CN105884856A - Application of tanshinone II A derivative in drugs - Google Patents
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Abstract
Tanshinone II A compounds are main lipid-soluble components of traditional Chinese medicine salviamiltiorrhiza btmge and have extensive pharmacological activity; the invention belongs to the technical fields of medicinal chemistry and drugs, and in particular, relates to the tanshinone II A derivatives (I), (II), (III) and (IV); the derivatives have good antitumor activity, and can be used for preparation of antitumor drugs.
Description
Technical field
The invention belongs to pharmaceutical chemistry and technical field of pharmaceuticals, be specifically related to class I tanshinone derivant, this analog derivative is the pharmaceutical composition of active component, its preparation method and this compounds and the medicinal application in tumor of the other drug compositions.
Background technology
Radix Salviae Miltiorrhizae (Salviamiltiorrhiza Btmge) belongs to Labiatae (Labiatae) Salvia (Salvia) plant.As Chinese medicine, Radix Salviae Miltiorrhizae has a wide range of applications in the area such as Chinese, Japanese, has the applicating history of nearly 2000, is the important goods in domestic and international medical material market.Radix Salviae Miltiorrhizae, calls Radix Salviae Miltiorrhizae, Radix Salviae Miltiorrhizae, Panax ginseng, is recorded in Eastern Han Dynasty's Shennong's Herbal the earliest, says: " main trusted subordinate's pathogen, borborygmus are faint such as leakes water, and cold and heat gather；Except abdominal mass, only excessive thirst, QI invigorating ", returned be classified as top grade.Due to Radix Salviae Miltiorrhizae extensively and significantly pharmacological action, in Japanese at the beginning of 20 generations in centurial year 60, tail swings the rivers such as mountain and begins to study the chemical composition of Radix Salviae Miltiorrhizae, and the main active of Radix Salviae Miltiorrhizae is fat-soluble diterpene quinone and water miscible phenol acid compounds.Both has resisting myocardial ischemia, increases coronary flow, improves cardiac function, antithrombotic and the regulation effect such as blood fat, antiinflammatory antioxidation, but emphasizes particularly on different fields.Water soluble ingredient is the most prominent with antioxidation etc., and fat soluble ingredient of red sage root acts on more notable with antibacterial, antiinflammatory, anticancer etc., and the multiformity of this effect Radix Salviae Miltiorrhizae just has the basis of extensive indication.
Tanshinone compound is the main liposoluble constituent of salviamiltiorrhizabung, has pharmacologically active widely, and wherein tanshinone ⅡA (TS) is the liposoluble constituent that in Radix Salviae Miltiorrhizae, content is the highest, is also assay material in pharmacopeia.At present, tanshinone ⅡA is used for the treatment in terms of cardiovascular and cerebrovascular disease, is seldom reported in the utilization in tumor and fat disease.
The whole world has millions of people to die from cancer every year at present, and new cases are also increasing year by year.China has million people to die from cancer every year, one of cancer ten big killers having become human health.
Summary of the invention
1. the tanshinone ⅡA derivant shown in formula (Ia) or its salt pharmacologically allowed,
Wherein R1For: H ,-halogen ,-OH ,-C=C-COOH ,-C=C-COO-C1-C5Alkyl ,-C=C-COO-aryl ,-C=C-COO-substituted aryl ,-C=C-COO-heteroaromatic ,-C=C-COO-replace heteroaromatic ,-CO-OC-C=C-COOH ,-CO-OC-C=C-COOC1-C5Alkyl ,-CO-OC-C=C-COO-aryl ,-CO-OC-C=C-COO-substituted aryl ,-C=C-COO-heteroaromatic ,-C=C-COO-replace heteroaromatic ,-CO-OC-(CH2)n、-CO-OC-(CH2) n-aryl ,-CO-OC-(CH2) n-substituted aryl ,-CO-OC-(CH2) n-heteroaromatic ,-CO-OC-(CH2) n-replaces heteroaromatic ,-CO-OC-(CH2) n-heterocyclic radical ,-CO-OC-(CH2) n-substituted heterocyclic radical ,-C=C-CONH ,-C=C-CON-C1-C5Alkyl ,-C=C-CON-(C1-C5Alkyl)2,-C=C-CON-aryl ,-C=C-CON-substituted aryl ,-C=C-CON-(aryl)2,-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C=C-CON-replace heteroaromatic ,-CO-OC-C=C-CONH ,-CO-OC-C=C-CON C1-C5Alkyl ,-CO-OC-C=C-CON (C1-C5Alkyl)2,-CO-OC-C=C-CON-aryl ,-CO-OC-C=C-CON-substituted aryl ,-CO-OC-C=C-CON-(aryl) 2 ,-CO-OC-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C-NO-C-(CH2)n、-C-NO-C-(CH2) n-aryl ,-C-NO-C-(CH2) n-substituted aryl ,-C-NO-C-(CH2) n-heteroaromatic ,-C-NO-C-(CH2) n-replaces heteroaromatic ,-C-NO-C-(CH2) n-heterocyclic radical ,-C-NO-C-(CH2) n-substituted heterocyclic radical ,-C-CN, wherein n is the integer of independent 0 to 5；
R2, R4 identical or different, each independently represent H, halogen, hydroxyl, carbonyl, amino, amide groups, aldehyde radical, heterocyclic radical ,-O-CO-(CH2)n-C1-C5Alkyl ,-O-CO-(CH2) n-aryl ,-O-CO-(CH2) n-substituted aryl ,-O-CO-(CH2) n-heteroaromatic ,-O-CO-(CH2) n-replaces heteroaromatic ,-O-CO-(CH2) n-heterocyclic radical ,-O-CO-(CH2) n-substituted heterocyclic radical ,-O-CO-(CH2)n-COOH、-O-CO-(CH2)n-COO-C1-C5Alkyl ,-O-CO-(CH2) n-COO-aryl ,-O-CO-(CH2) n-COO-substituted aryl ,-O-CO-(CH2) n-COO-heteroaromatic ,-O-CO-(CH2) n-COO-replaces heteroaromatic ,-O-CO-(CH2) n-COO-heterocyclic radical ,-O-CO-(CH2) n-COO-substituted heterocyclic radical ,-N-CO-(CH2)n-C1-C5Alkyl ,-N-CO-(CH2) n-aryl ,-N-CO-(CH2) n-substituted aryl ,-N-CO-(CH2) n-heteroaromatic ,-N-CO-(CH2) n-replaces heteroaromatic ,-N-CO-(CH2) n-heterocyclic radical ,-N-CO-(CH2) n-substituted heterocyclic radical ,-N-CO-(CH2)n-COOH、-N-CO-(CH2)n-COO-C1-C5Alkyl ,-N-CO-(CH2) n-COO-aryl ,-N-CO-(CH2) n-COO-substituted aryl ,-N-CO-(CH2) n-COO-heteroaromatic ,-N-CO-(CH2) n-COO-replaces heteroaromatic ,-N-CO-(CH2) n-COO-heterocyclic radical ,-N-CO-(CH2) n-COO-substituted heterocyclic radical, wherein n is the integer of independent 1 to 5；
R3For: H, halogen, hydroxyl, amino ,-NH-C1-C5Alkyl ,-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, heterocyclic radical；
C1、C2Form singly-bound or double bond；
Described tanshinone ⅡA derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine；
Described-(CH2) n-refers to straight or branched alkane or cycloalkane.
2. the tanshinone ⅡA derivant shown in formula (Ib) or its salt pharmacologically allowed,
Wherein R1For: H ,-halogen ,-OH ,-CO-OC-C=C-COOH ,-CO-OC-C=C-COO C1-C5Alkyl ,-CO-OC-C=C-COO-aryl ,-CO-OC-C=C-COO-substituted aryl ,-CO-OC-C=C-COO-heteroaromatic ,-CO-OC-C=C-COO-replace heteroaromatic ,-CO-OC-C=C-COO-heterocyclic radical ,-CO-OC-C=C-COO-substituted heterocyclic radical ,-CO-OC-(CH2)n、-CO-OC-(CH2) n-aryl ,-CO-OC-(CH2) n-substituted aryl ,-CO-OC-(CH2) n-heteroaromatic ,-CO-OC-(CH2) n-replaces heteroaromatic ,-CO-OC-(CH2) n-heterocyclic radical ,-CO-OC-(CH2) n-substituted heterocyclic radical ,-C=C-CONH ,-C=C-CON-C1-C5Alkyl ,-C=C-CON-(C1-C5Alkyl)2,-C=C-CON-aryl ,-C=C-CON-substituted aryl ,-C=C-CON-(aryl)2,-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C=C-CON-replace heteroaromatic ,-CO-OC-C=C-CONH ,-CO-OC-C=C-CON C1-C5Alkyl ,-CO-OC-C=C-CON (C1-C5Alkyl)2,-CO-OC-C=C-CON-aryl ,-CO-OC-C=C-CON-substituted aryl ,-CO-OC-C=C-CON-(aryl)2,-CO-OC-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C=C-CON-replace heteroaromatic ,-C-NO-C-(CH2)n、-C-NO-C-(CH2) n-aryl ,-C-NO-C-(CH2) n-substituted aryl ,-C-NO-C-(CH2) n-heteroaromatic ,-C-NO-C-(CH2) n-replaces heteroaromatic ,-C-NO-C-(CH2) n-heterocyclic radical ,-C-NO-C-(CH2) n-substituted heterocyclic radical ,-C-CN, wherein n is the integer of independent 0 to 5；
R2, R4 identical or different, each independently represent H, halogen, hydroxyl, carbonyl, amino, amide groups, aldehyde radical, heterocyclic radical ,-O-CO-(CH2)n-C1-C5Alkyl ,-O-CO-(CH2) n-aryl ,-O-CO-(CH2) n-substituted aryl ,-O-CO-(CH2) n-heteroaromatic ,-O-CO-(CH2) n-replaces heteroaromatic ,-O-CO-(CH2) n-heterocyclic radical ,-O-CO-(CH2) n-substituted heterocyclic radical ,-O-CO-(CH2)n-COOH、-O-CO-(CH2)n-COO-C1-C5Alkyl ,-O-CO-(CH2) n-COO-aryl ,-O-CO-(CH2) n-COO-substituted aryl ,-O-CO-(CH2) n-COO-heteroaromatic ,-O-CO-(CH2) n-COO-replaces heteroaromatic ,-O-CO-(CH2) n-COO-heterocyclic radical ,-O-CO-(CH2) n-COO-substituted heterocyclic radical ,-N-CO-(CH2)n-C1-C5Alkyl ,-N-CO-(CH2) n-aryl ,-N-CO-(CH2) n-substituted aryl ,-N-CO-(CH2) n-heteroaromatic ,-N-CO-(CH2) n-replaces heteroaromatic ,-N-CO-(CH2) n-heterocyclic radical ,-N-CO-(CH2) n-substituted heterocyclic radical ,-N-CO-(CH2)n-COOH、-N-CO-(CH2)n-COO-C1-C5Alkyl ,-N-CO-(CH2) n-COO-aryl ,-N-CO-(CH2) n-COO-substituted aryl ,-N-CO-(CH2) n-COO-heteroaromatic ,-N-CO-(CH2) n-COO-replaces heteroaromatic ,-N-CO-(CH2) n-COO-heterocyclic radical ,-N-CO-(CH2) n-COO-substituted heterocyclic radical, wherein n is the integer of independent 1 to 5；
R3For: H, halogen, hydroxyl, carbonyl, amino ,-NH-C1-C5Alkyl ,-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, heterocyclic radical；
C1、C2Form singly-bound or double bond；
Described tanshinone ⅡA derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine；
Described-(CH2) n-refers to straight or branched alkane or cycloalkane.
3. the tanshinone ⅡA derivant shown in formula (Ic) or its salt pharmacologically allowed,
Wherein, R1、R2、R3Identical or different, each independently represent H, halogen, hydroxyl, amino ,-NH-C1-C5Alkyl ,-N-(C1-C5Alkyl)2、-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, carboxyl ,-CONH-C1-C5Alkyl ,-CON-(C1-C5Alkyl)2,-CONH-aryl ,-CONH-substituted aryl ,-CON-(aryl)2,-CON-(substituted aryl)2,-CONH-heteroaromatic ,-CONH-replace heteroaromatic ,-CO-heterocyclic radical, heterocyclic radical, oxyl；
C1、C2Form singly-bound or double bond；
Described tanshinone ⅡA derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine；
4. the tanshinone ⅡA derivant shown in formula (Id) or its salt pharmacologically allowed,
Wherein, R1、R2、R3Identical or different, each independently represent H, halogen, hydroxyl, amino ,-NH-C1-C5Alkyl ,-N-(C1-C5Alkyl)2、-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, carboxyl ,-CONH-C1-C5Alkyl ,-CON-(C1-C5Alkyl)2,-CONH-aryl ,-CONH-substituted aryl ,-CON-(aryl)2,-CON-(substituted aryl)2,-CONH-heteroaromatic ,-CONH-replace heteroaromatic ,-CO-heterocyclic radical, heterocyclic radical, oxyl；
C1、C2Form singly-bound or double bond；
Described tanshinone ⅡA derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine；
5. the tanshinone ⅡA derivant as described in any one of claim 1,2 or 3 or its salt pharmacologically allowed application in preparing antitumor drug.
6. pharmaceutical composition, wherein contains tanshinone ⅡA derivant or its salt pharmacologically allowed of any one of claim 1,2,3 or 4 of therapeutically effective amount.
The english abbreviation implication related in the present invention is as follows:
SeO2(selenium dioxide), TEA (triethylamine), DMF (N, dinethylformamide), DCM (dichloromethane), DMAP (4-N, N-dimethylamino naphthyridine), PDC (Pyridinium dichromate), NSB (N-bromosuccinimide)
Accompanying drawing explanation
Fig. 1 is the compound reacting flow chart for formula Ia；Reagent and reaction condition be: a) Br2, HBr, DCM, RT；B) Methyl acrylate/EthylAcrylate/ButylAcrylate, TEA, Palladium acetate, Triphenyl phosphine, DMF, 100 DEG C；C) HCl, EtOH, RT；d)SOCl2, methylamine/N-methyl piperazine, DCM, RT；E) TEA, Palladium acetate, Triphenyl phosphine, DMF, 100 DEG C；F) SeO2, CN3CN, 44 DEG C；G) butenedioic anhydride, TEA, DMAP, DCM, RT；H) HCOH, Acetic Acid, CN3CN, 70 DEG C；I) cis-butenedioic anhydride, TEA, DMAP, DCM, RT；j)SOCl2, morpholine, DCM, RT；
Fig. 2 is the compound reacting flow chart for formula Ib；Reagent and reaction condition be: a) SeO2, dioxane, 90 DEG C；B) PDC, DCM, RT；C) Jones, acetone, RT；d)SOCl2, DEA/morpholine, DCM, RT；E) butenedioic anhydride, TEA, DMAP, DCM, RT；f)SOCl2, DEA/morpholine, DCM, RT；G) NBS, CCl4, THF, H2O, K2CO3, Reflux；H) cis-butenedioic anhydride, TEA, DMAP, DCM, RT；
Fig. 3 is the compound reacting flow chart for formula Ic and Id.Reagent and reaction condition be: a) Br2, HBr, DCM, RT；B) Ethylenediamine/morpholine/Imidazole, DCM, RT；C) NBS, CCl4, THF, H2O, K2CO3, Reflux；D) Benzoic Acid/butenedioic anhydride, TEA, DMAP, DCM, RT；E) BPO, CN3CN, Reflux；F) HCl, EtOH, RT；
Detailed description of the invention
Present disclosure is described in further detail by the embodiment below by way of specific embodiment.But embodiment should be interpreted as limitation of the present invention.In the case of without departing from the appeal thought of the present invention, the various replacement means made according to ordinary skill knowledge and conventional means or change, within being all contained in the present invention.
Embodiment 1
The preparation of compound 3,5,7
580mg (2mmol) tanshinone ⅡA is dissolved in 20mL dichloromethane, adds 0.5mL hydrobromic acid, adds 0.15mL (1.95mmol) bromine, lucifuge reaction 30min.After reaction stops, adding bisulfite saturated aqueous solution of sodium 30mL, stir 10min, washing, anhydrous sodium sulfate is dried.Column chromatography purification (PE: EA=36: 1), obtains compound 1.EI/MS (m/z): 372 (M+)。
220mg (0.75mmol) compound 1 is dissolved in 22mLDMF, add 0.3mL triethylamine (2.3mmol), 0.16mL (1.5mmol) ethyl acrylate, 38mg (0.15mol) triphenyl phosphorus, 17mg (0.075mmol) palladium, heat 100 DEG C of reaction 8h, after reaction terminates, sucking filtration, obtain filtrate, add 20mLEA, washing, anhydrous Na2SO4It is dried.Column chromatography purification (PE: EA=24: 1), obtains compound 3.1H NMR (300MHz, CDCl3): 1.32 (9H, m, CH3), 1.65 (2H, m, CH2), 1.87 (2H, m, CH2), 2.41 (3H, s, CH3), 3.21, (2H, t, CH2), 4.30 (2H, q, CH2), 6.46 (1H, d, CH, 7.52 (1H, d, CH), 7.67 (2H, dd, Ar) .ESI/MS (m/z): 393 [M+H].
390mg (1mmol) compound 3 is dissolved in 100ml ethanol, adds 6ml (5mmol) sodium hydroxide of 5%, 3h is stirred at room temperature, after reaction terminates, is concentrated in vacuo, add 20ml water dissolution, adjust PH to 4, and sucking filtration obtains compound 5.1H NMR (300MHz, CDCl3): 1.31 (6H, m, CH3), 1.64 (2H, m, CH2), 1.87 (2H, m, CH2), 2.41 (3H, s, CH3), 3.21, (2H, t, CH2), 6.46 (1H, d, CH, 7.52 (1H, d, CH), 7.67 (2H, dd, Ar), 11.2 (1H, s, COOH) .ESI/MS (m/z): 363 [M-].
365mg (1mmol) compound 5 is dissolved in 20ml anhydrous methylene chloride, add 0.22ml (3mmol) thionyl chloride, 1h is stirred at room temperature, it is concentrated in vacuo, add 20ml anhydrous methylene chloride, 120mg (1.2mmol) N methyl piperazine, 0.42ml (3mmol) triethylamine, 3h column chromatography purification (PE: EA=2: 1) is stirred at room temperature and obtains compound 7.1H NMR (300MHz, CDCl3): 1.31 (6H, m, CH3), 1.64 (2H, m, CH2), 1.87 (2H, m, CH2), 2.31 (4H, m, CH2) 2.41 (6H, m, CH3), 3.21, (2H, t, CH2), 3.54 (4H, m, CH2) 6.46 (1H, d, CH, 7.52 (1H, d, CH), 7.67 (2H, dd, Ar), 11.2 (1H, s, COOH) .ESI/MS (m/z): 347 [M+H].
Embodiment 2
The preparation of compound 10
372mg (1mmol) compound 1 is dissolved in 20mLDMF, add 0.3mL triethylamine (2.3mmol), 380mg (1.5mol) triphenyl phosphorus, 170mg (0.75mmol) palladium, heat 100 DEG C of reaction 16h to be spin-dried for, add water 30mL, DCM extraction, washing, anhydrous Na2SO4It is dried.Column chromatography purification (PE/EA=36: 1), obtains compound 8.
140mg (0.38mmol) compound 4 is dissolved in 15ml acetonitrile, and heated and stirred, to dissolving, adds selenium dioxide, and oil bath is warming up to 44 DEG C of heating reflux reaction 10h, it is cooled to room temperature, sucking filtration, obtains filtrate, 20ml 5%NaOH solution is washed 3 times, and brine washs, anhydrous Na2SO4It is dried.Column chromatography purification (PE/EA=12: 1), obtains compound 9.
31mg (0.1mmol) compound 5 is dissolved in 4mL dichloromethane, adds 15mg (0.15mmol) maleic anhydride, 0.03mL (0.3mmol) triethylamine, catalytic amount DMAP, 22h, stopped reaction are stirred at room temperature.Column chromatography purification (DCM: MeOH=10: 1), obtains compound 10.IR(KBr)vmax(cm-1): 3411043,3004.62,2559.39,2926.28,2868.62,1758.60,1677.62,1650.30,1573.60,1677.62,1650.30,1573.76,1455046,1275.62,1260.54,1202.72,1167.15,1095.84,767.38,759.58,748.76,741.83,705.07.1H NMR (300MHz, DMSO-D6): 1.30 (3H, m, CH3), 1.42 (3H, m, CH3), 2.18 (2H, m, CH2), 2.51 (3H, s, CH3), 2.66 (2H, m, CH2), 5.21 (1H, t, CH), 5.56 (1H, d, CH), 6.46 (1H, d, CH), 7.67 (2H, t, Ar), 7.82 (1H, d, CH) .ESI/MS (m/z): 407 [M-H].
Embodiment 3
The preparation of compound 12
117mg (0.4mmol) tanshinone ⅡA is dissolved in 10mL acetonitrile, adds 1.2mL (4.4mmol) formaldehyde .70 DEG C of back flow reaction 30min of 1d acetic acid, column chromatography purification (PE: EA=36: 1), obtains compound 11.1H NMR (300MHz, CDCl3): 1.32 (6H, s, CH3), 1.65 (2H, m, CH2), 1.77 (2H, m, CH2), 2.31 (3H, s, CH3), 3.19 (2H, t, CH2), 4.65 (2H, s, CH2), 7.63 (2H, dd, Ar).
65mg (0.2mmol) compound 11 is dissolved in 8mL dichloromethane, adds 60mg (0.6mmol) maleic anhydride, 0.1mL (0.6mmol) triethylamine, 12h, stopped reaction are stirred at room temperature.Column chromatography purification (PE: EA=1: 2), obtains compound 12.(KBr)vmax(cm-1): 2933.53,2737.67,2675.96,2491.11,1573.67,1475.38,1384.59,1275.40,1260.65,1192.28,875.61,864.02.1H NMR (300MHz, DMSO-D6): 1.32 (6H, s, CH3), 1.65 (2H, m, CH2), 1.77 (2H, m, CH2), 2.21 (3H, s, CH3), 3.18 (2H, t, CH2), 5.15 (2H, s, CH2), 5.56 (1H, d, CH), 6.76 (1H, d, CH), 7.81 (1H, d, Ar), 7.16 (1H, d, Ar) .ESI/MS (m/z): 421 [M-H].
Embodiment 4
The preparation of compound 18,20
1g (3.4mmol) tanshinone ⅡA is dissolved in 60ml dioxane, heated and stirred, to dissolving, adds selenium dioxide, and oil bath is warming up to 90 DEG C of heating reflux reaction 3h, it is cooled to room temperature, concentration is spin-dried for, and adds 60mlEA and dissolves, sucking filtration, obtain filtrate, 50ml 5%NaOH solution * 3 wherein, saturated aqueous common salt washs, anhydrous Na2SO4It is dried.Column chromatography purification (PE: EA=8: 1), obtains compound 13.1H NMR (300MHz, CDCl3): 1.18 (6H, s, CH3), 1.60 (2H, m, CH2), 1.72 (2H, m, CH2), 3.11 (2H, t, CH2, C-1), 4.60 (2H, s, CH2, C-18), 7.18 (1H, d, Ar), 7.51 (1H, d, Ar), 7.60 (1H, d, Ar).
100mg (0.32mmol) compound 13 is dissolved in 8mL dichloromethane, adds 48mg (0.32mmol) succinic anhydride, 0.08mL (1.64mmol) triethylamine, 6h, stopped reaction are stirred at room temperature.Column chromatography purification (PE: EA=1: 4), obtains compound 18.ESI-HRMS calcd for C23H22O7: 410.1366 found:m/z:411.1438 [M+H]+。
41mg (0.1mmol) compound 18 is dissolved in 4ml dichloromethane, adding 1.5ml thionyl chloride, room temperature reaction 3h, after reaction terminates, extract the thionyl chloride of remnants, add 4mL dichloromethane, 0.25mL morpholine, room temperature reaction 4h, add 15mL water, dichloromethane extracts, washing, anhydrous Na2SO4It is dried.Column chromatography purification (PE: EA=1: 4), obtains compound 20.IR(KBr)vmax(cm-1): 3414.57,3127.25,1740.35,1672.79,1638.16,1818.30,1400.63,1155.28.1H NMR (300MHz, CDCl3): 1.32 (6H, s, CH3), 1.65 (2H, m, CH2), 1.77 (2H, m, CH2), 2.63 (2H, t, CH2), 2.69, (2H, t, CH2), 3.10 (2H, t, CH2, C-1), 3.45-3.66 (8H, m, CH2), 5.26 (2H, s, CH2, C-18), 7.52 (1H, s, Ar), 7.55 (1H, d, Ar), 7.63 (1H, d, Ar) .ESI/MS (m/z): 480 [M+H], 502 [M+Na].
Embodiment 5
The preparation of compound 22
294mg (1mmol) tanshinone ⅡA is dissolved in 20mL carbon tetrachloride, 120mgNBS, and nitrogen is protected, heating reflux reaction 1h, stopped reaction, concentrates, and adds 15mlTHF, 45mL water, 100mg sodium bicarbonate, heating reflux reaction 4h.Concentrating, dichloromethane extracts, washing, anhydrous Na2SO4It is dried.Column chromatography purification (PE/EA=12: 1), obtains compound 21.
31mg (0.1mmol) compound 21 is dissolved in 4mL dichloromethane, adds 15mg (0.15mmol) maleic anhydride, 0.03mL (0.3mmol) triethylamine, catalytic amount DMAP, 22h, stopped reaction are stirred at room temperature.Column chromatography purification (DCM: MeOH=10: 1), obtains compound 22.IR(KBr)vmax(cm-1): 3411043,3004.62,2559.39,2926.28,2868.62,1758.60,1677.62,1650.30,1573.60,1677.62,1650.30,1573.76,1455046,1275.62,1260.54,1202.72,1167.15,1095.84,767.38,759.58,748.76,741.83,705.07.1H NMR (300MHz, DMSO-D6): 1.30 (3H, m, CH3), 1.42 (3H, m, CH3), 2.18 (2H, m, CH2), 2.51 (3H, s, CH3), 2.66 (2H, m, CH2), 5.21 (1H, t, CH), 5.56 (1H, d, CH), 6.46 (1 H, d, CH), 7.67 (2H, t, Ar), 7.82 (1H, d, CH) .ESI/MS (m/z): 407 [M-H].
Embodiment 6
The preparation of compound 24
31mg (0.1mmol) compound 11 is dissolved in 4mL dichloromethane, adds bromine 0.05ml bromine, 1h, stopped reaction is stirred at room temperature, adds bisulfite saturated aqueous solution of sodium 30mL, stirs 10min, and washing, anhydrous sodium sulfate is dried.Column chromatography purification (PE/EA=12: 1), obtains compound 24.1HNMR (300MHz, CDCl3): 1.30 (6H, s, CH3), 1.66 (2H, m, CH2), 1.77 (2H, m, CH2), 3.17 (2H, t, CH2), 4.60 (2H, s, CH2), 4.69 (2H, s, CH2), 7.61 (1H, d, Ar), 7.66 (1H, d, Ar).
Embodiment 7
The preparation of compound 31,32
294mg (1mmol) tanshinone ⅡA is dissolved in 20mL acetonitrile, adds 850mgBPO, back flow reaction 6h, stopped reaction, column chromatography purification (PE/EA=12: 1), obtains compound 23.1H NMR (300MHz, CDCl3): 1.32 (6H, s, CH3), 1.65 (2H, m, CH2), 1.77 (2H, m, CH2), 2.13 (3H, s, CH3), 3.19, (2H, t, CH2), 5.23 (2H, s, CH2), 7.52 (1H, d, Ar), 7.58 (1H, d, Ar) .ESI/MS (m/z): 334 [M+H].
294mg (1mmol) tanshinone ⅡA is dissolved in 20mL acetonitrile, adds 850mgBPO, back flow reaction 6h, stopped reaction, column chromatography purification (PE/EA=12: 1), 31 obtain compound 1H NMR (300MHz, CDCl3): 1.32 (6H, s, CH3), 1.65 (2H, m, CH2), 1.77 (2H, m, CH2), 2.13 (3H, s, CH3), 3.19, (2H, t, CH2), 7.58 (15H, d, Ar).
66mg (0.1mmol) is dissolved in 20mL ethanol, adds the hydrochloric acid 10ml of 5%, 3h is stirred at room temperature, and concentrates, and adds 20mlEA, washing, anhydrous Na2SO4It is dried.Column chromatography purification (PE/EA=12: 1), obtains compound 32.1H NMR (300MHz, CDCl3): 1.32 (6H, s, CH3), 1.65 (2H, m, CH2), 1.77 (2H, m, CH2), 2.31 (3H, s, CH3), 3.19 (2H, t, CH2).
Embodiment 8
The anti-tumor activity test of part of compounds
The tumor cell (A549, MCF-7, LnCaP) carrying out testing being in cell log trophophase is inoculated in 96 well culture plates by certain cell concentration, adding sieved sample (can directly add after suspension cell fishplate bar) after cultivating 24h, cell is at 37 DEG C of 5%CO2Under the conditions of continue to cultivate after 48 hours, add MTT and continue to cultivate 4 hours, be dissolved under microplate reader with DMSO and detect.
Testing result such as following table:
Claims (6)
1. the Tanshinone I I A derivant shown in formula (I a) or its salt pharmacologically allowed,
Wherein R1For: H ,-halogen ,-OH ,-C=C-COOH ,-C=C-COO-C1-C5Alkyl ,-C=C-COO-aryl ,-C=C-COO-substituted aryl ,-C=C-COO-heteroaromatic ,-C=C-COO-replace heteroaromatic ,-CO-OC-C=C-COOH ,-CO-OC-C=C-COO C1-C5Alkyl ,-CO-OC-C=C-COO-aryl ,-CO-OC-C=C-COO-substituted aryl ,-C=C-COO-heteroaromatic ,-C=C-COO-replace heteroaromatic ,-CO-OC-(CH2)n、-CO-OC-(CH2) n-aryl ,-CO-OC-(CH2) n-substituted aryl ,-CO-OC-(CH2) n-heteroaromatic ,-CO-OC-(CH2) n-replaces heteroaromatic ,-CO-OC-(CH2) n-heterocyclic radical ,-CO-OC-(CH2) n-substituted heterocyclic radical ,-C=C-CONH ,-C=C-CON-C1-C5Alkyl ,-C=C-CON-(C1-C5Alkyl)2,-C=C-CON-aryl ,-C=C-CON-substituted aryl ,-C=C-CON-(aryl)2,-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C=C-CON-replace heteroaromatic ,-CO-OC-C=C-CONH ,-CO-OC-C=C-CON C1-C5Alkyl ,-CO-OC-C=C-CON (C1-C5Alkyl)2,-CO-OC-C=C-CON-aryl ,-CO-OC-C=C-CON-substituted aryl ,-CO-OC-C=C-CON-(aryl)2,-CO-OC-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C-NO-C-(CH2)n、-C-NO-C-(CH2) n-aryl ,-C-NO-C-(CH2) n-substituted aryl ,-C-NO-C-(CH2) n-heteroaromatic ,-C-NO-C-(CH2) n-replaces heteroaromatic ,-C-NO-C-(CH2) n-heterocyclic radical ,-C-NO-C-(CH2) n-substituted heterocyclic radical ,-C-CN, wherein n is the integer of independent 0 to 5；
R2, R4 identical or different, each independently represent H, halogen, hydroxyl, carbonyl, amino, amide groups, aldehyde radical, heterocyclic radical ,-O-CO-(CH2)n-C1-C5Alkyl ,-O-CO-(CH2) n-aryl ,-O-CO-(CH2) n-substituted aryl ,-O-CO-(CH2) n-heteroaromatic ,-O-CO-(CH2) n-replaces heteroaromatic ,-O-CO-(CH2) n-heterocyclic radical ,-O-CO-(CH2) n-substituted heterocyclic radical ,-O-CO-(CH2)n-COOH、-O-CO-(CH2)n-COO-C1-C5Alkyl ,-O-CO-(CH2) n-COO-aryl ,-O-CO-(CH2) n-COO-substituted aryl ,-O-CO-(CH2) n-COO-heteroaromatic ,-O-CO-(CH2) n-COO-replaces heteroaromatic ,-O-CO-(CH2) n-COO-heterocyclic radical ,-O-CO-(CH2) n-COO-substituted heterocyclic radical ,-N-CO-(CH2)n-C1-C5Alkyl ,-N-CO-(CH2) n-aryl ,-N-CO-(CH2) n-substituted aryl ,-N-CO-(CH2) n-heteroaromatic ,-N-CO-(CH2) n-replaces heteroaromatic ,-N-CO-(CH2) n-heterocyclic radical ,-N-CO-(CH2) n-substituted heterocyclic radical ,-N-CO-(CH2)n-COOH、-N-CO-(CH2)n-COO-C1-C5Alkyl ,-N-CO-(CH2) n-COO-aryl ,-N-CO-(CH2) n-COO-substituted aryl ,-N-CO-(CH2) n-COO-heteroaromatic ,-N-CO-(CH2) n-COO-replaces heteroaromatic ,-N-CO-(CH2) n-COO-heterocyclic radical ,-N-CO-(CH2) n-COO-substituted heterocyclic radical, wherein n is the integer of independent 1 to 5；
R3For: H, halogen, hydroxyl, amino ,-NH-C1-C5Alkyl ,-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, heterocyclic radical；
C1、C2Form singly-bound or double bond；
Described Tanshinone I I A derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine；
Described-(CH2) n-refers to straight or branched alkane or cycloalkane.
2. the Tanshinone I I A derivant shown in formula (I b) or its salt pharmacologically allowed,
Wherein R1For: H ,-halogen ,-OH ,-CO-OC-C=C-COOH ,-CO-OC-C=C-COO C1-C5Alkyl ,-CO-OC-C=C-COO-aryl ,-CO-OC-C=C-COO-substituted aryl ,-CO-OC-C=C-COO-heteroaromatic ,-CO-OC-C=C-COO-replace heteroaromatic ,-CO-OC-C=C-COO-heterocyclic radical ,-CO-OC-C=C-COO-substituted heterocyclic radical ,-CO-OC-(CH2)n、-CO-OC-(CH2) n-aryl ,-CO-OC-(CH2) n-substituted aryl ,-CO-OC-(CH2) n-heteroaromatic ,-CO-OC-(CH2) n-replaces heteroaromatic ,-CO-OC-(CH2) n-heterocyclic radical ,-CO-OC-(CH2) n-substituted heterocyclic radical ,-C=C-CONH ,-C=C-CON-C1-C5Alkyl ,-C=C-CON-(C1-C5Alkyl)2,-C=C-CON-aryl ,-C=C-CON-substituted aryl ,-C=C-CON-(aryl)2,-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C=C-CON-replace heteroaromatic ,-CO-OC-C=C-CONH ,-CO-OC-C=C-CON C1-C5Alkyl ,-CO-OC-C=C-CON (C1-C5Alkyl)2,-CO-OC-C=C-CON-aryl ,-CO-OC-C=C-CON-substituted aryl ,-CO-OC-C=C-CON-(aryl)2,-CO-OC-C=C-CON-(substituted aryl)2,-C=C-CON-heteroaromatic ,-C=C-CON-replace heteroaromatic ,-C-NO-C-(CH2)n、-C-NO-C-(CH2) n-aryl ,-C-NO-C-(CH2) n-substituted aryl ,-C-NO-C-(CH2) n-heteroaromatic ,-C-NO-C-(CH2) n-replaces heteroaromatic ,-C-NO-C-(CH2) n-heterocyclic radical ,-C-NO-C-(CH2) n-substituted heterocyclic radical ,-C-CN, wherein n is the integer of independent 0 to 5；
R2, R4 identical or different, each independently represent H, halogen, hydroxyl, carbonyl, amino, amide groups, aldehyde radical, heterocyclic radical ,-O-CO-(CH2)n-C1-C5Alkyl ,-O-CO-(CH2) n-aryl ,-O-CO-(CH2) n-substituted aryl ,-O-CO-(CH2) n-heteroaromatic ,-O-CO-(CH2) n-replaces heteroaromatic ,-O-CO-(CH2) n-heterocyclic radical ,-O-CO-(CH2) n-substituted heterocyclic radical ,-O-CO-(CH2)n-COOH、-O-CO-(CH2)n-COO-C1-C5Alkyl ,-O-CO-(CH2) n-COO-aryl ,-O-CO-(CH2) n-COO-substituted aryl ,-O-CO-(CH2) n-COO-heteroaromatic ,-O-CO-(CH2) n-COO-replaces heteroaromatic ,-O-CO-(CH2) n-COO-heterocyclic radical ,-O-CO-(CH2) n-COO-substituted heterocyclic radical ,-N-CO-(CH2)n-C1-C5Alkyl ,-N-CO-(CH2) n-aryl ,-N-CO-(CH2) n-substituted aryl ,-N-CO-(CH2) n-heteroaromatic ,-N-CO-(CH2) n-replaces heteroaromatic ,-N-CO-(CH2) n-heterocyclic radical ,-N-CO-(CH2) n-substituted heterocyclic radical ,-N-CO-(CH2)n-COOH、-N-CO-(CH2)n-COO-C1-C5Alkyl ,-N-CO-(CH2) n-COO-aryl ,-N-CO-(CH2) n-COO-substituted aryl ,-N-CO-(CH2) n-COO-heteroaromatic ,-N-CO-(CH2) n-COO-replaces heteroaromatic ,-N-CO-(CH2) n-COO-heterocyclic radical ,-N-CO-(CH2) n-COO-substituted heterocyclic radical, wherein n is the integer of independent 1 to 5；
R3For: H, halogen, hydroxyl, carbonyl, amino ,-NH-C1-C5Alkyl ,-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, heterocyclic radical；
C1、C2Form singly-bound or double bond；
Described Tanshinone I I A derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine；
Described-(CH2) n-refers to straight or branched alkane or cycloalkane.
3. the Tanshinone I I A derivant shown in formula (I c) or its salt pharmacologically allowed,
Wherein, R1、R2、R3Identical or different, each independently represent H, halogen, hydroxyl, amino ,-NH-C1-C5Alkyl ,-N-(C1-C5Alkyl)2、-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, carboxyl ,-CONH-C1-C5Alkyl ,-CON-(C1-C5Alkyl)2,-CONH-aryl ,-CONH-substituted aryl ,-CON-(aryl)2,-CON-(substituted aryl)2,-CONH-heteroaromatic ,-CONH-replace heteroaromatic ,-CO-heterocyclic radical, heterocyclic radical, oxyl；
C1、C2Form singly-bound or double bond；
Described tanshinone ⅡA derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine.
4. the Tanshinone I I A derivant shown in formula (I d) or its salt pharmacologically allowed,
Wherein, R1、R2、R3Identical or different, each independently represent H, halogen, hydroxyl, amino ,-NH-C1-C5Alkyl ,-N-(C1-C5Alkyl)2、-NHCO-C1-C5Alkyl ,-NHCO-heteroaromatic, aldehyde radical, carboxyl ,-CONH-C1-C5Alkyl ,-CON-(C1-C5Alkyl)2,-CONH-aryl ,-CONH-substituted aryl ,-CON-(aryl)2,-CON-(substituted aryl)2,-CONH-heteroaromatic ,-CONH-replace heteroaromatic ,-CO-heterocyclic radical, heterocyclic radical, oxyl；
C1、C2Form singly-bound or double bond；
Described Tanshinone I I A derivant, described C1-C5Alkyl refer to methyl, ethyl, have optically active or without optically active propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, cyclopenta；
Described aryl refers to the aromatic ring functional group containing 5-10 atom, includes but not limited to phenyl, naphthyl, furyl, thiazolyl, thienyl, imidazole radicals, oxazolyl, quinolyl, indyl；
Described halogen refers to fluorine, chlorine, bromine, iodine；
Described heteroaromatic refers to the heterocycle functional group of 5-10 atom, includes but not limited to morpholine, piperazine, methyl piperazine, piperidines, pyridine, pyrazine.
5. the Tanshinone I I A derivant as described in any one of claim 1,2 or 3 or its salt pharmacologically allowed application in preparing antitumor drug.
6. pharmaceutical composition, wherein contains Tanshinone I I A derivant or its salt pharmacologically allowed of any one of claim 1,2,3 or 4 of therapeutically effective amount.
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| CN106810593A (en) * | 2016-12-26 | 2017-06-09 | 郑州大学 | A kind of bit esterified derivative of tanshinone compound 17 and its preparation technology and application |
| CN107698652A (en) * | 2017-09-28 | 2018-02-16 | 中山大学 | A kind of indoleamine 2 containing tanshinone compound, 3 dioxygenase inhibitors |
| CN108558626A (en) * | 2018-01-04 | 2018-09-21 | 中国科学院昆明植物研究所 | The preparation method of miltionone and dehydrogenation miltionone |
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| CN109824753A (en) * | 2018-11-20 | 2019-05-31 | 中国科学院昆明植物研究所 | Tanshinone IIA derivative with IDO/TDO double selectivity inhibitory activity |
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| CN108969472B (en) * | 2017-06-01 | 2021-04-30 | 南京科利泰医药科技有限公司 | Novel nano drug-loading system of tanshinone IIA polypeptide supermolecule hydrogel and preparation method thereof |
| CN107698652A (en) * | 2017-09-28 | 2018-02-16 | 中山大学 | A kind of indoleamine 2 containing tanshinone compound, 3 dioxygenase inhibitors |
| CN108558626A (en) * | 2018-01-04 | 2018-09-21 | 中国科学院昆明植物研究所 | The preparation method of miltionone and dehydrogenation miltionone |
| CN110016069A (en) * | 2018-01-09 | 2019-07-16 | 上海星叶医药科技有限公司 | Tanshinone IIA piperazine compounds and its preparation method and application |
| CN110016069B (en) * | 2018-01-09 | 2021-09-24 | 上海星叶医药科技有限公司 | Tanshinone IIA piperazine compound and preparation method and application thereof |
| CN109824753A (en) * | 2018-11-20 | 2019-05-31 | 中国科学院昆明植物研究所 | Tanshinone IIA derivative with IDO/TDO double selectivity inhibitory activity |
| CN109824753B (en) * | 2018-11-20 | 2021-11-26 | 中国科学院昆明植物研究所 | Tanshinone IIA derivative with IDO/TDO double-selective inhibitory activity |
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