CN103588766B - Containing 3-(1H-3-the indyl)-1H-pyrazole derivatives and its preparation method and application of 1,3,4-oxadiazoles - Google Patents
Containing 3-(1H-3-the indyl)-1H-pyrazole derivatives and its preparation method and application of 1,3,4-oxadiazoles Download PDFInfo
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- CN103588766B CN103588766B CN201310633382.7A CN201310633382A CN103588766B CN 103588766 B CN103588766 B CN 103588766B CN 201310633382 A CN201310633382 A CN 201310633382A CN 103588766 B CN103588766 B CN 103588766B
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- oxadiazoles
- compound
- indyl
- pyrazoles
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- 0 CCCC1=CC=C(C2=**(CC3=CC=CCC3)C(C3=*=C(*)*3)=C2)C2=CC=CCC12 Chemical compound CCCC1=CC=C(C2=**(CC3=CC=CCC3)C(C3=*=C(*)*3)=C2)C2=CC=CCC12 0.000 description 2
- DMUVQFCRCMDZPW-UHFFFAOYSA-N CCCc1c(CC)cccc1 Chemical compound CCCc1c(CC)cccc1 DMUVQFCRCMDZPW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to 3-(1H-3-the indyl)-1H-pyrazole derivatives and preparation method thereof containing 1,3,4-oxadiazoles and application.As shown in general formula I a or Ib containing 1,3,3-(1H-3-the indyl)-1H-pyrazole derivatives of 4-oxadiazoles and pharmacy acceptable salt thereof, the present invention also provides the preparation method of general formula I a or Ib compound and the application of the composition containing this compounds one or more in the medicine preparing treatment human body or veterinary cancer.
Description
Technical field
The present invention relates to 3-(1H-3-the indyl)-1H-pyrazole derivatives containing 1,3,4-oxadiazoles and Synthesis and applications thereof, belong to technical field of chemistry.
Background technology
Cancer is the general designation of a large class malignant tumour.The feature of cancer cells be unrestrictedly, hyperplasia without end, the nutritive substance in patient body is consumed in a large number; In the treatment of cancer, pharmacological agent is a very important link, the use of effective cancer therapy drug, patient can be helped to obtain longer survival time, have the hope survived, although had many cancer therapy drugs (such as: Plicamycin, Exemestane etc.) to be applied to clinical at present, but these medicines all exist the defects such as Antitumor test is narrow, toxic side effect is large, therefore design, synthesize new anticarcinogen tool that is efficient, low toxicity is of great significance.
Many indole derivatives achieve prominent achievement in the medical treatments such as Therapeutic cancer, acquired immune deficiency syndrome (AIDS), cardiovascular disorder.Such as: Indoprofen is used for the treatment of the ischemic cardiovascular change that cardiovascular disorder causes as arteriosclerosis, and Visken is applicable to sinus tachycardia, paroxysmal tachycardia and premature beat etc.At occurring in nature, many important alkaloids are all indole derivatives.Pyrazoles is the important anticancer drug effect functional group of a class.SU5416, SU6668, SU11248 3 of being that the method for Sugen company high flux screening obtains are connected to the indoles quinones anticancer compound of pyrazoles.Wherein, SU11248 is that a kind of Mutiple Targets inhibitor is (see Chen Fengsheng, Shi Min, Luo Rongcheng.Journal of Clinical Oncology, 2008,13 (3): 278-281), since listing in 2006, be mainly used in clinical treatment malignant stromal tumors or metastatic renal cell cancer.
Summary of the invention
Not enough for prior art, the invention provides 3-(1H-3-the indyl)-1H-pyrazole derivatives containing 1,3,4-oxadiazoles, the present invention also provides preparation method and the purposes of this derivative.
Technical scheme of the present invention is as follows:
1, containing 3-(1H-3-the indyl)-1H-pyrazole derivatives of 1,3,4-oxadiazoles
Containing 3-(1H-3-indyl)-1H-pyrazole derivatives and its pharmacy acceptable salt of 1,3,4-oxadiazoles, there is the structure shown in general formula I a or Ib,
Wherein R
1, R
2respective is independently H, C
1-C
4straight or branched alkyl, benzyl or mono-substituted benzyl; R
3for methyl or ethyl.
Preferably, R
1for n-propyl, 4-luorobenzyl; R
2for n-propyl, benzyl, 4-luorobenzyl, 4-methoxy-benzyl; R
3for methyl.
Further preferred, above-mentioned general formula I a or Ib compound are one of following:
5-[1-benzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (Ia
1),
5-[1-propyl group-3-(1-propyl group-1H-indoles)-1H-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (Ia
2),
5-[1-is to luorobenzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (Ia
3),
5-[1-is to methoxy-benzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (Ia
4),
5-[3-(1-is to luorobenzyl-1H-indol-3-yl)-1-propyl group-1H-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (Ia
5),
2-[1-benzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-base]-5-methylthio group-1,3,4-oxadiazoles (Ib
1),
2-methylthio group-5-[1-propyl group-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-base]-1,3,4-oxadiazoles (Ib
2).
2, containing the preparation method of 3-(1H-3-the indyl)-1H-pyrazole derivatives of 1,3,4-oxadiazoles
The preparation method of the compound of general formula I a or Ib of the present invention, step is as follows;
With 3-(1H-3-indyl)-1H-pyrazoles-5-carbohydrazide (1-5) for raw material and dithiocarbonic anhydride cyclization obtain target compound Ia, Ia and R
3i is obtained by reacting target compound Ib.
Reaction formula is as follows:
Reagent and condition: i, CS
2, KOH (82%)/EtOH, backflow; Ii, R
3i,K
2cO
3/ THF.
Wherein, R
1, R
2, R
3definition as described in above-mentioned general formula I a or Ib.
The synthesis of compound 1-5 can reference report method (magnifying equal people .ArchPharmRes, 2011,34,343-355).
The structural formula of compound 1-5 and target compound Ia or Ib is as following table 1:
Table 1
3, the pharmaceutical composition containing the compounds of this invention and application thereof
The pharmacy acceptable salt of the compound of general formula I a or Ib of the present invention, be react with acidic substance (as mineral acid), they include, but are not limited to: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc. form pharmacy acceptable salt, as corresponding hydrochloride, vitriol or phosphoric acid salt etc.Also can adopt and common are machine acid as generation salt such as formic acid, acetic acid, citric acid, tartrate, lactic acid, methylsulfonic acid, toxilic acids.
The compound of general formula I a or Ib of the present invention or its pharmacy acceptable salt, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carrier, vehicle or thinner.This pharmaceutical composition can make the formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material.Weighting agent is the composition of one or more that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tackiness agent comprises the composition of one or more of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises the composition of one or more of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
The compound or its salt of general formula I a or Ib of the present invention can be used as effective constituent for the preparation of the medicine for the treatment of human body or veterinary cancer.The activity data of general formula I a of the present invention or Ib compound is obtained by MTT experiment.
General formula I a of the present invention or Ib compound are effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 10mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking general formula I a of the present invention or Ib compound can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
1,3,4-furodiazole compound is widely used in the fields such as agricultural chemicals, medicine, material because having unique biological activity.The present invention has adopted indoles, pyrazoles and 1,3,4-oxadiazoles three class pharmacophoric group to synthesize containing 3-(1H-3-the indyl)-1H-pyrazole derivatives of 1,3,4-oxadiazoles, and has carried out anti-tumor activity experimental study.Experimental result shows compound of the present invention and has antiproliferative activity.This demonstrate the medicine that compound of the present invention can be used for preparing Therapeutic cancer.Detailed experimental study will be explained in an embodiment.
Embodiment
Below in conjunction with embodiment, the present invention is described further, it should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's derivation according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1, compound (Ia
1) synthesis
Compound (1) (200mg, 0.54mmol) is added in EtOH (5ml), adds KOH(55mg, 0.80mmol), drip CS
2(0.10mL, 1.7mmol), reflux 2.5 hours, adds water, dichloromethane extraction, merges organic phase, and a small amount of washing is once, dry, concentrating under reduced pressure, obtains light yellow chip solid 205mg, sherwood oil: silicagel column is crossed in ethyl acetate=1/2, obtains light yellow solid (Ia
1, 500mg, 40%), fusing point: 185 ~ 186 DEG C.
1HNMR(DMSO-d
6,400MHz)δ0.85(t,J=7.6Hz,3H),1.80-1.83(m,2H),2.50(s,1H),4.15-4.18(t,J=6.8Hz,2H),5.74-5.75(m,2H),7.09-7.12(m,1H),7.16-7.20(m,1H),7.24-7.28(m,3H),7.31-7.35(m,2H),7.52(d,J=8.0Hz,1H),7.97(s,1H),8.14(d,J=8.0Hz,1H).
Embodiment 2-5: the synthetic operation of reference example 1, can prepare Ia with different raw materials 1 according to method same above
2, Ia
3, Ia
4, Ia
5, compound structure and fusing point list in table 2.
Table 2
Embodiment 6 compound (Ib
1) synthesis
By compound (Ia
1) (400mg, 0.96mmol) be added in anhydrous THF (15ml), adds K
2cO
3(133mg, 0.96mmol) stirring at room temperature 1 hour, then adds CH
3i (0.08mL, 1.28mmol), stirring at room temperature 3 hours, adds water, extraction into ethyl acetate, merges organic phase, and a small amount of washing is once, dry, concentrating under reduced pressure, obtains pale yellowish oil thick liquid 367mg, sherwood oil: silicagel column is crossed in ethyl acetate=5/1, obtains light yellow solid (Ib
1, 108mg, 52%), fusing point: 105 ~ 106 DEG C.
1HNMR(CDCl
3,400MHz)δ0.99(t,J=8.0Hz,3H),1.89-1.98(m,2H),2,78(s,3H),4.15(t,J=6.8Hz,2H),5.96(s,2H),7.11(d,J=6.4Hz,1H),7.16-7.20(m,1H),7.18-7.32(m,3H),7.39-7.44(m,2H),7.59(d,J=10.4Hz,1H),8.19-8.25(m,1H).
Embodiment 7
According to method same above, Compound I a
2compounds ib is obtained with iodomethane reaction
2.
Table 3
Embodiment 8, compound antiproliferative activity are tested
Vitro culture human lung adenocarcinoma cell line (A549), human hepatoma cell strain (HepG2), human oophoroma cell line (Ho8910) and human leukemia cell line (KG-1), Growth of Cells is to logarithmic growth after date, collecting cell, centrifugal 5 minutes of 1000rpm, abandon supernatant, appropriate substratum suspends, by cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, adjustment cell concn to 1 × 10
4/ hole.Placement cell culture incubator (37 DEG C, 5%CO
2) in cultivate after 24h, add medicine to be measured, it is 0.4%DMSO substratum that negative control group adds final concentration, all establishes 3 multiple holes for each group.After cultivating 72h in incubator, every hole adds the MTT20 μ l of 5mg/ml, places 3h for 37 DEG C.Every hole adds 150 μ lDMSO, and 37 DEG C of shaking table vibrations 5min, 492nm/620nm survey absorbancy (OD).
Table 4 compound is to the growth inhibitory activity IC of four kinds of tumor cell lines
50value
Lipodox (Dox) is positive control drug; " ND " expression does not detect.
As can be seen from MTT experiment result, growth inhibitory activity by the time strong during compound of the present invention shows four kinds of cell strains.Can find that indole ring or pyrazole ring connecting one is conducive to active raising compared with macoradical by analyzing structure activity relationship; For HepG2, Ho8910 and A549 cell strain, introduce a F atom in the contraposition of benzyl and will contribute to improving antineoplastic activity.Compound I a
3very strong growth inhibitory activity is demonstrated to HepG2, Ho8910 and A549 cell strain, its IC
50value is respectively 9.39 μMs, 9.41 μMs and 14.60 μMs.Compound I a
5to the IC of A549
50value is 14.12 μMs, and its inhibit activities is slightly better than Ia
3.Result illustrates, the substituting group exchanging indole ring and pyrazole ring contributes to active raising.
Above experimental result shows that compound of the present invention has antiproliferative activity, can be used for the medicine preparing Therapeutic cancer.
Claims (3)
1. containing the 3-(1 of 1,3,4-oxadiazoles
h-3-indyl)-1
h-pyrazole derivatives and its pharmacy acceptable salt, it is characterized in that one of following compound:
5-[1-benzyl-3-(1-propyl group-1
h-indol-3-yl)-1
h-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (
ia 1 ),
[1-is to luorobenzyl-3-(1-propyl group-1 for 5-
h-indol-3-yl)-1
h-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (
ia 3 ),
[1-is to methoxy-benzyl-3-(1-propyl group-1 for 5-
h-indol-3-yl)-1
h-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (
ia 4 ),
[(1-is to luorobenzyl-1 for 3-for 5-
h-indol-3-yl)-1
-propyl group-1
h-pyrazoles-5-base]-1,3,4-oxadiazoles-2-mercaptan (
ia 5 ).
2. be used for the treatment of a pharmaceutical composition for human body or veterinary cancer, comprise compound described in claim 1 or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
3. the application of compound described in claim 1 in the medicine preparing treatment human body or veterinary cancer.
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| CN103965182A (en) * | 2014-05-22 | 2014-08-06 | 遵义医学院 | Medicament of 1,3,4-oxadiazole containing pyrazole compound prepared for treating tumor |
| CN104000817B (en) * | 2014-06-17 | 2016-03-23 | 遵义医学院 | One class is containing the purposes of pyrazole derivatives in preparation treatment, preventing tumor disease medicament of 1,3,4-oxadiazole quinoline |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321074A (en) * | 2011-06-07 | 2012-01-18 | 山东轻工业学院 | Indole ring-substituted pyrazole hydrazide derivative and preparation method and application thereof |
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| CN102321074A (en) * | 2011-06-07 | 2012-01-18 | 山东轻工业学院 | Indole ring-substituted pyrazole hydrazide derivative and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Design, synthesis and biological evaluation of a novel series of 1,3,4-oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole moiety as cytotoxic agents;Pushpan Puthiyapurayil et al.;《European Journal of Medicinal Chemistry》;20120406;第46卷;第205页及206页表1 * |
| Synthesis and cytotoxic activity of novel 3-(1H-indol-3-yl)-1H-pyrazole-5-carbohydrazide derivatives;Datong Zhang et al.;《European Journal of Medicinal Chemistry》;20111001;第5868页左栏引言 * |
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