CN110327315A - The purposes of curcumin derivate - Google Patents

The purposes of curcumin derivate Download PDF

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CN110327315A
CN110327315A CN201910785642.XA CN201910785642A CN110327315A CN 110327315 A CN110327315 A CN 110327315A CN 201910785642 A CN201910785642 A CN 201910785642A CN 110327315 A CN110327315 A CN 110327315A
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cox
inhibitor
compound
hydroxyl
methoxyl group
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王飞
阿彼察·苏萨朗
张国林
甘亚维·给缇喀拉
卢晓霞
瓦朗喀拉·仓罗
周宗元
仓察宛·仓谭
帕图瓦蒂·若玛尼
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King University Of Science And Technology
RAMKHAMHAENG UNIVERSITY
Valera, University of
Chengdu Institute of Biology of CAS
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King University Of Science And Technology
RAMKHAMHAENG UNIVERSITY
Valera, University of
Chengdu Institute of Biology of CAS
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Abstract

The present invention provides the purposes of curcumin derivate.Turmeric derivative or its salt shown in formula I are specifically provided in the drug for preparing Anti-inflammatory diseases and/or the purposes of COX inhibitor.Curcumin derivate of the present invention has good COX inhibitory activity and anti-inflammatory activity, can be used for preparing COX inhibitor and anti-inflammatory drug.Wherein, compound 6 and compound 7 are optimal for the effect of COX-2 inhibitory activity and anti-inflammatory activity.It can be used for preparing cox 2 inhibitor and anti-inflammatory drug.

Description

The purposes of curcumin derivate
Technical field
The invention belongs to field of medicinal chemistry, and in particular to the purposes of curcumin derivate.
Background technique
Non-steroidal anti-inflammatory drugs (Nonsteroidal Antiinflammatory Drugs, NSAIDs) is a kind of with anti- Inflammation effect and antipyretic, analgesic activity drug.Clinically for treat collagen tissue disease, such as rheumatism, rheumatoid arthritis, Osteoarthritis etc..The chemical structure of such drug is different from cortin antiinflammatory drugs, therefore referred to as non-steroidal anti-inflammatory drugs, Its mechanisms of anti-inflammatory inhibits the biosynthesis of prostaglandin (Prostaglandines, PGs) related in vivo with it.Non- steroid Body anti-inflammatory agent is disappeared by the biosynthesis for inhibiting cyclooxygenase (Cyclo-oxygenase, COX) to block prostaglandin with playing Scorching, antipyretic effect.But since cyclooxygenase COX is there are two kinds of hypotypes, i.e. COX-1 and COX-2, such drug is inhibiting While COX-2, to COX-1, there is also certain inhibiting effect, lead to thromboxane biosynthesis block, induce GI irritation.
Curcumin is a kind of chemical component extracted from the rhizome of zingiberaceous plant, the main turmeric isolated from turmeric Element is curcumin, and secondary curcuminoids include Demethoxycurcumin and Bisdemethoxycurcumin.Curcumin shows many Bioactivity, such as antioxidant activity, anti-inflammatory activity, anticancer activity, antiprotozoal activity and HIV-resistant activity.Curcumin analogue packet Tetrahydro curcumin, hexahydrocurcumin, tetrahydro Demethoxycurcumin and tetrahydro Bisdemethoxycurcumin etc. are included, it is now discovered that these Ingredient has been used as submember to be present in some plant species.It is reported that certain curcumin metabolins also show anti-inflammatory activity And antioxidant activity, tetrahydro curcumin and hexahydrocurcumin and glucuronic acid turmeric are found in mouse and human body at present Element and sulfuric acid curcumin are curcumin metabolin.In view of curcumin it has been found that multiple biological activities, many mechanisms in the world This curcumin lead compound has been used as to develop many curcumin analogues with different bioactivity.But about four The research of hydrogen Demethoxycurcumin and tetrahydro Bisdemethoxycurcumin and the like bioactivity is seldom.
Summary of the invention
The object of the present invention is to provide the purposes of curcumin derivate.
The present invention provides turmeric derivatives shown in formula I or its salt in drug and/or the COX suppression for preparing Anti-inflammatory diseases The purposes of preparation:
Wherein, L1For the group for connecting two phenyl ring, it is selected from R5Selected from H or methyl；
R1、R2、R3、R4Separately it is selected from H, hydroxyl, methoxyl group ,-O- acetyl group；
Work as L1It is selected fromWhen, R1≠ methoxyl group, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ hydroxyl Base；Or R1≠ H, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ hydroxyl；Or R1≠ H, R2≠ H, R3≠ hydroxyl, R4≠ hydroxyl；
Work as L1It is selected fromWhen, R1≠ methoxyl group, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ Hydroxyl；
Work as L1It is selected fromWhen, R1≠ methoxyl group, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ hydroxyl Base.
Further, the compound is one of following compounds:
Further, the COX inhibitor be -1 inhibitor of selective COX-2, it is Selective COX-2 inhibitor, non-selective COX inhibitor；
The COX inhibitor is: referring to inhibit the substance of cyclooxygenase.
The COX-1 inhibitor: refer to the substance for being able to suppress cyclooxygenase -1.
The cox 2 inhibitor: refer to the substance for being able to suppress cyclooxygenase-2.
Wherein, non-selective COX inhibitor may act as COX-1 inhibitor, and can be used as cox 2 inhibitor.
Further, the compound for preparing -1 inhibitor of selective COX-2 or its salt are one of following compounds:
- 1 inhibitor of selective COX-2: referring to and selectively inhibit COX-1 activity, influences on COX-2 smaller.
Further, the compound for preparing Selective COX-2 inhibitor or its salt are one of following compounds:
The Selective COX-2 inhibitor: referring to and selectively inhibit COX-2 activity, influences on COX-1 smaller.
Further, the compound for preparing non-selective COX inhibitor or its salt are one of following compounds:
Further, the inflammatory disease is arthralgia caused by arthritis, rheumatic disease and inflammation, fever, swells Swollen, stiff and arthralgia, rachitis, pancreatitis, migraine, primary dysmenorrhea, familial adenomatous polyposis, acute shoulder Bitterly, chronic back pain, acute gout, depression, schizophrenia, tendon and ligament pain, postoperative pain, cystic fibrosis, tooth The subacute and chronic eczema of Zhou Yan, skin；
Preferably, the arthritis is osteoarthritis, juvenile arthritis, rheumatoid arthritis；The acute shoulder pain For acute subacromial bursitis, supraspinatus tendinitis.
Further, the compound of the drug for preparing Anti-inflammatory diseases or its salt are one of following compounds:
The present invention also provides a kind of COX inhibitor, it be using compound above-mentioned or its salt as active constituent, in addition The preparation that pharmaceutically acceptable auxiliary material is prepared.
The present invention also provides a kind of drug of Anti-inflammatory diseases, it be with compound above-mentioned or its salt for activity at Point, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
Curcumin derivate of the present invention have good COX inhibitory activity and anti-inflammatory activity, can be used for preparing COX inhibitor and Anti-inflammatory drug.Wherein, compound 6 and compound 7 are optimal for the effect of COX-2 inhibitory activity and anti-inflammatory activity.It can be used for making Standby cox 2 inhibitor and anti-inflammatory drug.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
The compounds of this invention 18~39 can also be prepared by the following method in addition to that can buy.
The preparation of embodiment 1, compound 18-39
1, the preparation of compound 18-24
300mg compound 1 is dissolved in 4mL anhydrous pyridine at room temperature, the anhydrous Ac of 0.5mL is added2Reaction 1 is stirred at room temperature in O ~3 hours, obtain reaction solution.CH is used in reaction solution plus after 100mL water2Cl2Extraction 2 times, each 200mL merges organic after extraction Phase, organic phase 200mL H2O washing, then use Na2SO4It is dry, and solvent is removed under vacuum, crude product passes through column chromatography CH2Cl2- MeOH (99:1-90:10) gradient elution purifies to obtain compound.
Or, 100mg compound 2 is dissolved in 1.5mL anhydrous pyridine at room temperature, the anhydrous Ac of 0.2mL is added2O is stirred at room temperature Reaction 1~3 hour, obtains reaction solution.CH is used in reaction solution plus after 60mL water2Cl2Extraction 2 times, each 100mL is associated with after extraction Machine phase, organic phase 100mL H2O washing, then use Na2SO4It is dry, and solvent is removed under vacuum, crude product passes through column chromatography Method CH2Cl2- MeOH (99:1-90:10) gradient elution purifies to obtain compound.
Or, 50mg compound 3 is dissolved in 1mL anhydrous pyridine at room temperature, the anhydrous Ac of 0.1mL is added2O is stirred at room temperature anti- It answers 1~3 hour, obtains reaction solution.CH is used in reaction solution plus after 40mL water2Cl2Extraction 2 times, each 75mL merges organic after extraction Phase, organic phase 75mL H2O washing, then use Na2SO4It is dry, and solvent is removed under vacuum, crude product passes through column chromatography CH2Cl2- MeOH (99:1-90:10) gradient elution purifies to obtain compound.
By the available compound 18-24 of above method, the characterization result of compound 18-24 is as follows:
Mono- O- acetyl curcumin (18) yield: 27%, orange foam.IR(KBr)νmax:3420,1762,1627, 1508,1270,1190,1122,1031,966cm-1；1H NMR(400MHz,CDCl3)δ2.30(s,3H,OAc),3.84 and 3.90 (each s, 6H, 2 × OMe), 5.79 (s, 1H, H-4), 6.45 and 6.51 (each d, J=15.7Hz, 2H, H-2 And H-6), 6.89 (d, J=8.1Hz, H-5 '), 7.01 (br s, 1H, H-2 '), 7.02 (overlapping signal, 1H, H-6 '), 7.07 (s, 1H, H-2 "), 7.09-7.12 (m, 2H, H-5 " and H-6 "), 7.55 and 7.57 (each d, J= 15.7Hz,2H,H-1 and H-7)；EIMS m/z (rel.%): 410 (13, [M]+),368(40),350(100),191 (33),190(57),177(24)。
Two-O- acetyl curcumin (19) yields: 59%, yellow amorphous solid, m.p.163-165 DEG C of (lit.m.p.160 ℃)。
Mono- O'- acetyl Demethoxycurcumin (20) yield: 28%, orange amorphous solid, 127-129 DEG C of fusing point.IR (KBr)νmax:3448,1762,1627,1560,1508,1272,1207,968,838cm-1；1H NMR(3400MHz, CDCl3)δ2.29(s,3H,OAc),3.92(s,3H,OMe),5.80 and 5.85(each s,2H,H-4 and OH),6.47 (d, J=15.7Hz, 1H, H-6), 6.54 (d, J=15.7Hz, 1H, H-2), 6.91 (d, J=8.2Hz, 1H, H-5 "), 7.03 (br s, 1H, H-2 "), 7.11 (d, J=8.5Hz, 2H, H-3 ' and H-5 '), 7.11 (obscured signal, 1H, H- ), 6 " 7.54 (d, J=8.5Hz, 2H, H-2 ' and H-6 '), 7.58and 7.60 (each d, J=15.7Hz, 2H, H-1and H-7)；ESMS (+ve) m/z (rel.%): 381 (100, [M+H]+)。
Mono- O "-acetyl group demethoxycurcumin (21) yield: 21%, yellow amorphous solid, 166-168 DEG C of fusing point. IR(KBr)νmax:3448,1757,1627,1576,1508,1299,1145,1032,961,831cm-1；1H NMR (400MHz,CDCl3+2 drops of CD3OD)δ2.30(s,3H,OAc),3.85(s,3H,OMe),5.78(s,1H,H-4), 6.45 and 6.51 (each d, J=15.8Hz, 1H, H-2 and H-6), 6.80 (d, J=8.5Hz, 2H, H-3 ' and H- 5 '), 7.02 (d, J=8.1Hz, 1H, H-5 "), 7.08 (br s, 1H, H-2 "), 7.12 (dd, J=8.1Hz, 1.4,1H, H- ), 6 " 7.42 (d, J=8.5Hz, 2H, H-2 ' and H-6 '), 7.55 and 7.59 (each d, J=15.8Hz, 1H, H-1and H-7)；ESMS (+ve) m/z (rel.%): 381 (100, [M+H]+)。
Two-O- acetyl group Demethoxycurcumin (22) yields: 33%, the spicule of yellow aggregation (comes from CH2Cl2Just Hexane), fusing point: 140-141 DEG C.
Mono- O- acetyl group Bisdemethoxycurcumin (23) yield: 23%, yellow powder, 178-180 DEG C of fusing point.IR (KBr)νmax:3448,1735,1637,1604,1508,1374,1235,972,833cm-1；1H NMR(400MHz,CDCl3) δ 2.30 (s, 3H, OAc), 5.78 (s, 1H, H-4), 6.48 and, 6.54 (each d, J=15.8Hz, 2H, H-2 and H- 6), 6.83 (d, J=8.3Hz, 2H, H-3 ' and H-5 '), 7.11 (d, J=8.3Hz, 2H, H-3 " and H-5 "), 7.45 (d, J =8.3Hz, 2H, H-2 ' and H-6 '), 7.54 (d, J=8.3Hz, 2H, H-2 " andH-6 "), 7.60 (d, J=15.8Hz, 2H, H-1and H-7)；
ESMS (+ve) m/z (rel.%): 723 (100, [2M+Na]+).
Two-O- acetyl group Bisdemethoxycurcumin (24) yields: 54%, yellow needles are (by CH2Cl2N-hexane), Fusing point: 172-174 DEG C.
2, the preparation method of compound 4-7,25-29
100mg compound 1 is dissolved in 10mL EtOH, 50mg 10%Pd-C is added, after degassing, by mixture in room temperature Lower hydrogenation 4 hours.Mixture is filtered by siliceous earth column, evaporates solvent.Use CH2Cl2- MeOH (98:2-90:10) gradient Elution, obtains compound by pillar layer separation.
Or, 75mg compound 2 is dissolved in 7mL EtOH, 35mg 10%Pd-C is added, after degassing, by mixture in room Temperature lower hydrogenation 4 hours.Mixture is filtered by siliceous earth column, evaporates solvent.Use CH2Cl2- MeOH (98:2-90:10) ladder Degree elution, obtains compound by pillar layer separation.
Or, 20mg compound 2 is dissolved in 3mL EtOH, 20mg 10%Pd-C is added, after degassing, by mixture in room Temperature lower hydrogenation 4 hours.Mixture is filtered by siliceous earth column, evaporates solvent.Use CH2Cl2- MeOH (98:2-90:10) ladder Degree elution, obtains compound by pillar layer separation.
Pass through the available compound 25-29 of above method.
Compound 4-7 is prepared according to document the method:
Compound 4:S.-L.Lee, W.-J.Huang, W.W.Lin, S.-S.Lee, C.-H.Chen, Preparation and anti-inflammatory activities of diarylheptanoid and diarylheptylamine analogs,Bioorg.Med.Chem.13(2005)6175-6181.
Compound 5:S.-L.Lee, W.-J.Huang, W.W.Lin, S.-S.Lee, C.-H.Chen, Preparation and anti-inflammatory activities of diarylheptanoid and diarylheptylamine analogs,Bioorg.Med.Chem.13(2005)6175-6181.
Compound 6:E.Portes, C.Gardrat, A.Castellan, A comparative study on the antioxidant properties of tetrahydrocurcuminoids and curcuminoids, Tetrahedron63(2007)9092-9099.
Compound 7:E.Portes, C.Gardrat, A.Castellan, A comparative study on the antioxidant properties of tetrahydrocurcuminoids and curcuminoids,Tetrahedron 63(2007)9092-9099.
The characterization result of compound 4-7,25-29 are as follows:
Tetrahydro curcumin (4) yield: 65%, crystal is (from CH2Cl2In n-hexane), 93-94 DEG C of fusing point.
Hexahydrocurcumin (5) yield: 20%, white, amorphous solid, 81-82 DEG C of fusing point.
Octahydrocurcumin (26) yield: 15%, colorless viscous solid.
Tetrahydro Demethoxycurcumin (6) yield: 62%, faint yellow toughening oil.
Hexahydro Demethoxycurcumin (25a and 25b, 1:1 mixture) yield: 29%, colorless viscous solid.IR(KBr)ν max:3420,2937,1698,1614,1516,1455,1371,1234,1033,822cm1；1H NMR(400MHz,CDCl3)δ 1.58(m,2×1H),1.74(m,2×1H),2.48-2.53(m,2×2H),2.55-2.61(m,2×1H),2.66-2.73 (m, 2 × 3H), 2.80 (t, J=7.3Hz, 2 × 2H) (H-1, H-2, H-4, H-6, H-7), 3.84 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.00 (m, 2 × 1H, H-3 and H-5), 6.64 (br s, 2 × 1H, H-2 "), 6.66 (br d, J=7.9Hz, 2 × 1H, H-6 "), 6.72 and 6.73 (each d, J=8.5Hz, 2 × 2H, H-3 ' and H-5 '), 6.80 (d, J=7.9Hz, 2 × 1H, H-5 "), 7.00 and 7.02 (each d, J=8.5Hz, 2 × 2H, H-2 ' and H-6 ')；EIMS m/z (rel.%): 344 (11, [M]+),326(11),177(14),137(100),108(57),94(21).
Octahydro methoxyl group curcumin (27) yield: 6%, colorless viscous solid.IR(KBr)νmax:3420,2940,1615, 1515,1456,1234,1158,1033,824cm-1；1H NMR(400MHz,CDCl3+3drops of CD3OD)δ1.55- 1.96(m,6H,H-2,H-4,H-6),2.53-2.64(m,4H,H-1and H-7),3.80(m,2H,H-3and H-5),3.83 (s, 3H, OMe), 6.63 (br d, J=8.0Hz, 1H, H-5 "), 6.66 (br s, 1H, H-2 "), 6.71 (br d, J=8.2Hz, 2H, H-3 ' and H-5 '), 6.78 (br d, J=8.0Hz, 1H, H-6 "), 6.99 (br d, J=8.0Hz, 2H, H-2 ' and H- 6′)；ESMS (+ve) m/z (rel.%): 369 (100, [M+Na]+).
Tetrahydro Bisdemethoxycurcumin (7) yield: 60%, clear crystal (comes from Acetone-Benzene), fusing point: 110-111 ℃。
Hexahydro Bisdemethoxycurcumin (28) yield: 21%, white, amorphous solid, 120-121 DEG C of fusing point.IR (KBr)νmax:3374,2937,1702,1613,1515,1450,1216,1045,828,756cm1；1H NMR(400MHz, CDCl3+3drops of CD3OD)δ1.57(m,1H,H-6a),1.71(m,1H,H6b),2.48(m,2H)and 2.57(m,2H) (H-4 and H-7), 2.66 (t, J=7.2Hz, 2H, H-1), 2.77 (t, J=7.2Hz, 2H, H-2), 3.96 (m, 1H, H-5), 6.70 and 6.71 (each d, J=8.2Hz, 4H, H-3 ', H-5 ', H3 ", H-5 "), 6.96and 6.97 (each d, J= 8.2Hz,4H,H-2′,H-6′,H-2″,H-6″)；EIMS m/z (rel.%): 314 (1, [M]+),296(3),107(100),94 (31),77(44).
Octahydro bi-methoxy curcumin (29) yield: 10%, colorless viscous solid.IR(KBr)νmax:3376,2927, 1613,1514,1447,1230,825,753cm-1；1H NMR(400MHz,CDCl3+4drops of CD3OD)δ1.50(m, 2H,H-4),1.67(m,4H,H-2and H-6),2.55(m,4H,H-1 and H-7),3.75(m,2H,H-3 and H-5), 6.69 (d, J=8.2Hz, 4H, H-3 ', H-5 ', H-3 ", H-5 "), 6.96 (d, J=8.2Hz, 4H, H-2 ', H-6 ', H-2 ", H- 6″)；ESMS (+ve) m/z (rel.%): 655 (100, [2M+Na]+).
3, the preparation of compound 30-34
Reagent and condition: (i) p-Ts OH, benzene flow back 3 hours；(ii) THF, DDQ, environment temperature, 4 hours；(iii) H2, Pd-C, EtOH.
According to the method for report [C.Changtam, H.P.De Koning, H.Ibrahim, M.H.Sajid, M.K.Gould,A.Suksamrarn,Curcuminoid analogs with potent activity against Trypanosoma and Leishmaniaspecies, Eur.J.Med.Chem.45 (2010) 941-956.], by THF Middle to use 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) by 30 dehydrogenation of compound, respectively obtaining yield is 28%, 23% With 32% compound 31,32 and 33.The hydrogenation of compound 30 is obtained 34, yield 86%.
4, the preparation of compound 35,36
Compound 30 (250mg, 0.70mmol) is dissolved in pyridine (4mL) and NH is added2OH.HCl (105mg, 1.51mmol), reaction mixture is stirred 1.5 hours at 50 DEG C, uses H2O (250ml) handles reactant, uses EtOAc (150x2ml) extraction solution mixture, organic phase H2O (100ml) washing, uses anhydrous Na2SO4It is dry, and solvent is evaporated to It is dry.By using CH2Cl2The column chromatography eluting crude product of-MeOH (200:5) obtains 35 (225mg, 86%)
In the post-processing step of similar reaction condition and prepare compound 35 (50mg), by with NH2OMe·HCl (40mg) processing compound 30 carrys out prepare compound 36 (69%),
35 colorless viscous solid of compound.IR(KBr)νmax:3405,3018,2938,1607,1514,1464,1215, 1035,1151,756cm-1；1H NMR(400MHz,CDCl3+3drops of CD3OD)δ2.40(q-like,6.6Hz,2H,H- 6), 2.60 (t, J=7.4Hz, 2H, H-7), 2.68 (br s, 4H, H-1 and H2), 3.81 and 3.83 (each s, 6H, 2 ×OMe),6.00(m,2H,H-4 and H-5),6.61-6.66(m,4H,H2′,H-2″,H-5′,H-5″),6.79(br d,J =7.7Hz, 2H, H-6 ' and H-6 ")；ESMS (- ve) m/z (rel.%): 370 (100, [M-H]-).
36 colorless viscous solid of compound.IR(KBr)νmax:3425,2937,1604,1515,1463,1271,1152, 1050,816cm-1；1H NMR (400MHz, CDCl3) δ 2.47 (q-like, J=7.3Hz, 2H, H-6), 2.55 (m, 2H), 2.62(m,2H),2.73(m,2H)(H-1,H-2,H-7),3.83 and 3.84(each s,9H,3×OMe),5.46(s,2H, 2 × OH), 6.16 (dt, J=16.2,6.8Hz, 1H, H-5), 6.62-6.71 (m, 5H, H-4, H-2 ', H-2 ", H-5 ', H-5 "), 6.81 (dd, J=7.9,1.9Hz, 2H, H-6 ' and H-6 ")；ESMS (+ve) m/z (rel.%): 408 (100, [M+Na]+).
5, the preparation of compound 37,38,39
40mg di-methylation curcuminoids compound 12 is dissolved in 5mL EtOH, 20mg 10%Pd-C is added, in room temperature Mixture is filtered by siliceous earth column, evaporates solvent by lower hydrogenation 3 hours.Use CH2Cl2- MeOH (98:2-90:10) gradient Elution, obtains compound by pillar layer separation.
Or, 30mg di-methylation curcuminoids compound 15 is dissolved in 5mL EtOH, 15mg 10%Pd-C is added, It hydrogenates 3 hours at room temperature, mixture is filtered by siliceous earth column, evaporates solvent.Use CH2Cl2-MeOH(98:2-90:10) Gradient elution obtains compound by pillar layer separation.
Or, 15mg di-methylation curcuminoids compound 17 is dissolved in 4mL EtOH, 7mg 10%Pd-C is added, in room Temperature lower hydrogenation 3 hours, mixture is filtered by siliceous earth column, evaporates solvent.Use CH2Cl2- MeOH (98:2-90:10) ladder Degree elution, obtains compound by pillar layer separation.
Pass through the available compound 37,38 and 39 of above method.
Dimethyl tetrahydro demethoxycurcumin (38) yield: 78%, colorless viscous solid.IR(KBr)νmax:2930, 1703,1611,1514,1463,1246,1156,1030cm-1；1H NMR(CDCl3)δ2.53(m,4H),2.74-2.85(m, 6H)(H-1,H-2,H-4,H-6 and H-7),3.75(s,3H,OCH3),3.83(s,6H,2×OMe),5.40(s,1H,H- 4), 6.68 (br s, 1H, H-2 "), 6.69 (m, 1H, H-5 "), 6.76 (m, 1H, H-6 "), 6.80 (d, J=8.4Hz, 2H, H-3 ' And H-5 '), 7.07 (br d, J=8.4Hz, 2H, H-2 ' and H-6 ')；ESMS (+ve) m/z (rel.%): 393 (100, [M +Na]+).
Dimethyl tetrahydro Bisdemethoxycurcumin (39) yield: 75%.ESMS (+ve) m/z:703 [2M+Na]+。
Anti- COX-1 and COX-2 activity in embodiment 2, full cell assay system
1. experimental material: all tissue culture components are purchased from Gibco BRL (Gaithersburg, MD).Aspirin and Calcium ion carrier A 23187 is purchased from Sigma (St.Louis, MO).3H-PGE2With anti-PGE2Antibody is purchased from NEN Life respectively Science (Boston, MA) and Upstate Biotechnology (Upstate, NY) or Sigma (St.Louis, MO).
2. experimental method: by the COX-1 (COX-1 of immortalized mouse-/-) and COX-2 (COX-2-/-) protoblast be added it is non- The Dubelcco of necessary amino acid (0.1mM), glutamine (292mg/l), ascorbic acid (50mg/l) and 10%FCS improve her Ge Er culture medium (DMEM) culture, with 1x105A cell/ml is inoculated in 96 orifice plates.Cell is being contained into 5%CO at 37 DEG C2's It is incubated 72 hours in humidified incubator.Then cell is washed with the DMEM culture medium without FCS, and contains carrier or medicine with 83 μ l The plasma-free DMEM medium preincubate of object 30 minutes.Aspirin or test compound are dissolved and connected in ethyl alcohol or DMSO Continuous dilution, is then added into culture medium, the ultimate density of ethyl alcohol and DMSO are respectively 1% and 0.1%.After preculture, Culture medium is removed, is handled cell 30 minutes with the serum free medium containing carrier or drug and 2 μM of A23187 immediately.Then from Media samples are collected in hole, analyze PGE as described previously by radio immunoassay (RIA)2Concentration.For showing to PGE2 There is the sample of inhibiting effect, further measure 50 value of IC, aspirin is used as COX inhibitor.
3. experimental result:
Table 1, the anti-COX-1 of curcumin analogue and COX-2 activity
Table 1 is continuous
aAs a result (IC50, μM) is the average value of COX-1 and COX-2 half maximum suppression concentration measured twice.With it is average The deviation of value is less than the 10% of average value.
bIt indicates COX-2 selectivity index (COX-1IC50/COX-2IC50), ND expression does not determine.
Test result shows: curcumin derivate of the present invention has COX inhibitory activity, and part is by selective depression The activity of COX-1 or COX-2.Compound 6 and compound 7 are most active compounds, they are respectively than aspirin activity High 298 times and 388 times, to the selective inhibitory of COX-2 respectively about more than 20 times and 27 times.
Embodiment 3, anti-inflammatory activity measurement and cytotoxicity analysis
1. experimental method:
264.7 cell of RAW (ATCC, Rockville, MD, USA) is cultivated at (DMEM), with 1x105A cell/cm224 It is grown 24 hours on orifice plate.With curcumin and the like pretreatment cell 1 hour before 5ng/ml LPS is stimulated 24 hours. According to the explanation of manufacturer, cell-free culture supernatants liquid is collected by using business ELISA assay kit and carries out TNF- The enzyme linked immunosorbent assay (ELISA) (ELISA) of α, IL-1 β and IL-6.
By African green monkey kidney cell (Vero) (CLS Cell Lines Service GmbH, Eppelheim, Germany) with 4.5×104A cell/cm2Density be inoculated with and make its grow 48 hours.Vero cell (CLS Cell Lines Service GmbH, Eppelheim, Germany) with 4.5 × 104/cm2Density be inoculated with and make its grow 48 hours.Then various concentration is used Curcumin and the like processing cell 24 hours.Then cell and 0.5mg/ml MTT solution are incubated 3 hours again, is discarded Solution.Formazan crystalline product is dissolved in the DMSO of every 200 μ l of hole.Existed using microplate reader (Thermo Fisher, USA) The absorbance of formazan solution is measured under 560nm wavelength.Cell viability: [(Abs is calculated using following equationtreated sample/ Absuntreated sample)×100]
2. experimental result
The proinflammatory cytokine generation and its cytotoxicity to Vero cell that table 2 inhibits curcumin and the like.
aAs a result (IC50, μM) is the half maximum suppression concentration of proinflammatory cytokine.Numerical value indicates independent experiment three times Average value ± SEM.Compared with dexamethasone, significant level*p<0.05。
bAs a result (IC50, μM) is the half-maximal cell toxic concentration to normal Vero cell.Numerical value indicates independent three times Average value ± the SEM of experiment, compared with curcumin (1), significant level§p<0.05。
cND is not determined.
Test result shows: compound 1 is 31.53 ± 4.80,11.33 ± 0.83 and 10.60 ± 1.14 μM in IC50 value When, it is inhibited to the secretion of tumor necrosis factor-alpha (TNF-α), -1 β and IL-6 of interleukins (IL) respectively.For The inhibiting effect of IL-1 β, compound 1 and 2 can significantly reduce the secretory volume of IL-1 β compared with anti-inflammatory agent dexamethasone.Three kind four The generation of 4,6 and 7 energy of hydrogen analog different degrees of decrease these three proinflammatory cytokine TNF-α, IL-1 β and IL-6.These Analog can inhibit the generation of three kinds of proinflammatory cytokines, and inhibiting effect is suitable with drug.In addition tetrahydro analog 4,6 and The abated effect of 7 and three kind of curcuminoids, 1,2 and 3 couple of IL-6 secretion is consistent.Meanwhile compound 6 and compound 7 are shown Inhibition TNF-α, IL-1 β and IL-6 generate effect it is suitable with anti-inflammatory agent dexamethasone, and to Vero cell have it is the smallest carefully Cellular toxicity.Illustrate that curcumin derivate of the invention can be anti-inflammatory, is used to prepare the drug of Anti-inflammatory diseases.
To sum up, curcumin derivate of the present invention has good COX inhibitory activity and anti-inflammatory activity, can be used for preparing COX suppression Preparation and anti-inflammatory drug.Wherein, compound 6 and compound 7 are optimal for the effect of COX-2 inhibitory activity and anti-inflammatory activity.It can It is used to prepare cox 2 inhibitor and anti-inflammatory drug.

Claims (10)

1. turmeric derivative or its salt shown in formula I are in the drug for preparing Anti-inflammatory diseases and/or the purposes of COX inhibitor:
Wherein, L1For the group for connecting two phenyl ring, it is selected from R5Selected from H or methyl；
R1、R2、R3、R4Separately it is selected from H, hydroxyl, methoxyl group ,-O- acetyl group；
Work as L1It is selected fromWhen, R1≠ methoxyl group, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ hydroxyl；Or Person R1≠ H, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ hydroxyl；Or R1≠ H, R2≠ H, R3≠ hydroxyl, R4≠ hydroxyl；
Work as L1It is selected fromWhen, R1≠ methoxyl group, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ hydroxyl Base；
Work as L1It is selected fromWhen, R1≠ methoxyl group, R2≠ methoxyl group, R3≠ hydroxyl, R4≠ hydroxyl.
2. purposes according to claim 1, it is characterised in that: the compound is one of following compounds:
3. purposes according to claim 1 or 2, it is characterised in that: the COX inhibitor be -1 inhibitor of selective COX-2, Selective COX-2 inhibitor, non-selective COX inhibitor；
Wherein, non-selective COX inhibitor may act as COX-1 inhibitor, and can be used as cox 2 inhibitor.
4. purposes according to claim 3, it is characterised in that: the compound for preparing -1 inhibitor of selective COX-2, or Its salt is one of following compounds:
5. purposes according to claim 3, it is characterised in that: the compound for preparing Selective COX-2 inhibitor, or Its salt is one of following compounds:
6. purposes according to claim 3, it is characterised in that: the compound for preparing non-selective COX inhibitor, or Its salt is one of following compounds:
7. purposes according to claim 3, it is characterised in that: the inflammatory disease is arthritis, rheumatic disease causes Arthralgia and inflammation, fever, swelling, stiff and arthralgia, rachitis, pancreatitis, migraine, primary dysmenorrhea, family Race's Adenomatous Polyposis, acute shoulder pain, chronic back pain, acute gout, depression, schizophrenia, tendon and ligament pain, Postoperative pain, cystic fibrosis, periodontitis, the subacute and chronic eczema of skin；
Preferably, the arthritis is osteoarthritis, juvenile arthritis, rheumatoid arthritis；The acute shoulder pain is anxious Property subacromial bursitis, supraspinatus tendinitis.
8. purposes according to claim 3, it is characterised in that: the compound of the drug for preparing Anti-inflammatory diseases, or Its salt is one of following compounds:
9. a kind of COX inhibitor, it is characterised in that: it is to be with the described in any item compounds of claim 4~6 or its salt Active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
10. a kind of drug of Anti-inflammatory diseases, it is characterised in that: it is with compound according to any one of claims 8 or its salt for work Property ingredient, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
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