CN103588766A - 1,3,4-oxadiazole-containing 3-(1H-3-indolyl)-1H-pyrazole derivatives and their preparation method and use - Google Patents

1,3,4-oxadiazole-containing 3-(1H-3-indolyl)-1H-pyrazole derivatives and their preparation method and use Download PDF

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CN103588766A
CN103588766A CN201310633382.7A CN201310633382A CN103588766A CN 103588766 A CN103588766 A CN 103588766A CN 201310633382 A CN201310633382 A CN 201310633382A CN 103588766 A CN103588766 A CN 103588766A
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oxadiazoles
compound
pyrazoles
propyl group
benzyl
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CN103588766B (en
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张大同
徐荣荣
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Qilu University of Technology
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    • 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
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Abstract

The invention relates to 1,3,4-oxadiazole-containing 3-(1H-3-indolyl)-1H-pyrazole derivatives and their preparation method and use. The invention provides the 1,3,4-oxadiazole-containing 3-(1H-3-indolyl)-1H-pyrazole derivatives shown in the general formula Ia or Ib and their pharmaceutically acceptable salts, and also provides the preparation method of the 1,3,4-oxadiazole-containing 3-(1H-3-indolyl)-1H-pyrazole derivatives shown in the general formula Ia or Ib and a use of a composition of the one or more 1,3,4-oxadiazole-containing 3-(1H-3-indolyl)-1H-pyrazole derivatives in preparation of drugs for treating human or animal cancers.

Description

Contain 3-(1H-3-indyl)-1H-pyrazole derivatives of 1,3,4-oxadiazoles and its preparation method and application
Technical field
The present invention relates to, containing the 3-(1H-3-indyl) of 1,3,4-oxadiazoles-1H-pyrazole derivatives and preparation and application, 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 effectively use of cancer therapy drug, can help patient to obtain longer survival time, have the hope surviving, for example, although there have been at present many cancer therapy drugs (: Plicamycin, Exemestane etc.) to be applied to clinical, but these medicines all exist the defects such as antitumor spectrum is narrow, toxic side effect is large, therefore design, synthetic new anticarcinogen tool efficient, low toxicity are of great significance.
Many indole derivatives are being obtained prominent achievement aspect the medical treatments such as treatment cancer, acquired immune deficiency syndrome (AIDS), cardiovascular disorder.For example: 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 are 3 indoles quinones anticancer compounds that are connected to pyrazoles that Sugen company obtains by the method for high flux screening.Wherein, SU11248 be a kind of many target spots inhibitor (referring to 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:
1,3-(1H-3-the indyl)-1H-pyrazole derivatives that contains 1,3,4-oxadiazoles
Containing 3-(1H-3-the indyl)-1H-pyrazole derivatives of 1,3,4-oxadiazoles with and pharmacy acceptable salt, there is the structure shown in general formula I a or Ib,
Figure BDA0000425991240000011
R wherein 1, R 2independent is separately 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-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 1),
5-[1-propyl group-3-(1-propyl group-1H-indoles)-1H-pyrazoles-5-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 2),
5-[1-is to luorobenzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-yl]-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-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 4),
5-[3-(1-is to luorobenzyl-1H-indol-3-yl)-1-propyl group-1H-pyrazoles-5-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 5),
2-[1-benzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-yl]-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-yl]-1,3,4-oxadiazoles (Ib 2).
2, the preparation method who contains 3-(1H-3-the indyl)-1H-pyrazole derivatives of 1,3,4-oxadiazoles
The preparation method of the compound of general formula I a of the present invention or Ib, step is as follows;
3-(1H-3-the indyl)-1H-pyrazoles-5-carbohydrazide (1-5) of take obtains target compound Ia, Ia and R as raw material and dithiocarbonic anhydride cyclization 3i reaction obtains target compound Ib.
Reaction formula is as follows:
Figure BDA0000425991240000021
Reagent and condition: i, CS 2, KOH (82%)/EtOH, refluxes; Ii, R 3i,K 2cO 3/ THF.
Wherein, R 1, R 2, R 3definition described in above-mentioned general formula I a or Ib.
Compound 1-5 synthetic can reference report method (magnify equal people .Arch Pharm Res, 2011,34,343-355).
The structural formula of compound 1-5 and target compound Ia or Ib is as following table 1:
Table 1
Figure BDA0000425991240000022
Figure BDA0000425991240000031
3, the pharmaceutical composition that contains the compounds of this invention and application thereof
The pharmacy acceptable salt of the compound of general formula I a of the present invention or Ib, be to 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 of the present invention or Ib or its pharmacy acceptable salt, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made 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, can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle in described pharmacy or bromatology.
Composition of the present invention, can accept auxiliary material in described pharmacy or bromatology.Weighting agent is one or more the composition 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 one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
The compound or its salt of general formula I a of the present invention or Ib can be used as effective constituent for the preparation of the medicine for the treatment of human body or animal cancer.The activity data of general formula I a of the present invention or Ib compound is tested acquisition by MTT.
General formula I a of the present invention or Ib compound are effective in quite wide dosage range.The dosage of for example taking every day, within the scope of 10mg-1000mg/ people, is divided into once or administration for several times.The actual dosage of 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 person's of being treated physical state, route of administration, age, body weight, the individual reaction to medicine, the severity of symptom etc.
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 adopts indoles, pyrazoles and 1,3,4-oxadiazoles, three class pharmacophoric groups to synthesize 3-(1H-3-the indyl)-1H-pyrazole derivatives containing 1,3,4-oxadiazoles, and has carried out anti-tumor activity experimental study.Experimental result shows that compound of the present invention has antiproliferative activity.This has shown that compound of the present invention can be used for the medicine of preparation treatment 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 is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's derivation according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1, compound (Ia 1) synthetic
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 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 ℃. 1H?NMR(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, with different raw material 1, according to above same method, can prepare Ia 2, Ia 3, Ia 4, Ia 5, compound structure and fusing point are listed in table 2.
Table 2
Embodiment 6 compound (Ib 1) synthetic
By compound (Ia 1) (400mg, 0.96mmol) be added in anhydrous THF (15ml), adds K 2cO 3(133mg, 0.96mmol) stirring at room 1 hour, then adds CH 3i (0.08mL, 1.28mmol), stirring at room 3 hours, adds water, ethyl acetate extraction, merges organic phase, and a small amount of washing once, dry, concentrating under reduced pressure, obtains light yellow oily 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 ℃. 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 above same method, Compound I a 2make compounds ib with iodomethane reaction 2.
Table 3
Figure BDA0000425991240000061
Embodiment 8, the experiment of compound antiproliferative activity
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, adjust cell concn to 1 * 10 4/ hole.Placement cell culture incubator (37 ℃, 5%CO 2) middle cultivation after 24h, adding medicine to be measured, it is 0.4%DMSO substratum that negative control group adds final concentration, each group is all established 3 multiple holes.In incubator, cultivate after 72h, every hole adds the MTT20 μ l of 5mg/ml, places 3h for 37 ℃.Every hole adds 150 μ l DMSO, 37 ℃ of shaking table vibration 5min, and 492nm/620nm surveys absorbancy (OD).
The growth inhibitory activity IC of table 4 compound to four kinds of tumor cell lines 50value
Figure BDA0000425991240000062
The positive contrast medicine of Lipodox (Dox); " ND " represents not detect.
From MTT experimental result, can find out, compound of the present invention is waited until strong growth inhibitory activity during four kinds of cell strains have been demonstrated.By analyzing structure activity relationship, can find that on indole ring or pyrazole ring, connecting one is conducive to active raising compared with macoradical; For HepG2, Ho8910 and A549 cell strain, in the contraposition of benzyl, introduce a F atom and will contribute to improve antineoplastic activity.Compound I a 3hepG2, Ho8910 and A549 cell strain are demonstrated to very strong growth inhibitory activity, its IC 50value is respectively 9.39 μ M, 9.41 μ M and 14.60 μ M.Compound I a 5iC to A549 50value is 14.12 μ M, and it suppresses activity and is slightly better than Ia 3.Presentation of results, the substituting group of exchange 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 of preparation treatment cancer.

Claims (6)

  1. Containing 3-(1H-3-the indyl)-1H-pyrazole derivatives of 1,3,4-oxadiazoles with and pharmacy acceptable salt, there is the structure shown in general formula I a or Ib,
    Figure FDA0000425991230000011
    R wherein 1, R 2independent is separately H, C 1-C 4straight or branched alkyl, benzyl or mono-substituted benzyl; R 3for methyl or ethyl.
  2. 2. the compound of claim 1, is characterized in that, R 1for n-propyl, 4-luorobenzyl; R 2for n-propyl, benzyl, 4-luorobenzyl, 4-methoxy-benzyl; R 3for methyl.
  3. 3. claim 1 or 2 compound, it is characterized in that one of following compound:
    5-[1-benzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 1),
    5-[1-propyl group-3-(1-propyl group-1H-indoles)-1H-pyrazoles-5-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 2),
    5-[1-is to luorobenzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-yl]-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-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 4),
    5-[3-(1-is to luorobenzyl-1H-indol-3-yl)-1-propyl group-1H-pyrazoles-5-yl]-1,3,4-oxadiazoles-2-mercaptan (Ia 5),
    2-[1-benzyl-3-(1-propyl group-1H-indol-3-yl)-1H-pyrazoles-5-yl]-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-yl]-1,3,4-oxadiazoles (Ib 2).
  4. 4. the preparation method of compound as claimed in claim 1 or 2, step is as follows:
    3-(1H-3-the indyl)-1H-pyrazoles-5-carbohydrazide (1-5) of take obtains target compound Ia, Ia and R as raw material and dithiocarbonic anhydride cyclization 3i reaction obtains target compound Ib;
    Reaction formula is as follows:
    Figure FDA0000425991230000012
    Reagent and condition: i, CS 2, KOH (82%)/EtOH, refluxes; Ii, R 3i,K 2cO 3/ THF;
    Wherein, R 1, R 2, R 3definition described in above-mentioned general formula I a or Ib.
  5. 5. prepare treatment human body or an animal cancer drug composition, comprise compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle described in claim 1-3 any one.
  6. 6. the application of compound in the medicine of preparation treatment human body or animal cancer described in claim 1-3 any one.
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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
CN104000817A (en) * 2014-06-17 2014-08-27 遵义医学院 Preparation for medicine curing and preventing tumors and containing pyrazole derivatives of 1, 3, 4-oxadiazoles

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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

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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

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104000817A (en) * 2014-06-17 2014-08-27 遵义医学院 Preparation for medicine curing and preventing tumors and containing pyrazole derivatives of 1, 3, 4-oxadiazoles
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

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