CN103086925B - Benzoyl urea derivative with active anticancer and its production and use - Google Patents
Benzoyl urea derivative with active anticancer and its production and use Download PDFInfo
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Abstract
The present invention relates to the benzoyl urea derivative with active anticancer.Also relate to preparation and this compounds purposes on the medicine of preparation treatment cancer of this compounds.The present invention is presented as in some aspects, and poly (ADP-ribose) polymerase (PARP) inhibitor or its metabolite are the compounds represented by formula (I), or its pharmaceutically acceptable salt, or its prodrug, wherein, and R1、R2、R3、R4And R5Be defined in the specification.
Description
Technical field
The present invention relates to the benzoyl urea derivative and metabolite thereof with active anticancer.The present invention also relates to the synthesis of this kind of cancer therapy drug and the method using this compounds for treating cancer.
Background technology
Poly (ADP-ribose) polymerase (PARP) inhibitor is the cancer therapy drug that a class is new.At present, most of anticarcinogens are all kill cancerous cell by the DNA in damage cancerous cell, but the DNA being damaged can be repaired by poly (ADP-ribose) polymerase and be regenerated by cancerous cell.Therefore, it is suppressed that poly (ADP-ribose) polymerase just can the reparation of damaged dna chain in anticancer, thus helping standard care (chemotherapy or radiotherapy) to kill cancerous cell (Ossovskayaetal.US20090149397；Shermanetal.US20090131529and20090123419).
It is interesting that halonitro and nitroso-group estrogen compound can be used for treating cancer, especially breast carcinoma；It is furthermore interesting that, the fragrant halonitro of simple in construction and nitroso compound are also found to have significantly high anti-tumor activity, especially for breast carcinoma, this compounds is proved to be poly (ADP-ribose) polymerase (PARP) inhibitor (Kunetal.US5464871).It practice, aromatic nitro compound first changes into aromatic nitroso compound in vivo, and the latter is only the reactive compound suppressing tumor growth.Owing to aromatic nitroso compound is relatively poor at the water solublity of physiological ph, stability is limited again, therefore, it is difficult to predict whether these compounds can arrive cancerous cell, aromatic nitro compound does not then have these problems, so they desirable prodrugs that are aromatic nitroso compound.The medicine being in forefront in poly (ADP-ribose) AG14361 is the Iniparib (BSI-201) of Sanofi-Aventis, and it is exactly an aromatic nitro compound, is a cancer therapy drug very likely.
Iniparib is to what spread in second phase clinic, and the breast carcinoma (mTNBC) in triple feminine genders shows good therapeutic effect (O ' Shaughnessyetal.NEJM, 2011,364 (3), 205)；Not long ago, if Sanofi-Aventis reports brief three phase clinical effectiveness cancer patients previously other anticarcinogen not used of this medicine treatment mTNBC, then Iniparib can not extend the life of these patients or slow down the process of cancer, but as used one or both anticarcinogens before cancer patient, then the curative effect that Iniparib shows is consistent with second phase clinical effectiveness.At present, Iniparib treats the clinical trial of breast carcinoma, pulmonary carcinoma and other cancer and proceeds.
The chemical constitution of Iniparib is 4-iodo-3-nitrobenzamide, and compared with the active anticancer of Iniparib, the heterocyclic carbamate derivatives that a class is new is found to have higher active anticancer (Chinese Patent Application No.: CN201010532658.9).The present invention provides the benzoyl urea derivative that a class is new, and this compounds is also more more effective cancer therapy drug than Iniparib.
Summary of the invention
An object of the present invention is in that to disclose the new cancer therapy drug benzoyl urea derivative of a class or its pharmaceutically useful salt.
Compound of the present invention can use formula (I) to represent:
Wherein
R1、R2And R3Independently selected from following group: hydrogen, substituted or unsubstituted (C1-C5) alkyl, substituted or unsubstituted (C3-C5) thiazolinyl, substituted or unsubstituted (C3-C5) alkynyl, substituted or unsubstituted (C3-C5) cycloalkyl；R1And R2Substituted or unsubstituted five, six or heptatomic ring can also be collectively formed by ring；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring can also be collectively formed by ring；Wherein above-mentioned substituted or unsubstituted (C3-C5) thiazolinyl, substituted or unsubstituted (C3-C5) double bond of alkynyl preferably thiazolinyl and three keys of alkynyl are not joined directly together with the atom N of urea；
R4It is nitro or nitroso-group；
R5It is iodine or acetenyl；
Or it is acceptable salt pharmaceutically, or its prodrug.
" replacement " recited above refers to and can be selected from following group: hydroxyl, (C1-C5) alkyl, (C2-C5) thiazolinyl, (C2-C5) alkynyl, (C3-C5) cycloalkyl, (C1-C5) alkoxyl, amino, (C1-C5) alkyl amino, two (C1-C5) alkyl amino, (C1-C5) alkyl sulfenyl, halogen, it is preferable that the substituent group of hydroxyl, methoxyl group, amino, methylamino, dimethylamino, methyl mercapto and halogen replaces.
Wherein above-mentioned R1、R2And R3It preferably is selected from hydrogen, substituted or unsubstituted (C1-C5) alkyl, R1And R2Ring collectively forms substituted or unsubstituted five, six or heptatomic ring；R2And R3Ring collectively forms substituted or unsubstituted four, five, six or heptatomic ring.
It is further preferred that R1、R2And R3Independently selected from hydrogen, substituted or unsubstituted (C1-C5) alkyl.
Most preferably R1、R2And R3Independently selected from hydrogen, methyl, ethyl, propyl group or normal-butyl.
Wherein R4Preferred nitro.
More specifically, wherein said Formula (I) is selected from:
1-(the iodo-3-nitro benzoyl of 4-)-3,3-dimethyl ureas (I-1)
1-(the iodo-3-nitro benzoyl of 4-) urea (I-2)
1-(the iodo-3-nitro benzoyl of 4-)-3-MU (I-3)
1-(the iodo-3-nitro benzoyl of 4-)-3-ethyl carbamide (I-4)
1-(the iodo-3-nitro benzoyl of 4-)-3-propyl group urea (I-5)
1-(the iodo-3-nitro benzoyl of 4-)-3-Butylurea (I-6)
1-(4-iodine 3-nitro benzoyl)-3-amyl group urea (I-7)
1-(the iodo-3-nitro benzoyl of 4-)-3-isopropyl urea (I-8)
1-(the iodo-3-nitro benzoyl of 4-)-3-isobutyl group urea (I-9)
1-(the iodo-3-nitro benzoyl of 4-)-3-methyl-3-ethyl carbamide (I-10)
1-(the iodo-3-nitro benzoyl of 4-)-1,3-dimethyl urea (I-11)
1-(the iodo-3-nitro benzoyl of 4-)-3,3-diethyl ureas (I-12)
1-(the iodo-3-nitro benzoyl of 4-)-3,3-dipropyl ureas (I-13)
1-(the iodo-3-nitro benzoyl of 4-)-2-imidazolone (I-14)
1-(the iodo-3-nitro benzoyl of 4-)-3-methyl-2-imidazolone (I-15)
N-(the iodo-3-nitro benzoyl of 4-) pyrrolidin-1-yl Methanamide (I-16)
N-(the iodo-3-nitro benzoyl of 4-)-1-piperidine-1-Methanamide (I-17)
1-(the iodo-3-nitro benzoyl of 4-)-1,3,3-trimethyl-urea (I-18)
1-(the iodo-3-nitro benzoyl of 4-)-1-ethyl-3,3-dimethyl urea (I-19)
1-(the iodo-3-nitro benzoyl of 4-)-1-propyl group-3,3-dimethyl urea (I-20)
1-(the iodo-3-nitro benzoyl of 4-)-1-butyl-3,3-dimethyl urea (I-21)
1-(the iodo-3-nitro benzoyl of 4-)-1-methyl-3,3-diethyl urea (I-22)
1-(the iodo-3-nitro benzoyl of 4-)-1-methyl-3,3-dipropyl urea (I-23)
1-(the iodo-3-nitro benzoyl of 4-)-1-ethyl-3,3-dipropyl urea (I-24)
1-(the iodo-3-nitro benzoyl of 4-)-1,3,3-tripropyl urea (I-25)
1-(the iodo-3-nitro benzoyl of 4-)-1-butyl-3,3-dipropyl urea (I-26)
1-(4-acetenyl-3-nitro benzoyl)-3,3-diethyl ureas (I-27)
1-(4-acetenyl-3-nitro benzoyl)-3-amyl group urea (I-28)
1-(4-acetenyl-3-nitro benzoyl)-3-methyl-3-ethyl carbamide (I-29)
1-(4-acetenyl-3-nitro benzoyl)-3,3-dipropyl ureas (I-30)
1-(4-acetenyl-3-nitro benzoyl)-3,3-dibutyl ureas (I-31)
N-(4-acetenyl-3-nitro benzoyl) pyrrolidin-1-yl Methanamide (I-32)
N-(4-acetenyl-3-nitro benzoyl)-1-piperidine-1-Methanamide (I-33)
1-(4-acetenyl-3-nitro benzoyl)-3,3-dimethyl ureas (I-34)
1-(4-acetenyl-3-nitro benzoyl) urea (I-35)
1-(4-acetenyl-3-nitro benzoyl)-3-MU (I-36)
1-(4-acetenyl-3-nitro benzoyl)-3-ethyl carbamide (I-37)
1-(4-acetenyl-3-nitro benzoyl)-3-propyl group urea (I-38)
1-(4-acetenyl-3-nitro benzoyl)-3-Butylurea (I-39)
1-(4-acetenyl-3-nitro benzoyl)-3-isopropyl urea (I-40)
1-(4-acetenyl-3-nitro benzoyl)-3-isobutyl group urea (I-41)
1-(4-acetenyl-3-nitro benzoyl)-1,3-dimethyl urea (I-42)
1-(4-acetenyl-3-nitro benzoyl)-1,3,3-trimethyl-urea (I-43)
1-(4-acetenyl-3-nitro benzoyl)-1-ethyl-3,3-dimethyl urea (I-44)
1-(4-acetenyl-3-nitro benzoyl)-1-propyl group-3,3-dimethyl urea (I-45)
1-(4-acetenyl-3-nitro benzoyl)-1-butyl-3,3-dimethyl urea (I-46)
1-(4-acetenyl-3-nitro benzoyl)-1-methyl-3,3-diethyl urea (I-47)
1-(4-acetenyl-3-nitro benzoyl)-1-methyl-3, base urea (I-48) in 3-bis-
1-(4-acetenyl-3-nitro benzoyl)-1-ethyl-3,3-dipropyl urea (I-49)
1-(4-acetenyl-3-nitro benzoyl)-1,3,3-tripropyl urea (I-50)
1-(4-acetenyl-3-nitro benzoyl)-1-butyl-3,3-dipropyl urea (I-51)
1-(4-acetenyl-3-nitro benzoyl)-2-imidazolone (I-52)
1-(4-acetenyl-3-nitro benzoyl)-3-methyl-2-imidazolone (I-53).
A second aspect of the present invention also discloses the application that formula (I) compound and pharmaceutical composition thereof are used for treating in the medicine of cancer in preparation.Described cancer includes colon cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, gastric cancer, acute leukemia, chronic leukemia, carcinoma of prostate, people's uterus carcinoma, cancer of pancreas, hepatocarcinoma, the brain cancer, cns tumor, bladder cancer, renal carcinoma, skin carcinoma, neck cancer, myosarcoma, lymphatic cancer, osteocarcinoma and other type of cancer.Also disclose the compound represented by formula (I) and pharmaceutical composition to be caused at preparation treatment cell proliferation and/or the destruction of angiogenesis, associate or application in the medicine of adjoint disease simultaneously.
Another aspect of the present invention is in that disclosing formula (I) compound is used for the application in the medicine of the treatment disease relevant to poly (ADP-ribose) polymerase (PARP) inhibitor in preparation.The disease relevant to poly (ADP-ribose) polymerase (PARP) inhibitor includes cancer, apoplexy (Stroke), myocardial infarction (Myocardialinfarction), neurodegenerative disease (Neuodegenerativediseases) etc..Further aspect of the present invention provides the compound represented by formula (I) using effective dose or the pharmaceutical composition containing compound represented by formula (I) and individually or is used in combination with other medicines to carry out treating and is caused by the destruction of cell proliferation and/or angiogenesis, associate or the method for adjoint disease.Pharmaceutical composition of the present invention can also comprise the pharmaceutically suitable carrier compatible with formula (I) compound.Formula (I) compound with general dosage administration, such as injection type and peroral dosage form, including capsule, tablet, powder, cachet, suspendible liquor or solution, preferentially can be administered in the way of injection.Dosage form and Pharmaceutical composition can use conventional pharmaceutically useful excipient and additive and conventional technology to prepare.Described pharmaceutically useful excipient and additive include avirulent compatible filler, binding agent, disintegrating agent, buffer agent, preservative, antioxidant, lubricant, correctives, thickening agent, coloring agent, emulsifying agent etc..
The preparation method that another aspect of the present invention is in that openly described benzoyl urea derivative.
A further object of the present invention there are provided the method (shown in following reaction equation 1) that one prepares Formula (I).The method is R suitable in formula (I) compound1、R2、R3For hydrogen, substituted or unsubstituted (C1-C5) alkyl, substituted or unsubstituted (C3-C5) thiazolinyl, substituted or unsubstituted (C3-C5) alkynyl, substituted or unsubstituted (C3-C5) cycloalkyl；R1And R2Substituted or unsubstituted five, six or heptatomic ring can also be collectively formed by ring；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring4For nitro, R5Situation during for iodine, as being used for preparing compound I-1, compound I-2, compound I-3, compound I-4, compound I-5, compound I-6, compound I-7, compound I-8, compound I-9, compound I-10, compound I-11, compound I-12, compound I-13, compound I-14, compound I-15, compound I-16, compound I-17.
A further object of the present invention there are provided the method (shown in following reaction equation 2) preparing Formula (I) with Compound II per I for raw material.The method is R suitable in formula (I) compound2、R3For hydrogen, substituted or unsubstituted (C1-C5) alkyl, substituted or unsubstituted (C3-C5) thiazolinyl, substituted or unsubstituted (C3-C5) alkynyl, substituted or unsubstituted (C3-C5) cycloalkyl；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring1For substituted or unsubstituted (C1-C5) alkyl, substituted or unsubstituted (C3-C5) thiazolinyl, substituted or unsubstituted (C3-C5) alkynyl, substituted or unsubstituted (C3-C5) cycloalkyl, R4For nitro, R5For the situation of iodine, as being used for preparing compound I-18, compound I-19, compound I-20, compound I-21, compound I-22, compound I-23, compound I-24, compound I-25, compound I-26.Wherein X is halogen.
It is still another object of the present invention to provide the method (shown in following reaction equation 3) that one prepares Formula (I).The method is R suitable in formula (I) compound2、R3For hydrogen, substituted or unsubstituted (C1-C5) alkyl, substituted or unsubstituted (C3-C5) thiazolinyl, substituted or unsubstituted (C3-C5) alkynyl, substituted or unsubstituted (C3-C5) cycloalkyl；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring1For hydrogen, R4For nitro, R5Situation during for acetenyl, as being used for preparing compound I-27, compound I-28, compound I-29, compound I-30, compound I-31, compound I-32, compound I-33.
It is still another object of the present invention to provide the method (shown in following reaction equation 4) that one prepares Formula (I).The method is R suitable in formula (I) compound1、R2、R3For hydrogen, substituted or unsubstituted (C1-C5) alkyl, substituted or unsubstituted (C3-C5) thiazolinyl, substituted or unsubstituted (C3-C5) alkynyl, substituted or unsubstituted (C3-C5) cycloalkyl；R1And R2Substituted or unsubstituted five, six or heptatomic ring can also be collectively formed by ring；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring4For nitro, R5Situation during for acetenyl, as being used for preparing compound I-34, compound I-35, compound I-36, compound I-37, compound I-38, compound I-39, compound I-40, compound I-41, compound I-42, compound I-43, compound I-44, compound I-45, compound I-46, compound I-47, compound I-48, compound I-49, compound I-50, compound I-51, compound I-52, compound I-53.
Part term used in the present invention definition is as follows:
" halogen " refers to fluorine, chlorine, bromine and iodine.
" alkyl " refers to straight chain or the aliphatic hydrocarbon group with side chain when being used as a group or a group a part of.Prioritizing selection is C1-C5Alkyl.The example of alkyl group includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group etc..
The aliphatic hydrocarbon group containing a carbon-carbon double bond is referred to when " thiazolinyl " is as a group or a group a part of, can also with side chain for straight chain.Prioritizing selection is C3-C5Thiazolinyl.The example of alkenyl group includes, but are not limited to pi-allyl, crotyl etc..
The aliphatic hydrocarbon group containing a triple carbon-carbon bonds is referred to when " alkynyl " is as a group or a group a part of, can also with side chain for straight chain.Prioritizing selection is C3-C5Alkynyl.The example of alkynyl group includes, but are not limited to propargyl, 2-butyne base etc..
Additionally, term " pharmaceutically acceptable salt " refers to that above-claimed cpd can keep original biological activity and be suitable for some salt of medical usage.The pharmaceutically acceptable salt of the compound represented by formula (I) can be slaine and the amine salt of suitable acid formation, slaine preferred as alkali, alkali salt, suitable acid includes mineral acid and organic acid, for instance acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-methyl benzenesulfonic acid etc..Particularly preferably be hydrochloric acid, hydrobromic acid, phosphoric acid and sulphuric acid, it is most preferred that be hydrochlorate.
" cycloalkyl " refers to saturated or fractional saturation carbocyclic ring.With the ring of 3-5 carbon atom composition for prioritizing selection.Example includes, but are not limited to: cyclopropyl, cyclobutyl, cyclopenta etc..
" alkoxyl " refers to the group of (alkyl-O-).Wherein, alkyl is shown in relevant definition herein.C1-C5Alkoxyl be prioritizing selection.The example includes, but are not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy etc..
We have found that, the compounds of this invention is highly active tumor growth inhibitors.
It is further elucidated with the present invention by the examples below.Embodiment gives preparation and the dependency structure appraising datum of the representative compound represented by formula (I).Mandatory declaration, following embodiment is an illustration for the present invention rather than limitation of the present invention.
In following Examples, unless otherwise, all temperature are Celsius temperature, and unless otherwise, various initiation materials and reagent are all from commercially available.Marketable material and reagent are all without being further purified direct use, unless otherwise.
Glass drying oven oven drying and/or heat drying.Reaction glass silica gel-60F254 flat board (0.25mm) (TLC) is tracked.Analytical thin layer chromatography is also launched with suitable solvent ratios (v/v).For reaction end when on TLC, initial substance exhausts.
1HNMR collection of illustrative plates is to measure with Bruker instrument (400MHz) and obtain, and chemical shift ppm represents.Use tetramethylsilane internal standard (0.00ppm).1The method for expressing of HNMR: s=is unimodal, d=doublet, t=triplet, m=multiplet, br=broadens, the doublet of dd=doublet, the doublet of dt=triplet.If provide coupling constant, its unit is Hz.
Mass spectrum is to measure with LC/MS instrument to obtain, and Ionization mode can be ESI or APCI.
The equal unmodified of all fusing points.
Example below is merely illustrative the synthetic method of the particular compound invented.But not any restriction in synthetic method.Compound unlisted below, it is also possible to with following same synthetic route and synthetic method, select suitable raw starting material, the reaction condition adjustment of the common-sense suitable a little in the place being necessary can be prepared.
Specific embodiments
The preparation of embodiment 1:1-(the iodo-3-nitro benzoyl of 4-)-3,3-dimethyl ureas (compound I-1):
Reaction bulb adds 70 grams of iodo-3-nitrobenzoic acids (Compound II per-1) of (0.239 mole) 4-and 350 milliliters of N, dinethylformamide (DMF), stirring and dissolving, mixed liquor ice-water bath is cooled to 0～10 DEG C, drip 61 milliliters of (0.84 mole) thionyl chlorides, drip and finish recession deicing water-bath, room temperature reaction 1 hour, it is cooled to 0～10 DEG C again, add 490 milliliters of (6.1 moles) pyridines, 105 grams of (1.19 moles) 1, 1-dimethyl urea, react 1 hour, reactant liquor is poured in 4 liter of 1% dilute hydrochloric acid, stirring, precipitate out solid, filter, water washing is to neutral.Then in filter cake, add 2 liters of ethyl acetate; heat to 75 DEG C after it is completely dissolved; add 200 grams of anhydrous sodium sulfates, 20 grams of activated carbon decolorizings, filter; filtrate concentrates; precipitate out solid gradually, filter, dry to obtain 1-(the iodo-3-nitro benzoyl of 4-)-3; 3-dimethyl urea (compound I-1) 36.4 grams, yield is 42%.1HNMR (400MHz, DMSO-d6): δ 2.94 (s, 6H), 7.83 (d, 1H, J=8.1Hz), 8.25 (d, 1H, J=8.2Hz), 8.35 (s, 1H), 10.45 (s, 1H)；MS (m/z): 364 [M+H].
With the iodo-3-nitrobenzoic acid (Compound II per-1) of 4-for raw material, select suitable reagent, prepare following compound by embodiment 1 method:
The preparation of embodiment 18:1-(the iodo-3-nitro benzoyl of 4-)-1,3,3-trimethyl-urea (compound I-18):
250 milliliters of single port bottles add 10 grams of (0.0275 mole) 1-(the iodo-3-nitro benzoyl of 4-)-3, 3-dimethyl urea (compound I-1) and 100 milliliters of N, dinethylformamide, stirring and dissolving, it is subsequently adding 12.7 grams of (0.092 mole) Anhydrous potassium carbonates and 16.7 milliliters of (0.268 mole) iodomethane, room temperature reaction 1 hour, TLC detection reaction is complete, add 100 milliliters of water, ethyl acetate (200 milliliters × 3) extracts, merge organic facies, anhydrous sodium sulfate dries, filter, concentration, column chromatography for separation (ethyl acetate/normal hexane is as eluant), crystallization obtains 1-(the iodo-3-nitro benzoyl of 4-)-1, 3, 3-trimethyl-urea (compound I-18) 5.5 grams, yield is 53%.1HNMR (400MHz, DMSO-d6): δ 2.86 (s, 6H), 3.10 (s, 3H), 7.45 (dd, 1H, J1=8.1Hz, J2=1.4Hz), 8.01 (d, 1H, J=1.4Hz), 8.18 (d, 1H, J=8.1Hz)；MS (m/z): 378 [M+H].
Select suitable raw material (compound I-1, compound I-12, compound I-13) and reagent, prepare following compound respectively by embodiment 18 method:
The preparation of embodiment 27:1-(4-acetenyl-3-nitro benzoyl)-3,3-diethyl ureas (compound I-27):
nullReaction bulb adds 10 grams of (52.6 mMs) 4-acetenyl-3-nitrobenzamide (compound IV) (preparation of this compound is with reference to patent CN201010532658.9) and 300 milliliter 1，2-dichloroethanes，Cryosel bath is cooled to-6 DEG C，Add 3.3 milliliters of (37 mMs) oxalyl chlorides，Room temperature reaction 4 hours，It is then heated to 60 DEG C react 0.5 hour，React complete，Concentrating under reduced pressure boils off solvent，Add 75 milliliters of oxolanes，Ice-water bath is lowered the temperature，Add 5.2 milliliters of (51 mMs) diethylamine，Reaction precipitates out solid，Filter，Ethyl acetate/normal hexane (1: 1) washing leaching cake，Re-crystallizing in ethyl acetate obtains 1-(4-acetenyl-3-nitro benzoyl)-3，3-diethyl urea (compound I-27) 3 grams，Yield is 19.7%.1HNMR (400MHz, DMSO-d6): δ 1.12 (t, 6H, J=7.0Hz), 3.35 (m, 4H), 4.97 (s, 1H), 7.93 (d, 1H, J=8.0Hz), 8.14 (dd, 1H, J1=8.1Hz, J2=1.5Hz), 8.50 (d, 1H, J=1.4Hz), 10.48 (s, 1H)；MS (m/z): 288 [M-H].
With 4-acetenyl-3-nitrobenzamide (compound IV) for raw material, select suitable reagent, prepare following compound by embodiment 27 method:
The preparation of embodiment 34:1-(4-acetenyl-3-nitro benzoyl)-3,3-dimethyl ureas (I-34):
nullStep one: add 5 grams of (13.77 mMs) 1-(the iodo-3-nitro benzoyl of 4-)-3 in single port bottle，3-dimethyl urea (compound I-1)，4.3 milliliters of triethylamines and 75 milliliters of oxolanes，Nitrogen protection，Magnetic agitation，It is subsequently adding 0.5 gram of (0.712 mM) double; two (triphenyl phosphorus) palladium chloride、0.3 gram of (1.57 mMs) Hydro-Giene (Water Science).、7.4 milliliters of (52 mMs) trimethylsilyl acetylenes，Room temperature reaction 15 minutes，TLC detection reaction is complete，Concentrating under reduced pressure boils off solvent，Add 100 milliliters of extraction into ethyl acetate，Merge organic facies，50 milliliters of aqueous ammonium chloride solutions wash three times，Anhydrous sodium sulfate dries，Activated carbon decolorizing，Filter，Filtrate is concentrated into dry，Column chromatography for separation (ethyl acetate/normal hexane is as eluant)，Crystallization obtains 1-[4-(2-is trimethyl silicon based) acetenyl-3-nitro benzoyl]-3，3-dimethyl urea (compound V-1) 2.5 grams，Yield is 54.5%.1HNMR (400MHz, DMSO-d6): δ 0.27 (s, 9H), 2.94 (s, 6H), 7.86 (d, 1H, J=7.7Hz), 8.13 (d, 1H, J=7.6Hz), 8.50 (s, 1H), 10.39 (s, 1H)；MS (m/z): 334 [M+H].
Step 2: add 2.5 grams of (7.5 mMs) 1-[4-(2-is trimethyl silicon based) acetenyl-3-nitro benzoyl]-3 in reaction bulb, 3-dimethyl urea (compound V-1) and 25 milliliters of oxolanes, magnetic agitation, liquid nitrogen cooling is to less than-35 DEG C, add 20 milliliters of tetrahydrofuran solutions dissolved with 2 grams of (6.34 mMs) tetrabutyl ammonium fluorides, after 3 minutes, react complete, reactant liquor is poured in 1N aqueous hydrochloric acid solution, precipitate out solid, filter, water washing filter cake is to neutral, dry, activated carbon decolorizing, re-crystallizing in ethyl acetate obtains 1-(4-acetenyl-3-nitro benzoyl)-3, 3-dimethyl urea (compound I-34) 1.2 grams, yield is 61.2%.1HNMR (400MHz, DMSO-d6): δ 2.96 (s, 6H), 4.96 (s, 1H), 7.93 (d, 1H, J=8.1Hz), 8.17 (dd, 1H, J1=8.1Hz, J2=1.8Hz), 8.54 (d, 1H, J=1.7Hz), 10.52 (s, 1H)；MS (m/z): 260 [M-H].
Select suitable raw material (compound I-2, compound I-3, compound I-4, compound I-5, compound I-6, compound I-8, compound I-9, compound I-11, compound I-18, compound I-19, compound I-20, compound I-21, compound I-22, compound I-23, compound I-24, compound I-25, compound I-26, compound I-14, compound I-15) and reagent, prepare following compound respectively by embodiment 34 method:
The Pharmacodynamics screening of the compounds of this invention, carries out in the following manner
1. cell is cultivated
Human colon cancer cells's strain (COLO205 and HCT-116), mankind mastopathy cell's strain (MCF-7 and MDA-MB435), Human Lung Cancer cell strain (A549 and NCI460), human leukemia (HL-60), human prostata cancer (BXPC-3), people's uterus carcinoma (HELA), be all obtained from ATCC.COLO205, HL-60 cell is incubated at containing 2mM/L-paddy ammonia phthalein amine, 10%FBS, 1.0mM Sodium Pyruvate RPMI1640 in.HCT-116, MCF-7, A549, NCI460, BXPC-3, HELA cell is incubated at containing 2mM/L-glutamine, 10%FBS DMEM in.MDA-MB435 cell is incubated at containing 2mM/L-glutamine, 10%FBS L-15 in.COLO205 and HL-60 cell is inoculated in 96 orifice plates, 150 μ L/ holes, 8000, every hole cell, by 96 orifice plates in 37 DEG C, 5%CO2, 100% relative humidity incubator preculture 24 hours.HCT-116, MCF-7, NCI460, HELA and MDA-MB435 cell are inoculated in 96 orifice plates, and every hole is 5000 cells；A549 and BXPC-3 cell is inoculated in 96 orifice plates, and every hole is 10000 cells, by 96 orifice plates in 37 DEG C, and 5%CO2, 100% relative humidity incubator preculture 24 hours, make cell attachment.
2. SCREENED COMPOUND
Timezero control wells at every kind of cell strain adds the fixing cell of 50% (mass/volume) TCA of 50 μ L pre-coolings.Other holes add the compound 50 μ L of variable concentrations, effect 48h, each drug level sets 3 multiple holes, and set blank (cell culture fluid, without cell), (be not added with medicine without medicine control wells, add equivalent complete medium), positive drug comparison BSI-201, be placed in 37 DEG C, 5%CO2Incubator cultivates 48h under complete wet (100% relative humidity) condition.
3. cell detection
The fixing cell of 50% (mass/volume) TCA of 50 μ L pre-coolings is added on culture fluid liquid level.Then placing 1h in 4 DEG C, abandon supernatant, each hole deionized water wash 5 times, to remove TCA and serum albumin etc..Dried in atmosphere, every hole adds 0.4%SRB (using 1% peracetic acid formulation) the about 100 μ L of q.s, and room temperature places 20～30min.Discard liquid in each hole, quickly wash 5 times with 1% acetic acid, remove unconjugated dyestuff, until unconjugated dyestuff rinsed clean.Air drying is until after cannot see dampness, dissolve with 200 μ LTrisbase, vibrate 5min or impact mixing up and down with Tip head on oscillator plate, and on multi-functional instrument (M5detectionsystem, MDGroupLtd.) measure, 690nm blank returns to zero, and detection wavelength is 515nm.
XL-fit is used to draw dose-effect curve to measure its GI50Value.
4. the selection result
nullBy pharmacy in vitro screening experiment，Using BSI-201 (Iniparib) as positive drug，Result display compound I-1、I-2、I-3、I-4、I-5、I-6、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20、I-21、I-22、I-23、I-24、I-25、I-26、I-27、I-28、I-29、I-30、I-31、I-32、I-33、I-34、I-35、I-36、I-37、I-38、I-39、I-40、I-41、I-42、I-43、I-44、I-45、I-46、I-47、I-48、I-49、I-50、I-51、I-52、I-53 has suppression tumor cell proliferation effect；Wherein, compound I-27 drug effect on the 9 strain tumor cell lines surveyed is more than 20 times of positive drug BSI-201；I-29, I-32, I-36, I-42, I-44, I-45, I-48 drug effect is slightly worse than I-27.The selection result is in Table 1:
Table 1 compound (I) is to inhibiting tumour cells active part data
| Cell strain | MDA-MB435 | NCI460 | HCT116 | HL60 | COLO205 | A549 | BXPC3 | HELA | MCF-7 |
| BSI-201 | 67.949 | 90.034 | 98.595 | 39.18 | 131.86 | 104.5 | 81.172 | 51.265 | 60.355 |
| I-1 | 39.93 | - | 84.733 | 15.294 | 58.838 | - | - | 100.264 | 79.824 |
| Cell strain | MDA-MB435 | NCI460 | HCT116 | HL60 | COLO205 | A549 | BXPC3 | HELA | MCF-7 |
| I-2 | 32.485 | - | - | - | - | - | 55.287 | - | - |
| I-3 | ND | - | - | - | - | - | 140.98 | - | - |
| I-4 | 46.743 | - | - | - | - | - | ND | - | - |
| I-5 | - | - | 203.852 | 171.046 | - | - | - | - | - |
| I-6 | - | - | 218.589 | ND | - | - | - | - | - |
| I-7 | - | - | - | ND | - | - | - | - | - |
| I-8 | - | - | ND | 201.853 | - | - | - | - | - |
| I-9 | - | - | - | 227.28 | - | - | - | - | - |
| I-10 | 37.452 | 75.107 | 50.084 | 21.7 | - | 81.57 | - | 43.136 | 51.833 |
| I-11 | - | - | 55.245 | 26.698 | - | - | - | - | - |
| I-12 | - | - | 177.565 | 96.7 | - | - | - | - | - |
| I-13 | 50.568 | - | - | - | - | - | - | 70.758 | 123.168 |
| I-14 | 103.691 | - | - | - | - | - | - | 113.879 | 166.451 |
| I-15 | - | 86.584 | - | 63.067 | - | - | - | - | 92.866 |
| I-16 | 57.431 | - | - | - | - | - | - | 59.544 | 103.581 |
| I-17 | - | 208.4 | - | 206.787 | - | - | - | - | 153.2 |
| I-18 | 64.659 | 151.178 | 76.779 | 12.335 | 33.634 | 72.782 | - | 32.629 | 13.308 |
| I-19 | 23.201 | 46.169 | 52.207 | - | - | - | - | 21.146 | 127.273 |
| I-20 | 14.224 | 44.39 | 54.504 | - | - | 45.461 | - | - | 46.903 |
| I-21 | - | 70.664 | - | - | - | - | - | - | 56.031 |
| I-22 | 100.95 | - | - | - | - | - | - | 104.527 | 158.651 |
| I-23 | 24.483 | 81.382 | - | 36.794 | - | 82.404 | - | - | 54.74 21 --> |
| I-24 | - | 99.951 | - | 32.3 | - | - | - | - | 57.73 |
| I-25 | - | 51.311 | - | - | - | - | - | - | 94.433 |
| I-26 | - | 189.06 | - | - | - | - | - | - | 156.952 |
| I-27 | 3.719 | 13.232 | 5.135 | 1.346 | 3.132 | - | - | 11.947 | 8.954 |
| I-28 | - | - | - | 7.983 | 93.975 | - | - | - | - |
| I-29 | 8.49 | 22.747 | - | 2.676 | 9.58 | 25.385 | - | - | 8.56 |
| I-30 | 14.518 | 10.953 | - | - | - | - | 12.002 | 4.993 | 22 |
| I-31 | 2.137 | ND | - | 8.397 | - | - | ND | - | 32.234 |
| I-32 | - | 11.167 | - | - | - | - | - | 5.329 | - |
| I-33 | 3.539 | 27.187 | - | - | - | - | - | - | 6.637 |
| I-34 | 7.352 | 20.103 | 4.665 | - | - | 4.112 | - | 18.04 | - |
| I-35 | - | - | 36.324 | - | - | - | - | - | - |
| I-36 | - | - | 2.67 | - | - | 5.511 | - | - | - |
| I-37 | - | - | 26.353 | - | - | 7.598 | - | - | - |
| I-38 | - | - | - | 34.087 | ND | - | - | - | - |
| I-39 | - | - | - | 21.768 | 42.122 | - | - | - | - |
| I-40 | - | - | 25.245 | - | - | - | - | - | - |
| I-41 | - | - | - | 9.583 | 32.002 | - | - | - | - |
| I-42 | - | - | - | 2.943 | - | - | - | - | - |
| Cell strain | MDA-MB435 | NCI460 | HCT116 | HL60 | COLO205 | A549 | BXPC3 | HELA | MCF-7 |
| I-43 | 8.564 | 25.003 | - | 2.13 | 6.845 | - | - | 14.431 | - |
| I-44 | - | 12.821 | - | - | - | - | - | 9.951 | - |
| I-45 | 3.698 | - | - | 3.194 | - | - | - | - | 8.398 |
| I-46 | - | 3.977 | - | - | - | - | - | - | 10.049 |
| I-47 | - | 13.876 | - | - | - | - | - | 7.509 | - |
| I-48 | 3.145 | 25.043 | - | - | - | 5.660 | 7.571 | - | 5.437 |
| I-49 | - | - | - | - | - | - | - | 12.681 | 11.581 |
| I-50 | - | - | - | - | - | - | - | 38.753 | 23.172 |
| I-51 | - | - | - | - | - | - | - | 38.079 | 39.904 |
| I-52 | - | 38.993 | - | - | - | - | - | 36.074 | - |
| I-53 | 5.913 | 28.1 | - | - | - | - | - | - | 6.493 |
Illustrate: in table 1 (-) represent that activity is not tested；(ND) represent that compound has an activity, but GI50Value is not measured when the test used.
The all documents mentioned in the present invention are incorporated as reference all in this application, are individually recited as reference such just as each section of document.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application appended claims limited range equally.
Claims (20)
1. the compound represented by formula (I), or its pharmaceutically acceptable salt:
Wherein
R1、R2And R3Independently selected from following group: hydrogen, substituted or unsubstituted C1-C5Alkyl, substituted or unsubstituted C3-C5Thiazolinyl, substituted or unsubstituted C3-C5Alkynyl, substituted or unsubstituted C3-C5Cycloalkyl；R1And R2Substituted or unsubstituted five, six or heptatomic ring can also be collectively formed by ring；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring can also be collectively formed by ring；
Wherein, described replacement refers to that to be selected from following group replaced: hydroxyl, C1-C5Alkyl, C2-C5Thiazolinyl, C2-C5Alkynyl, C3-C5Cycloalkyl, C1-C5Alkoxyl, amino, C1-C5Alkyl amino, two (C1-C5) alkyl amino, C1-C5Alkyl sulfenyl, halogen；
R4It is nitro or nitroso-group；
R5It is iodine or acetenyl.
2. compound as claimed in claim 1, wherein said replacement refers to that to be selected from following group replaced: hydroxyl, methoxyl group, amino, methylamino, dimethylamino, methyl mercapto and halogen.
3. compound as claimed in claim 1, wherein, R1、R2And R3Independently selected from hydrogen, substituted or unsubstituted C1-C5Alkyl；R1And R2Substituted or unsubstituted five, six or heptatomic ring can also be collectively formed by ring；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring can also be collectively formed by ring.
4. compound as claimed in claim 3, wherein, R1、R2And R3Independently selected from hydrogen, substituted or unsubstituted C1-C5Alkyl.
5. compound as claimed in claim 2, wherein R1、R2And R3Independently selected from hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group or amyl group.
6. compound as claimed in claim 5, wherein R1、R2And R3Independently selected from hydrogen, methyl, ethyl, propyl group or normal-butyl.
7. compound as in any one of the preceding claims, wherein R4For nitro.
8. the compound as described in any one of claim 1～6, wherein R5For iodine.
9. the compound as according to any one of claim 1～6, wherein R5For acetenyl.
10. compound as claimed in claim 1, wherein said substituted or unsubstituted C3-C5Thiazolinyl, substituted or unsubstituted C3-C5Alkynyl is the double bond of thiazolinyl and three keys of alkynyl are not joined directly together with the atom N of urea.
11. compound as claimed in claim 1, wherein said Formula (I) is selected from:
1-(the iodo-3-nitro benzoyl of 4-)-3,3-dimethyl ureas (I-1)
1-(the iodo-3-nitro benzoyl of 4-) urea (I-2)
1-(the iodo-3-nitro benzoyl of 4-)-3-MU (I-3)
1-(the iodo-3-nitro benzoyl of 4-)-3-ethyl carbamide (I-4)
1-(the iodo-3-nitro benzoyl of 4-)-3-propyl group urea (I-5)
1-(the iodo-3-nitro benzoyl of 4-)-3-Butylurea (I-6)
1-(4-iodine 3-nitro benzoyl)-3-amyl group urea (I-7)
1-(the iodo-3-nitro benzoyl of 4-)-3-isopropyl urea (I-8)
1-(the iodo-3-nitro benzoyl of 4-)-3-isobutyl group urea (I-9)
1-(the iodo-3-nitro benzoyl of 4-)-3-methyl-3-ethyl carbamide (I-10)
1-(the iodo-3-nitro benzoyl of 4-)-1,3-dimethyl urea (I-11)
1-(the iodo-3-nitro benzoyl of 4-)-3,3-diethyl ureas (I-12)
1-(the iodo-3-nitro benzoyl of 4-)-3,3-dipropyl ureas (I-13)
1-(the iodo-3-nitro benzoyl of 4-)-2-imidazolone (I-14)
1-(the iodo-3-nitro benzoyl of 4-)-3-methyl-2-imidazolone (I-15)
N-(the iodo-3-nitro benzoyl of 4-) pyrrolidin-1-yl Methanamide (I-16)
N-(the iodo-3-nitro benzoyl of 4-)-1-piperidine-1-Methanamide (I-17)
1-(the iodo-3-nitro benzoyl of 4-)-1,3,3-trimethyl-urea (I-18)
1-(the iodo-3-nitro benzoyl of 4-)-1-ethyl-3,3-dimethyl urea (I-19)
1-(the iodo-3-nitro benzoyl of 4-)-1-propyl group-3,3-dimethyl urea (I-20)
1-(the iodo-3-nitro benzoyl of 4-)-1-butyl-3,3-dimethyl urea (I-21)
1-(the iodo-3-nitro benzoyl of 4-)-1-methyl-3,3-diethyl urea (I-22)
1-(the iodo-3-nitro benzoyl of 4-)-1-methyl-3,3-dipropyl urea (I-23)
1-(the iodo-3-nitro benzoyl of 4-)-1-ethyl-3,3-dipropyl urea (I-24)
1-(the iodo-3-nitro benzoyl of 4-)-1,3,3-tripropyl urea (I-25)
1-(the iodo-3-nitro benzoyl of 4-)-1-butyl-3,3-dipropyl urea (I-26)
1-(4-acetenyl-3-nitro benzoyl)-3,3-diethyl ureas (I-27)
1-(4-acetenyl-3-nitro benzoyl)-3-amyl group urea (I-28)
1-(4-acetenyl-3-nitro benzoyl)-3-methyl-3-ethyl carbamide (I-29)
1-(4-acetenyl-3-nitro benzoyl)-3,3-dipropyl ureas (I-30)
1-(4-acetenyl-3-nitro benzoyl)-3,3-dibutyl ureas (I-31)
N-(4-acetenyl-3-nitro benzoyl) pyrrolidin-1-yl Methanamide (I-32)
N-(4-acetenyl-3-nitro benzoyl)-1-piperidine-1-Methanamide (I-33)
1-(4-acetenyl-3-nitro benzoyl)-3,3-dimethyl ureas (I-34)
1-(4-acetenyl-3-nitro benzoyl) urea (I-35)
1-(4-acetenyl-3-nitro benzoyl)-3-MU (I-36)
1-(4-acetenyl-3-nitro benzoyl)-3-ethyl carbamide (I-37)
1-(4-acetenyl-3-nitro benzoyl)-3-propyl group urea (I-38)
1-(4-acetenyl-3-nitro benzoyl)-3-Butylurea (I-39)
1-(4-acetenyl-3-nitro benzoyl)-3-isopropyl urea (I-40)
1-(4-acetenyl-3-nitro benzoyl)-3-isobutyl group urea (I-41)
1-(4-acetenyl-3-nitro benzoyl)-1,3-dimethyl urea (I-42)
1-(4-acetenyl-3-nitro benzoyl)-1,3,3-trimethyl-urea (I-43)
1-(4-acetenyl-3-nitro benzoyl)-1-ethyl-3,3-dimethyl urea (I-44)
1-(4-acetenyl-3-nitro benzoyl)-1-propyl group-3,3-dimethyl urea (I-45)
1-(4-acetenyl-3-nitro benzoyl)-1-butyl-3,3-dimethyl urea (I-46)
1-(4-acetenyl-3-nitro benzoyl)-1-methyl-3,3-diethyl urea (I-47)
1-(4-acetenyl-3-nitro benzoyl)-1-methyl-3,3-dipropyl urea (I-48)
1-(4-acetenyl-3-nitro benzoyl)-1-ethyl-3,3-dipropyl urea (I-49)
1-(4-acetenyl-3-nitro benzoyl)-1,3,3-tripropyl urea (I-50)
1-(4-acetenyl-3-nitro benzoyl)-1-butyl-3,3-dipropyl urea (I-51)
1-(4-acetenyl-3-nitro benzoyl)-2-imidazolone (I-52)
1-(4-acetenyl-3-nitro benzoyl)-3-methyl-2-imidazolone (I-53).
12. the preparation method of formula (I) compound described in claim 1, described method includes: be obtained by reacting with the urea shown in Formula VII by the compound shown in Formula II:
Wherein, R1、R2、R3For hydrogen, substituted or unsubstituted C1-C5Alkyl, substituted or unsubstituted C3-C5Thiazolinyl, substituted or unsubstituted C3-C5Alkynyl, substituted or unsubstituted C3-C5Cycloalkyl；R1And R2Substituted or unsubstituted five, six or heptatomic ring can also be collectively formed by ring；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring4For nitro, R5For iodine.
13. the preparation method of formula (I) compound described in claim 1, described method includes: by the compound shown in formula III and R1X is obtained by reacting:
Wherein, R2、R3For hydrogen, substituted or unsubstituted C1-C5Alkyl, substituted or unsubstituted C3-C5Thiazolinyl, substituted or unsubstituted C3-C5Alkynyl, substituted or unsubstituted C3-C5Cycloalkyl；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring1For substituted or unsubstituted C1-C5Alkyl, substituted or unsubstituted C3-C5Thiazolinyl, substituted or unsubstituted C3-C5Alkynyl, substituted or unsubstituted C3-C5Cycloalkyl, R4For nitro, R5For iodine, X is halogen.
14. the preparation method of formula (I) compound described in claim 1, described method includes: the amine of the compound shown in Formulas I V and Formula VIII depicted is obtained by reacting:
Wherein, R2、R3For hydrogen, substituted or unsubstituted C1-C5Alkyl, substituted or unsubstituted C3-C5Thiazolinyl, substituted or unsubstituted C3-C5Alkynyl, substituted or unsubstituted C3-C5Cycloalkyl；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring1For hydrogen, R4For nitro, R5For acetenyl.
15. the preparation method of formula (I) compound described in claim 1, described method includes: the compound desiliconization base shown in Formula V obtains:
Wherein, R1、R2、R3For hydrogen, substituted or unsubstituted C1-C5Alkyl, substituted or unsubstituted C3-C5Thiazolinyl, substituted or unsubstituted C3-C5Alkynyl, substituted or unsubstituted C3-C5Cycloalkyl；R1And R2Substituted or unsubstituted five, six or heptatomic ring can also be collectively formed by ring；R2And R3Substituted or unsubstituted four, five, six or heptatomic ring, R can also be collectively formed by ring4For nitro, R5For acetenyl.
16. pharmaceutical composition, including formula (I) compound any one of the claim 1～10 of effective dose or their pharmaceutically acceptable salts.
17. the compound as according to any one of claim 1～11 is used for the application in the medicine of the treatment disease relevant to poly polymerase (PARP) inhibitor in preparation.
18. apply as claimed in claim 17, the wherein said disease selected from cancer relevant to poly polymerase (PARP) inhibitor, apoplexy, myocardial infarction, neurodegenerative disease.
19. the compound as according to any one of claim 1～11 is used for the application treating in the medicine of cancer in preparation.
20. apply as claimed in claim 19, wherein said cancer includes colon cancer, breast carcinoma, pulmonary carcinoma, ovarian cancer, gastric cancer, acute leukemia, chronic leukemia, carcinoma of prostate, people's uterus carcinoma, cancer of pancreas, hepatocarcinoma, the brain cancer, cns tumor, bladder cancer, renal carcinoma, skin carcinoma, neck cancer, myosarcoma, lymphatic cancer, osteocarcinoma and other type of cancer.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110344421.2A CN103086925B (en) | 2011-11-04 | 2011-11-04 | Benzoyl urea derivative with active anticancer and its production and use |
| PCT/CN2012/083431 WO2013064029A1 (en) | 2011-11-04 | 2012-10-24 | Benzoylurea derivative with anticancer activity and preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201110344421.2A CN103086925B (en) | 2011-11-04 | 2011-11-04 | Benzoyl urea derivative with active anticancer and its production and use |
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| CN103086925A CN103086925A (en) | 2013-05-08 |
| CN103086925B true CN103086925B (en) | 2016-07-06 |
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| TWI690512B (en) * | 2014-03-07 | 2020-04-11 | 瑞士商赫爾辛保健股份有限公司 | p-SUBSTITUTED ASYMMETRIC UREAS AND MEDICAL USES THEREOF |
| CN105326821A (en) * | 2015-09-23 | 2016-02-17 | 华东理工大学 | Novel anticancer application of substituted ureas micromolecule cyclophilin A inhibitor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049497A (en) * | 1989-07-28 | 1991-02-27 | 石原产业株式会社 | Benzoyl urea compounds that replaces or their salt, they the preparation method and contain the anti-tumor compositions of such material |
| CN1850794A (en) * | 2006-05-30 | 2006-10-25 | 中国医学科学院医药生物技术研究所 | 3-amido substituted nenzoyl urea compound, and its antitumor action |
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2011
- 2011-11-04 CN CN201110344421.2A patent/CN103086925B/en not_active Expired - Fee Related
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- 2012-10-24 WO PCT/CN2012/083431 patent/WO2013064029A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049497A (en) * | 1989-07-28 | 1991-02-27 | 石原产业株式会社 | Benzoyl urea compounds that replaces or their salt, they the preparation method and contain the anti-tumor compositions of such material |
| CN1850794A (en) * | 2006-05-30 | 2006-10-25 | 中国医学科学院医药生物技术研究所 | 3-amido substituted nenzoyl urea compound, and its antitumor action |
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| CN103086925A (en) | 2013-05-08 |
| WO2013064029A1 (en) | 2013-05-10 |
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