CN101103004A - Novel cis-imidazolines - Google Patents
Novel cis-imidazolines Download PDFInfo
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- CN101103004A CN101103004A CNA2005800184339A CN200580018433A CN101103004A CN 101103004 A CN101103004 A CN 101103004A CN A2005800184339 A CNA2005800184339 A CN A2005800184339A CN 200580018433 A CN200580018433 A CN 200580018433A CN 101103004 A CN101103004 A CN 101103004A
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Abstract
The present invention relates to compounds of the formula (I), and the pharmaceutically acceptable salts and esters thereof, a process for their manufacture, medicaments containing them as well as the use of these compounds as pharmaceutically active agents. The compounds show antiproliferative activity and may be especially useful for the treatment of cancer.
Description
The present invention relates to the chirality cis-imidazolines, these compounds are the interactional micromolecular inhibitors of MDM2-p53.P53 is a tumor suppressor protein, plays an important role in the provide protection of antagonism cancer development.It protects cell integrity, and prevents the permanent impaired clone's of cell propagation by induced growth stagnation or apoptosis.On molecular level, p53 is the transcription factor that can activate the series of genes that relates to cell cycle and apoptosis adjusting.P53 is strong cell cycle inhibitor, and it is closely regulated by MDM2 on cell levels.MDM2 and p53 form feedback control loop.MDM2 can and suppress the ability of its trans-activation p53-regulatory gene in conjunction with p53.In addition, MDM2 has mediated the ubiquitin dependency degraded of p53.P53 can activate the MDM2 expression of gene, thus the MDM2 protein level of rising cell.In normal proliferative cell, this feedback control loop is guaranteed all to remain on MDM2 and p53 low-level.MDM2 still is the cofactor of E2F, and it plays an important role in Cycle Regulation.
The ratio of MDM2 and p53 (E2F) is regulated unusually in many cancers.For example, show that the frequent molecular defect that occurs has influenced the MDM2 proteolytic degradation in the p16INK4/p19ARF locus.Suppressing to have MDM2-p53 in the tumour cell of wild type p53 interacts and should cause accumulation, cell cycle arrest and/or the apoptosis of p53.Therefore, the MDM2 antagonist, as independent medicament or and other antitumor therapy combination of wide spectrum, a new way of cancer therapy can be provided.The feasibility of this strategy is used to suppress the interactional different macromole instruments of MDM2-p53 (for example, antibody, antisense oligonucleotide, peptide) by use and shows.MDM2 also by as the conservative calmodulin binding domain CaM of p53 in conjunction with E2F, and the E2F-dependent transcription of activating cells cyclin A shows that the MDM2 antagonist may work in the p53 mutant cells.
Wells etc. are at J.Org.Chem., and 1972,37, reported the synthetic of imidazolines among the 2158-2161.Hunter etc. are at Can.J.Chem., and 1972, Vol.50, reported the preparation of amarin(e) and different amarin(e) compound among the 669-77, these compounds before had been studied and had been used for chemoluminescence (McCapra etc., Photochem.and Photobiol.1965,4,1111-1121).Zupanc etc. are at Bull.Soc.Chem.﹠amp; Tech. (Yugoslavia) 1980-81,27/28, reported among the 71-80 and in the preparation of EDTA derivative, used triarylimidazoles quinoline compounds as raw material.
The EP363061 of Matsumoto has reported the imidazolidine derivatives that can be used as immunomodulator.According to the show, these compounds all have hypotoxicity.Hinting treating and/or preventing to rheumatoid arthritis, multiple sclerosis, general lupus, lupus erythematosus and rheumatic fever.The WO00/78725 of Choueiry etc. has reported the method that is used to make the substituted amidine compound, and points out that tetrahydroglyoxaline-type compound also can be used for treating diabetes or relative disease, comprises the glucose control of weakening.
The US6 that authorizes on September 9th, 2003,617,346B1 and the US6 that authorizes on May 11st, 2004,734,302B2 discloses relevant racemize cis-imidazolines.US6,734,302B2 discloses the wide kind of closely-related racemic compound especially, and it generally includes the claimed compound of the present invention, just except the narrow kind of chirality and The compounds of this invention.
The invention provides at least a formula I compound,
X wherein
1, X
2, Y
1, Y
2With R as described herein, and pharmaceutical salts and ester.
The invention provides the chirality cis-imidazolines, it is the interactional micromolecular inhibitor of MDM2-p53.Acellular and show that based on the mensuration of cell compound of the present invention suppresses the interaction of MDM2 albumen and p53-sample peptide, its effectiveness is about 100 times of p53 derived peptide.In mensuration based on cell, these compound exhibits mechanism (mechanistic) activity.The cancer cells that incubation has wild type p53 causes the proteic accumulation of p53, the p21 gene that p53-regulates induce and the cell cycle in G1 and the stagnation of G2 phase, cause the effective external antiproliferative activity of relative wild type p53 cell.On the contrary, in the cancer cells that has mutant p53 under the suitable compound concentration, do not observe these activity.Therefore, the MDM2 antagonistic activity is related with its mechanism of action probably.These compounds can be carcinostatic agents effectively and optionally.
The invention provides at least a formula I compound and pharmaceutical salts and ester,
Wherein
R represents to contain at least one heteroatomic saturated or undersaturated 5 to the 6 yuan of ring that is selected from S, N and O; And optional be selected from following group replacement: low alkyl group, cycloalkyl ,-C (O)-R
1, hydroxyl, the low alkyl group that is replaced by hydroxyl, the low alkyl group, the quilt-NH that are replaced by lower alkoxy
2The low alkyl group, the quilt-SO that replace
2Low alkyl group, quilt-C (O)-R that-low alkyl group replaces
1The low alkyl group that replaces ,-the NH-low alkyl group ,-N (low alkyl group)
2,-SO
2-low alkyl group ,=O ,-CH
2C (O) CH
3Or contain, two or three heteroatomic 5 to 6 yuan of saturated rings that are selected from S, N and O; R
1Be selected from hydrogen, low alkyl group ,-NH
2,-NH-low alkyl group ,-N (low alkyl group)
2, replaced by hydroxyl low alkyl group, by NH
2The low alkyl group that replaces or contain, two or three heteroatomic 5 to 6 yuan of saturated rings that are selected from S, N and O;
X
1And X
2Be independently selected from hydrogen, lower alkoxy ,-CH
2OCH
3,-CH
2OCH
2CH
3,-OCH
2CF
3,-OCH
2CH
2F;
Y
1And Y
2Be selected from independently of one another-Cl ,-Br ,-NO
2,-C ≡ N and-C ≡ CH; And 4 and 5 absolute stereo chemical structure of tetrahydroglyoxaline ring is respectively S and R (suc as formula painting among the I).
In a preferred embodiment, the invention provides at least a compound that is selected from formula I compound and pharmaceutical salts and ester,
Wherein,
R is selected from and contains at least one heteroatomic saturated and undersaturated 5 yuan and 6 yuan of rings, and wherein said heteroatoms is selected from S, N and O; And described 5 yuan and 6 yuan ring is optional to be selected from following group replacement: low alkyl group, cycloalkyl, the low alkyl group, the quilt-NH that are replaced by hydroxyl
2The low alkyl group that replaces ,-the N-low alkyl group ,-SO
2CH
3,=O ,-CH
2C (O) CH
3With contain at least one heteroatomic 5 yuan and 6 yuan of saturated rings that are selected from S, N and O,
X
1And X
2Be independently selected from hydrogen, lower alkoxy ,-CH
2OCH
3,-CH
2OCH
2CH
3,-OCH
2CF
3,-OCH
2CH
2F,
Y
1And Y
2Be selected from independently of one another-Cl ,-Br ,-NO
2,-C ≡ N and-C ≡ CH; And 4 and 5 absolute stereo chemical structure of tetrahydroglyoxaline ring is respectively S and R (suc as formula painting among the I).
Also preferred compound is Y wherein
1And Y
2Be selected from independently of one another-Cl and-the formula I compound of Br.
Also preferred compound is such formula I compound, and wherein R is
Piperazinyl, this piperazinyl are selected from least one following group and are replaced: low alkyl group, cycloalkyl, C (O) R
1, the low alkyl group, the quilt-NH that are replaced by hydroxyl
2The low alkyl group, quilt-C (O) R that replace
1The low alkyl group that replaces ,-the N-low alkyl group ,-SO
2CH
3,=O ,-CH
2C (O) CH
3, perhaps piperidyl, this piperidyl are selected from least one following group and are replaced: the C1-C3 alkyl ,-the C1-C2 alkoxyl group ,-C (O) CH
3,-SO
2CH
3,-C (O) ,-OH ,-CH
2NH
2,-C (O) CH
2NH
2,-C (O) CH
2OH ,-C (O) C (OH) CH
2OH ,-CH
2C (OH) CH
2OH ,-C (O) N (CH
2)
2,-C (O) NH
2, and-C (O) N (CH
3) CH
3,-N (CH
3) CH
3, pyrrolidyl and piperidyl.
Also preferred such formula I compound, wherein adjacent X
1Group be selected from lower alkoxy ,-OCH
2CF
3With-OCH
2CH
2F, and the X of contraposition
2Group is a lower alkoxy.
Also more preferably such compound, wherein adjacent X
1Group be selected from oxyethyl group, isopropoxy ,-OCH
2CF
3With-OCH
2CH
2F, and the X of contraposition
2Group is selected from methoxyl group and oxyethyl group.
Another preferred embodiment of the present invention provides formula I-A compound and pharmaceutical salts thereof,
Wherein
Piperazinyl or piperidyl that R is replaced by following group:
The C1-C4-alkyl;
-C (O)-(C1-C4-alkyl);
Tetramethyleneimine-1-base;
＝O；
-CH
2-C (O)-morpholino;
-CH
2-C (O)-N (C1-C4-alkyl)
2
-(CH
2)
n-SO
2-(C1-C4-alkyl);
X
1Be-O-(C1-C4-alkyl);
X
2Be hydrogen or-O-(C1-C4-alkyl);
N is 0,1 or 2; And
4 and 5 absolute stereo chemical structure of tetrahydroglyoxaline ring is respectively S and R.
More preferably such formula I compound, wherein R is selected from the piperazinyl of piperazinyl and replacement.
Such compound is for example:
1-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-ethyl ketone;
4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-2-ketone;
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ketone;
4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-2-ketone;
1-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-ethyl ketone;
2-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-1-morpholine-4-base-ethyl ketone;
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-ketone; With
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-(4-methyl-piperazine-1-yl)-ketone.
" significant quantity " is meant prevention, alleviates or improve disease symptoms or extended treatment experimenter survival time is effectively measured.
" halogen " is meant fluorine, chlorine, bromine or iodine.
" heteroatoms " is meant the atom that is selected from N, O and S.
" IC
50" be meant the concentration of the active needed specific compound that suppresses 50% concrete measurement.
In addition, as described later, can measure IC
50
" alkyl " expression straight or branched aliphatic saturated hydrocarbon.
" low alkyl group " expression C1-C6 alkyl, and comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 2-butyl, amyl group, hexyl etc.Usually, the preferred C1-C4 alkyl of low alkyl group, more preferably C1-C3 alkyl.
" cycloalkyl " is meant the partially or completely saturated monovalence cyclic hydrocarbon group of the non-aromatic that contains 3 to 8 atoms.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
" alkoxyl group " expression-O-alkyl." lower alkoxy " expression-O-low alkyl group.
With 5 to 6 yuan of statements that ring is relevant defined above " contain at least one heteroatoms " and be meant that described ring contains one or more, preferred 1,2 or 3 heteroatoms.
" medicinal ester " is meant the formula I compound that contains carboxyl of conventional esterification, and this ester has kept the biopotency and the character of formula I compound, and (in body) resolves into corresponding active carboxylic acid in vivo.
Relevant ester class and be used for the information of purposes of the ester class of delivery of pharmaceutical compounds can be at Designof Prodrugs, Bundgaard H edits in (Elsevier, 1985) and obtains.Also can be referring to H.Ansel etc., Pharmaceutical Dosage Forms and Drug Delivery Systems (nineteen ninety-five the 6th edition) 108-109 page or leaf; Krogsgaard-Larsen etc., Textbook of Drug Design andDevelopment (second edition in 1996) 152-191 page or leaf.
" pharmaceutical salts " is meant conventional acid salt or base addition salt, and described salt has kept the biopotency and the character of The compounds of this invention, and is to be formed by suitable non-toxic organic or mineral acid or organic or inorganic alkali.The example of acid salt comprises from mineral acid and organic acid derives and those next salt, described mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid, organic acid such as tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid etc.The example of base addition salt comprises the salt derived from ammonium, potassium, sodium and quaternary ammonium hydroxide, described oxyhydroxide such as tetramethylammonium hydroxide.With medical compounds (being medicine) chemical modification salify is pharmacist's technique known, in order to physics and chemical stability, water absorbability, flowability and the solvability of the improvement that obtains compound.Referring to, H.Ansel etc. for example, Pharmaceutical DosageForms and Drug Delivery Systems (nineteen ninety-five the 6th edition), 196 and the 1456-1457 page or leaf.
" medicinal " as pharmaceutical carrier, vehicle etc., is meant on the pharmacology acceptable and nontoxic basically to the administration object of particular compound.
" replacement " is meant that replacement can occur in one or more positions, and unless stated otherwise, the substituting group on each replacement site all is independently selected from the option of regulation.
" treatment significant quantity " refers at least a remarkable inhibition human tumor cells, comprises human tumor cell line propagation and/or prevents the consumption of the specified compound of its differentiation.
Advantageously show the IC of about 0.020 μ M as the The compounds of this invention that exemplifies to about 20 μ M
50Value.
Compound of the present invention can be used for treatment or control cell proliferation disorders, particularly tumor disease.These compounds can be used for the treatment of or the controlled entity knurl with the preparation that contains these compounds, such as mammary gland, colon, lung and tumor of prostate.
The treatment significant quantity of The compounds of this invention refers to effective prevention, alleviation or improves disease symptoms or prolong the consumption that the experimenter that treats of institute is survived.The scope of determining to belong to art technology of treatment significant quantity.
The treatment significant quantity of The compounds of this invention or dosage can change in grace period and can measure according to mode well known in the art.Can adjust this dosage according to individual need in every kind of particular case, described particular case comprises one or more particular compound, route of administration, the situation of being treated of institute's administration and the patient who is treated.In general, be about in body weight under the situation of adult oral or parenterai administration of 70Kg, about 10mg is to about 10,000mg, and preferably about 200mg is extremely about 1, and the per daily dose of 000mg should be suitable, but, when treatment needs, can surpass the upper limit.Can be with per daily dose with single dose or divided dose form administration, or with regard to parenterai administration, can be with the continuous infusion form administration.
The present invention also provides pharmaceutical composition, and it comprises at least a formula I compound or pharmaceutically acceptable salt thereof or ester and pharmaceutical carrier or vehicle.
Compound of the present invention can be according to 1 preparation of following scheme.
Scheme 1
Synthetic starting from solvent such as ethanol, benzo imido-ester 2 (uses hydrogen chloride gas to be prepared by corresponding benzonitrile in ethanol, US6,617,346B1) with diamines 1 as meso-1,2-pair-(4-chloro-phenyl-)-ethane-1, the 2-diamines (according to Jennerwein, M. etc., Cancer Res.Clin.Oncol.1988,114,347-58; Vogtle, F.; Goldschmitt, E.Chem.Ber.1976,109, the program preparation that 1-40 describes) linked reaction.In the presence of alkali such as triethylamine,, obtain racemic amino formyl chloride 4 with tetrahydroglyoxaline 3 light gas disposal.Use chiral chromatography can separate the enantiomorph of urea chloride racemic modification-4.Can use chiral stationary phase R, R-Whelk-O1 available from Regis Technologies.Required enantiomorph 5A provides formula I compound with the coupling of the amido (being expressed as the R group) that suits.
If desired, can use suitable amido (being expressed as the R group) by the racemic formula I compound of racemic modification-6 preparation.The enantiomorph that can separate I then by chiral chromatography.Can use chiral stationary phase Diacel ChiralPak OD or AD.
The absolute stereo chemical structure of the active enantiomorph of I be based on itself and human MDM2 title complex crystalline structure and definite (Vassilev etc., Science, 2004,303,844-848).
It is in order to help to understand the present invention that the following examples and reference are provided, and true scope of the present invention is as described in the appended claim book.
Embodiment 1
Cis-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-1H-imidazoles, according to US6,617, the described program preparation of 346B1.
Embodiment 2
Cis-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-1H-imidazoles, according to US6,617, the described program preparation of 346B1.
Embodiment 3
1-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro-
Imidazoles-1-carbonyl]-piperazine-1-yl }-ethyl ketone
To the cis-4 that is cooled to 0 ℃, 5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-1H-imidazoles (5.48g, 12.03mmol, embodiment 2) methylene dichloride (100mL) solution in order add triethylamine (11.8mL, 84.21mmol) photoreactive gas (30.53mL, 60.15mmol, 21% toluene solution).Reaction mixture is stirred 0.5h in 0 ℃ under argon gas, perhaps till thin-layer chromatography (silica gel, 100% ethyl acetate) shows that raw material does not remain.Removal of solvent under reduced pressure and excessive reagent, and with resistates vacuum-drying 1h.Resistates is dissolved in the methylene dichloride (100mL), adds 1-ethanoyl piperazine (1.619g, methylene dichloride 12.63mmol) (10mL) solution then.With reaction mixture stirring at room 1h (perhaps until can't see raw material) by thin-layer chromatography.Add saturated sodium bicarbonate solution (10mL).(2 * 50mL) extract product with methylene dichloride.(1 * 20mL) washs, dry (anhydrous sodium sulphate) and vacuum concentration with salt solution with organic layer.Thick resistates flash chromatography (Biotage system, KP-Sil
TM32-63 μ m, 60 silica gel) purifying, use 100% eluent ethyl acetate, use the ethyl acetate solution wash-out of 5% methyl alcohol then, obtain racemize-1-{4-[4,5-is two-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl-ethyl ketone, for orange foam (～7.2g).It is used methylene dichloride and ether recrystallization (6.721g, white solid).At process flash chromatography (Biotage system, KP-Sil
TM32-63 μ m, 60 silica gel) purifying, use 100% ethyl acetate, after using the ethyl acetate solution wash-out of 5% methyl alcohol then, from mother liquor, reclaim the racemize-1-{4-[4 of additional quantity, 5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-ethyl ketone (201mg, brown).Ultimate production: 6.922g (94%).HR-MS (ES, m/z): C
32H
35N
4O
4Cl
2[(M+H)
+] calculated value 609.2030, the actual measurement 609.2045.
By chiral chromatography (Daicel ChiralPak OD, with 1: 1 ethanol and hexane wash-out) separation of racemic-1-{4-[4,5-is two-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, and 5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-enantiomorph of ethyl ketone.Effusive first peak is required enantiomorph from post, 1-{4-[(4S, 5R)-4, and 5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-ethyl ketone.LR-MS(APCI)：609.12[(M+H)
+]。
Embodiment 4
4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-miaow Azoles-1-carbonyl]-piperazine-2-ketone, according to the similar fashion of describing with embodiment 3, from cis-4,5-is two-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, and 5-dihydro-1H-imidazoles (embodiment 2) and 2-piperazine ketone prepare.HR-MS (ES, m/z): C
30H
31N
4O
4Cl
2[(M+H)
+] calculated value 581.1717, the actual measurement 581.1709.
Embodiment 5
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro-imidazol- -1-yl]-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ketone, according to the similar fashion of describing with embodiment 3, from cis-4,5-is two-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, and 5-dihydro-1H-imidazoles (embodiment 2) and 4-(1-pyrrolidyl) piperidines prepare.HR-MS (ES, m/z): C
35H
41N
4O
3Cl
2[(M+H)
+] calculated value 635.2550, the actual measurement 635.2558.
Embodiment 6
(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro-imidazol-
-1-carbonyl chloride
To the cis-4 that is cooled to 0 ℃, 5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol-(5g, 10.98mmol, embodiment 2) methylene dichloride (50mL) solution in add triethylamine (3mL respectively, 21.96mL) photoreactive gas (8.7mL, 16.47mmol ,～20% toluene solution).Reaction mixture is stirred 30min at 0 ℃, and excessive reagent and solvent are removed in decompression then.With resistates place methylene dichloride (～100mL), and by silica gel (～50g) plug filtering solution.The hexane solution washing silica gel of ethyl acetate with 20%.Vacuum concentrated filtrate, and with resistates flash chromatography (Biotage system, KP-Sil
TM32-63 μ m, 60 silica gel, the hexane solution wash-out of ethyl acetate with 5%, 10%, 20%) purifying, obtain racemize-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride, be white solid (4.31g, 76%).
Use is filled with R, the Waters Delta Prep4000 of the spherical Kromasil silica gel of R-Whelk-O1 (available from Regis Technologies) and Modcol spring post (50mm * 70cm), by chiral chromatography separation of racemic-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the enantiomorph of 5-dihydro-imidazol--1-carbonyl chloride.Elutriant: the hexane solution of 30% methylene dichloride.Flow velocity: 85mL/min.Feeding quantity :～2g.Effusive first peak is required enantiomorph from post, (4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride.
Embodiment 7
(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride, adopt and embodiment 6 described similar fashion, from 4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4, the preparation of 5-dihydro-imidazol-(embodiment 1) photoreactive gas.
Embodiment 8
4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine
Piperazine-2-ketone
To (the 4S that is cooled to 0 ℃, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (100mg, 0.211mmol, embodiment 7) methylene dichloride (3mL) solution in add respectively triethylamine (30 μ L, 0.211mmol) and 2-piperazine ketone (23mg, 0.232mmol).Behind the 15min, thin-layer chromatography (silica gel, the hexane solution of 20% ethyl acetate) shows does not have raw material residual.Reaction mixture is packed in the quick silicagel column (12g).(use the Intelliflash280 system through the flash column chromatography purifying, ethyl acetate solution wash-out with 5% methyl alcohol and 0.1% triethylamine), obtain 4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-2-ketone, be white foam (69mg).HR-MS (ES, m/z): C
30H
31N
4O
4Cl
2[(M+H)
+] calculated value 581.1717, actual measurement 581.1717
Embodiment 9
1-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]- Piperazine-1-yl }-ethyl ketone, adopt and embodiment 8 described similar fashion, from (4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (embodiment 7) and the preparation of 1-ethanoyl piperazine.HR-MS (ES, m/z): C
30H
31N
4O
3Cl
2[(M+H)
+] calculated value 565.1768, actual measurement 565.1772.
Embodiment 10
2-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]- Piperazine-1-yl }-1-morpholine-4-base-ethyl ketoneAdopt and embodiment 8 described similar fashion, from (4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (embodiment 7) and 1-morpholine-4-base-2-piperazine-1-base-acetophenone hydrochloride (Oakwood Chemicals) preparation.HR-MS (ES, m/z): C
34H
38N
5O
4Cl
2[(M+H)
+] calculated value 650.2296, actual measurement 650.2299.
Embodiment 11
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-[4-(2-
Methylsulfonyl-ethyl)-piperazine-1-yl]-ketone
(1.8mL, (1.50g is in methyl alcohol 8mmol) (84mL) solution 20.1mmol) to join 1-(tert-butoxycarbonyl) piperazine with the methyl ethylene sulfone.With reaction mixture at stirring at room 4h and be concentrated into white solid.With flash column chromatography (silica gel is with the dichloromethane solution wash-out of 1-5% methyl alcohol) purifying solid, obtain 1-tert-butoxycarbonyl-4-(2-methylsulfonyl ethyl) piperazine, be white solid (2.29g, 95%).
With hydrochloric acid (42mL, 168mmol, 1 of 4M, 4-dioxane solution) join refrigerative 1-tert-butoxycarbonyl-4-(2-methylsulfonyl ethyl) piperazine (2.29g, 7.8mmol) 1, in 4-diox (42mL) solution.Mixture in stirred overnight at room temperature, is concentrated then, obtain 1-(2-methylsulfonyl ethyl) piperazine dihydrochloride, be white solid (2.05g).
The program of using embodiment 8 to describe; in methylene dichloride with (4S; 5R)-4; 5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4; 5-dihydro-imidazol--1-carbonyl chloride (embodiment 7) and 1-(2-methylsulfonyl ethyl)-piperazine dihydrochloride reaction, obtain [(4S, 5R)-4; 5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-ketone.HR-MS (ES, m/z): C
31H
35N
4O
4SCl
2[(M+H)
+] calculated value 629.1751, actual measurement 629.1757.
Embodiment 12
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro-imidazol- -1-yl]-(4-methyl-piperazine-1-yl)-ketone, adopt and embodiment 8 described similar fashion, from (4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (embodiment 6) and the preparation of 1-methylpiperazine.HR-MS (ES, m/z): C
31H
35N
4O
4SCl
2[(M+H)
+] calculated value 629.1751, actual measurement 629.1757.
Embodiment 13
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro-imidazol- -1-yl]-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-ketoneAdopt and embodiment 8 described similar fashion, from (4S, 5R)-4; 5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (embodiment 6) and 1-(2-methylsulfonyl ethyl) piperazine (embodiment 11) preparation.LR-MS：673.3[(M+H)
+]。
Embodiment 14
2-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro- Imidazoles-1-carbonyl]-piperazine-1-yl }-N, N-dimethyl-ethanamide, adopt and embodiment 8 described similar fashion, from (4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (embodiment 6) and N, N-dimethyl-2-piperazine-1-base-ethanamide (OakwoodChemicals) preparation.LR-MS：652.3[(M+H)
+]。
Embodiment 15
2-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro- Imidazoles-1-carbonyl]-piperazine-1-yl }-1-morpholine-4-base-ethyl ketoneAdopt and embodiment 8 described similar fashion, from (4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (embodiment 6) and 1-morpholine-4-base-2-piperazine-1-base-acetophenone hydrochloride (OakwoodChemicals) preparation.LR-MS：694.3[(M+H)
+]。
Embodiment 16
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4, the 5-dihydro-imidazol- -1-yl]-(4-ethylsulfonyl-piperazine-1-yl)-ketoneAdopt and embodiment 8 described similar fashion; from (4S; 5R)-4; 5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride (embodiment 6) and 1-ethylsulfonyl-piperazine (from 1-tert-butoxycarbonyl-piperazine and ethyl sulfonyl chloride preparation) preparation.LR-MS：659.2[(M+H)
+]。
Embodiment 17
Active determination in vitro
Measure the interactional ability between compound inhibition p53 and the MDM2 albumen by ELISA (enzyme linked immunological absorption detects), the MDM2 of GST mark of wherein recombinating combines (B ttger etc. with the peptide of the MDM2-interaction area that is similar to p53, J.Mol.Bio.1997, Vol.269, the 744-756 page or leaf).This peptide is fixed on the surface of 96 orifice plates by the hole bonded N-end vitamin H with streptavidin-coating.Exist down at anti--MDM2 mouse monoclonal antibody (SMP-14, Santa CruzBiotech), MDM2 is joined in each hole.After removing unconjugated MDM2 albumen, two anti-(the resisting-mouse IgG that add the peroxidase connection, Roche MolecularBiochemicals), and by adding peroxidase substrate (MTB Microwell PeroxydaseSubstrate System, Kirkegaard﹠amp; Perry Labs), measure the amount of peptide-bonded MDM2 with colorimetric titration.
Be equipped with test board in order to the below legal system: with streptavidin (the PBS solution of 5mg/ml) coating 2 hours, spend the night then with PBS (salt solution of phosphate buffered) washing, and with 4 ℃ the 150 μ L sealing damping fluid sealing that in PBS, contains 2mg/ml bovine serum albumin (Sigma) and 0.05%Tween20 (Sigma).Biotinylated peptide (1 μ M) in the 50 μ L sealing damping fluid is joined in each hole, and after 1h is hatched, carry out general washing.On 96 other orifice plates, dilute test compounds, and divide and be added to the mixture that contains MDM2 albumen and anti--MDM2 mixtures of antibodies for three times and hatch in the plate.After 20min is hatched, the inclusion in the plate is transferred to test panel, hatched again 1 hour.To resist-mouse IgG two is anti-to be added on the test panel, carries out and use subsequently the PBS solution washing three times of 0.05%Tween20.At last, add peroxidase substrate, and (MR7000 Dynatech) reads absorption value at 450nm to use plate reader to each hole.Measure the inhibition activity of test mixing thing, represent with respect to the per-cent of bonded MDM2 in the untreated hole, and calculate IC with bonded MDM2 in the hole of handling
50
The shown bioactive IC that is applicable to motif compound of the present invention
50Scope be about 0.020 μ M to about 20 μ M.The concrete data of some embodiment are as follows:
| Embodiment | IC 50(μM) |
| 4 | 0.604 |
| 5 | 0.071 |
Claims (26)
1. a formula I compound and pharmaceutical salts and ester,
Wherein
R represents to contain at least one heteroatomic saturated or undersaturated 5 to the 6 yuan of ring that is selected from S, N and O; And
Optional quilt is selected from following group and replaces: low alkyl group, cycloalkyl ,-C (O)-R
1, hydroxyl, the low alkyl group that is replaced by hydroxyl, the low alkyl group, the quilt-NH that are replaced by lower alkoxy
2The low alkyl group, the quilt-SO that replace
2Low alkyl group, quilt-C (O)-R that-low alkyl group replaces
1The low alkyl group that replaces ,-the NH-low alkyl group ,-N (low alkyl group)
2,-SO
2-low alkyl group ,=O ,-CH
2C (O) CH
3Or contain, two or three heteroatomic 5 to 6 yuan of saturated rings that are selected from S, N and O;
R
1Be selected from hydrogen, low alkyl group ,-NH
2,-NH-low alkyl group ,-N (low alkyl group)
2, replaced by hydroxyl low alkyl group, by NH
2The low alkyl group that replaces or contain, two or three heteroatomic 5 to 6 yuan of saturated rings that are selected from S, N and O;
X
1And X
2Be independently selected from hydrogen, lower alkoxy ,-CH
2OCH
3,-CH
2OCH
2CH
3,-OCH
2CF
3,-OCH
2CH
2F;
Y
1And Y
2Be selected from independently of one another-Cl ,-Br ,-NO
2,-C ≡ N and-C ≡ CH; And 4 and 5 absolute stereo chemical structure of tetrahydroglyoxaline ring is respectively S and R.
2. formula I compound according to claim 1, wherein
R is selected from and contains at least one heteroatomic saturated and undersaturated 5 yuan and 6 yuan of rings, wherein said heteroatoms is selected from S, N and O, and described 5 yuan and 6 yuan ring is optional is selected from following group replacement: low alkyl group, cycloalkyl, the low alkyl group, the quilt-NH that are replaced by hydroxyl
2The low alkyl group that replaces, N-low alkyl group ,-SO
2CH
3,=O ,-CH
2C (O) CH
3With contain at least one heteroatomic 5 yuan and 6 yuan of saturated rings that are selected from S, N and O;
X
1And X
2Be independently selected from hydrogen, lower alkoxy ,-CH
2OCH
3,-CH
2OCH
2CH
3,-OCH
2CF
3,-OCH
2CH
2F;
Y
1And Y
2Be selected from independently of one another-Cl ,-Br ,-NO
2,-C ≡ N and-C ≡ CH, and 4 and 5 absolute stereo chemical structure of tetrahydroglyoxaline ring is respectively S and R.
3. compound according to claim 1 and 2, wherein Y
1And Y
2Be selected from independently of one another-Cl and-Br.
4. compound according to claim 3, wherein
R is a piperazinyl, and this piperazinyl is selected from least one following group and replaces: low alkyl group, cycloalkyl, C (O) R
1, hydroxyl, the low alkyl group that is replaced by hydroxyl, the low alkyl group, the quilt-NH that are replaced by lower alkoxy
2The low alkyl group, quilt-C (O) R that replace
1The low alkyl group, the N (low alkyl group) that replace
2,-SO
2CH
3,=O ,-CH
2C (O) CH
3And wherein
R
1Be selected from hydrogen, low alkyl group ,-NH
2,-N-low alkyl group, the low alkyl group that is replaced by hydroxyl, by NH
2The low alkyl group that replaces; Perhaps
Piperidyl, this piperidyl are selected from least one following group and are replaced: the C1-C3 alkyl ,-the C1-C2 alkoxyl group ,-C (O) CH
3,-SO
2CH
3,-C (O) ,-OH ,-CH
2NH
2,-C (O) CH
2NH
2,-C (O) CH
2OH ,-C (O) C (OH) CH
2OH ,-CH
2C (OH) CH
2OH ,-C (O) N (CH
2)
2,-C (O) NH
2, and-C (O) N (CH
3) CH
3,-N (CH
3) CH
3, pyrrolidyl and piperidyl.
5. compound according to claim 4, wherein adjacent X
1Group be selected from lower alkoxy ,-OCH
2CF
3With-OCH
2CH
2F, and the X of contraposition
2Group is a lower alkoxy.
6. compound according to claim 5, wherein adjacent X
1Group be selected from oxyethyl group, isopropoxy ,-OCH
2CF
3With-OCH
2CH
2F, and the X of contraposition
2Group is selected from methoxyl group and oxyethyl group.
7. compound according to claim 6, wherein R is a piperazinyl, this piperazinyl is selected from least one following group and is replaced: low alkyl group, cycloalkyl, C (O)-R
1, hydroxyl, the low alkyl group that is replaced by hydroxyl, the low alkyl group, the quilt-NH that are replaced by lower alkoxy
2The low alkyl group, the quilt-C (O)-R that replace
1The low alkyl group that replaces, N-low alkyl group ,-SO
2CH
3,=O ,-CH
2C (O) CH
3, wherein
R
1Be selected from hydrogen, low alkyl group ,-NH
2,-N-low alkyl group, the low alkyl group that is replaced by hydroxyl, by NH
2The low alkyl group that replaces; Perhaps
Piperidyl, this piperidyl are selected from least one following group and are replaced: the C1-C3 alkyl ,-the C1-C2 alkoxyl group ,-C (O) CH
3,-SO
2CH
3,-C (O) ,-OH ,-CH
2NH
2,-C (O) CH
2NH
2,-C (O) CH
2OH ,-C (O) C (OH) CH
2OH ,-CH
2C (OH) CH
2OH ,-C (O) N (CH
2)
2,-C (O) NH
2, and-C (O) N (CH
3) CH
3,-N (CH
3) CH
3, pyrrolidyl and piperidyl.
8. compound according to claim 1 and the pharmaceutical salts thereof of formula I-A,
Wherein
Piperazinyl or piperidyl that R is replaced by following group:
The C1-C4-alkyl;
-C (O)-(C1-C4-alkyl);
Tetramethyleneimine-1-base;
＝O；
-CH
2-C (O)-morpholino;
-CH
2-C (O)-N (C1-C4-alkyl)
2
-(CH
2)
n-SO
2-(C1-C4-alkyl);
X
1Be-O-(C1-C4-alkyl);
X
2Be hydrogen or-O-(C1-C4-alkyl);
N is 0,1 or 2; And
4 and 5 absolute stereo chemical structure of tetrahydroglyoxaline ring is respectively S and R.
9. the compound of claim 1, wherein said compound is
1-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-ethyl ketone;
4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-2-ketone;
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-(4-tetramethyleneimine-1-base-piperidines-1-yl)-ketone;
4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-2-ketone;
1-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-ethyl ketone;
2-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-1-morpholine-4-base-ethyl ketone;
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-ketone; Or
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-(4-methyl-piperazine-1-yl)-ketone;
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-[4-(2-methylsulfonyl-ethyl)-piperazine-1-yl]-ketone;
2-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-N, N-dimethyl-ethanamide;
2-{4-[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl]-piperazine-1-yl }-1-morpholine-4-base-ethyl ketone; Perhaps
[(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-yl]-(4-ethylsulfonyl-piperazine-1-yl)-ketone.
10. a method that suppresses tumor growth comprises the formula I compound according to claim 1 to patient's drug treatment significant quantity of needs treatment.
11. a pharmaceutical composition, it comprises formula I compound according to claim 1 and pharmaceutical carrier or vehicle.
12. the compound of a following formula:
(4S, 5R)-4,5-pair-(chloro-phenyl)-2-(2-isopropoxy-4-methoxyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride, perhaps
(4S, 5R)-4,5-pair-(4-chloro-phenyl)-2-(2-oxyethyl group-phenyl)-4,5-dihydro-imidazol--1-carbonyl chloride.
13. a method for preparing formula I compound according to claim 1, this method comprises the enantiomorph of separation of racemic carbonyl chloride,
Use the suitable R-required enantiomorph of amine groups coupling, wherein R, Y then
1, Y
2, X
1And X
2Has the implication that provides in the claim 1.
14. pharmaceutical composition according to claim 11 is used for the treatment of the disease based on MDM2 albumen and p53 sample peptide interaction.
15. pharmaceutical composition according to claim 11 is used for the treatment of the disease based on MDM2 albumen and p53 peptide interaction.
16. be used for the treatment of the pharmaceutical composition according to claim 11 of cancer.
17. be used for the treatment of the pharmaceutical composition according to claim 11 of solid tumor.
18. compound according to claim 1 is used for the treatment of the application based on the disease of MDM2 albumen and p53 sample peptide interaction.
19. compound according to claim 1 is used for the treatment of the application based on the disease of MDM2 albumen and p53 peptide interaction.
20. compound according to claim 1 is used for the treatment of the application of cancer.
21. compound according to claim 1 is used for the treatment of the application of solid tumor.
22. be used for the treatment of based on the application in the medicine of the disease of MDM2 albumen and p53 sample peptide interaction in preparation according to the compound of claim 1.
23. compound according to claim 1 is used for the treatment of based on the application in the medicine of the disease of MDM2 albumen and p53 peptide interaction in preparation.
24. compound according to claim 1 is used for the treatment of application in the medicine of cancer in preparation.
25. compound according to claim 1 is used for the treatment of application in the medicine of solid tumor in preparation.
26. aforesaid the present invention.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58044104P | 2004-06-17 | 2004-06-17 | |
| US60/580,441 | 2004-06-17 | ||
| US60/674,196 | 2005-04-22 |
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| Publication Number | Publication Date |
|---|---|
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ID=39036723
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|---|---|---|---|
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| ZA (1) | ZA200610303B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242417A (en) * | 2012-02-02 | 2013-08-14 | 北京北大维信生物科技有限公司 | Sterol derivative, and preparation method and application thereof |
| CN103923067A (en) * | 2014-04-29 | 2014-07-16 | 湖北工业大学 | Small-molecule inhibitor of Mdm<X>/Mdm<2>, as well as preparation method and applications |
| CN110088081A (en) * | 2017-06-16 | 2019-08-02 | 尤尼蒂生物技术公司 | Synthetic method of the preparation for the pure cis--imidazolinium compounds of mapping of medicinal usage |
-
2005
- 2005-06-08 CN CNA2005800184339A patent/CN101103004A/en active Pending
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242417A (en) * | 2012-02-02 | 2013-08-14 | 北京北大维信生物科技有限公司 | Sterol derivative, and preparation method and application thereof |
| CN103242417B (en) * | 2012-02-02 | 2016-04-06 | 北京北大维信生物科技有限公司 | A kind of sterol derivative and preparation method thereof and application |
| CN103923067A (en) * | 2014-04-29 | 2014-07-16 | 湖北工业大学 | Small-molecule inhibitor of Mdm<X>/Mdm<2>, as well as preparation method and applications |
| CN110088081A (en) * | 2017-06-16 | 2019-08-02 | 尤尼蒂生物技术公司 | Synthetic method of the preparation for the pure cis--imidazolinium compounds of mapping of medicinal usage |
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