine hydrate, uses 5ml acetate dissolution, heating
To backflow, after reacting 6 hours, completely, combiflash companion separates (CH in TLC display reaction2Cl2: CH3OH
=100:4) obtain faint yellow solid 0.14g, yield 28.2%.
1H NMR(300MHz,DMSO-d6)δ:14.04(s,1H),7.62(s,1H),7.47-7.53(m,
4H),7.21-7.36(m,5H),7.15(s,1H),6.87(s,1H),6.02(s,1H),3.95(m,2H),3.58
(m,1H),2.66(m,1H),1.88(m,2H).ESI-MS(m/z):462.31[M+1]+.
Embodiment 6～31:
By 2mmol brominated alkanes and 2mmol potassium carbonate, join the 5mL ethanol of 1mmol embodiment 5
In solution, after stirring 6 hours at 80 DEG C, completely, combiflash companion separates (CH in TLC display reaction2Cl2:
CH3OH=100:2) white or faint yellow solid, yield 35.4～67.9% are obtained.
Table 1 embodiment 6～31 compound structure, title, hydrogen spectrum and mass spectrometric data
Above racemic modification can prepare optical isomer by chirality, and specific experiment method is as follows:
Chiralcel AD-H column25cm×0.46cm(CH3OH,2.5mL/min,UV detection at220
nm).(such as: Chen Demiao etc., " analytical chemistry " the 01st phase: 75-78 in 2007) such as: such as: embodiment
12 and 30.
A pair optical isomer of embodiment 12:
(+)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one, mp:79-80 DEG C.1H NMR(600MHz,DMSO-d6)δ:7.60(s,1H),7.53(d,
2H,J=8.4Hz),7.43-7.49(m,2H),7.23-7.40(m,10H),7.14(s,1H),6.87(s,1H),
6.02(s,1H),5.56(d,2H,J=5.4Hz),3.96(m,2H),3.60(m,1H),2.68(m,1H),
1.89(m,2H).ESI-MS(m/z):552.43[M+H]+.[α]D=+58.6°(c=2.31in CH3OH).
(-)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one, mp:77-79 DEG C.1H NMR(600MHz,DMSO-d6)δ:7.60(s,1H),7.55(d,
2H,J=8.4Hz),7.43-7.49(m,2H),7.23-7.40(m,10H),7.14(s,1H),6.87(s,1H),
6.02(s,1H),5.56(d,2H,J=5.4Hz),3.96(m,2H),3.60(m,1H),2.68(m,1H),
1.89(m,2H).ESI-MS(m/z):552.50[M+H]+.[α]D=-57.6°(c=2.21in CH3OH).
A pair optical isomer of embodiment 30:
(+)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin
[3,4-c] pyrazoles-6 (1H)-one .mp:82-83 DEG C .1H NMR (600MHz, DMSO-d6)δ:7.61(s,
1H),7.53(d,2H,J=8.4Hz),7.48-7.50(m,4H),7.21-7.30(m,7H),7.15(s,1H),
6.88(s,1H),6.02(s,1H),5.55(d,2H,J=4.8Hz),3.96(m,2H),3.60(m,1H),2.67
(m,1H),1.90(m,2H).ESI-MS(m/z):570.51[M+H]+.[α]D=+94.9°(c=1.26in
CH3OH).
(-)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin
[3,4-c] pyrazoles-6 (1H)-one .mp:81-82 DEG C .1H NMR (600MHz, DMSO-d6)δ:7.60(s,
1H),7.53(d,2H,J=9.0Hz),7.48-7.50(m,4H),7.21-7.30(m,7H),7.14(s,1H),
6.87(s,1H),6.01(s,1H),5.54(d,2H,J=4.8Hz),3.96(m,2H),3.60(m,1H),2.67
(m,1H),1.90(m,2H).ESI-MS(m/z):570.46[M+H]+.[α]D=-85.6°(c=1.24in
CH3OH).
Embodiment 32: fluorescence polarization method measures p53-MDM2 protein binding inhibitory activity
The inhibitory activity of MDM2 is measured with the p53 being combined with MDM2 residue 1-118.This compound
The published crystal structure (Kussie etc., Science274:948-953 (1996)) of thing confirms containing p53
The segment of binding site, and we have resolved p53 peptide analogues MPRFMDYWEGLN's
X-diffraction structure (Bottger etc., J.Mol.Biol.269:744-756 (1997)). this example uses
5-FAM-(β-A)-(β-A)-FM-Aib-pY-(6-Cl-DL-Trp)-E-Ac3c-LN-NH2(PMDM6-F), its
KdReach 1nM.
By 5 μ L test compounds, MDM2 (10nM) and PMDM6-F (10nM) (buffer:100mM
Tripotassium phosphate, pH7.5；100μg/mL BGG；0.02% sodium azide) add 96 hole black flat-bottom enzyme marks
To final volume 125 μ L in plate, incubated at room, after 2 hours, reads fluorescence polarization with Biotek-Synergy2
Value.Draw curve with Graphpad Prism, calculate protein binding inhibition constant (Ki).Chemical combination of the present invention
Its scope of thing 0.015 μM to > 100 μMs.
By highly active compound nutlin-3(Shanghai Haoyuan Chemexpress) with same bar
Part is made into positive reference substance solution.
Result of the test is shown in Table 2, and wherein, sample refers to the pyrrolidone compound (example of preparation in corresponding embodiment
Such as embodiment 5 i.e.: 5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one.
Table 2 tests compound to p53-MDM2 protein-interacting inhibition constant Ki(unit: μM)
| Sample ID | Ki(μM) | Sample ID | Ki(μM) |
| Embodiment 5 | 47.42 | Embodiment 19 | 0.06 |
| Embodiment 6 | 0.17 | Embodiment 20 | ‐‐ |
| Embodiment 7 | ‐‐ | Embodiment 21 | 16.02 |
| Embodiment 8 | 3.82 | Embodiment 22 | 1.9 |
| Embodiment 9 | 6.78 | Embodiment 23 | 0.28 |
| Embodiment 10 | ‐‐ | Embodiment 24 | 2.51 |
| Embodiment 11 | ‐‐ | Embodiment 25 | 2.48 |
| Embodiment 12 | 0.25 | Embodiment 26 | 0.96 |
| Embodiment 13 | 0.11 | Embodiment 27 | 121.74 |
| Embodiment 14 | 0.23 | Embodiment 28 | 0.72 |
| Embodiment 15 | 10.8 | Embodiment 29 | 0.49 |
| Embodiment 16 | 0.66 | Embodiment 30 | 0.08 |
| Embodiment 17 | 13.24 | Embodiment 31 | 28.16 |
| Embodiment 18 | 56.5 | nutlin‐3 | 0.09 |
More than test result indicate that, the most compounds of the present invention has preferable p53-MDM2 albumen
Interaction inhibitory activity, multiple compounds are better than or are equivalent to positive control drug nutlin-3.
The RAW264.7 cells in vitro antiinflammatory experiment of embodiment 33:LPS induction
Cell strain selects RAW264.7(mouse macrophage, ATCC#TIB-71) test, by the
Two crude drug teaching and research rooms of pharmaceutical college of army medical university are frozen and pass on.Culture fluid is that DMEM+10%FBS+ is dual anti-.
Sample preparation: with DMSO(Merck) dissolve after, add PBS (-) be made into the molten of 1000 μ g/ml
Liquid or uniform suspension, then with containing DMSO PBS (-) dilution.
By 0.25% trypsinization of RAW264.7 cell, collecting cell, piping and druming uniformly, adds culture medium
Cell concentration is adjusted to 1 × 106Cell/mL, is seeded to 96 orifice plates by cell, every hole 100 μ l, in 37 DEG C,
Under the conditions of 5%CO2 overnight.Discard culture fluid next day, add the 100uL culture medium containing 2 μ g/mL LPS,
The medicine of each concentration that 100 μ l configure, in 37 DEG C, 5%CO is added after cultivating 1h2Under the conditions of cultivate
24h.Absorption culture supernatant 100uL is in 96 orifice plates, and every hole adds 100uL Griess reagent, whirlpool
Vibration is allowed to mix, and room temperature lucifuge stands 30min, by microplate reader OD value at 540nm wavelength.By upper
Clear liquid discards, and adds the cell culture fluid containing 2mg/mL MTT, in 37 DEG C, 5%CO2 in every hole
Under the conditions of cultivate 4h, supernatant discarded, add 200uL DMSO by purple crystal dissolve, use microplate reader
OD value at wavelength is surveyed under 570nm.Calculation of half inhibitory concentration IC50。
Result of the test is shown in Table 3, and wherein, sample refers to the pyrrolidone compound (example of preparation in corresponding embodiment
Embodiment 8 is i.e.: 5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-pi-allyl-3-phenyl-4,5-pyrrolin
[3,4-c] pyrazoles-6 (1H)-one.
Compounds towards macrophages RAW264.7 anti-inflammatory activity (unit: μ g/ml) tested by table 3
More than test result indicate that, the compound of the present invention has preferable anti-inflammatory activity, can be as good
Antiinflammatory.
Embodiment 34: Cytostatic to tumor cell is tested
The compound of the present invention has been carried out Cytostatic to tumor cell test, and test method uses conventional
Mtt assay (as Lv Qiujun edits " developmental pharmacology research method ", Chemical Industry Press, 2007:
242-243).
Cell strain selects the A549 (human lung adenocarcinoma cell) and natural p53 of natural expression wild type p53 to lack
The NCI-H1299(human lung adenocarcinoma cell lost) carry out control experiment, by Shanghai Institute of Pharmaceutical Industry's pharmacology
Laboratory is frozen and passes on.Culture fluid is that DMEM+10%FBS+ is dual anti-.
MTT solution prepare: weigh MTT0.5 gram, be dissolved in 100ml phosphate buffer (PBS) or
Without in phenol red culture medium, with 0.22 μm membrane filtration to remove the antibacterial in solution, put 4 DEG C of lucifuges and protect
Deposit.
Sample preparation: with DMSO(Merck) dissolve after, add PBS (-) be made into the molten of 1000 μ g/ml
Liquid or uniform suspension, then with containing DMSO PBS (-) dilution.
Highly active compound nutlin-3 is made into positive reference substance solution with same condition.Mtt assay.
It is 5-6 × 10 that the 96 every holes of orifice plate add concentration4The cell suspension 100 μ l of individual/ml, puts 37 DEG C, 5%CO2Training
Support in case.After 24h, addition sample liquid, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO2Effect 72h.
Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate, 100 μ l/ holes, put cultivation after effect 4h
In case, after dissolving, survey 570nm OD value by the full-automatic microplate reader of MK-2.Calculation of half inhibitory concentration IC50。
Result of the test is shown in Table 4, and wherein, sample refers to the pyrrolidone compound (example of preparation in corresponding embodiment
Embodiment 5 is i.e.: 5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one.
The half-inhibition concentration IC of compound on tumor cell tested by table 450(unit: μ g/ml)
More than test result indicate that, the most compounds of the present invention has good anti-tumor activity, Duo Gehua
Compound is higher than positive control drug nutlin-3, can be as good antitumor agent.
Embodiment 35: the anti tumor activity in vitro of optical isomer
Anti tumor activity in vitro with reference to the experimental technique test optical isomer of embodiment 34.
Cell strain selects the A549 (human lung adenocarcinoma cell) and natural p53 of natural expression wild type p53 to lack
Lose NCI-H1299(human lung adenocarcinoma cell), U2OS(human osteosarcoma cell), Saos-2(people's skeletonization
Sarcoma cell) carry out control experiment, frozen and pass on by Shanghai Institute of Pharmaceutical Industry's pharmacological evaluation room.
Experimental result such as table 5:
The activity of table 5 optical isomer
More than test result indicate that, the optical isomer of the compounds of this invention the most all has good antitumor and lives
Property, also above positive control drug nutlin-3, can be as good antitumor agent.
To sum up, therefore the compounds of this invention and its esters may be used for preparing p53-MDM2 albumen phase interaction
Use micromolecular inhibitor.
The ultimate principle of the present invention, principal character and advantages of the present invention have more than been shown and described.The industry
Skilled person will appreciate that, the present invention is not restricted to the described embodiments, in above-described embodiment and description
The principle that the present invention is simply described described, the present invention is also without departing from the spirit and scope of the present invention
Having various changes and modifications, these changes and improvements both fall within scope of the claimed invention.This
Bright claimed scope is defined by appending claims and equivalent thereof.
Claims (6)
1. a pyrrolidone compound and pharmaceutical salts thereof, it is characterised in that described compound is selected from following:
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles-6 (1H)-
Ketone,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-methyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-normal-butyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-pi-allyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-propargyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-cyclohexyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-octyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-isopropyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-cyclobutyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-heptyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-cyclopenta-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-pro-pyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-ethyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrazoles
-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-pentyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-n-hexyl-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-isobutyl group-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-(2-(tetrahydrochysene-2H-pyrans)-2-ethoxy)-3-phenyl
-4,5-pyrrolin [3,4-c] pyrazoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-(2-ethoxy)-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-neighbour's luorobenzyl-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
5-(3-(1H-imidazoles) propyl group)-4-(4-the bromophenyl)-1-tert-butyl group-3-phenyl-4,5-pyrrolin [3,4-c] pyrrole
Azoles-6 (1H)-one,
2-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) ethyl acetate,
4-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) ethyl n-butyrate.,
3-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) ethyl propionate,
4-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) butanoic acid,
5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
3-(5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-6 oxo-3-phenyl-5,6-pyrrolin [3,4-c] pyrrole
Azoles-1 (4H) propanoic acid,
(+)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
(-)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-benzyl-3-phenyl-4,5-pyrrolin [3,4-c]
Pyrazoles-6 (1H)-one,
(+)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin
[3,4-c] pyrazoles-6 (1H)-one, or
(-)-5-(3-(1H-imidazoles) propyl group)-4-(4-bromophenyl)-1-is to luorobenzyl-3-phenyl-4,5-pyrrolin
[3,4-c] pyrazoles-6 (1H)-one.
A kind of pyrrolidone compound the most according to claim 1 and pharmaceutical salts thereof, it is characterised in that institute
The pharmaceutical salts stated is acylate or inorganic acid salt.
A kind of pyrrolidone compound the most according to claim 2 and pharmaceutical salts thereof, it is characterised in that nothing
Machine acid refers to hydrochloric acid, sulphuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid or nitric acid；Organic acid refers to acetic acid, horse
Come sour, fumaric acid, tartaric acid, succinic acid, lactic acid, p-methyl benzenesulfonic acid, salicylic acid or oxalic acid.
A kind of pyrrolidone compound the most according to claim 1 and pharmaceutical salts thereof are at preparation p53-MDM2
Application in protein-interacting micromolecular inhibitor.
A kind of pyrrolidone compound the most according to claim 1 and pharmaceutical salts thereof are preparing antitumor drug
Or the application in anti-inflammatory drug.
A kind of pyrrolidone compound the most according to claim 5 and pharmaceutical salts thereof are preparing antitumor drug
Or the application in anti-inflammatory drug, it is characterised in that tumor therein refer to esophagus, stomach, intestinal, oral cavity,
Pharynx, larynx, lung, mammary gland, uterus, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone,
The cancer that connective tissue, skin, eye, brain and central nervous system position occur, or thyroid carcinoma, white
Disorders of blood, suddenly king's evil, lymphoma, myeloma.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070148185A1 (en) * | 2005-10-14 | 2007-06-28 | Dharmender Rathore | Novel therapeutic target for protozoal diseases |
| RU2320661C2 (en) * | 2006-03-15 | 2008-03-27 | Государственное образовательное учреждение высшего профессионального образования "Пермская государственная фармацевтическая академия Федерального агентства по здравоохранению и социальному развитию Российской Федерации" (ГОУ ВПО ПГФА Росздрава) | 1,4,5,6-tetrahydro-6-oxo-5-(2-piperazinoethyl)-4-phenyl-3-(4-chlorophenyl)pyrrolo[3.4-c]pyrazole dihydrochloride eliciting hypotensive and anti-coagulant activity |
| CN101679246A (en) * | 2007-03-30 | 2010-03-24 | 盐野义制药株式会社 | Novel pyrrolinone derivative and medicinal composition containing the same |
| US20110183939A1 (en) * | 2008-09-25 | 2011-07-28 | Shionogi & Co., Ltd. | Novel pyrolinone derivative and pharmaceutical composition comprising the same |
| WO2012046030A2 (en) * | 2010-10-07 | 2012-04-12 | Riotech Pharmaceuticals Ltd | Phosphodiesterase inhibitors |
| CN102603717A (en) * | 2012-01-09 | 2012-07-25 | 中国人民解放军第二军医大学 | Pyrrylketone compound and application thereof as drug |
-
2014
- 2014-02-19 CN CN201410056585.9A patent/CN103819476B/en not_active Expired - Fee Related
- 2014-03-04 WO PCT/CN2014/000195 patent/WO2014134968A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070148185A1 (en) * | 2005-10-14 | 2007-06-28 | Dharmender Rathore | Novel therapeutic target for protozoal diseases |
| RU2320661C2 (en) * | 2006-03-15 | 2008-03-27 | Государственное образовательное учреждение высшего профессионального образования "Пермская государственная фармацевтическая академия Федерального агентства по здравоохранению и социальному развитию Российской Федерации" (ГОУ ВПО ПГФА Росздрава) | 1,4,5,6-tetrahydro-6-oxo-5-(2-piperazinoethyl)-4-phenyl-3-(4-chlorophenyl)pyrrolo[3.4-c]pyrazole dihydrochloride eliciting hypotensive and anti-coagulant activity |
| CN101679246A (en) * | 2007-03-30 | 2010-03-24 | 盐野义制药株式会社 | Novel pyrrolinone derivative and medicinal composition containing the same |
| US20110183939A1 (en) * | 2008-09-25 | 2011-07-28 | Shionogi & Co., Ltd. | Novel pyrolinone derivative and pharmaceutical composition comprising the same |
| WO2012046030A2 (en) * | 2010-10-07 | 2012-04-12 | Riotech Pharmaceuticals Ltd | Phosphodiesterase inhibitors |
| CN102603717A (en) * | 2012-01-09 | 2012-07-25 | 中国人民解放军第二军医大学 | Pyrrylketone compound and application thereof as drug |
Non-Patent Citations (5)
| Title |
|---|
| A three-dimensional pharmacophore modelling of ITK inhibitors and virtual screening for novel inhibitors;V. Bagga 等;《SAR and QSAR in Environmental Research》;20110309;第22卷(第1-2期);第171-190页，尤其第185页具体化合物 * |
| Diverse inhibitor chemotypes targeting Trypanosoma cruzi CYP51;Shamila S. Gunatilleke 等;《PLoS Neglected Tropical Diseases》;20120731;第6卷(第7期);STN标引的RN：866247-18-9的化合物 * |
| Identification of Novel Adenosine A2A Receptor Antagonists by Virtual Screening;Christopher J. Langmead 等;《Journal of Medicinal Chemistry》;20120117;第55卷(第5期);第1904-1909页，尤其Figure 1 * |
| Three-component condensation of methyl acylpyruvates with aromatic aldehydes and ethylenediamine. Chemical properties of the products;V. L. Gein 等;《Russian Journal of General Chemistry》;20051231;第75卷(第2期);第254-260页，尤其第258页Scheme 4 * |
| Three-component reaction of methyl 2,4-dioxo-4-phenylbutanoate and methyl 2,4-dioxopentanoate with aromatic aldehydes and propane-1,2-diamine and chemical properties of the products;V. L. Gein 等;《Russian Journal of General Chemistry》;20101231;第46卷(第6期);第875-883页，尤其第877页Scheme 2 * |
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| WO2014134968A1 (en) | 2014-09-12 |
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