CN106366151A - Oleanolic acid-3-one derivative having antitumor effects, preparation method, and application thereof - Google Patents

Oleanolic acid-3-one derivative having antitumor effects, preparation method, and application thereof Download PDF

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CN106366151A
CN106366151A CN201610716482.XA CN201610716482A CN106366151A CN 106366151 A CN106366151 A CN 106366151A CN 201610716482 A CN201610716482 A CN 201610716482A CN 106366151 A CN106366151 A CN 106366151A
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oleanolic acid
ketone
triazole
methyl ester
optically active
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CN106366151B (en
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刘洋
程卯生
李凤然
王帅
卫高菲
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin

Abstract

The invention belongs to the technical field of medicines and provides an oleanolic acid-3-one derivative which is represented as the following general formula. In the general formula, R is defined as the specification. The invention also relates to the preparation method of the compounds and potential applications of the compounds as antitumor medicines.

Description

Have oleanolic acid -3- ketone derivatives of antitumor action and preparation method thereof and Purposes
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of oleanolic acid -3- ketone derivatives containing triazole group Preparation method and medical usage are and in particular to the oleanolic acid -3- ketone-(1 '-substituted-phenyl -1h-1 ', 2 ', 3 '-three nitrogen of novelty Azoles -4 '-yl) preparation method of methyl compound and the inhibited proliferation to tumor cell, in terms of preparing antitumor drug There is potential application.
Background technology
Oleanolic acid is widely distributed a kind of pentacyclic triterpenoid in nature, has multiple important biologies and lives Property, such as antitumor, anti-hiv virus, liver protection, antiinflammatory etc., but activity is weaker, and bioavailability low so as to application in clinic Limited.
Research shows, oleanolic acid has different degrees of inhibitory activity to various tumor cell strains, in many animals mould Evident in efficacy to the prevention and treatment of cancer in type, display after activity rating has clear and definite anticancer property.Oleanolic acid dialogue Disorders of blood cell hl-60 has apoptotic activity, action pathway be by active cell Caspase-3 and apoptosis protein- 9, cracking (the acta biochim biophys sinica 2007,39:803 of simultaneous dna repair enzyme (parp) 809).Oleanolic acid can also induce Mus breast epithelial cell differentiation (archives of pharmacal research 1998,21:398 405), inducing mouse granulocyte leukemia (m1) cell and Human acute promyelocytic leukemia (hl-60) Cell differentiation (chem pharm bull 1992,40:401 405).Fernandes etc. finds that oleanolic acid can suppress k562 Leukaemia grow and promote its apoptosis it is often more important that, for tolerance vincristine k562 cell multidrug resistance strain (mdr) still there is Inhibit proliferaton effect (cancer lett 2003,190:165 169).
Become 3- ketone-oleanolic acid, anti-tumor activity is significantly improved, in body after oleanolic acid 3 β-oh is oxidized There is significant inhibitory activity to Various Tissues tumor cell outward；Experiment in vivo shows that it can Selective depression melanoma simultaneously Growth, and cell toxicity medicament different from the past, it also has the anti-angiogenesis activity of uniqueness, the poison to normal cell Property very little, this may being capable of relevant (the cancer lett 2006,233:289 of inducing malignant melanoma cell differentiation with it 296).
The present invention has synthesized the new oleanolic acid -3- ketone derivatives of a class, and is verified by external activity screening study Its anti-tumor activity and unique tumor cell selective action.
Content of the invention
It is an object of the invention to the design oleanolic acid -3- ketone new with synthesis one class-(1 '-substituted-phenyl -1h-1 ', 2 ', 3 '-triazole -4 '-yl) methyl compound, carry out the medicine innovative research with treating cancer.
In order to complete the purpose of the present invention, can adopt the following technical scheme that
The present invention is the new oleanolic acid derivate being related to have formula (i) structure, and its optically active body, diastereomeric Isomer.
Wherein,
R is any one group in following groups: (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro, (5) C1-c4 acyl group.
R is preferably any one group in following groups: (1) hydrogen atom, (2) fluorine atom, (3) chlorine atom, (4) bromine is former Son, (5) cyano group, (6) nitro, (7) acetyl group.
The present invention is preferably as follows the oleanolic acid derivate of structure, and its optically active body, diastereomer,
It is selected from:
In order to prepare the compound described in formula (i) of the present invention, and its optically active body, such is synthesized using following route Compound: in the water and dichloromethane mixed solution of potassium carbonate, with tetrabutyl ammonium bromide as phase transfer catalyst, oleanolic acid 1 is reacted with propargyl bromide and obtains intermediate 2, and the c3 hydroxyl of intermediate 2 is obtained 3- ketone product 3 through Jones reagent oxidation, its again with Various substituted aryl azide compounds are in tertiary butanol and water mixed solution, raw in situ with sodium ascorbate by anhydrous cupric sulfate , there are 1,3 Dipolar Cycloaddition, obtain the compound of formula (i) in cu (i) catalysis becoming.
Reaction equation is as follows:
Specifically, its reaction condition is as follows:
reagents and conditions:(a)k2co3,tbab,h2o,ch2cl2；(b)cro3·h2so4,acetone, 0℃；(c)sodium ascorbate,cuso4·5h2o,t-buoh,h2o,60℃.
Wherein,
R is as described in claim and description.
Specific embodiments
Contact following examples, are better understood with compound and their preparation of the present invention, and these embodiments are intended to Illustrate rather than limit the scope of the present invention.
Embodiment 1: oleanolic acid -3- ketone-(1 '-phenyl -1h-1 ', 2 ', 3 '-triazole -4 '-yl) methyl ester (t1)
By oleanolic acid 1 (2.0g, 4.4mmol), k2co3Powder (1.8g, 13.1mmol) and tbab (290.0mg, 0.9mmol) it is dissolved in 1ml water and the mixed solution of 200ml dichloromethane, add propargyl bromide (1.0g, 8.8mmol), room Lower stirring reaction 5h of temperature, washing, saturation nacl is washed, anhydrous naso4It is dried, filters, concentrate, column chromatography (petroleum ether: ethyl acetate =9:1), obtain 1.93g white solid 2, yield 89.1%.
Compound 2 (3.0g, 6.0mmol) is dissolved in 50ml acetone, be slowly added dropwise at 0 DEG C jones reagent (2.3ml, 12.0mmol).Stirring reaction 30 minutes, sucking filtration, acetone is evaporated off, adds the dissolving of 80ml ethyl acetate, wash (2 × 10ml).Have Machine layer obtains 2.64g compound 3, yield 88.5% through column chromatography (petroleum ether: ethyl acetate=5:1) purification after concentrating.
Compound 3 (120.0mg, 0.2mmol) is dissolved in 15ml t-buoh-h2In o (2:1), sequentially add Vitamin C Sour sodium (38.7mg, 0.2mmol) and cuso4·5h2O (24.1mg, 0.1mmol), stirs 5min, then to this mixed solution Middle addition phenylazide (1.0mmol), reacts 1h in 60 DEG C.Concentrate, dchloromethane, washing, saturation nacl is washed, anhydrous naso4Dry filter, concentrates, column chromatography (petroleum ether: ethyl acetate=8:1), obtains yellow solid t1, yield 87.4%.
mp 92.1-93.9℃；1h nmr(600mhz,cdcl3)δ8.07(s,1h),7.95(s,1h),7.75-7.69(m, 1h), 7.61 (d, j=8.0hz, 1h), 7.56 (dd, j=5.7,3.3hz, 1h), 7.43 (t, j=8.1hz, 1h), 5.35- 5.24 (m, 3h), 4.29-4.21 (m, 1h), 2.90 (dd, j=13.8,3.9hz, 1h), 2.57-2.50 (m, 1h), 1.13 (s, 3h),1.09(s,3h),1.03(s,3h),0.95(s,3h),0.93(s,3h),0.92(s,3h),0.48(s,3h)；13c nmr (150mhz,cdcl3)δ217.68,177.81,167.75,144.03,143.61,137.84,132.46,131.85, 131.08,130.88,128.80,123.62,123.34,122.71,122.30,118.94,68.16,57.20,55.22, 47.39,46.78,46.74,45.79,41.79,41.47,39.25,39.09,38.74,36.69,34.11,33.82, 33.04,32.40,32.14,30.67,30.37,29.70,28.93,27.59,26.48,25.62,23.75,23.57, 23.43,22.99,22.95,21.44,19.50,16.65,14.93,14.05,10.97；esi-ms(m/z):634.6[m+na ]+.
Embodiment 2: oleanolic acid -3- ketone-[1 '-(2 "-fluorophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t2)
The compounds process for production thereof of embodiment 2, with embodiment 1, simply replaces aziminobenzene using adjacent fluorophenyl nitrine, obtains To yellow solid t2, yield 88.2%.
mp 177.5-179.6℃；1h nmr(600mhz,cdcl3) δ 8.45 (d, j=8.9hz, 2h), 8.19 (s, 1h), 8.00 (d, j=8.9hz, 2h), 5.32 (d, j=20.0hz, 3h), 2.90 (dd, j=13.7,3.3hz, 1h), 2.58-2.51 (m,1h),1.14(s,3h),1.09(s,3h),1.02(s,3h),0.94(s,3h),0.94(s,3h),0.92(s,3h),0.55 (s,3h)；13c nmr(150mhz,cdcl3)δ217.49,177.86,147.32,144.69,143.58,141.04,126.35, 125.54,122.47,122.34,120.47,57.11,55.27,47.41,46.83,46.76,45.74,41.81,41.47, 39.27,39.10,36.70,34.10,33.77,33.02,32.37,32.16,30.66,29.70,27.62,26.38, 25.66,23.57,23.44,22.97,22.69,21.44,19.49,16.65,14.88,14.12；esi-ms(m/z):652.8 [m+na]+.
Embodiment 3: oleanolic acid -3- ketone-[1 '-(3 "-fluorophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t3)
The compounds process for production thereof of embodiment 3, with embodiment 1, simply replaces aziminobenzene using a fluorophenyl nitrine, obtains To white solid t3, yield 84.2%.
mp 167.2-170.1℃；1h nmr(600mhz,cdcl3) δ 8.05 (s, 1h), 7.71 (d, j=8.8hz, 2h), 7.54 (d, j=8.8hz, 2h), 5.34-5.28 (m, 3h), 2.90 (dd, j=13.6,3.8hz, 1h), 2.57-2.51 (m, 1h),1.14(s,3h),1.09(s,3h),1.04(s,3h),0.94(s,3h),0.94(s,3h),0.92(s,3h),0.52(s, 3h)；13c nmr(150mhz,cdcl3)δ217.59,177.80,144.03,143.63,135.43,134.69,129.94, 122.47,122.30,121.60,57.26,55.24,47.39,46.78,45.78,41.80,41.47,39.26,39.10, 36.70,34.11,33.80,33.04,32.37,32.15,30.67,29.70,27.62,26.46,25.65,23.58, 23.44,22.96,22.69,21.43,19.51,16.66,14.88,14.12；esi-ms(m/z):652.6[m+na]+.
Embodiment 4: oleanolic acid -3- ketone-[1 '-(4 "-fluorophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t4)
The compounds process for production thereof of embodiment 4, with embodiment 1, simply uses and replaces aziminobenzene to fluorophenyl nitrine, obtain To white solid t4, yield 83.3%.
mp 161.9-163.6℃；1h nmr(600mhz,cdcl3) δ 8.02 (s, 1h), 7.73 (dd, j=7.8,5.7hz, 2h), 7.25 (t, j=8.4hz, 2h), 5.35-5.25 (m, 3h), 2.90 (dd, j=13.8,3.9hz, 1h), 2.59-2.50 (m,1h),1.14(s,3h),1.09(s,3h),1.04(s,3h),0.94(s,3h),0.93(m,3h),0.92(s,3h),0.53 (s,3h)；13c nmr(150mhz,cdcl3)δ217.59,177.80,163.73,161.25,143.93,143.64,133.22, 122.69,122.48,122.40,122.30,116.85,116.62,57.30,55.25,47.39,46.78,45.79, 41.81,41.48,39.27,39.11,36.71,34.11,33.81,33.05,32.38,32.16,31.93,30.67, 29.71,29.37,27.63,26.47,25.66,23.59,23.44,22.96,22.70,21.42,19.52,16.66, 14.89,14.12；esi-ms(m/z):653.3[m+na]+.
Embodiment 5: oleanolic acid -3- ketone-[1 '-(4 "-chlorphenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t5)
The compounds process for production thereof of embodiment 5, with embodiment 1, simply replaces aziminobenzene using rubigan nitrine, obtains To white solid t5, yield 84.5%.
mp 170.8-173.0℃；1h nmr(600mhz,cdcl3) δ 8.05 (s, 1h), 7.69 (d, j=8.8hz, 2h), 7.65 (d, j=8.9hz, 2h), 5.30 (dt, j=19.0,7.9hz, 3h), 2.90 (dd, j=13.7,4.1hz, 1h), 2.58- 2.51(m,1h),1.13(s,3h),1.09(s,3h),1.04(s,3h),0.94(s,3h),0.93(s,3h),0.92(s,3h), 0.51(s,3h)；13c nmr(150mhz,cdcl3)δ217.70,177.80,144.05,143.62,135.90,132.92, 122.52,122.43,122.29,121.82,57.25,55.23,47.39,46.77,46.75,45.77,41.79,41.46, 39.24,39.09,36.69,34.11,33.80,33.04,32.37,32.14,30.67,29.70,27.61,26.45, 25.64,23.58,23.43,22.95,21.44,19.50,16.66,14.88,14.12；esi-ms(m/z):668.6[m+na ]+.
Embodiment 6: oleanolic acid -3- ketone-[1 '-(4 "-bromophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t6)
The compounds process for production thereof of embodiment 6, with embodiment 1, simply replaces aziminobenzene using p-bromophenyl nitrine, obtains To yellow solid t6, yield 90.9%.
mp 75.5-78.0℃；1h nmr(600mhz,cdcl3) δ 7.94 (s, 1h), 7.75 (dd, j=7.4,1.7hz, 1h), 7.67-7.61 (m, 2h), 7.48 (dd, j=7.6,1.2hz, 1h), 5.35-5.29 (m, 3h), 2.90 (dd, j=13.8, 3.9hz,1h),2.58-2.52(m,1h),2.22(s,3h),1.15(s,3h),1.10(s,3h),1.05(s,3h),1.00(s, 3h),0.93(s,3h),0.92(s,3h),0.68(s,3h)；13c nmr(150mhz,cdcl3)δ217.71,199.24, 177.67,143.70,136.27,134.32,131.85,129.93,129.07,125.59,122.28,57.36,55.26, 47.41,46.80,45.79,41.82,41.41,39.31,39.11,36.73,34.12,33.81,33.04,32.32, 32.16,30.67,29.70,29.19,27.67,26.49,25.70,23.58,23.47,22.97,21.45,19.56, 16.85,14.99；esi-ms(m/z):714.6[m+na]+.
Embodiment 7: oleanolic acid -3- ketone-[1 '-(3 "-bromophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t7)
The compounds process for production thereof of embodiment 7, with embodiment 1, simply replaces aziminobenzene using a bromophenyl nitrine, obtains To yellow solid t7, yield 89.4%.
mp 73.5-76.0℃；1h nmr(600mhz,cdcl3) δ 7.98 (s, 1h), 7.63 (d, j=9.0hz, 2h), 7.03 (d, j=9.0hz, 2h), 5.34-5.26 (m, 3h), 4.11 (q, j=7.0hz, 2h), 2.90 (dd, j=13.8, 3.9hz,1h),2.57-2.50(m,1h),1.13(s,3h),1.09(s,3h),1.03(s,3h),0.94(s,3h),0.94(s, 3h),0.92(s,3h),0.53(s,3h)；13c nmr(150mhz,cdcl3)δ217.74,177.79,159.36,143.65, 143.42,130.15,122.73,122.27,122.09,115.26,63.96,57.28,55.19,47.37,46.76, 45.79,41.79,41.46,39.25,39.08,36.70,34.10,33.81,33.05,32.37,32.13,30.67, 29.70,27.61,26.52,25.65,23.59,23.44,22.94,21.40,19.53,16.66,14.93,14.71；esi- ms(m/z):714.6[m+na]+.
Embodiment 8: oleanolic acid -3- ketone-[1 '-(4 "-cyano-phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t8)
The compounds process for production thereof of embodiment 8, with embodiment 1, simply uses and replaces aziminobenzene to cyano-phenyl nitrine, Obtain yellow solid t8, yield 85.1%.
mp 70.5-72.3℃；1h nmr(600mhz,cdcl3) δ 8.16 (d, j=2.7hz, 1h), 8.00 (t, j= 7.7hz, 1h), 7.48 (dd, j=13.0,7.4hz, 1h), 7.38-7.31 (m, 2h), 5.34-5.30 (m, 3h), 2.91 (dd, j =13.8,3.9hz, 1h), 2.58-2.50 (m, 1h), 1.14 (s, 3h), 1.10 (s, 3h), 1.04 (s, 3h), 0.95 (s, 3h), 0.94(s,3h),0.92(s,3h),0.57(s,3h)；13c nmr(150mhz,cdcl3)δ217.75,177.63,154.52, 152.03,143.65,130.31,130.23,125.26,125.22,124.80,122.32,117.18,116.99,57.32, 55.23,47.39,46.79,45.80,41.80,41.45,39.26,39.10,36.71,34.12,33.82,33.06, 32.37,32.15,31.93,30.68,29.71,29.66,29.37,27.63,26.53,25.68,23.59,23.43, 22.97,22.72,22.70,21.42,19.55,16.58,14.91,14.12；esi-ms(m/z):659.6[m+na]+.
Embodiment 9: oleanolic acid -3- ketone-[1 '-(4 "-nitrobenzophenone) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t9)
The compounds process for production thereof of embodiment 9, with embodiment 1, simply replaces aziminobenzene using p-nitrophenyl nitrine, Obtain white solid t9, yield 89.9%.
mp 85.7-88.2℃；1h nmr(600mhz,cdcl3) δ 8.16 (s, 1h), 8.15 (d, j=2.2hz, 2h), 7.90 (d, j=8.6hz, 2h), 5.34-5.30 (m, 3h), 2.90 (dd, j=13.8,4.0hz, 1h), 2.68 (s, 3h), 2.57-2.50(m,1h),2.40-2.34(m,1h),2.06-1.16(m,25h),1.14(s,3h),1.09(s,3h),1.02 (s,3h),0.94(s,3h),0.92(s,3h),0.91(s,3h),0.53(s,3h)；13c nmr(150mhz,cdcl3)δ 217.56,196.42,177.81,144.24,143.61,139.95,136.97,130.08,122.42,122.31,120.03, 57.22,55.22,47.38,46.80,46.76,45.77,41.80,41.47,39.25,39.09,36.69,34.09, 33.80,33.04,32.37,32.14,30.67,27.62,26.67,26.45,25.65,23.58,23.44,22.97, 21.42,19.50,16.64,14.88,14.12；esi-ms(m/z):679.6[m+na]+.Embodiment 10: oleanolic acid -3- Ketone-[1 '-(2 "-nitrobenzophenone) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester (t10)
The compounds process for production thereof of embodiment 10, with embodiment 1, simply replaces aziminobenzene using O-Nitrophenylfluorone nitrine, Obtain white solid t10, yield 87.5%.
mp 91.3-93.2℃；1h nmr(600mhz,cdcl3) δ 8.07 (s, 1h), 7.76 (d, 2h), 7.56 (t, j= 7.9hz, 2h), 7.47 (t, j=17.0,9.5hz, 1h), 5.44-5.24 (m, 3h), 4.15 (q, j=7.1hz, 1h), 2.91 (dd, j=13.8,4.2hz, 1h), 2.11-1.16 (m, 25h), 1.13 (s, 3h), 1.09 (s, 3h), 1.02 (s, 3h), 0.94 (s,3h),0.92(s,3h),0.91(s,3h),0.51(s,3h)；13c nmr(150mhz,cdcl3)δ217.73,177.78, 143.76,143.64,136.93,129.75,128.86,122.58,122.28,120.46,77.35,77.24,77.03, 76.72,60.39,57.32,55.19,47.37,46.77,46.75,45.78,41.78,41.47,39.23,39.08, 36.68,34.09,33.81,33.05,32.38,32.12,30.67,27.61,26.52,25.64,23.59,23.43, 22.94,21.39,19.51,16.63,14.88；esi-ms(m/z):679.6[m+na]+.
Embodiment 11: oleanolic acid -3- ketone-[1 '-(3 "-nitrobenzophenone) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] first Ester (t11)
The compounds process for production thereof of embodiment 11, with embodiment 1, simply replaces aziminobenzene using m-nitro base nitrine, Obtain 197.33mg white solid t11, yield 79.26%.
mp 153.9-156.7℃；1h nmr(600mhz,cdcl3) δ 8.61 (s, 1h), 8.35 (d, j=8.3hz, 1h), 8.20 (d, j=13.6hz, 2h), 7.79 (t, j=8.2hz, 1h), 5.35-5.29 (m, 3h), 2.91 (d, j=9.6hz, 1h), 2.57-2.51(m,1h),2.40-2.33(m,1h),2.20-1.17(m,38h),1.14(s,3h),1.09(s,3h),1.02 (s,3h),0.95(s,3h),0.92(s,3h),0.92(s,3h),0.54(s,3h)；13c nmr(150mhz,cdcl3)δ 217.56,177.85,148.98,144.57,143.59,137.65,131.02,125.93,123.30,122.62,122.35, 115.28,57.17,55.25,47.39,46.83,46.75,45.77,41.83,41.49,39.29,39.09,36.69, 34.10,33.81,33.03,32.40,32.17,31.93,30.67,29.70,29.66,29.36,27.63,26.42, 25.65,23.58,23.44,22.98,22.72,21.41,19.49,16.68,14.83,14.12；esi-ms(m/z):679.6 [m+na]+.
Embodiment 12: oleanolic acid -3- ketone-[1 '-(4 "-acetyl phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] first Ester (t12)
The compounds process for production thereof of embodiment 12, with embodiment 1, simply uses and replaces aziminobenzene to acetyl aziminobenzene, Obtain yellow solid t12, yield 89.0%.
mp 132.5-134.7℃；1h nmr(600mhz,cdcl3) δ 8.07 (s, 1h), 7.54 (ddd, j=8.8,8.2, 4.1hz, 3h), 7.20-7.17 (m, 1h), 5.34-5.26 (m, 3h), 4.24 (dd, j=11.5,5.9hz, 1h), 2.92-2.88 (m,1h),2.57-2.50(m,1h),2.40-2.34(m,1h),1.13(s,3h),1.09(s,3h),1.03(s,3h),0.94 (s,3h),0.92(s,6h),0.50(s,3h)；13c nmr(150mhz,cdcl3)δ217.69,177.80,144.02, 143.62,131.26,131.17,130.88,128.81,122.59,122.30,115.86,115.76,115.73,115.65, 108.43,108.17,68.16,57.22,55.21,47.38,46.78,46.74,45.77,41.78,41.47,39.24, 39.08,38.74,36.69,34.10,33.80,33.04,32.38,32.12,30.67,30.37,28.93,27.60, 26.48,25.63,23.75,23.58,23.42,22.99,22.94,21.38,19.49,16.65,14.85,14.05；esi- ms(m/z):676.7[m+na]+.
Embodiment 13: oleanolic acid -3- ketone-[1 '-(2 "-acetyl phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] first Ester (t13)
The compounds process for production thereof of embodiment 13, with embodiment 1, simply replaces aziminobenzene using adjacent acetyl aziminobenzene, Obtain white solid t13, yield 79.6%.
mp 96.5-98.2℃；1h nmr(600mhz,cdcl3) δ 8.14 (s, 1h), 7.94 (d, j=8.7hz, 2h), 7.88 (d, j=8.7hz, 2h), 5.33-5.29 (m, 3h), 2.90 (dd, j=13.6,3.8hz, 1h), 2.58-2.52 (m, 1h),1.14(s,3h),1.09(s,3h),1.03(s,3h),0.94(s,3h),0.94(s,3h),0.92(s,3h),0.53(s, 3h)；13c nmr(150mhz,cdcl3)δ217.47,177.84,144.55,143.57,139.69,133.92,122.32, 120.53,117.58,112.59,57.12,55.26,47.40,46.81,46.75,45.73,41.80,41.46,39.26, 39.10,36.69,34.10,33.77,33.02,32.36,32.15,30.66,29.69,27.61,26.38,25.66, 23.57,23.43,22.96,21.46,19.48,16.64,14.87；esi-ms(m/z):676.7[m+na]+.
Embodiment 14: oleanolic acid -3- ketone-[1 '-(3 "-acetyl phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] first Ester (t14)
The compounds process for production thereof of embodiment 14, with embodiment 1, simply replaces aziminobenzene using 3- acetyl aziminobenzene, Obtain white solid t14, yield 86.7%.
mp 70.2-73.1℃；1h nmr(600mhz,cdcl3) δ 8.30 (s, 1h), 8.16 (s, 1h), 8.04 (d, j= 8.2hz, 2h), 7.68 (t, j=7.9hz, 1h), 5.355.27 (m, 3h), 2.91 (dd, j=13.7,4.0hz, 1h), 2.70 (s,3h),2.55-2.49(m,1h),1.13(s,3h),1.08(s,3h),1.01(s,3h),0.94(s,3h),0.91(s, 3h),0.89(s,3h),0.52(s,3h；13c nmr(150mhz,cdcl3)δ217.72,196.44,177.78,144.12, 143.58,138.55,137.34,130.24,128.52,124.68,122.58,122.32,119.60,77.36,77.05, 76.73,57.26,55.18,47.36,46.78,46.74,45.76,41.79,41.47,39.24,39.07,36.67, 34.09,33.80,33.04,32.37,32.13,30.67,29.69,27.61,26.73,26.49,25.64,23.58, 23.42,22.95,21.39,19.50,16.64,14.86；esi-ms(m/z):676.7[m+na]+.
The pharmacological research of the synthetic product of the present invention
Human cervical carcinoma cell hela, human liver cancer cell hepg2, human colon cancer cell hct116, human melanoma cell A375-s2, human fibrosarcoma cell ht-1080 be purchased from american type culturecollection (atcc, Rockville, md, usa).Cell is seeded in containing in 10% hyclone, the rpmi-1640 culture fluid of 2% L-Glutamine, 37 DEG C, 5%co2Cultivate in incubator.
From the tumor cell of exponential phase, after pancreatin digestion, with the rpmil640 culture containing 10% calf serum Basigamy becomes 5 × 104The cell suspension of/ml, is seeded in 96 well culture plates, every hole 100 μ l, 37 DEG C, 5%co2Culture 24h.Experiment Organize the culture fluid containing variable concentrations sample more renewing, matched group then changes the culture fluid containing equal-volume solvent, and every group sets 3 Individual parallel hole, 37 DEG C, 5%co2Culture 48h.Abandoning supernatant, is carefully washed 2 times with pbs, and every hole adds 100 μ l freshly prepared Culture medium containing 0.5mg/ml mtt, 37 DEG C are continued culture 4h.Careful supernatant discarded, and add 150 μ l dmso, shaken with miniature After swinging device mixing 10min, measure optical density value at 492nm with microplate reader.
It is calculated as follows the suppression ratio of drug on tumor cell growth:
Growth of tumour cell suppression ratio (%)
=[a492(negative control)-a492(dosing group)]/a492(negative control) × 100%
Therefrom obtain the half-inhibition concentration (ic of sample50).
Inhibitory action ic to five kinds of human cancer cell in-vitro multiplications for the compound50(μm)
Data above discloses, and the compound of the brand new being obtained by the present invention, to human melanoma cell a375-s2 Specific inhibited proliferation can be produced with human fibrosarcoma cell ht-1080, and to human cervical carcinoma cell hela, human liver cancer Cell hepg2, human colon cancer cell hct116 etc. is insensitive.Thus embody the significant tumor of oleanolic acid -3- ketone derivatives Cell selective acts on, and has the potentiality for specific tumors medicine for the exploitation.

Claims (9)

1. the oleanolic acid derivate with antitumor action of the class shown in formula (i), and its optically active body, diastereomeric Isomer:
Wherein:
R is any one group in following groups: (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro, (5) c1-c4 Acyl group.
2. compound according to claim 1, and its optically active body, diastereomer, wherein,
R is (1) hydrogen atom, (2) halogen atom, (3) cyano group, (4) nitro, (5) acetyl group.
3. compound according to claim 1 and 2, and its optically active body, diastereomer,
Wherein,
R is hydrogen atom, fluorine atom, chlorine atom, bromine atoms, cyano group, nitro, acetyl group.
4. the compound described in claim 1-3 any one, and its optically active body, diastereomer, it is selected from:
T1: oleanolic acid -3- ketone-(1 '-phenyl -1h-1 ', 2 ', 3 '-triazole -4 '-yl) methyl ester,
T2: oleanolic acid -3- ketone-[1 '-(2 "-fluorophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T3: oleanolic acid -3- ketone-[1 '-(3 "-fluorophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T4: oleanolic acid -3- ketone-[1 '-(4 "-fluorophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T5: oleanolic acid -3- ketone-[1 '-(4 "-chlorphenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T6: oleanolic acid -3- ketone-[1 '-(4 "-bromophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T7: oleanolic acid -3- ketone-[1 '-(3 "-bromophenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T8: oleanolic acid -3- ketone-[1 '-(4 "-cyano-phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T9: oleanolic acid -3- ketone-[1 '-(4 "-nitrobenzophenone) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T10: oleanolic acid -3- ketone-[1 '-(2 "-nitrobenzophenone) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T11: oleanolic acid -3- ketone-[1 '-(3 "-nitrobenzophenone) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T12: oleanolic acid -3- ketone-[1 '-(4 "-acetyl phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T13: oleanolic acid -3- ketone-[1 '-(2 "-acetyl phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
T14: oleanolic acid -3- ketone-[1 '-(3 "-acetyl phenyl) -1h-1 ', 2 ', 3 '-triazole -4 '-yl] methyl ester,
Its structure is as follows:
5. compound described in claim 1 and its optically active body, the preparation method of diastereomer it is characterised in that:
The synthetic method of formula (i) compound is as follows:
In the water and dichloromethane mixed solution of potassium carbonate, with tetrabutyl ammonium bromide as phase transfer catalyst, oleanolic acid 1 with Propargyl bromide reaction obtains intermediate 2, and the c3 hydroxyl of intermediate 2 is obtained 3- ketone product 3 through Jones reagent oxidation, its again with various The aryl azide compound replacing is in tertiary butanol and water mixed solution, generated in-situ with sodium ascorbate by anhydrous cupric sulfate Cu (i) is catalyzed, and 1,3 Dipolar Cycloaddition occurs, obtains the compound of formula (i)；
Reaction equation is as follows:
Wherein, r is as claimed in claim 1.
6. a kind of pharmaceutical composition, comprises the compound described in claim 1-4 any one and its optically active body, diastereomeric Isomer and pharmaceutically acceptable carrier.
7. a kind of pharmaceutical preparation, comprises the compound described in claim 1-4 any one and its optically active body, and diastereomeric is different Pharmaceutical composition described in structure body or claim 6.
8. the compound described in claim 1-4 any one and its optically active body, diastereomer or claim 6 institute State pharmaceutical preparation described in pharmaceutical composition or claim 7 application in preparing antitumor drug.
9. the compound described in claim 1-4 any one and its optically active body, diastereomer or claim 6 institute State pharmaceutical preparation the answering in preparation treatment melanoma and fibrosarcoma medicine described in pharmaceutical composition or claim 7 With.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106967146A (en) * 2017-05-16 2017-07-21 烟台大学 Oleanolic acid terazole derivatives and its production and use
CN109232703A (en) * 2018-10-22 2019-01-18 郑州大学 Containing 16- (1 '-aromatic radical -1 ', 2 ', 3 '-triazoles) methylene-androstane -17- ketone derivatives
CN111961110A (en) * 2020-09-17 2020-11-20 昆明理工大学 Oleanolic acid C-3 sugar conjugate, preparation method thereof and application thereof in resisting influenza virus
CN114456225A (en) * 2022-02-11 2022-05-10 北京青颜博识健康管理有限公司 3 alpha-oleanolic acid derivative serving as hyaluronidase inhibitor and application of derivative in cosmetic products
CN114456225B (en) * 2022-02-11 2022-09-09 北京青颜博识健康管理有限公司 3 alpha-oleanolic acid derivative serving as hyaluronidase inhibitor and application of derivative in cosmetic product
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