CN101028263A - Use of substituted isoandrographolide derivative - Google Patents
Use of substituted isoandrographolide derivative Download PDFInfo
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- CN101028263A CN101028263A CN 200710019981 CN200710019981A CN101028263A CN 101028263 A CN101028263 A CN 101028263A CN 200710019981 CN200710019981 CN 200710019981 CN 200710019981 A CN200710019981 A CN 200710019981A CN 101028263 A CN101028263 A CN 101028263A
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Abstract
An application of the substituted isoandrographolide derivative and its pharmacologically acceptable salt in preparing COX-2 expression depressant and/or TNF-alpha depressant and/or IL-6 depressant is disclosed.
Description
Technical field
The andrographolidume derivative that the present invention relates to replace, it is used to prepare the purposes of medicine, prepares the purposes of COX-2 expression inhibitor, TNF-alpha inhibitor and IL-6 inhibitor specifically.
Background technology
TNF-α is a kind of precursor inflammatory cytokine, is mainly produced by mononuclear cell and macrophage, participates in many inflammatory reaction processes.Endotoxin (LPS) is the derivant of TNF-α.Discover that TNF-α has multiple biological activity: (1) is killed and wounded or is suppressed tumor cell; (2) phagocytic activity of raising neutrophilic granulocyte increases superoxide anion and produces, and participates in inflammatory reaction; (3) infection etc.According to the literature, the TNF-alpha inhibitor can be used for rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, the joint of vertebral column inflammation, inflammatory bowel (crohn and ulcerative colitis), heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute marrow type leukemia, parkinson, acquired immune deficiency syndrome and dementia and syndrome, presenile dementia, depression, sepsis, septicemia, septic shock, behcets disease, graft versus host disease, uveitis, Wegener ' s granuloma, the Xiu Gelianshi xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection, the treatment of various disease conditions such as obesity.(Ogata H，Hibi T.et al.Curr Pharm Des.2003，9(14)：1107-1113；Moller DR.et al.J Intern Med.2003 Jan，253(1)：31-40；Taylor PC.et al.CurrPharm Des.2003，9(14)：1095-1106；Wilkinson N.et al.Arch Dis Child.2003，88(3)：186-191；Nishimura F.et al.J Periodontol.2003 Jan，74(1)：97-102；Weinberg JM.et al.Cutis.2003，71(1)：41-45；Burnham E.et al.Crit Care Med.2001 Mar，29(3)：690-691；Sack M.et al.PharmacolTher.2002，94(1-2)：123-135；Barnes PJ.et al.Annu Rev Pharmacol Toxicol.2002，42：81-98；Mageed RA.et al.Lupus.2002，11(12)：850-855)
IL-6 has another name called B-cell stimulating factor, and various kinds of cell can both be spontaneous or produces IL-6 under other factors is stimulated.Poly in many cytokines such as IL-1, TNF, interferon and the serum can both strengthen different cell IL-6 expression of gene, and IL-6 plays an important role in periphery and central nervous system's growth, differentiation, regeneration and degeneration.Discover that the IL-6 inhibitor can be used for the treatment of various disease conditions such as Alzheimer, schizophrenia, cancer, gouty arthritis, rigid spine disease, diabetes, depression.(Handraskar B, Mitchell DH.Hepatograstroenterology.1998,45 (23): 1807-1812; Rosler N, Wichart I, Jollinger KA.Acta Neurol Scand.2001,103 (2): 126-130; Castrili G, Tatone D, Dioduro MG, et al.Br J Cancer.1997,75 (6): 855-859; Punzi L, Calo L, Plobani M.Crit Rev ClinLab Sci.2002,39 (1): 63-88; Maes M, et al.AmJ Psychiatry.1993,150:1189-1193; Jahromi MM, Millward BA, Demaine AG.J Interferon Cytokine Res.2000,20:885-888; Permitted wisdom, etc. Chinese neuropsychiatric disease magazine .1999,25 (2): 98)
Cyclooxygenase (COX) is the key enzyme that conversion of arachidonic acid is converted into prostaglandin.COX is an embrane-associated protein, is present in nuclear membrane and microsomal membrane, and it has 2 kinds of isozyme: COX-1 and COX-2.COX-2 is considered to " immediately-early genes ", though the Placenta Hominis of some tissues such as brain, kidney, latter half of gestation is expressed COX-2 under the normal physiological state, detect in most tissues less than, have only as the cell abduction delivering COX-2 rapidly that is upset.These stimulating factors mainly comprise various somatomedin: as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factor (TGF), hepatocyte growth factor (HGF), cytokine (as ET-1, Endothelin 1), serum, lipopolysaccharide (LPS), carcinogen (as Buddhist ripple esterdiol) and hyperosmotic state etc.(Sano H，Kawahito Y，Wilder RI，et al.Cancer Res，1995，55(17)：3785-3789；Sugiyama T，Yoshimoto T，Sato R，et al.J Cardiovasc Pharmacol，2004，44(1)：S332-335)
Many-sided studies show that such as epidemiology, Experiment of Zoology and cytologic experiment in recent years, COX-2 is ubiquity overexpression phenomenon in kinds of tumors, Masferrer etc. detect the expression of COX-2 in all kinds of tumors of kind more than 150, and can clearly detect the existence of COX-2 in most of tumor neogenetic blood vessels.This shows that COX-2 might play corresponding effect in the new vessels of tumor inducing and thing followed metastatic disease.These phenomenons prompting COX-2 has the important physical function in the generation and the development of tumor and in shifting, the increase of its expression may be a tumorigenic early stage incident, the level that detects COX-2 has the early diagnosis of the tumor of helping, and the expression that suppresses COX-2 has the tumor treatment of helping.In addition, discover that COX-2 might regulate P-gp by PKC or PKA approach and express, thereby participate in the pathological process of tumor multi-medicine drug-resistant.Therefore, COX-2 may become the novel targets of the new tumor multi-medicine drug-resistant medicament research and development that reverses the P-gp mediation safely and effectively.(Masferrer JL，Leahy KM，Koki AT，et al.Cancer Res，2000，60(4)：1306-1311；Zhang H，Sun XF.Am J Gastro，2002，97(4)：1037-1041；Williams CS.Smalley W，DuBois RN.JClin Invest，1997，100(6)：1325-1329；Kinoshita T，Takahashi Y，Sakashita T，et al.Biochim-Biophys Acta，1999，1438(1)：120-130；Kojima M，Morisaki T，Lzubara K，et al.Oncogene，2000，19(9)：1225-1231；Patel VA，Dunn MJ，Sorokin A.J Biol Chem，2002，277：38915-38920；DraperMP，Martell RL，Levy SB.Br J Cancer，1997，75：810-815；Negishi M，Sugimoto Y，Ichikawa A.Prog Lipid Res，1993，32：417-434.)
Bibliographical information is arranged, COX-2 plays a role in pathological processes such as cardiovascular disease such as atherosclerosis, thrombosis, myocardial ischemia-anoxemia, heart failure, suppresses the expression of COX-2 and the new method that selective COX-2-inhibitor 2 may become the above-mentioned disease of treatment.(Linton MF，Fazio S.Curr Opin L ipidol，2002，13(5)：497-504；JacksonSP，Schoen-waelder SM.Nat Rev Drug Discov，2003，2(10)：775-789；Schmedtje JF Jr，Ji YS，Liu WL，et al.JBiol Chem，1997，272(1)：601-608；Wong SC，Fukuchi M，Melnyk P，et al.Circulation，1998，98(2)：100-103.)
Bibliographical information is arranged, and COX-2 participates in neural a lot of physiology and pathological process, as: the synapse transmission of excitatory neuron, inflammatory process, hyperpathia and various brain injury (TBI, cerebrovascular and epilepsy); Also participate in neurodegenerative disease such as Alzheimer and Parkinsonian pathological process.Suppress the expression of COX-2 and the new method that selective COX-2-inhibitor 2 may become the above-mentioned disease of treatment.(Wang Bingang, Li Gaili. Chinese clinical rehabilitation, 2005,9 (33): 133-135.)
Andrographolide (Andrographolide) is one of main effective ingredient of acanthaceous plant Herba Andrographis Andrographis paniculata (Burm.f.) Nees.Has analgesic, antiinflammatory (Deng Wenlong, Deng. Acta Pharmaceutica Sinica, 1980,590), analgesia, antibiotic (Xu Luoshan etc. 15 (10):, China's pharmacognosy (volume two). Beijing: Chinese Medicine science and technology publishing house, 1996:1580), physiologically active widely such as blood sugar lowering, atherosclerosis, be mainly used in the treatment upper respiratory tract infection clinically.Along with to the deepening continuously of andrographolide pharmacological research, it has shown tempting application prospect at aspects such as immunomodulating, antiviral, antitumor.(Dai Guifu, Wang Junfeng, He Shuaiwei, etc. Chinese patent medicine, 2006,28 (7): 1032-1035.)
Bibliographical information is arranged, andrographolide can increase the expression of TNF-α, be a kind of nonspecific immunologic function stimulant (Rajagopal S.et al, Journal of Experimental Therapeutics and Onlology, 2003 (3): 147-158).
Bibliographical information is arranged, andrographolide can suppress by the expression of the inductive intercellular adhesion molecule-1 of TNF-α (ICAM-1) and the adhesion between endotheliocyte and the mononuclear cell, infer relevant (the Habtemariam S.Phytotherapy Research 1998 of antiinflammatory action of andrographolide with ICAM-1 pathology approach, 12:37-40), researcher infers that andrographolide has effect to the downstream factor of inflammation pathological process, but does not disclose the direct repression of andrographolide to the precursor inflammatory factor TNF-α of upstream.
Bibliographical information is arranged, andrographolide can suppress TNF-α in the inductive macrophage of lipopolysaccharide (LPS), the expression of IL-12, infer that thereby andrographolide is the expression that suppresses TNF-α in the inductive macrophage of LPS by the activation that suppresses ERK, but this path and IL-12 are irrelevant, andrographolide may be by acting on AKt, Protein kinase C, and the one or more molecules among the Ets-2 etc. are regulated and control the expression of IL-12.(Lin HQ，Ling Kong，Guo JS，et al.Biol.Pharm.Bull.2006，29(2)：220-224.)
Other has bibliographical information, and dehydrorographolide mono succinate potassium salt can directly destroy endotoxin structure, and the activity of a large amount of inflammatory factors by suppressing its release that mediates such as TNF-α, IL-1, IL-6 plays the effect of anti-endotoxin.
Do not see in the existing document that relevant andrographolidume derivative has the activity report that suppresses COX-2, TNF-α and IL-6 expression.
Summary of the invention
The object of the present invention is to provide a kind of purposes of andrographolidume derivative of new replacement.The purposes for preparing COX-2 expression inhibitor and/or TNF-alpha inhibitor and/or IL-6 inhibitor specifically.
Summary of the invention is as follows in detail:
The present invention has synthesized a series of general formulas (I) chemical compound and pharmaceutically acceptable salt thereof:
R
1Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue;
R
2Represent hydrogen, or R
1With R
2Representative=N-R together
7
R
3Representation hydroxy; the alkoxyl of the straight or branched of C1～C8; the alkanoyl of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8 replaces or unsubstituted fragrant oxygen base; replace or unsubstituted aromaticacyl radical; replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue, or R
1, R
2With R
3Form hexatomic ring or the heptatomic ring that contains carbon and oxygen together;
R
4Represent hydrogen;
R
5Represent the alkyl of the straight or branched of C1～C8, or R
4With R
5Represent "=CH together
2",
R
6Representative
R
7Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue;
R
8Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue;
X represents oxygen, sulfur, NR
9R
9Represent hydrogen; the alkyl of the straight or branched of C1～C8; the alkoxyl of the straight or branched of C1～C8; the alkanoyl of the straight or branched of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8; the alkyl halide acyl group of the straight or branched of C1～C8; replace or unsubstituted aryl; replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted heterocyclic base; replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue.
The alkyl of above-mentioned C1～C8 is meant the alkyl of the straight or branched of 1～8 carbon.For example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, hexyl, heptyl, octyl group etc.
The alkoxyl of above-mentioned C1～C8 is meant the alkoxyl of the straight or branched of 1～8 carbon.For example methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen, hexyloxy, heptan oxygen base, octyloxy etc.
The alkanoyl of above-mentioned C1～C8 is meant the alkanoyl of the straight or branched of 1～8 carbon.For example formoxyl, acetyl group, propiono, different propiono, bytyry, isobutyryl, uncle's bytyry, secondary bytyry, valeryl, valeryl, caproyl, heptanoyl group, caprylyl etc.
The alkylhalide group of above-mentioned C1～C8 is meant the alkyl of the straight or branched of 1～8 carbon that contains halogen.For example chloromethyl, 1-chloroethyl, 1-chloropropyl, 1-chloro isopropyl, 1-chlorobutyl, 1-chlorine isobutyl group, the chlorine tert-butyl group, 1-chlorine sec-butyl, 1-chlorine amyl group, 1-chlorine neopentyl, 1-chlorine hexyl, 1-chlorine heptyl, 1-chlorine octyl group etc.
The halogen alkoxyl of above-mentioned C1～C8 is meant the alkoxyl of the straight or branched of 1～8 carbon that contains halogen.For example 1-chloroethoxy, 1-chlorine propoxyl group, 1-chlorine isopropoxy, 1-chlorine butoxy, 1-chlorine isobutoxy, chlorine tert-butoxy, 1-chlorine sec-butoxy, 1-chlorine amoxy, 1-chlorine neopentyl oxygen, 1-chlorine hexyloxy, 1-chlorine oxygen in heptan base, 1-chlorine octyloxy etc.
The alkyl halide acyl group of above-mentioned C1～C8 is meant the alkanoyl of the straight or branched of 1～8 carbon that contains halogen.The for example secondary bytyry of chloracetyl, 1-chlorine propiono, the different propiono of 1-chlorine, 1-chlorobutyryl, 1-chlorine isobutyryl, chlorine uncle bytyry, 1-chlorine, 1-chlorine valeryl, 1-chlorine valeryl, 1-chlorine caproyl, 1-chlorine heptanoyl group, 1-chlorine caprylyl etc.
The aryl of above-mentioned replacement is meant and contains 1～5 substituent aromatic ring.These substituent groups can be chlorine, nitro, methoxyl group, methyl, formoxyl etc.
The fragrant oxygen base of above-mentioned replacement is meant and contains 1～5 substituent fragrant oxygen ring.These substituent groups can be chlorine, nitro, methoxyl group, methyl, formoxyl etc.
The aromaticacyl radical of above-mentioned replacement is meant and contains 1～5 substituent fragrant acyl ring.These substituent groups can be chlorine, nitro, methoxyl group, methyl, formoxyl etc.
The heterocyclic base of above-mentioned replacement is meant and contains 1～5 substituent fragrant heterocycle.These substituent groups can be chlorine, nitro, methoxyl group, methyl, formoxyl etc.
The fragrant hetero-oxy of above-mentioned replacement is meant and contains the assorted oxygen ring of 1～5 substituent virtue.These substituent groups can be chlorine, nitro, methoxyl group, methyl, formoxyl etc.
The assorted acyl group of the virtue of above-mentioned replacement is meant and contains the assorted acyl ring of 1～5 substituent virtue.These substituent groups can be chlorine, nitro, methoxyl group, methyl, formoxyl etc.
Preferred chemical compound is:
R wherein
1With R
2Representative=N-R together
7, R
7Representation hydroxy, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8 replaces or unsubstituted aromaticacyl radical R
3Representation hydroxy, the alkanoyl of the straight or branched of C1～C8 replaces or unsubstituted fragrant oxygen base, replaces or unsubstituted aromaticacyl radical, or R
1, R
2With R
3Form the heptatomic ring that contains carbon and oxygen together.
The structure of part of compounds is:
R
3 R
7
IB
1 OH OH
IB
2 OH OCH
3
R
9
IC
1 H
IC
2 CH
3
IC
3 CH
2CH
2CH
3
IC
4 CH
2CH
2CH
2CH
3
R
9
ID
1 H
ID
2 CH
3
ID
3 CH
2CH
2CH
3
ID
4 CH
2CH
2CH
2CH
3
R
9
IE
1 H
IE
2 CH
3
IE
3 CH
2CH
2CH
3
IE
4 CH
2H
2CH
2CH
3
According to the present invention, pharmaceutically acceptable salt comprises the base addition salts that forms with following inorganic base: with the salt of metal, particularly alkali metal, alkaline-earth metal and transition metal (for example potassium, sodium, magnesium, aluminum, calcium etc.) formation.
The compound of Formula I preparation method, method is as follows:
The IA compounds: 3 of andrographolide (1), 19-hydroxyl carry out ketal protection and make 2,2 and reflux in dichloromethane with PDC; generate 3; 3 with acid, anhydride, acyl chlorides generation acylation reaction, generation 4,4 usefulness acetic acid and water (V: V=7: 3) remove protecting group and get goal object IA.
Concrete reactions steps is:
The IB compounds: andrographolide (1) reflux dewatering in pyridine generates 5,5 and generates 6,6 with the triphenylchloromethane reaction and generate 7,7 through the PDC oxidation and generate 8,8 with the oxammonium hydrochloride. reaction and generate IB with the formic acid reaction
1, IB
1With acid, anhydride, acyl chloride reaction, get goal object IB.
Concrete reactions steps is:
The IC compounds: andrographolide (1) is used sodium borohydride, and Nickel dichloride hexahydrate reduction generation 9,9 and generation 10,10 of hydrogen chloride gas precursor reactant and amine reaction obtain goal object IC.Same this method, andrographolide (1) is used sodium borohydride, and Nickel dichloride hexahydrate reduction generation 11,11 and generation 12,12 of hydrogen chloride gas precursor reactant and amine reaction obtain goal object ID.
Concrete reactions steps is:
The IE compounds: andrographolide (1) reflux dewatering generation 5,5 in pyridine is reacted with hydrogen reducing generation 13,13 and generation 14,14 of hydrogen chloride gas precursor reactant and amine under the catalysis of palladium carbon, obtains goal object IE.
Concrete reactions steps is:
Wherein the chemical compound 2 and 3 the list of references method that is prepared as obtain (Srinivas Nanduri, Sriram Rajagopal, enkateswarlu Akella.US 6576662B2.2003): the list of references method that is prepared as of chemical compound 5 obtains (Liu Hongmin, Xu Haiwei, Wang Huifang. with sugar and andrographolide is that raw material synthesizes 1,2-and 1,3-glycol cyclic phosphate. Zhengzhou University's journal, 2004,36 (2): 67-70); The chemical compound 9 and 11 the list of references method that is prepared as obtain (Wu Xiaoming is etc. the selective reduction of andrographolide for Wang Xinyang, Huang Wenlong. Chinese pharmaceutical chemistry magazine, 2003,13 (5): 291-293).
Below be the pharmacological experiment data of part of compounds of the present invention:
1, chemical compound is to the inhibitory action of normal COX-2 expression in the mouse macrophage and the inductive COX-2 expression of lipopolysaccharide (LPS)
Western blotting immunoassay: get the macrophage of mice J774A.1, add chemical compound to be tried, andrographolide, the solvent control hatching 24h of 20 μ M.Prepare cytolysate as usual.Bio-Rad analysis of protein reagent is measured protein concentration.This albumen (10 μ g) is dissolved into the 10%Bis-Tris gel again and is transferred on the nitrocellulose filter.Under 4 ℃, this film is placed the TBS buffer immunoblotting sealing that contains 5% nonfat milk, with COX-1, COX-2 or the hatching of actin antibody are spent the night.The link coupled secondary antibody of reuse horseradish peroxidase is carried out two resistive connections and is merged adding Western Lightning Chemiluminesence reagent colour development.Calculate trace density with Image J software for calculation at last.Chemical compound is to normal COX-2 expresses and the inductive COX-2 of lipopolysaccharide (LPS) expresses in the mouse macrophage inhibitory action such as table 1, and the result shows that chemical compound all shows the inhibitory action that COX-2 is expressed, wherein IA
3, IB
8The inhibitory action that the inductive COX-2 of LPS is expressed has surpassed andrographolide.
The inhibitory action that table 1. chemical compound is expressed normal COX-2 expression and the inductive COX-2 of LPS in the mouse macrophage
| Normal(％) | LPS-induced(％) | |
| Control | 100 | 100 |
| Andrographolide | 75 | 85 |
| IA 1 | 93 | 99 |
| IA 3 | 76 | 79 |
| IA 2 | 105 | 99 |
| IB 8 | 60 | 64 |
| IC 2 | 64 | 150 |
| ID 1 | 51 | 106 |
| IC 3 | 106 | 123 |
| IB 1 | 64 | 104 |
| IB 10 | 60 | 95 |
| IB 3 | 107 | 185 |
| IB 2 | 80 | 96 |
| IA 4 | 192 | 132 |
| IA 5 | 264 | 178 |
| IA 6 | 218 | 138 |
| IA 8 | 178 | 105 |
2, chemical compound is to the inhibitory action of normal IL-6/TNF-alpha expression and the inductive IL-6/TNF-alpha expression of lipopolysaccharide (LPS) in the mouse macrophage
The enzyme-linked immunosorbent assay analysis (ELISA) of IL-6 and TNF-α: get the macrophage of mice J774A.1, add chemical compound to be tried, andrographolide, the solvent control hatching 24h of 20 μ M.Collect culture medium, centrifugal five minutes (14000rpm).Getting supernatant divides into groups in-70 ℃ of preservations.Content with TNF-α and IL-6 in the ELISA test kit detection culture medium of mice TNF-α and IL-6.The albumen total concentration of living cells group is measured with Bio-Rad analysis of protein reagent.Get the total amount of TNF-α and IL-6 in the culture medium according to Tot Prot.Chemical compound is to normal IL-6 expresses and the inductive IL-6 of LPS expresses in the mouse macrophage inhibitory action such as table 2, and the result shows that chemical compound all shows the inhibitory action that IL-6 is expressed, wherein IA
2, IA
3, IA
4, IA
5The inhibitory action that the inductive IL-6 of LPS is expressed of these 4 chemical compounds has surpassed andrographolide, IA
6Inhibitory action and andrographolide suitable.Chemical compound is to the inhibitory action such as the table 3 of normal TNF-alpha expression and the inductive TNF-alpha expression of LPS in the mouse macrophage, and the result shows that chemical compound all shows the inhibitory action to the TNF-alpha expression, wherein IA
3, IA
4, IA
5The inhibitory action to the inductive TNF-alpha expression of LPS of these 3 chemical compounds has surpassed andrographolide, IA
6Inhibitory action and andrographolide suitable.
The inhibitory action that table 2. chemical compound is expressed normal IL-6 expression and the inductive IL-6 of LPS in the mouse macrophage
| Normal(％) | LPS induced IL-6(％) | |
| Control | 100 | 100 |
| Andrographolide | 49.21 | 56 |
| IA 1 | 82.56 | 74.67 |
| IA 3 | 81.97 | 37.53 |
| IA 2 | 82.93 | 46.61 |
| IC 2 | 39.44 | 123.79 |
| ID 1 | 37.18 | 111.92 |
| IC 3 | 65.30 | 135.91 |
| IB 1 | 36.90 | 119.47 |
| IB 10 | 53.82 | 100.56 |
| IB 3 | 66.25 | 194.95 |
| IB 2 | 81.92 | 88.18 |
| IA 4 | 58.56 | 29.21 |
| IA 5 | 127.68 | 32.1 |
| IA 6 | 96.05 | 56.87 |
| IA 8 | 70.14 | 44.64 |
Table 3. chemical compound is to the inhibitory action of normal TNF-alpha expression and the inductive TNF-alpha expression of LPS in the mouse macrophage
| Normal(％) | LPS induced TNF-α(％) | |
| Control | 100 | 100 |
| Andrographolide | 63.94 | 62.54 |
| IA 1 | 69.97 | 96.87 |
| IA 3 | 92.88 | 60.8 |
| IA 2 | 79.62 | 75.95 |
| IC 2 | 55.20 | 264.29 |
| ID 1 | 76.47 | 214.17 |
| IC 3 | 90.99 | 267.38 |
| IB 1 | 65.48 | 173.57 |
| IB 10 | 61.76 | 156.82 |
| IB 3 | 117.56 | 315.90 |
| IB 2 | 103.39 | 130.06 |
| IA 4 | 65.78 | 59.96 |
| IA 5 | 152.29 | 41.60 |
| IA 6 | 148.86 | 61.03 |
| IA 8 | 115.10 | 94.36 |
Above pharmacology data shows that general formula of the present invention (I) chemical compound has stronger inhibition COX-2 to be expressed, suppress the TNF-alpha expression, suppress the effect that IL-6 expresses.
The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I) compound or pharmaceutically acceptable salt thereof or the pharmaceutically acceptable carrier as activating agent.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, is meant one or more inert, atoxic solids or liquid filler material, diluent, auxiliary agent etc., and their not reverse and reactive compounds or patient have an effect.
The dosage form of the present composition can be a dosage form commonly used on the pharmaceuticss such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection.
Tablet for oral use and capsule contain traditional excipient such as implant, diluent, lubricant, dispersant and binding agent.
The various dosage forms of pharmaceutical composition of the present invention can be prepared according to the method for knowing in the pharmaceutical field.
The dosage of above activating agent will be different because of prescription.
Usually, proved favourable amount, for reaching required result, the total amount of formula (1) chemical compound of every kilogram of administration in per 24 hours is about 0.01-800mg, and preferred total amount is 0.1-800mg/kg.If necessary, with the form administration of single dose several times.
Yet, if necessary, also can depart from above-mentioned consumption, promptly this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time and the interval of seriousness, preparation and administration.
By the following examples the present invention is further described.
The specific embodiment:
Embodiment 1
3, the preparation of 19-isopropylidene andrographolide (2):
Add 15.0g andrographolide (1) (42.9mmol) in the 500ml round-bottomed flask, 20ml 2, the 2-dimethoxy propane, and catalytic amount p-methyl benzenesulfonic acid pyridiniujm (PPTs), 300ml benzene, 40ml DMSO, reflux 30min, reaction is finished.Reactant liquor is chilled to room temperature, add triethylamine (about 10ml) and transfer PH=8, add 200ml benzene dilute reaction solution, saturated aqueous common salt (300ml * 3) washing, anhydrous sodium sulfate drying, filtering and concentrating, there is solid to separate out, filter white solid 15.0g, yield 90%, mp:194-196 ℃ (document mp:194.5 ℃).
Embodiment 2
3, the preparation of 19-isopropylidene-12-hydroxyl-andrographolide (3):
Add 4.0g2 (10.3mmol) in the 100ml round-bottomed flask, 5.0gPDC (13.3mmol), 60ml dichloromethane, reflux, TLC monitoring reaction.Reaction is finished, and stops heating, is chilled to room temperature, column chromatography for separation (petroleum ether: ethyl acetate=3: 2) get white solid 2.8g, yield 70%.
Embodiment 3
12-propionyloxy-14-desoxyandrographolide (IA
1) preparation:
Add 1.0g3 (2.6mmol) in the 50ml round-bottomed flask, 2ml propionic andydride (21.2mol), catalytic amount DMAP, the 25ml dichloromethane, 25 ℃ are reacted 12h, pressure reducing and steaming solvent down, residue 150ml acetic acid ethyl dissolution, saturated common salt washing, anhydrous sodium sulfate drying, boil off solvent, get light grease 4, add acetic acid 7ml, water 3ml, 25 ℃ are reacted 1h, reactant liquor 100ml acetic acid ethyl dissolution, saturated aqueous common salt down, saturated sodium bicarbonate solution washs to pH and is about 7, anhydrous sodium sulfate drying boils off solvent, gets light grease, column chromatography for separation (petroleum ether: ethyl acetate=3: 2), get white solid 0.63g, yield 60%, mp:141-142 ℃.
IR(KBr)v：3342，3133，2939，2864，1754，1730，1646，1446，1341，11185，1031.
1H-NMR(CDCl
3，300MHz)δ：7.35(s，1H，14-H)，5.69(t，1H，12-H)，4.90(s，1H，17-H)，4.83(s，2H，15-H)，4.76(s，1H，17-H)，4.14(d，1H，3-H)，3.46(t，1H，19-H)，3.29(t，1H，19-H)，2.42(brs，-OH)，2.38(q，2H，-
CH 2-C＝O)，1.24(s，3H，18-CH
3)，1.17(t，3H，
CH 3CH
2C＝O)，0.64(s，3H，20-CH
3)；MS(ESI，m/z)：429.1(M+Na)
+(base peak).
The positive hexylyloxy of 12--14-desoxyandrographolide (IA
2) preparation:
With reference to IA
1Preparation method, by 3 with n-caproic anhydride make IA
2, column chromatography for separation (petroleum ether: ethyl acetate=3: 1), get white solid, yield 60%, mp:98-103 ℃.
IR(KBr)v：3413，3316，2929，2853，1766，1719，1643，1450，1244，1040.
1H-NMR(CDCl
3，300MHz)δ：7.32(s，1H，14-H)，5.67(t，1H，12-H)，4.89(s，1H，17-H)，4.81(s，2H，15-H)，4.74(s，1H，17-H)，4.17(d，1H，3-H)，3.46(t，1H，19-H)，3.43(t，1H，19-H)，2.80(brs，-OH)，2.30(t，2H，-
CH 2-C＝O)，1.23(s，3H，18-CH
3)，0.91(t，3H，
CH 3(CH
2)
4C＝O)，0.62(s，3H，20-CH
3)；MS(ESI，m/z)：471.2(M+Na)
+(base peak).
12-benzoyloxy group-14-desoxyandrographolide (IA
3) preparation:
With reference to IA
1Preparation method, by 3 with Benzenecarbonyl chloride. make IA
3, column chromatography for separation (petroleum ether: ethyl acetate=2: 1), get white solid, yield 57%, mp:177-180 ℃.
IR(KBr)v：3524，3482，2943，2866，1749，1702，1452，1270，1037.
1H-NMR(CDCl
3，300MHzδ：8.05(d，2H，Ph)，7.59(t，1H，Ph)，7.50-7.42(t，3H，Ph，14-H)，5.93(t，1H，12-H)，4.94-4.85(d，4H，17-H，15-H)，4.15(t，1H，3-H)，3.47(t，1H，19-H)，3.31(t，1H，19-H)，2.03(brs，-OH)，1.27(s，3H，18-CH
3)，0.66(s，3H，20-CH
3)；MS(ESI，m/z)：493.2(M+K)
+(base peak).
Embodiment 4
12-p-nitrophenyl acyloxy-14-desoxyandrographolide (IA
4) preparation:
Add 1.0g3 (2.6mmol) in the 50ml round-bottomed flask, 0.47g Nitrodracylic acid (2.8mmol), 25ml dichloromethane, DMAP catalytic amount, stirring at room 30min.Ice bath adds 0.66gDCC (3.2mmol) down, continues to stir 10h, filters, filtrate boils off solvent, residue 25ml acetic acid ethyl dissolution is put refrigerator overnight, filters, filtrate boils off solvent and gets light grease 4, add acetic acid 7ml, water 3ml, 25 ℃ are reacted 1h down, reactant liquor 100ml acetic acid ethyl dissolution, saturated aqueous common salt, saturated sodium bicarbonate solution wash to pH and are about 7, anhydrous sodium sulfate drying, boil off solvent, get light grease, column chromatography for separation (petroleum ether: ethyl acetate=1: 1), get white solid 0.64g, yield 50%, mp:119-122 ℃.
IR(KBr)v：3409，3111，2950，2873，1729，1625，1545，1452，1279，897，724.
1H-NMR(CDCl
3，300MHz)δ：9.25-9.14(d，4H，Ph)，7.50(s，1H，14-H)，6.00(t，1H，12-H)，4.98(s，1H，17-H)，4.91(s，2H，15-H)，4.86(s，1H，17-H)，4.18(m，1H，3-H)，3.43(t，1H，19-H)，3.30(t，1H，19-H)，1.23(s，3H，18-CH
3)，0.68(s，3H，20-CH
3)；MS(ESI，m/z)：475(M-NO
2+Na)
+(base peak).
12-is to methylbenzene acyloxy-14-desoxyandrographolide (IA
5) preparation:
With reference to IA
4Preparation method, by 3 with p-methylbenzoic acid make IA
5, column chromatography for separation (petroleum ether: ethyl acetate=1: 1), get white solid, yield 47%, mp:176-178 ℃.
IR(KBr)v：3472，2938，2866，1744，1700，1636，1445，1200，1037，828.
1H-NMR(CDCl
3，300MHz)δ：7.85(d，2H，Ph)，7.41(m，3H，Ph，14-H)，5.92(t，1H，12-H)，4.93(s，1H，17-H)，4.84(s，2H，15-H)，4.18(d，1H，3-H)，3.49(t，1H，19-H)，3.31(d，1H，19-H)，1.23(s，3H，18-CH
3)，0.65(s，3H，20-CH
3)；MS(ESI，m/z)：491(M+Na)
+(base peak).
12-(3,4-methylene-dioxy cinnamoyloxy group)-14-desoxyandrographolide (IA
6) preparation:
With reference to IA
4Preparation method, by 3 and 3, the 4-dimethoxy-cinnamic acid makes IA
6, column chromatography for separation (petroleum ether: ethyl acetate=3: 2), get white solid, yield 50%, mp:158-161 ℃.
IR(KBr)v：3413，2938，1754，1704，1495，1445，1250，1160，1034，926.
1H-NMR(CDCl
3，300MHz)δ：7.62(d，1H，Ph)，7.57(s，1H，Ph)，7.02(d，2H，Ph，14-H)，6.83(d，1H，Ph-
CH＝CH-)，6.28(d，1H，Ph-CH＝
CH-)，6.02(s，2H，-O-
CH 2-O-)，5.81(t，1H，12-H)，4.92(s，1H，17-H)，4.84(m，3H，15-H，17-H)，4.18(m，1H，3-H)，3.47(t，1H，19-H)，3.32(t，1H，19-H)，1.22(s，3H，18-CH
3)，0.65(s，3H，20-CH
3)；MS(ESI，m/z)：547(M+Na)
+(base peak).
12-(3,4-methylene-dioxy-6-Nitrobenzol acyloxy)-14-desoxyandrographolide (IA
8) preparation:
With reference to IA
4Preparation method, by 3 and 3,4-methylene-dioxy-6-nitrobenzoic acid makes IA
8, column chromatography for separation (petroleum ether: ethyl acetate=3: 2), get white solid, yield 40%, mp:166-169 ℃.
IR(KBr)v：3404，2938，2873，1733，1636，1614，1527，1434，1329，1102，1034，922，634.
1H-NMR(CDCl
3，300MHz)δ：7.46(s，1H，Ph)，7.38(s，1H，Ph)，7.03(s，1H，14-H)，6.18(s，2H，-O-
CH 2-O-)，5.88(t，1H，12-H)，4.92(s，1H，17-H)，4.87(s，2H，15-H)，4.80(s，1H，17-H)，4.17(d，1H，3-H)，3.45(s，1H，19-H)，3.32(t，1H，19-H)，1.22(s，3H，18-CH
3)，0.64(s，3H，20-CH
3)；MS(ESI，m/z)：566(M+Na)
+(basepeak).
12-O-methoxy benzoyl group-14-desoxyandrographolide (IA
11) preparation:
With reference to IA
4Preparation method, by 3 with o-methoxybenzoic acid make IA
11, column chromatography for separation (petroleum ether: ethyl acetate=1: 1), get white solid, yield 45%, mp:166-169 ℃.
IR(KBr)v：3488，2945，2866，1733，1639，1610，1509，1290，1254，1034.
1H-NMR(CDCl
3，300MHz)δ：8.00(d，2H，Ph)，7.39(s，1H，Ph)，6.94(d，2H，Ph，14-H)，5.90(t，1H，12-H)，4.92(s，1H，17-H)，4.83(s，3H，15-H，17-H)，4.18(d，1H，3-H)，3.89(s，3H，-OCH
3)3.48(t，1H，19-H)，3.31(d，1H，19-H)，1.26(s，3H，18-CH
3)，0.65(s，3H，20-CH
3)；MS(ESI，m/z)：507(M+Na)
+(base peak).
Embodiment 5
11, the preparation of 12-dehydrorographolide (5):
Add 3.0g1 (8.6mmol) in the 25ml round-bottomed flask, 0.6gAl
2O
3(5.9mmol), the 8ml pyridine, reflux 12h, it is steady to be chilled to the chamber, removes by filter Al
2O
3, use the chloroform washing leaching cake, the mother solution evaporated under reduced pressure gets yellow oil, column chromatography for separation (petroleum ether: ethyl acetate=1: 1), get white solid 2.5g, yield 88%.
Embodiment 6
19-triphenyl-3-oxime-11,12-dehydrorographolide (IB
3) preparation:
Add 2.0g5 (6.0mmol) in the 50ml round-bottomed flask, 1.7g triphenylchloromethane (7.8mmol), dichloromethane 30ml.Stirring and dissolving adds 0.73ml N-methylmorpholine (6.6mmol), stirring at room 12h, boil off solvent, residue 150ml acetic acid ethyl dissolution, saturated common salt washing, anhydrous sodium sulfate drying, boil off solvent, get yellow oil, ethyl acetate-petroleum ether recrystallization gets 6, white solid 2.87g, yield 83%.
Add 2.0g6 (3.5mmol) in the 50ml round-bottomed flask, 2.0gPDC (5.2mmol), 25ml dichloromethane, reflux, TLC monitoring reaction.Reaction is finished, and stops heating, is chilled to room temperature, column chromatography for separation (petroleum ether: ethyl acetate=2: 1) get 7, white solid 1.0g, yield 50%.
Add 1.0g7 (1.7mmol) in the 25ml round-bottomed flask, 0.15g oxammonium hydrochloride. (2.1mmol), 5ml pyridine, 40 ℃ of reaction 5h, boil off solvent, residue 150ml acetic acid ethyl dissolution, saturated common salt washing, anhydrous sodium sulfate drying, boil off solvent, get white solid, re-crystallizing in ethyl acetate gets white solid 0.6g, yield 58%.mp：163℃(dec.)。
IR(KBr)v：3419，3075，2938，2859，1754，1639，1488，1383，1077.
1H-NMR(CDCl
3，300MHz)δ：8.05(s，1H，N-OH)，7.42-7.11(m，16H，Ph，14-H)，6.90(q，1H，11-H)，6.15(d，1H，12-H)，4.79(s，2H，15-H)，4.72(s，1H，17-H)，4.49(s，1H，17-H)，3.33(d，1H，19-H)，3.15(d，1H，19-H)，2.98(d，1H，9-H)，1.36-1.24(d，6H，18-CH
3，20-CH
3)；MS(ESI，m/z)：610(M+Na)
+(base peak).
Embodiment 7
3-oxime-11,12-dehydrorographolide (IB
1) preparation:
Add 0.5g IB in the 50ml round-bottomed flask
3(0.85mmol), 10ml dichloromethane, 5ml formic acid, 25 ℃ are stirred 30min down, boil off solvent, residue 100ml acetic acid ethyl dissolution, saturated aqueous common salt, saturated sodium bicarbonate solution washs to pH and is about 7, anhydrous sodium sulfate drying boils off solvent, gets the lightpink solid, ethyl alcohol recrystallization gets white solid 0.2g, yield 68%.mp：131-134℃。
IR(KBr)v：3436，3083，2945，1837，1751，1639，1448，1383，1272，1091，1001.
1H-NMR(CDCl
3，300MHz)δ：7.18(s，1H，14-H)，6.93(q，1H，11-H)，6.15(d，1H，12-H)，4.82(s，3H，15-H，17-H)，4.58(s，1H，17-H)，3.80(d，1H，19-H)，3.46(d，1H，19-H)，3.02(d，1H，9-H)，1.26(s，3H，18-CH
3)，0.93(s，3H，20-CH
3)；
13C-NMR(CDCl
3，75MHz)δ：164.9，147.7，143.1，135.7，129.2，127.9，121.4，109.6，69.6，65.2，60.9，54.9，45.5，38.7，36.7，36.5，23.6，22.9，18.1，15.0；MS(ESI，m/z)：368.2(M+Na)
+(base peak).
Embodiment 8
3-acetyl oxime-19-acetyl group-11,12-dehydrorographolide (IB
4) preparation:
Add 0.2g IB in the 25ml round-bottomed flask
1(0.58mmol), 0.2ml acetic anhydride (2.1mol), catalytic amount DMAP, the 10ml dichloromethane, 25 ℃ are reacted 12h, pressure reducing and steaming solvent, residue 100ml acetic acid ethyl dissolution down, the saturated common salt washing, anhydrous sodium sulfate drying, boil off molten, column chromatography for separation (petroleum ether: ethyl acetate=2: 1), get light yellow oil 0.15g, yield 60%.
IR(KBr)v：3083，2938，2859，1740，1643，1445，1372，1236，1081，1041.
1H-NMR(CDCl
3，300MHz)δ：7.18(s，1H，14-H)，6.94(q，1H，11-H)，6.15(d，1H，12-H)，4.83(s，3H，15-H，17-H)，4.66(d，1H，19-H)，4.60(s，1H，17-H)，3.85(d，1H，19-H)，3.18(d，1H，9-H)，2.17(s，3H，
CH 3C＝O)，2.02(s，3H，
CH 3C＝O)，1.36(s，3H，18-CH
3)，1.05(s，3H，20-CH
3)；MS(ESI，m/z)：452.2(M+Na)
+(basepeak).
3-propionyl oxime-19-propiono-11,12-dehydrorographolide (IB
5) preparation:
With reference to IB
4Preparation method, by IB
1Make IB with propionic andydride
5, column chromatography for separation (petroleum ether: ethyl acetate=2: 1), get light yellow oil, yield 62%.
IR(KBr)v：3083，2931，2859，1733，1639，1455，1380，1347，1196，1077.
1H-NMR(CDCl
3，300MHz)δ：7.18(s，1H，14-H)，6.93(q，1H，11-H)，6.15(d，1H，12-H)，4.83(s，1H，15-H)，4.83(s，2H，15-H，17-H)，4.73(d，1H，19-H)，4.60(s，1H，17-H)，3.85(d，1H，19-H)，3.19(d，1H，9-H)，2.43(q，2H，CH
3 CH 2C＝O)，2.30(q，2H，CH
3 CH 2C＝O)，1.37(s，3H，18-CH
3)，1.17(s，3H，20-CH
3)，1.07(s，3H，
CH 3CH
2C＝O)，1.05(s，3H，
CH 3CH
2C＝O)；MS(ESI，m/z)：480.2(M+Na)
+(base peak).
The positive hexanoyl oxime-19-positive caproyl-11 of 3-, 12-dehydrorographolide (IB
6) preparation:
With reference to IB
4Preparation method, by IB
1Make IB with n-caproic anhydride
6, column chromatography for separation (petroleum ether: ethyl acetate=3: 1), get light yellow oil, yield 48%.
IR(KBr)v：3080，2956，2931，2871，1736，1643，1455，1378，1242，1164，1098.
1H-NMR(CDCl
3，300MHz)δ：7.18(s，1H，14-H)，6.95(q，1H，11-H)，6.15(d，1H，12-H)，4.83(s，3H，15-H，17-H)，4.72(d，1H，19-H)，4.60(s，1H，17-H)，3.84(s，1H，19-H)，3.18(d，1H，9-H)，2.38(t，2H，-
CH 2C＝O)，2.25(t，2H，-
CH 2C＝O)，1.34(s，3H，18-CH
3)，1.06(s，3H，20-CH
3)，0.99(d，6H，
CH 3(CH
2)
4C＝O)；MS(ESI，m/z)：564.3(M+Na)
+(base peak).
3-benzoyl oxime-19-benzoyl-11,12-dehydrorographolide (IB
7) preparation:
With reference to IB
4Preparation method, by IB
1Make IB with Benzenecarbonyl chloride.
7, column chromatography for separation (petroleum ether: ethyl acetate=2: 1), get light yellow oil, yield 40%.
IR(KBr)v：3075，2978，2937，2866，1748，1720，1601，1450，1270，1059，896，710.
1H-NMR(CDCl
3，300MHz)δ：8.04(m，4H，Ph)，7.57(m，2H，Ph)，7.47(m，4H，Ph)，7.18(s，1H，14-H)，6.96(q，1H，11-H)，6.15(d，1H，12-H)，4.82(t，4H，15-H，17-H，19-H)，4.63(s，1H，17-H)，4.22(d，1H，19-H)，3.37(d，1H，9-H)，1.28(s，3H，18-CH
3)，1.14(s，3H，20-CH
3)；MS(ESI，m/z)：576.2(M+Na)
+(base peak).
Embodiment 9
3-is to chlorobenzoyl oxime-11,12-dehydrorographolide (IB
8) preparation:
Add 0.5g IB in the 50ml round-bottomed flask
3(0.85mmol), 0.15g parachlorobenzoic-acid (0.g4mmol), 25ml dichloromethane, DMAP catalytic amount, stirring at room 30min.Ice bath adds 0.22gDCC (1.1mmol) down, continues to stir 10h, filters, filtrate boils off solvent, and residue 25ml acetic acid ethyl dissolution is put refrigerator overnight, filter, filtrate boils off solvent and gets light grease 4, adds dichloromethane 10ml, formic acid 5ml, 25 ℃ are reacted 30min down, steaming desolventizes, reactant liquor 100ml acetic acid ethyl dissolution, saturated aqueous common salt, saturated sodium bicarbonate solution washs to pH and is about 7, anhydrous sodium sulfate drying boils off solvent, gets light grease, column chromatography for separation (petroleum ether: ethyl acetate=2: 1), get white solid 0.12g, yield 30%, mp:123-125 ℃.
IR(KBr)v：3480，3299，3075，2960，2851，1751，1744，1664，1441，1351，1167，1021.
1H-NMR(CDCl
3，300MHz)δ：7.99(d，2H，Ph)，7.46(d，2H，Ph)，7.18(s，1H，14-H)，6.92(q，1H，11-H)，6.12(d，1H，12-H)，4.82(d，3H，15-H，17-H)，4.60(d，1H，17-H)，3.92(d，1H，19-H)，3.60(m，1H，19-H)，2.99(m，1H，9-H)，2.80(brs，1H，-OH)，1.33(s，3H，18-CH
3)，0.96(s，3H，20-CH
3)；MS(ESI，m/z)：506.1(M+Na)
+(base peak).
3-phenylacetyl oxime-11,12-dehydrorographolide (IB
9) preparation:
With reference to IB
8Preparation method, by IB
3Make IB with phenylacetic acid
9, column chromatography for separation (petroleum ether: ethyl acetate=2: 1), get white solid, yield 35%, mp:154-155 ℃.
IR(KBr)v：3503，3090，2929，2854，1748，1642，1596，1346，1104，1050.
1H-NMR(CDCl
3，300MHz)δ：7.31(s，5H，Ph)，7.19(s，1H，14-H)，6.91(q，1H，11-H)，6.15(d，1H，12-H)，4.83(s，3H，15-H，17-H)，4.58(s，1H，17-H)，3.79(m，3H，19-H，Ph-
CH 2-)，3.48(d，1H，19-H)，2.84(m，1H，9-H)，1.33(s，3H，18-CH
3)，0.91(s，3H，20-CH
3)；MS(ESI，m/z)：486.2(M+Na)
+(base peak).
3-cinnamoyl oxime-19-cinnamoyl-11,12-dehydrorographolide (IB
10) preparation:
With reference to IB
8Preparation method, by IB
1Make IB with cinnamic acid
10, column chromatography for separation (petroleum ether: ethyl acetate=3: 1), get light yellow solid, yield 50%, mp:77-80 ℃.
IR(KBr)v：2931，2851，1748，1708，1634，1448，1308，1159，983.
1H-NMR(CDCl
3，300MHz)δ：7.78(d，1H，Ph-C
H＝CH-)，7.70(d，1H，Ph-C
H＝CH-)，7.53(m，4H，Ph)，7.36(m，6H，Ph)，7.18(s，1H，14-H)，6.95(q，1H，11-H)，6.54(d，1H，Ph-CH＝C
H-)，6.38(d，1H，Ph-CH＝C
H-)，6.17(d，1H，12-H)，4.86(s，1H，17-H)，4.82(s，2H，15-H)，4.75(d，1H，19-H)，4.62(s，1H，17-H)，4.12(d，1H，19-H)，3.27(d，1H，9-H)，1.26(s，3H，18-CH
3)，1.07(s，3H，20-CH
3)；MS(ESI，m/z)：628.3(M+Na)
+(basepeak).
Embodiment 10
3-methyloxime-11,12-dehydrorographolide (IB
2) preparation:
Add 1.0g7 (1.7mmol) in the 25ml round-bottomed flask, 0.18g methoxy amine hydrochlorate (2.1mmol), 5ml pyridine, 40 ℃ of reaction 5h boil off solvent, residue 150ml acetic acid ethyl dissolution, the saturated common salt washing, anhydrous sodium sulfate drying boils off solvent, gets light yellow oil, add dichloromethane 10ml, formic acid 5ml, 25 ℃ are reacted 30min down, and steaming desolventizes, reactant liquor 100ml acetic acid ethyl dissolution, saturated aqueous common salt, saturated sodium bicarbonate solution wash to pH and are about 7, anhydrous sodium sulfate drying, boil off solvent, get light yellow solid, ethyl alcohol recrystallization gets white solid 0.34g, yield 55%.mp：163℃(dec.)。
IR(KBr)v：3439，3083，2974，2945，1747，1636，1441，1351，1297，1048.
1H-NMR(CDCl
3，300MHz)δ：7.18(s，1H，14-H)，6.91(q，1H，11-H)，6.14(d，1H，12-H)，4.82(t，3H，15-H，17-H)，4.57(s，1H，17-H)，3.84(s，3H，-OCH
3)，3.78(d，1H，19-H)，3.46(t，1H，19-H)，1.27(s，3H，18-CH
3)，0.88(s，3H，20-CH
3)C
13-NMR(CDCl
3.75MHz)δ：172.5，163.8，147.7，143.0，135.7，129.2，121.4，109.5，69.5，65.2，61.6，60.8，54.7，44.9，38.6，36.6，36.3，23.7，19.0，14.9；MS(ESI，m/z)：360(M+H)
+(basepeak).
Embodiment 11
12,13-dihydro andrographolide (9) and 14-deoxidation-12, the preparation of 13-dihydro andrographolide (11):
1.0g (2.9mmol) 1 adding is had in the three-necked bottle of agitator, thermometer, reflux condensing tube, add 30ml methanol, heating in water bath makes dissolving fully.Remove water-bath, treat that temperature reduces to 40 ℃, add 0.22g (0.93mmol) Nickel dichloride hexahydrate, stirring and dissolving forms light green solution.Use cryosel instead and bathe, the control temperature adds 0.25g (6.6mmol) sodium borohydride in batches under-5-5 ℃, add in about 30min.Finish, under this temperature, continue stirring reaction 30min (TLC follows the tracks of reaction).Add the ice-cold saturated aqueous common salt of 40ml, stir 20min, ethyl acetate (50ml * 4) extraction, merge organic layer, saturated common salt washing, anhydrous sodium sulfate drying, filtering and concentrating promptly separates out 12, the crystallization of 13-dihydro andrographolide, sucking filtration, oven dry gets 90.6g, filtrate is through column chromatography, and (v: v=1: 1) eluting gets 110.15g to petroleum ether-ethyl acetate, white solid, yield 10%, mp:156-158 ℃.(v: v=2: 3) eluting gets 90.1g to petroleum ether-ethyl acetate, white solid, yield 70%, mp:168-170 ℃.
Embodiment 12
15-chloro-12, the preparation of 13-dihydro andrographolic acid methyl ester (10):
In 50ml two neck bottles, add 1.0g 9 (2.8mmol), the absolute methanol of 25ml, wherein a bottleneck is the reflux condensing tube that has drying tube, another bottleneck is jumped a queue, and places 70 ℃ of oil baths, is heated to methanol eddy, fed exsiccant hydrogen chloride gas about 6 hours, remove oil bath, be chilled to room temperature, ethyl acetate (50ml * 3) extraction, merge organic layer, the saturated common salt washing, saturated sodium bicarbonate solution is washed till neutrality, saturated common salt washing again, anhydrous sodium sulfate drying, filtering and concentrating, through silica gel column chromatography, petroleum ether: eluent ethyl acetate (v: v=1: 1) get white solid 0.4g, yield 35%, mp:110-114 ℃.
IR(KBr)v：3430，3328，2931，1747，1639，1448，1380，1207，1084，1027
1H-NMR(CDCl
3，300MHz)δ：4.77(s，2H，17-H)，4.19(t，1H，14-H)，4.10(q，1H，19-H)，3.74(q，1H，19-H)，3.46(m，2H，15-H)，2.95(d，1H，3-H)，2.03(s，3H，-OCH
3)，1.22(s，3H，18-CH
3)，0.86(s，3H，20-CH
3)；MS(ESI，m/z)：425(M+Na)
+(base peak).
15-chloro-14-deoxidation-12, the preparation of 13-dihydro andrographolic acid methyl ester (12):
Preparation method with reference to 10 makes 12, column chromatography for separation (petroleum ether: ethyl acetate=2: 1), get colourless oil, yield 48% by 11.
IR(KBr)v：3459，2937，2866，1765，1450，1420，1235，1046.
1H-NMR(CDCl
3，300MHz)δ：4.33(d，1H，17-H)，4.15(d，1H，17-H)，3.67(s，3H，-OCH
3)，3.58-3.20(m，5H，3-H，15-H，19-H)，2.31(m，1H，13-H)，1.18(s，3H，18-CH
3)，0.87(s，3H，20-CH
3)；
13C-NMR(CDCl
3，75MHz)δ：178.5，139.0，126.1，81.7，65.3，53.2，52.0，47.3，42.9，41.9，41.8，40.1，37.6，34.5，33.6，28.9，27.8，26.0，25.5，21.4，18.3；MS(ESI，m/z)：409(M+Na)
+(base peak).
Embodiment 13
12,13-dihydro Herba Andrographis lactams (IC
1) preparation:
Add 0.5g 10 (1.2mmol) in the 25ml round-bottomed flask, 5ml methanol after the stirring and dissolving, adds the 5ml strong aqua ammonia, and stirring is spent the night.Put and continue reaction in 40 ℃ of oil baths, TLC follows the tracks of reaction, and reaction is finished, remove methanol under reduced pressure, ethyl acetate (50ml * 3) extraction merges organic layer, the saturated common salt washing, 10% salt pickling, saturated sodium bicarbonate solution is washed till pH and is about 7, saturated common salt washing again, anhydrous sodium sulfate drying, filtering and concentrating, through the C-18 column chromatography, 75% methanol-eluted fractions gets white solid 0.15g, yield 34%, mp:88-91 ℃.
IR(KBr)v：3486，3249，2931，1672，1618，1445，1376，1272，1034.
1H-NMR(DMSO-d
6，300MHz)δ：7.43(s，1H，-NH)，5.01(q，2H，17-H)，4.27(q，1H，14-H)，4.04(dd，1H，15-H)，3.85(dd，1H，15-H)，3.29(m，1H，19-H)，3.22(m，1H，19-H)，2.98(d，1H，J＝10.5Hz，3-H)，1.07(s，3H，18-H)，0.86(s，3H，20-H)；
13C-NMR(DMSO-d
6，75MHz)δ：177.5，140.4，125.7，79.1，67.8，63.2，51.9，50.7，47.3，42.6，38.6，34.9，34.2，28.2，26.5，25.0，23.4，20.7，19.6，19.4；MS(ESI，m/z)：352(M+H)
+(base peak).
N-methyl isophthalic acid 2,13-dihydro Herba Andrographis lactams (IC
2) preparation:
With reference to IC
1Preparation method, by 10 with methylamine make IC
2, through the C-18 column chromatography, 70% methanol-eluted fractions gets white solid, yield 40%, mp:70-75 ℃.
IR(KBr)v：3402，2933，2869，1751，1669，1491，1443，1401，1207，1106，1038.
1H-NMR(CDCl
3，300MHz)δ：4.24-4.21(m，2H，17-H)，3.49-3.23(m，6H，14-H，15-H，3-H，19-H)，2.88(s，3H，-NCH
3)，2.30(s，1H，13-H)，1.21(s，3H，18-CH
3)；
13C-NMR(CDCl
3，75MHz)δ：174.4，139.1，126.1，80.7，66.9，64.2，57.2，51.8，48.1，42.7，38.4，34.7，33.9，29.7，28.1，26.3，24.8，22.1，20.8，19.4，18.8；MS(ESI，m/z)：366(M+H)
+(base peak).
N-n-pro-pyl-12,13-dihydro Herba Andrographis lactams (IC
3) preparation:
With reference to IC
1Preparation method, by 10 with n-propylamine make IC
3, through the C-18 column chromatography, 60% methanol-eluted fractions gets white solid, yield 30%, mp:90-95 ℃.
IR(KBr)v：3537，3378，2938，1751，1661，1632，1445，1380，1196，1037.
1H-NMR(CDCl
3，300MHz)δ：4.45(s，1H，17-H)，4.24(d，1H，17-H)，3.58(dd，1H，14-H)，3.50(m，1H，15-H)，3.32(m，4H，15-H，3-H，-NCH
2-)，3.00(m，2H，19-H)，2.40(m，1H，13-H)，1.58(s，3H，18-CH
3)，1.23(s，3H，20-CH
3)，0.91(s，3H，-NCH
2CH
2 CH 3)；
13C-NMR(CDCl
3，75MHz)δ：174.3，139.2，126.6，80.7，67.0，64.2，54.9，51.8，48.4，44.1，42.7，38.4，34.7，33.9，28.1，26.3，24.7，22.5，20.8，20.5，19.4，18.8，11.2；MS(ESI，m/z)：416(M+Na)
+(base peak).
14-deoxidation-12,13-dihydro Herba Andrographis lactams (ID
1) preparation:
With reference to IC
1Preparation method, by 12 with ammonia make ID
1, column chromatography for separation (petroleum ether: ethyl acetate=1: 1), get white solid, yield 46%, mp:90-92 ℃.
IR(KBr)v：3413，2937，2866，1688，1448，1369，1243，1200，1036.
1H-NMR(CDCl
3，300MHz)δ：5.70(brs，1H，-NH)，4.13(m，2H，17-H)，3.33(m，5H，3-H，15-H，19-H)，2.88(brs，-OH)，1.22(s，3H，18-CH
3)，0.78(s，3H，20-CH
3)；
13C-NMR(CDCl
3，75MHz)δ：180.1，138.9，126.7，80.7，64.2，51.8，42.7，41.2，40.3，38.5，33.9，31.4，28.1，27.4，25.8，22.4，20.8，19.4，18.5；MS(ESI，m/z)：336(M+H)
+(base peak).
N-methyl isophthalic acid 4-deoxidation-12,13-dihydro Herba Andrographis lactams (ID
2) preparation:
With reference to IC
1Preparation method, by 12 with methylamine make ID
2, column chromatography for separation (petroleum ether: ethyl acetate=3: 2), get colorless oil, yield 30%.
IR(KBr)v：3413，2937，2866，1688，1448，1369，1243，1200，1036.
1H-NMR(CDCl
3，300MHz)δ：4.23(m，2H，17-H)，3.46-3.28(m，5H，3-H，15-H，19-H)，2.83(s，3H，-NCH
3)，1.23(s，3H，18-CH
3)，0.83(s，3H，20-CH
3)；
13C-NMR(CDCl
3，75MHz)δ：177.0，138.9，126.0，80.6，64.4，51.8，47.7，42.7，42.2，42.0，37.7，34.9，33.9，31.7，29.7，28.1，25.7，24.6，22.5，20.8，18.8；MS(ESI，m/z)：372(M+Na)
+(base peak).
Claims (10)
1. following general formula (I) chemical compound, DL body, optical isomer and pharmaceutically acceptable salt thereof the purposes in preparation COX-2 expression inhibitor and/or TNF-alpha inhibitor and/or IL-6 inhibitor:
Wherein: R
1Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue;
R
2Represent hydrogen, or R
1With R
2Representative=N-R together
7
R
3Representation hydroxy; the alkoxyl of the straight or branched of C1～C8; the alkanoyl of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8 replaces or unsubstituted fragrant oxygen base; replace or unsubstituted aromaticacyl radical; replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue, or R
1, R
2With R
3Form hexatomic ring or the heptatomic ring that contains carbon and oxygen together;
R
4Represent hydrogen;
R
5Represent the alkyl of the straight or branched of C1～C8, or R
4With R
5Represent "=CH together
2",
R
6Representative
R
7Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue;
R
8Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue;
X represents oxygen, sulfur, NR
9
R
9Represent hydrogen; the alkyl of the straight or branched of C1～C8; the alkoxyl of the straight or branched of C1～C8; the alkanoyl of the straight or branched of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8; the alkyl halide acyl group of the straight or branched of C1～C8; replace or unsubstituted aryl; replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted heterocyclic base; replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue.
In above-mentioned replacement or the unsubstituted aryl; the group that replaces is selected from hydroxyl; the alkyl of the straight or branched of C1～C8, the straight or branched alkoxyl of C1～C8, the straight or branched alkanoyl of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, halogen; nitro, amino.
In above-mentioned replacement or the unsubstituted fragrant oxygen base; the group that replaces is selected from hydroxyl; the alkyl of the straight or branched of C1～C8, the straight or branched alkoxyl of C1～C8, the straight or branched alkanoyl of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, halogen; nitro, amino.
In above-mentioned replacement or the unsubstituted aromaticacyl radical; the group that replaces is selected from hydroxyl; the alkyl of the straight or branched of C1～C8, the straight or branched alkoxyl of C1～C8, the straight or branched alkanoyl of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, halogen; nitro, amino.
In above-mentioned replacement or the unsubstituted heterocyclic base; the group that replaces is selected from hydroxyl; the alkyl of the straight or branched of C1～C8, the straight or branched alkoxyl of C1～C8, the straight or branched alkanoyl of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, halogen; nitro, amino.
In above-mentioned replacement or the unsubstituted fragrant hetero-oxy; the group that replaces is selected from hydroxyl; the alkyl of the straight or branched of C1～C8, the straight or branched alkoxyl of C1～C8, the straight or branched alkanoyl of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, halogen; nitro, amino.
In the assorted acyl group of above-mentioned replacement or unsubstituted virtue; the group that replaces is selected from hydroxyl; the alkyl of the straight or branched of C1～C8, the straight or branched alkoxyl of C1～C8, the straight or branched alkanoyl of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, halogen; nitro, amino.
2. according to general formula (I) chemical compound and the pharmaceutical salts thereof of claim 1: R wherein
1Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue; R
2Represent hydrogen, or R
1With R
2Representative=N-R together
7R
3Representation hydroxy; the alkoxyl of the straight or branched of C1～C8; the alkanoyl of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8 replaces or unsubstituted fragrant oxygen base; replace or unsubstituted aromaticacyl radical; replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue, or R
1, R
2With R
3Form hexatomic ring or the heptatomic ring that contains carbon and oxygen together; R
4Represent hydrogen; R
5Represent the alkyl of the straight or branched of C1～C8, or R
4With R
5Represent "=CH together
2",
R
6Representative
R
7Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue; R
8Represent hydrogen; hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8; the alkyl halide acyl group of the straight or branched of C1～C8 replaces or unsubstituted fragrant oxygen base, replaces or unsubstituted aromaticacyl radical; replace or unsubstituted fragrant hetero-oxy; replace or the assorted acyl group of unsubstituted virtue, X represents oxygen, sulfur.
3. according to general formula (I) chemical compound and the pharmaceutical salts thereof of claim 1: R wherein
1Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue; R
2Represent hydrogen, or R
1With R
2Representative=N-R together
7R
3Representation hydroxy; the alkoxyl of the straight or branched of C1～C8; the alkanoyl of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8 replaces or unsubstituted fragrant oxygen base; replace or unsubstituted aromaticacyl radical; replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue, or R
1, R
2With R
3Form hexatomic ring or the heptatomic ring that contains carbon and oxygen together; R
4Represent hydrogen; R
5Represent the alkyl of the straight or branched of C1～C8, or R
4With R
5Represent "=CH together
2",
R
6Representative
X represents NR
9R
7Represent hydrogen, hydroxyl, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8, the halogen alkoxyl of the straight or branched of C1～C8, the alkyl halide acyl group of the straight or branched of C1～C8, replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue; R
9Represent hydrogen; the alkyl of the straight or branched of C1～C8; the alkoxyl of the straight or branched of C1～C8; the alkanoyl of the straight or branched of C1～C8; the alkylhalide group of the straight or branched of C1～C8; the halogen alkoxyl of the straight or branched of C1～C8; the alkyl halide acyl group of the straight or branched of C1～C8; replace or unsubstituted aryl; replace or unsubstituted fragrant oxygen base, replace or unsubstituted aromaticacyl radical, replace or unsubstituted heterocyclic base; replace or unsubstituted fragrant hetero-oxy, replace or the assorted acyl group of unsubstituted virtue.
4. according to the chemical compound and the pharmaceutical salts thereof of the general formula (I) of claim 2: R wherein
1Representation hydroxy; R
2Represent hydrogen; R
3Representation hydroxy; R
4With R
5Representative together "==CH
2"; R
6Representative
R
8Represent the alkanoyl of the straight or branched of C1～C8, replace or unsubstituted aromaticacyl radical, X represents oxygen.R
1With R
2Representative=N-R together
7R
3Representation hydroxy, the alkanoyl of the straight or branched of C1～C8 replaces or unsubstituted fragrant oxygen base, replaces or unsubstituted aromaticacyl radical, or R
1, R
2With R
3Form the heptatomic ring that contains carbon and oxygen together; R
4With R
5Representative together "==CH
2"; R
6Representative
R
7Representation hydroxy, the alkoxyl of the straight or branched of C1～C8, the alkanoyl of the straight or branched of C1～C8 replaces or unsubstituted aromaticacyl radical; X represents oxygen.
5. according to the chemical compound and the pharmaceutical salts thereof of the general formula (I) of claim 3: R
1Representation hydroxy; R
2Represent hydrogen; R
3Representation hydroxy; R
4With R
5Representative together "==CH
2"; R
6Representative
X represents NR
9, R
9Represent hydrogen, the straight or branched alkyl of C1～C8 replaces or unsubstituted aryl.R
1Representation hydroxy; R
2Represent hydrogen; R
3Representation hydroxy; R
4Represent hydrogen; R
5Represent methylidene, or R
4With R
5Representative together "==CH
2"; R
6Representative
X represents nitrogen, NR
9, R
9Represent hydrogen, the straight or branched alkyl of C1～C8 replaces or unsubstituted aryl.
6. according to the chemical compound of claim 4, wherein chemical compound can be following arbitrary chemical compound and pharmaceutical salts thereof:
12-propionyloxy-14-desoxyandrographolide (IA
1)
12 α-propionyloxy-14-desoxyandrographolide
12 β-propionyloxy-14-desoxyandrographolide
The positive hexylyloxy of 12--14-desoxyandrographolide (IA
2)
12 α-positive hexylyloxy-14-desoxyandrographolide
12 β-positive hexylyloxy-14-desoxyandrographolide
12-benzoyloxy group-14-desoxyandrographolide (IA
3)
12 α-benzoyloxy group-14-desoxyandrographolide
12 β-benzoyloxy group-14-desoxyandrographolide
12-p-nitrophenyl acyloxy-14-desoxyandrographolide (IA
4)
12 α-p-nitrophenyl acyloxy-14-desoxyandrographolide
12 β-p-nitrophenyl acyloxy-14-desoxyandrographolide
12-is to methylbenzene acyloxy-14-desoxyandrographolide (IA
5)
12 α-to methylbenzene acyloxy-14-desoxyandrographolide
12 β-to methylbenzene acyloxy-14-desoxyandrographolide
12-(3,4-methylene-dioxy cinnamoyloxy group)-14-desoxyandrographolide (IA
6)
12 α-(3,4-methylene-dioxy cinnamoyloxy group)-14-desoxyandrographolide
12 β-(3,4-methylene-dioxy cinnamoyloxy group)-14-desoxyandrographolide
12-(3,4-dimethoxy benzoyloxy group)-14-desoxyandrographolide (IA
7)
12 α-(3,4-dimethoxy benzoyloxy group)-14-desoxyandrographolide
12 β-(3,4-dimethoxy benzoyloxy group)-14-desoxyandrographolide
12-(3,4-methylene-dioxy-6-Nitrobenzol acyloxy)-14-desoxyandrographolide (IA
8)
12 α-(3,4-methylene-dioxy-6-Nitrobenzol acyloxy)-14-desoxyandrographolide
12 β-(3,4-methylene-dioxy-6-Nitrobenzol acyloxy)-14-desoxyandrographolide
12-phenylacetyl Oxy-1 4-desoxyandrographolide (IA
9)
12 α-phenylacetyl Oxy-1 4-desoxyandrographolide
12 β-phenylacetyl Oxy-1 4-desoxyandrographolide
12-(α-Naphthoyloxy)-14-desoxyandrographolide (IA
10)
12 α-(α-Naphthoyloxy)-14-desoxyandrographolide
12 β-(α-Naphthoyloxy)-14-desoxyandrographolide
12-O-methoxy benzoyl group-14-desoxyandrographolide (IA
11)
12 α-O-methoxy benzoyl group-14-desoxyandrographolide
12 β-O-methoxy benzoyl group-14-desoxyandrographolide
3-oxime-11,12-dehydrorographolide (IB
1)
3-methyloxime-11,12-dehydrorographolide (IB
2)
19-triphenyl-3-oxime-11,12-dehydrorographolide (IB
3)
3-acetyl oxime-19-acetyl group-11,12-dehydrorographolide (IB
4)
3-propionyl oxime-19-propiono-11,12-dehydrorographolide (IB
5)
The positive hexanoyl oxime-19-positive caproyl-11 of 3-, 12-dehydrorographolide (IB
6)
3-benzoyl oxime-19-benzoyl-11,12-dehydrorographolide (IB
7)
3-is to chlorobenzoyl oxime-11,12-dehydrorographolide (IB
8)
3-phenylacetyl oxime-11,12-dehydrorographolide (IB
9)
3-cinnamoyl oxime-19-cinnamoyl-11,12-dehydrorographolide (IB
10)
7. according to the chemical compound of claim 5, wherein chemical compound can be following arbitrary chemical compound and pharmaceutical salts thereof:
12,13-dihydro Herba Andrographis lactams (IC
1)
13 α-12,13-dihydro Herba Andrographis lactams
13 β-12,13-dihydro Herba Andrographis lactams
N-methyl isophthalic acid 2,13-dihydro Herba Andrographis lactams (IC
2)
N-methyl isophthalic acid 3 α-12,13-dihydro Herba Andrographis lactams
N-methyl isophthalic acid 3 β-12,13-dihydro Herba Andrographis lactams
N-n-pro-pyl-12,13-dihydro Herba Andrographis lactams (IC
3)
N-n-pro-pyl-13 α-12,13-dihydro Herba Andrographis lactams
N-n-pro-pyl-13 β-12,13-dihydro Herba Andrographis lactams
N-normal-butyl-12,13-dihydro Herba Andrographis lactams (IC
4)
N-normal-butyl-13 α-12,13-dihydro Herba Andrographis lactams
N-normal-butyl-13 β-12,13-dihydro Herba Andrographis lactams
14-deoxidation-12,13-dihydro Herba Andrographis lactams (ID
1)
14-deoxidation-13 α-12,13-dihydro Herba Andrographis lactams
14-deoxidation-13 β-12,13-dihydro Herba Andrographis lactams
N-methyl isophthalic acid 4-deoxidation-12,13-dihydro Herba Andrographis lactams (ID
2)
N-methyl isophthalic acid 4-deoxidation-13 α-12,13-dihydro Herba Andrographis lactams
N-methyl isophthalic acid 4-deoxidation-13 β-12,13-dihydro Herba Andrographis lactams
N-n-pro-pyl-14-deoxidation-12,13-dihydro Herba Andrographis lactams (ID
3)
N-n-pro-pyl-14-deoxidation-13 α-12,13-dihydro Herba Andrographis lactams
N-n-pro-pyl-14-deoxidation-13 β-12,13-dihydro Herba Andrographis lactams
N-normal-butyl-14-deoxidation-12,13-dihydro Herba Andrographis lactams (ID
4)
N-normal-butyl-14-deoxidation-13 α-12,13-dihydro Herba Andrographis lactams
N-normal-butyl-14-deoxidation-13 β-12,13-dihydro Herba Andrographis lactams
14-deoxidation-12,13-dihydro-17-methyl Herba Andrographis lactams (IE
1)
14-deoxidation-13 α/β-12,13-dihydro-17 α/Beta-methyl Herba Andrographis lactams
N-methyl isophthalic acid 4-deoxidation-12,13-dihydro-17-methyl Herba Andrographis lactams (IE
2)
N-methyl isophthalic acid 4-deoxidation-13 α/β-12,13-dihydro-17 α/Beta-methyl Herba Andrographis lactams
N-n-pro-pyl-14-deoxidation-12,13-dihydro-17-methyl Herba Andrographis lactams (IE
3)
N-n-pro-pyl-14-deoxidation-13 α/β-12,13-dihydro-17 α/Beta-methyl Herba Andrographis lactams
N-normal-butyl-14-deoxidation-12,13-dihydro-17-methyl Herba Andrographis lactams (IE
4)
N-normal-butyl-14-deoxidation-13 α/β-12,13-dihydro-17 α/Beta-methyl Herba Andrographis lactams
8. the purposes of any one chemical compound of claim 1-10 in preparation TNF-alpha inhibitor, wherein said TNF-alpha inhibitor can be used for treating being selected from down organizes in the disease one or more: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, the joint of vertebral column inflammation, inflammatory bowel (crohn and ulcerative colitis), heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute marrow type leukemia, parkinson, acquired immune deficiency syndrome and dementia and syndrome, presenile dementia, depression, sepsis, septicemia, septic shock, behcets disease, graft versus host disease, uveitis, Wegener ' s granuloma, the Xiu Gelianshi xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection, fat.
9. the purposes of any one chemical compound of claim 1-10 in preparation IL-6 inhibitor, wherein said IL-6 inhibitor can be used for treating being selected from down organizes in the disease one or more: Alzheimer, schizophrenia, cancer, gouty arthritis, rigid spine disease, diabetes, depression.
10. the purposes of any one chemical compound of claim 1-10 in preparation COX-2 expression inhibitor, wherein said COX-2 expression inhibitor can be used for treating being selected from down organizes in the disease one or more: cancer, tumor multi-medicine drug-resistant, atherosclerosis, thrombosis, myocardial ischemia-anoxemia, heart failure, cerebrovascular, epilepsy, Alzheimer, parkinson.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710019981 CN101028263A (en) | 2007-02-06 | 2007-02-06 | Use of substituted isoandrographolide derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710019981 CN101028263A (en) | 2007-02-06 | 2007-02-06 | Use of substituted isoandrographolide derivative |
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| CN101028263A true CN101028263A (en) | 2007-09-05 |
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ID=38713915
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|---|---|---|---|
| CN 200710019981 Pending CN101028263A (en) | 2007-02-06 | 2007-02-06 | Use of substituted isoandrographolide derivative |
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| CN (1) | CN101028263A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829110A (en) * | 2010-05-20 | 2010-09-15 | 中国药科大学 | The purposes of andrographolidume derivative in the preparation inverase |
| CN102863408A (en) * | 2011-07-06 | 2013-01-09 | 重庆莱美药业股份有限公司 | Preparation method of andrographolide |
| CN103539764A (en) * | 2012-07-13 | 2014-01-29 | 华南理工大学 | 12-p-methyl benzene acyloxy-14-deoxidized andrographolide photoaffinity labeling molecular probe, and preparation method and pharmaceutical composition thereof |
| CN103768053A (en) * | 2013-12-27 | 2014-05-07 | 哈尔滨珍宝制药有限公司 | Novel application of dehydroandrographolide derivative |
| CN105732547A (en) * | 2016-03-25 | 2016-07-06 | 重庆莱美药业股份有限公司 | Preparation method of dehydrated andrographolide diacid half ester basic salt |
| CN106606506A (en) * | 2015-10-21 | 2017-05-03 | 复旦大学 | Use of enantio-labdane-type diterpene compounds in preparation of anti-complement drugs |
| CN108148022A (en) * | 2016-12-02 | 2018-06-12 | 上海迪诺医药科技有限公司 | Andrographolide class compound, its pharmaceutical composition and application |
| CN108888619A (en) * | 2018-09-12 | 2018-11-27 | 山东省文登整骨医院 | Application of the andrographolide in treatment acute gouty arthritis drug |
| CN110963894A (en) * | 2018-09-30 | 2020-04-07 | 沈阳药科大学 | Andrographolide compound and preparation method and application thereof |
| WO2024019661A1 (en) * | 2022-07-22 | 2024-01-25 | National University Of Singapore | Labdane based compounds and uses thereof |
-
2007
- 2007-02-06 CN CN 200710019981 patent/CN101028263A/en active Pending
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829110A (en) * | 2010-05-20 | 2010-09-15 | 中国药科大学 | The purposes of andrographolidume derivative in the preparation inverase |
| CN102863408A (en) * | 2011-07-06 | 2013-01-09 | 重庆莱美药业股份有限公司 | Preparation method of andrographolide |
| CN102863408B (en) * | 2011-07-06 | 2015-04-22 | 重庆莱美药业股份有限公司 | Preparation method of andrographolide |
| CN103539764A (en) * | 2012-07-13 | 2014-01-29 | 华南理工大学 | 12-p-methyl benzene acyloxy-14-deoxidized andrographolide photoaffinity labeling molecular probe, and preparation method and pharmaceutical composition thereof |
| CN103539764B (en) * | 2012-07-13 | 2015-07-15 | 华南理工大学 | 12-p-methyl benzene acyloxy-14-deoxidized andrographolide photoaffinity labeling molecular probe, and preparation method and pharmaceutical composition thereof |
| CN103768053A (en) * | 2013-12-27 | 2014-05-07 | 哈尔滨珍宝制药有限公司 | Novel application of dehydroandrographolide derivative |
| CN103768053B (en) * | 2013-12-27 | 2016-03-02 | 哈尔滨珍宝制药有限公司 | The purposes of dehydrorographolide derivant |
| CN106606506A (en) * | 2015-10-21 | 2017-05-03 | 复旦大学 | Use of enantio-labdane-type diterpene compounds in preparation of anti-complement drugs |
| CN105732547A (en) * | 2016-03-25 | 2016-07-06 | 重庆莱美药业股份有限公司 | Preparation method of dehydrated andrographolide diacid half ester basic salt |
| CN105732547B (en) * | 2016-03-25 | 2018-06-12 | 重庆莱美隆宇药业有限公司 | A kind of preparation method of Dehydro and drographolide diacid half esters |
| CN108148022A (en) * | 2016-12-02 | 2018-06-12 | 上海迪诺医药科技有限公司 | Andrographolide class compound, its pharmaceutical composition and application |
| CN108148022B (en) * | 2016-12-02 | 2023-04-18 | 江西青峰药业有限公司 | Andrographolide compound, pharmaceutical composition and application thereof |
| CN108888619A (en) * | 2018-09-12 | 2018-11-27 | 山东省文登整骨医院 | Application of the andrographolide in treatment acute gouty arthritis drug |
| CN110963894A (en) * | 2018-09-30 | 2020-04-07 | 沈阳药科大学 | Andrographolide compound and preparation method and application thereof |
| CN110963894B (en) * | 2018-09-30 | 2022-09-02 | 沈阳药科大学 | Andrographolide compound and preparation method and application thereof |
| WO2024019661A1 (en) * | 2022-07-22 | 2024-01-25 | National University Of Singapore | Labdane based compounds and uses thereof |
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