CN101829108B - Application of diterpene ginkgolide - Google Patents
Application of diterpene ginkgolide Download PDFInfo
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- CN101829108B CN101829108B CN200910056941.6A CN200910056941A CN101829108B CN 101829108 B CN101829108 B CN 101829108B CN 200910056941 A CN200910056941 A CN 200910056941A CN 101829108 B CN101829108 B CN 101829108B
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Abstract
The invention relates to the technical field of medicines, in particular to application of diterpene ginkgolide. The invention discloses the application of diterpene ginkgolide shown as a general structural formula I or pharmaceutically acceptable salts thereof or prodrugs or isomers or plant extracts with the diterpene ginkgolide as a JAK-STAT signal transduction pathway inhibitor. The compound shown as the general structural formula I or pharmaceutically acceptable salts or prodrugs or isomers or plant extracts with the diterpene ginkgolide are used as the JAK-STAT signal transduction pathway inhibitor, have higher particularity, and can effectively inhibit a JAK-STAT signal transduction pathway, and meanwhile, compared with a cyclophosphamide group, the diterpene ginkgolide has low toxicity.
Description
Technical field
The present invention relates to medical technical field, relate in particular to a kind of purposes of diterpene ginkgolide.
Background technology
Janus kinases (JAK) belongs to family tyrosine kinase, is made up of JAK1, JAK2, JAK3 and TYK2.JAK plays an important role in cytokine signaling conduction, and the downstream substrate of kinases JAK family comprises signal transduction agent and the activator (STAT) of transcription factor.JAK-STAT signal path is a cell signal path very close with Growth of Cells, propagation and differentiation relation, and its basic process can be summarized as: 1. cytokine is combined with its respective ligand; 2. receptor and JAKs assemble, the contiguous mutual phosphorylation of JAKs and being activated; 3. the tyrosine residue phosphorylation of the upper corresponding site of the JH1 domain catalysis STATs of JAKs, the tyrosine residue effect of phosphorylation and STATs is activated in the SH2 functional areas of STATs and receptor simultaneously; 4. thereby STATs enters in core and transcribes with some other transcription factor interaction controlling gene.Wherein STAT3 is the important member of STATs family.STAT3 signal transduction pathway acts on DNA fragmentation special in nucleus after being activated by parts such as extracellular cytokine, somatomedin, transcribing of regulation and control target gene, is promoting tumor cell proliferation, inhibition tumor cell apoptosis, is promoting the aspects such as Invasion and Metastasis and immunologic escape to play an important role.
The abnormal cell reaction that a lot of diseases all cause with the event mediating by above-mentioned signal path is relevant.These diseases include, but not limited to autoimmune disease, inflammatory disease, osteopathia, metabolic disease, nerve and neurodegenerative disease, cancer, cardiovascular diseases, allergy and asthma, Alzheimer and the disease relevant with hormone.Therefore, the great efforts of medicinal chemical aspect found can be effectively as the kinases inhibitor of therapeutic agent.The pharmaceutical intervention of JAK/STAT approach was commented on [Frank.Mol.Med.5., the people such as 432-456 (1999) and Seidel, Oncogene, 19,2654-2656 (2000)].
The Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) is the root of Isolated From Thymelaeaceae Species Stellera chamaejasme L. or euphorbia plant Euphorbia fischeriana S teud．.Euphorbia fischeriana S teud． (Euphorbia fischeriana Steud), is herbaceos perennial, originates in the ground such as Liaoning, Jilin, Hebei, Heilungkiang, the Inner Mongol.Euphorbia fischeriana S teud． begins to be loaded in Shennong's Herbal, bitter in the mouth, pungent, and property is flat, and poisonous, having relieves oedema or abdominal distension through diuresis or purgation eliminates the phlegm, effect of removing mass parasite killing, cure mainly edema abdominal distention, expectorant, food, malnutrition due to parasitic infestation, trusted subordinate's pain, chronic tracheitis, cough, asthma, the tuberculosis such as lymph node, skin, bone, scabies, the diseases such as hemorrhoid complicated by anal fistula.Among the peoplely be mainly used to treat the disease such as tumor, tuberculosis.
Euphorbia fischeriana S teud． contains number of chemical composition, is mainly diterpene and triterpenoid compound, also has tannin, steroidal, anthraquinone, flavone etc.Modern pharmacology research shows, Jolkinolide B has significant antiproliferative activity to human prostata cancer LNCaP cell, thereby this activity may be synthetic (Liu W K.Biochem Pharmacol.2002,63 (5): 951) that play a role of the absorption inhibition DNA by lowering bromine deoxidation pyrimidine.People's researchs such as Yang Hongwu show, the active component of the Radix Euphorbiae Pekinensis Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) all presents inhibition proliferation function (Yang Hongwu in various degree to U937 cell, Hela cell and QRH-7701 cell, Wang Zheng, Zheng Xuemin. the research of Euphorbia fischeriana S teud． active component extracorporeal anti-tumor. Liaoning Journal of Traditional Chinese Medicine, 2002,29 (1): 53-54).The people such as Zhao Kuijun study and show, the Radix Euphorbiae Pekinensis Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) presents stronger bacteriostasis under 1/100 dilution factor, and MIC is 1/3200.The In Vitro Bacteriostasis of 5 kinds of solvent extractable matters also having studied Radix Euphorbiae Pekinensis Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) root to tubercule bacillus.Result shows under 1/400 dilution factor, all there is bacteriostasis, and what wherein bacteriostasis was the strongest is ligroin extraction, and MIC is 1/3200.
Therefore, up to the present, there is not bibliographical information Euphorbia fischeriana S teud． extract to there is the effect that suppresses JAK-STAT signal path.The present invention is initiative achievement in research.
Summary of the invention
The present invention aims to provide the purposes of diterpene ginkgolide aspect inhibition JAK-STAT signal transduction pathway.
A first aspect of the present invention, the plant extract that a kind of diterpene ginkgolide as shown in general structure I or its pharmaceutically acceptable salt or prodrug or its isomer is provided or has contained it is as the purposes of JAK-STAT signal pathway inhibitor,
Wherein, R
1can be H, nitro, amino, alkyl, alkenyl, assorted alkyl, alkoxyalkyl, alkene oxygen base, alkynyloxy group, amino, alkyl amino, aminoalkyl, hydroxyalkyl, alkyl amino-carbonyl, sulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, aryl, aryl alkyl, cycloalkyl aryl, heteroaryl, heterocyclic radical or R
6oC (O) R
7;
R
2and R
2' can be independently alkyl, alkenyl, assorted alkyl, alkoxyalkyl, alkene oxygen base, alkynyloxy group, amino, alkyl amino, aminoalkyl, alkyl amino-carbonyl, sulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group, H or-OH;
R
3, R
4, R
4' and R
5can be independently H, alkyl, alkenyl, assorted alkyl, alkoxyl, alkoxyalkyl, alkene oxygen base, alkynyloxy group, amino, alkyl amino, aminoalkyl, alkoxy carbonyl group, alkyl amino-carbonyl, sulfonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, acyl group or hydroxyl;
R
6can be alkyl, Heterocyclylalkyl, amino;
R
7can be alkyl, alkenyl, assorted alkyl, alkyl amino, aminoalkyl, alkyl amino-carbonyl, alkyl sulphonyl, alkyl sulphinyl, amino-sulfonyl, aryl alkyl, cycloalkyl aryl, heteroaryl or heterocyclic radical;
In above group, can not be substituted or be replaced by one or more substituent groups separately, these substituent groups comprise: halogen ,=O ,=S ,-CN ,-NO
2,-CF
3,-OCF
3, alkyl, alkenyl, alkynyl group, haloalkyl, haloalkenyl group, halo alkynyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, alkene oxygen base, alkynyloxy group, amino, alkyl amino, sulfonyl, alkyl sulphonyl, amino-sulfonyl, alkoxyalkyl ,-COOH ,-SH and acyl group.
In preference, described R
2and R
2' independent for H or-OH and while being H when different, the general structure of described diterpene ginkgolide can be formula II or III
In preference, described R
1can be alkyl, hydroxyalkyl or R
6oC (O) R
7; R
6for alkyl, R
7for alkyl or aryl.
In preference, described alkyl is C
1～C
6alkyl, wherein preferable methyl;
In another preference, described hydroxyalkyl is-CH
2oH;
In preference, described R
3for C
1～C
6alkyl, wherein preferable methyl; ;
In preference, described R
4and R
4' can be independently C
1～C
6alkyl, wherein preferable methyl;
In preference, described R
5can be H or-OH.
In another preference, described diterpene ginkgolide can be following compounds:
jolkinolide?B、17-hydroxy-jolkinolide?B、17-hydroxyjolkinolide?Baceticacidester、17-hydroxyjolkinolide?B?benzoic?acid?ester。
Wherein be preferably 17-hydroxy-jolkinolide B.
In another preference, be euphorbia plant extract suc as formula the plant extract of the diterpene ginkgolide shown in I described containing.
In another preference, described euphorbia plant is the root of Euphorbia fischeriana S teud．, especially Euphorbia fischeriana S teud．.
In another preference, purposes of the present invention refers to that diterpene ginkgolide or its prodrug or its pharmaceutically acceptable salt apply in preparation treatment autoimmune disease, inflammation, osteopathia, metabolic disease, nerve and neurodegenerative disease, cancer, cardiovascular diseases, allergy and asthmatic medicament.
Described autoimmune disease is transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis or multiple sclerosis.
Described cancer, includes but not limited to osteocarcinoma class, comprising: Ewing sarcoma, osteosarcoma, chondrosarcoma etc.; Brain and cns tumor, comprising: acoustic neuroma, neuroblastoma, neuroglia tumor and other cerebral tumors, tumor of spinal cord; Endocrine cancer class, comprising: adrenocortical carcinoma, pancreas cancer, hypophysis cerebri cancer, thyroid carcinoma, parathyroid gland cancer, thymic carcinoma, multiple endocrine neoplasm; Human primary gastrointestinal cancers class, comprising: gastric cancer, esophageal carcinoma, carcinoma of small intestine, hepatocarcinoma, cholangiocarcinoma, gastrointestinal class cancerous tumour, carcinoma of gallbladder; Apparatus urogenitalis cancer class, comprising: carcinoma of testis, carcinoma of penis, carcinoma of prostate; Gynecological cancer class, comprising: cervical cancer, ovarian cancer, cancer of vagina, uterus/carcinoma of endometrium, pudendum cancer, gestational trophoblastic tumor, carcinoma of fallopian tube, sarcoma of uterus; Head and tumor colli class, comprising: oral cancer, lip cancer, glandula cancer, larynx cancer, hypopharyngeal cancer, positive pharyngeal cancer, rhinocarcinoma, nasal sinus cancer, nasopharyngeal carcinoma; Leukemia class, comprising: leukemia of children, acute lymphatic leukemia, acute myelogenous leukemia, chronic lymphatic leukemia, chronic lymphocytic leukemia, a shape cellularity leukemia, acute promyelocytic leukemia, plasma cell leukemia; Bone marrow cancer blood disorder, comprising: bone marrow poorly differentiated syndrome, myeloproliferative disease, aplastic anemia, model standing grain Buddhist nun anemia, idiopathic macroglobulinemia disease; Pulmonary carcinoma class, comprising: small cell lung cancer, nonsmall-cell lung cancer; Lymphatic cancer class, comprising: Hodgkin, non-Hodgkin′s lymphomas, skin-type T-cell lymphoma, around T-cell woods bar tumor, AIDS dependency lymphoma; Cancer eye class, comprising: retinoblastoma, uveal; Skin carcinoma class, comprise: melanoma, nonmelanoma skin cancer, Merkel cell cancer, soft tissue sarcoma class, for example: child's soft tissue sarcoma, adult soft tissue sarcoma, kaposi sarcoma, urinary system cancer, comprising: renal carcinoma wilms' tumor, wing skin cancer, carcinoma of urethra and metastatic cell cancer.Wherein preferably neurogliocytoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, breast carcinoma, osteocarcinoma, skin carcinoma, lymphatic cancer, leukemia, cervical cancer or ovarian cancer.
Accompanying drawing explanation
Shown in Fig. 1, the Western blotting figure of JAK1, JAK2 and TYK2 after 17-hydroxy-jolkinolide B processes.
Shown in Fig. 2, the 17-hydroxy-jolkinolide B various dose time is processed the Western blotting figure of rear JAK2.
The specific embodiment
Inventor is through extensive and deep research, find that diterpene ginkgolide or its pharmaceutically acceptable salt or prodrug or its isomer or the plant extract that contains it have the effect that suppresses JAK-STAT signal transduction pathway, and can be by these approach treatment tumors.On this basis, complete the present invention.
Part term definition used in the present invention is as follows:
" cancer " generally refers to the disease that is grown to widely feature with the sexual abnormality out of control of cell.
" halogen " refers to fluorine, chlorine, bromine and iodine.
" alkyl " refers to straight chain or the aliphatic hydrocarbon group with side chain while being used as the part of a group or a group.Preferential selection alkyl is C
1-C
14alkyl; More preferably be chosen as: C
1-C
10alkyl; Override is chosen as C
1-C
6, unless otherwise.Straight chain or with the C of side chain
1-C
6the example of alkyl includes, but are not limited to: methyl, ethyl, n-pro-pyl, 2-propyl group, normal-butyl, isobutyl group, tertiary butyl, hexyl etc.
" alkyl amino " comprises two kinds of alkyl monosubstituted amino and dialkyl amidos, unless otherwise." alkyl monosubstituted amino " refers to: (alkyl-NH)-group; " dialkyl amido " refers to: ((alkyl) 2N)-group.Wherein, alkyl is shown in relevant definition herein.This alkyl group is preferentially selected C
1-C
6alkyl group.Example includes, but are not limited to: N-methylamino, N-ethylamino-, N-isopropylamine base, N, N-(diethyl) amido etc.
" aminoalkyl " refers to: (amino-alkyl)-group.Wherein, alkyl is shown in relevant definition herein.Example includes, but are not limited to: amino-ethyl, 1-aminopropyl, 1-aminopropyl etc.
" arylamino " comprises two kinds of list-arylamino and two-arylaminos, except as otherwise noted.List-arylamino refers to: (aryl-) group of NH-; Two-arylamino refers to the group of formula (aryl) 2N-; Relevant portion is herein shown in the definition of aryl.
" acyl group " and comprise (alkyl-CO)-group and (aryl-CO)-group, except as otherwise noted.Wherein alkyl or aryl is all shown in relevant definition herein.The example of acyl group includes, but are not limited to: acetyl group, propiono, isobutyryl, benzoyl etc.
" amide groups " comprise (alkyl-CONH)-group and (aryl-CONH)-group, except as otherwise noted.Wherein, alkyl or aryl is all shown in relevant definition herein.The example of amide groups includes, but are not limited to: acetamido, propionamido-, amide-based small, isobutyl amide, benzamido etc.
" thiazolinyl " refers to the aliphatic hydrocarbon group that at least contains a carbon-to-carbon double bond during as a group or a group a part of, and can be straight chain also can be with side chain.Preferential selection has C
2-C
14thiazolinyl.C
2-C
12better; That the most preferentially select is C
2-C
6thiazolinyl.This group can contain multiple pairs of keys and its conformation can respectively do for oneself E or Z in its main chain.The example of alkenyl group includes, but are not limited to: vinyl, acrylic etc.
" alkoxyl " refer to (alkyl-O)-group.Wherein, alkyl is shown in relevant definition herein.C
1-C
6alkoxyl be preferential selection.The example includes, but are not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy etc.
" alkene oxygen base " refer to (thiazolinyl-O)-group.Wherein, thiazolinyl is shown in relevant definition herein.C
1-C
6alkene oxygen base be preferential selection.
" alkynyloxy group " refer to (alkynyl-O)-group.Wherein, alkynyl is shown in relevant definition herein.C
1-C
6alkynyloxy group be preferential selection.
" alkoxy carbonyl group " refer to (alkyl-O-C (O))-group.Wherein, alkyl is shown in relevant definition herein.The preferential alkyl group of selecting is C
1-C
6alkyl.The example includes, but are not limited to: methoxycarbonyl group, carbethoxyl group etc.
" alkyl sulphinyl " refer to (alkyl-S (O))-group.Wherein, alkyl is shown in relevant definition herein.The preferential alkyl of selecting is C
1-C
6alkyl group.Alkyl sulphinyl group includes, but are not limited to: methylsulfinyl, ethyl sulfinyl etc.
" alkyl sulphonyl " refers to (alkyl-S (O)
2-O)-group.Wherein, alkyl is shown in relevant definition herein.This preferential alkyl of selecting is C
1-C
6alkyl group.The example includes, but are not limited to: mesyl, ethylsulfonyl etc.
" alkyl amino aryl " refers to alkyl amino-aromatic yl group.Wherein, alkyl amino is shown in relevant definition herein.
" cycloalkyl " refers to the carbocyclic ring of monocycle, condensed ring or the volution of saturated or fractional saturation.Ring take 3-9 carbon atom composition is selected as preferential.Example includes, but are not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.
" cycloalkyl-alkyl " refers to cycloalkyl-alkyl group.Wherein, cycloalkyl is shown in relevant definition herein with moieties.Monocycle alkyl alkyl group includes, but are not limited to: cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl, suberyl methyl etc.
" Heterocyclylalkyl " refers to that at least containing one is selected from N, S, the heteroatomic cycloalkyl of O.Preferably contain 1-3 hetero atom.Preferred ring is 3-14 person's ring, and the ring of more preferably selecting is 4-7 person's ring.Heterocyclylalkyl includes, but are not limited to: pyrrolidinyl, pyrrolin base, nafoxidine base, pyrazoline base, piperidyl, morpholine tetrahydrofuran base, tetrahydrochysene thio-furan base, THP trtrahydropyranyl etc.
" heterocycloalkenyl " refers to the Heterocyclylalkyl that at least contains two keys.Heterocyclylalkyl is shown in relevant definition herein.
" Heterocyclylalkyl alkyl " refers to: (Heterocyclylalkyl-alkyl)-group.Wherein, Heterocyclylalkyl is shown in relevant definition herein with moieties.Heterocyclylalkyl alkyl group includes, but are not limited to: (2-tetrahydrofuran base) methyl, (2-tetrahydrochysene thio-furan base) methyl etc.
The group that " assorted alkyl " refers to straight chain or contain branched alkyl, and in main chain, at least contain one or more S of being selected from, the hetero atom of O and N.Preferential selection contains 2-14 atomic link.Assorted alkyl includes, but are not limited to: ethers, thioether class, alkyl esters, second or trialkyl amines, alkyl sulfinic acid class etc.
" aryl " refers to as the part of a group or a group: monocycle or the condensed ring of (1) armaticity; The preferential armaticity carbocyclic ring (annular atoms is the ring-shaped structure of carbon) of selecting to have 5-12 carbon atom.The example of aryl includes, but are not limited to: phenyl, naphthyl; (2) can the saturated carbocyclic ring in coupling part, for example: phenyl and C
5-7cycloalkyl or C
5-7cycloalkenyl groups system condenses mutually and forms a circulus.Example includes, but are not limited to: tetralyl, indenyl or hydrogen indenyl etc.Aromatic yl group can be replaced by one or more substituent groups.
" aryl alkenyl " refers to: (aryl-thiazolinyl)-group.Wherein, aryl is shown in relevant definition herein with thiazolinyl.Exemplary aryl alkenyl group includes, but are not limited to: phenyl acrylic etc.
" aralkyl " refers to: (aryl-alkyl)-group.Wherein, aryl is shown in relevant definition herein with moieties.Exemplary aromatic alkyl group includes, but are not limited to: benzyl, phenethyl, 1-menaphthyl etc.
" cycloalkenyl group " refers to nonaro-maticity monocycle or multi-ring ring system.It at least contains a carbon-to-carbon double bond and every ring preferably has 5-10 carbon atom.Exemplary monocycle shape cyclenes basic ring includes, but are not limited to: cyclopentenes, cyclohexene or cycloheptene.Cycloalkenyl group group can be replaced by one or more substituent groups.
" heteroaryl " refers to monocycle or the multi-ring aromatic heterocycle condensing.Preferential selection contained one or more N of being selected from, and O is or/and heteroatomic 5-7 person's aromatic rings of S.Typical heteroaryl substituent group comprises example, but is not limited to: furyl, thienyl, pyrroles, pyrazoles, triazole, thiazole, pyridine, pyrimidine, pyrazine, indole, benzimidazole etc.
" heteroarylalkyl " refers to: (heteroaryl-alkyl)-group.Wherein, heteroaryl is shown in relevant definition herein with moieties.Exemplary heteroarylalkyl group includes, but are not limited to: furfuryl, 3-furylmethyl, 2-picolyl etc.
Compound of the present invention is preferably 17-hydroxy-jolkinolide B: it extracts and obtain from euphorbia plant Euphorbia fischeriana S teud． (Euphorbia fischeriana Steud), the especially root of Euphorbia fischeriana S teud．.
Term " pharmaceutically acceptable salt " refers to that above-claimed cpd can keep original biological activity and be suitable for some salt of medical usage.The pharmaceutically acceptable salt of the represented compound of general formula (I) has two kinds of formation forms: the one, and the salt forming with acid; Another is the salt forming with alkali or alkali metal.Comprise mineral acid and organic acid with the acid of the represented compound formation pharmaceutically acceptable salt of general formula (I).Suitable mineral acid comprises: hydrochloric acid, sulphuric acid and phosphoric acid.Suitable organic acid can be selected from aliphatic, cycloaliphatic, armaticity, heterocyclic carboxylic acid and sulphonic acids organic acid; The example includes but not limited to: formic acid, acetic acid, propanoic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkyl sulfonic acid etc.Comprise with the alkali metal of the represented compound formation pharmaceutically acceptable salt of general formula (I): lithium, sodium, potassium, magnesium, calcium, aluminum or zinc etc.
The present invention includes the represented compound of general formula (I) and possible various isomery patterns thereof.Comprise: the geometric isomer of non-mirror image isomer, mirror image isomer, tautomer and " E " or " Z " configurational isomer etc.
The present invention includes the represented compound of general formula (I) and possible raceme thereof or/and mirror image isomerism thing/or/and the mixture of non-mirror image isomerism thing.
In addition, the represented compound of general formula (I) is also contained solvation and the non-solvated pattern of this compound in application.Therefore, the various compound with specified structure that includes, comprises its hydration and anhydrous mould assembly formula.
Except the represented compound of general formula (I), different specific embodiments comprise: pharmaceutically acceptable salt, the active metabolite of prodrug and these compounds.Pharmaceutically acceptable salt with these metabolite.
" prodrug " is the represented derivant of a kind of general formula (I), by means of the mode of metabolism in vivo, it for example, become to the represented compound of general formula (I) in vivo transforming (: by hydrolysis, reduce or oxidation).For example, compound and acid reaction represented general formula (I), that contain oh group can be prepared into corresponding ester.Corresponding ester is prodrug, can be hydrolyzed to parent drug in vivo.The acid that is applicable to preparing " prodrug " includes but not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene-bis-beta-hydroxyethyl base naphthoic acid, gentisic acid, hydroxyethylsulfonic acid., methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid etc.
Can be by the direct administration of plant extract that contains formula I compound.Conventionally, by weight should be at 0.01-99.9% in the purity of extract Chinese style I compound, be more preferably 20-98%.Also can make after the formula I compound of respective pure form or the preparation of various forms of formula I compounds, for administration.
Purposes
Compound shown in formula I of the present invention or its pharmaceutically acceptable salt or prodrug or its isomer or the plant extract that contains it can be used for JAK inhibitor, can suppress JAK-STAT signal transduction pathway, be particularly useful for the inhibition of STAT3 signal transduction pathway, described inhibitor can be used for treating tumor.
The effective dose of active component used can change with the order of severity of mode of administration and disease to be treated.For most of large mammal, the accumulated dose that imposes effective ingredient every day is about 0.01-1000mg.Conventionally, the scope of adult's clinical administration amount is 0.01-200mg/ day, is preferably 0.05-100mg/ day.
Conventionally, in the time that the present composition is used for such use, they can make with one or more pharmaceutically acceptable carriers or mixed with excipients the pharmaceutical dosage form of different way of administration, as tablet, capsule, powder, granule, syrup, solution, oral liquid, spirit, tincture, aerosol, powder spray, injection, injectable sterile powder, suppository etc.
" pharmaceutically acceptable " composition is to be applicable to people and/or animal and the material that has rational benefit/risk ratio without excessive bad side reaction (as toxicity, stimulation and allergy)." pharmaceutically acceptable carrier " is acceptable solvent, suspending agent or the excipient pharmaceutically or on food for diterpene ginkgolide of the present invention or its physiologically acceptable salt being sent to animal or human.Carrier can be liquid or solid.
Compound of the present invention can be through oral, intravenous, intramuscular or subcutaneous route administration.
Dosage form that can oral administration administration in above-mentioned dosage form is: tablet, capsule, powder, granule, syrup, solution, spirit.Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, kaolin, micropowder silica gel, Pulvis Talci, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpyrrolidone.And liquid carrier comprises: sterilized water, ethanol, Polyethylene Glycol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami).In the process of pharmaceutical compositions, normally used adjuvant comprises: flavoring agent, coloring agent, antiseptic (as oxybenzene alkyl butyl ester, sodium benzoate, sorbic acid) and antioxidant (as vitamin E, vitamin C, sodium pyrosulfite and dibenzylatiooluene).
The dosage form that can be used for injection administration in above-mentioned dosage form comprises: injection, injectable sterile powder, they are that medicine and one or more pharmaceutically acceptable mixed with excipients are made to the form for drug administration by injection.Solvent comprises: sterilized water, ethanol, glycerol, propylene glycol, Polyethylene Glycol.In addition, also need to add antibacterial (as benzyl alcohol, butyl hydroxybenzoate, thimerosal), isoosmotic adjusting agent (as sodium chloride, glucose), suspending agent (as sodium carboxymethyl cellulose, methylcellulose), solubilizing agent (tween 80, lecithin), antioxidant (as vitamin E, vitamin C, sodium pyrosulfite) and filler (as lactose, mannitol).
From being easy to the position of preparation and administration, preferred pharmaceutical composition is solid-state composition, the especially capsule of tablet and solid-filling or liquid filling.Preferred oral administration.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can combination in any.All features that this case description discloses can with any composition forms use, each feature disclosing in description, can anyly provide the alternative characteristics of identical, impartial or similar object to replace.Therefore apart from special instruction, the feature disclosing is only the general example of equalization or similar features.
Major advantage of the present invention is:
Compound shown in formula I of the present invention or its pharmaceutically acceptable salt or prodrug or its isomer or the plant extract that contains it have higher specificity as JAK inhibitor, can effectively suppress JAK-STAT signal transduction, compared with cyclophosphamide group, toxicity of compound of the present invention is low simultaneously.
Below in conjunction with specific embodiment, further set forth the present invention.These embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, the condition of conventionally advising according to normal condition or according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio and umber all by weight.
Embodiment 1 compound preparation
The extraction of Euphorbia fischeriana S teud． with separate:
To buying Euphorbia fischeriana S teud． (Euphorbia fishcerianaSteud.) the root 10Kg from Xujiahui, Shanghai prepared slices of Chinese crude drugs factory, with 95% three times (50L × 3) of industrial alcohol room temperature extraction, combining extraction liquid, concentrating under reduced pressure is except obtaining ethanol extract after desolventizing.Ethanol extract is scattered in to hot water, uses respectively petroleum ether (5L × 3), chloroform extraction (5L × 3), obtain petroleum ether extractum 300g, chloroform extractum 883g.[elution system is as petroleum ether-acetone take normal phase silicagel column for chloroform extract, petroleum ether-ethyl acetate, cyclohexane extraction-acetone], gel column LH-20[elution system chloroform-methanol=5: 1] separate with reverse phase silica gel post (Rp-18) [elution system is methanol-water], coarse-grain is purified with method for crystallising, therefrom obtain jolkinolide B (3.6g), 17-hydroxyjolkinolide B (1.3g) and 17-hydroxyjolkinolide B acetic acidester (15mg).
The preparation method of derivant:
Getting 17-hydroxy-jolkinolide B 20mg is dissolved in 1 milliliter of anhydrous pyridine, under agitation drip 0.5 milliliter of Benzenecarbonyl chloride., room temperature is placed and is spent the night, pour in frozen water, leach precipitate, washing, dry, with ethyl alcohol recrystallization, measure through MS and NMR that to determine that it is 17-hydroxyjolkinolide Bbenzoic acid ester structure as follows:
Embodiment 217-hydroxy-jolkinolide B suppresses STAT3 signal path
Experiment material:
1) cell strain: stable transfection the HepG2 cell of STAT3-luciferase reporter plasmid.
2) IL-6 (purchased from Peprotech Asia)
3) medicine to be measured: 17-hydroxy-jolkinolide B, embodiment 1 prepares;
4) luciferase detection kit (purchased from Promega)
Experimental technique:
1) the HepG2 cell that growth conditions is good, trypsinization, with α MEM culture medium re-suspended cell and adjust cell concentration to 2 × 105/ml, gets 100 μ l cell suspension inoculations in 96 orifice plates, in 37 ℃, 5% CO2 incubator, cultivate 48 hours, until cell is completely adherent;
2), in the time that Growth of Cells to density is 60-70%, it is divided into following 3 groups at random:
A. negative control group, does not add IL-6 and medicine to be measured;
B.IL-6 group, add IL-6 to final concentration be 10ng/ml, hatch 6 hours;
C. medication group, adds medicine to be measured to final concentration to be respectively 20,10,5,1 μ M, hatches 1 hour, then to add final concentration be the IL-6 of 10ng/ml, hatches 6 hours.
3) take out 96 orifice plates, careful suction abandoned culture medium, with PBS (phosphate buffer) washing 3 times;
4) every hole adds 30 μ l 1x luciferase lysates (CCLR), shake gently 10-15 minute, after the complete cracking of cell, sucked in the eppendorf pipe of 1.5ml, whirlpool concussion 1 minute, centrifugal 2 minutes of 13200rpm, sucks supernatant in another centrifuge tube;
5) in 96 hole check-out consoles, add 20 μ l cell pyrolysis liquids and 30 μ l luciferase substrates, mix gently, in luminometer (TECAN GENion), detect.
6) method of use Westernblotting, probing into 17-hydroxy-jolkinolide B affects the mechanism of STAT3 signal transduction pathway.
Experimental result:
Table 1 17-hydroxy-jolkinolide B suppresses the vigor of STAT3 signal path
As shown in table 1,17-hydroxy-jolkinolide B can suppress the activation of the JAK-STAT signal transduction pathway of being induced by IL-6, experimental group (20,10,5 μ M) suppression ratio is respectively 85%, 71%, 59%, prompting 17-hydroxy-jolkinolide B may be by suppressing JAK-STAT signal transduction pathway, regulate and control the expression of some related gene, thus performance antitumor action.Westernblotting result shows, as shown in Figure 1, in HepG2 cell, observes 17-hydroxy-jolkinolide B and can impel the dimerization of JAK1, JAK2 and TYK2.As shown in Figure 2,17-hydroxy-jolkinolideB presents dosage and time dependence to the facilitation of JAK2 dimerization.
Inhibitory action to kinds of tumor cells growth in embodiment 3 in vitro testses
In-vitro Culture of Human Fetal renal carcinoma 293 cells, human hepatoma HepG2 cell, human breast carcinoma MDA-MB-468, MDA-MB-231, MDA-MB-453, MCF-7 cell, people's gastric cancer HGC cell, human lymphoma U937 cell, human cervical carcinoma Hela cell.Growth of Cells is to logarithmic growth after date, and with trypsin digestion cell, centrifugal 5 minutes of 1000rpm, abandons supernatant, and appropriate culture medium suspends, and adjusts cell concentration to 3.5 104/ml.By cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ l, place (37 ℃ of cell culture incubators, 5%) in, cultivate after 24h, each medication group adds respectively 17-hydroxy-jolkinolide B, 17-hydroxyjolkinolide B, 17-hydroxyjolkinolide B acetic acid ester, the 17-hydroxyjolkinolide Bbenzoic acid ester 100 μ l of cell culture medium dilution, final concentration is 20 μ M, negative control group 0.5%DMSO, all establishes 3 multiple holes for each group.In incubator, cultivate after 72h, every hole adds the MTT 20 μ l of 5mg/ml, places 4h for 37 ℃.Every hole adds 200 μ l DMSO, 37 ℃ of shaking table joltings 30 minutes, and 492nm/620nm surveys absorbance (OD).OD value is carried out to t check, and calculate the suppression ratio of medicine to each growth of tumour cell: suppression ratio=(matched group OD value-administration group OD value)/matched group OD value × 100%.
Cultured Mouse sarcoma S180 cell, human leukemia Jurkat cell.Growth of Cells is to logarithmic growth after date, collecting cell, and centrifugal 5 minutes of 1000rpm, abandons supernatant, and appropriate culture medium suspends, and adjusts cell concentration to 1.1 105/ml.By cell suspension inoculation in 96 porocyte culture plates, every hole 90 μ l, the every hole of medication group adds 17-hydroxy-jolkinolide B (formula II) 10 μ 1 of cell culture medium dilution, final concentration is 20 μ M, blank group adds the cell culture medium of equivalent, all establish 6 multiple holes for each group, 3 hole dosings, 3 holes are blank.Negative control group 0.5%DMSO.In incubator, cultivate after 66h, every hole adds the MTT 10 μ l of 5mg/ml, places 4h for 37 ℃.Every hole adds three liquid (5%SDS, 10mMHCl, 5% isopropyl alcohol), 100 μ l, and 37 ℃ are spent the night.492nm/620nm surveys absorbance (OD).OD value is carried out to t check, and calculate the suppression ratio of medicine to each growth of tumour cell: suppression ratio=(matched group OD value-administration group OD value)/matched group OD value × 100%.
The inhibitory action of table 2 17-hydroxy-jolkinolide B to kinds of tumor cells growth
Purposes
Compound shown in formula I of the present invention or its pharmaceutically acceptable salt or prodrug or its isomer or the plant extract that contains it can be used for JAK inhibitor, can suppress JAK-STAT signal transduction pathway, be particularly useful for the inhibition of STAT3 signal transduction pathway, described inhibitor can be used for treating tumor.
The effective dose of active component used can change with the order of severity of mode of administration and disease to be treated.For most of large mammal, the accumulated dose that imposes effective ingredient every day is about 0.01-1000mg.Conventionally, the scope of adult's clinical administration amount is 0.01-200mg/ day, is preferably 0.05-100mg/ day.
Conventionally, in the time that the present composition is used for such use, they can make with one or more pharmaceutically acceptable carriers or mixed with excipients the pharmaceutical dosage form of different way of administration, as tablet, capsule, powder, granule, syrup, solution, oral liquid, spirit, tincture, aerosol, powder spray, injection, injectable sterile powder, suppository etc.
" pharmaceutically acceptable " composition is to be applicable to people and/or animal and the material that has rational benefit/risk ratio without excessive bad side reaction (as toxicity, stimulation and allergy)." pharmaceutically acceptable carrier " is acceptable solvent, suspending agent or the excipient pharmaceutically or on food for diterpene ginkgolide of the present invention or its physiologically acceptable salt being sent to animal or human.Carrier can be liquid or solid.
Compound of the present invention can be through oral, intravenous, intramuscular or subcutaneous route administration.
Dosage form that can oral administration administration in above-mentioned dosage form is: tablet, capsule, powder, granule, syrup, solution, spirit.Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose, kaolin, micropowder silica gel, Pulvis Talci, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpyrrolidone.And liquid carrier comprises: sterilized water, ethanol, Polyethylene Glycol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami).In the process of pharmaceutical compositions, normally used adjuvant comprises: flavoring agent, coloring agent, antiseptic (as oxybenzene alkyl butyl ester, sodium benzoate, sorbic acid) and antioxidant (as vitamin E, vitamin C, sodium pyrosulfite and dibenzylatiooluene).
The dosage form that can be used for injection administration in above-mentioned dosage form comprises: injection, injectable sterile powder, they are that medicine and one or more pharmaceutically acceptable mixed with excipients are made to the form for drug administration by injection.Solvent comprises: sterilized water, ethanol, glycerol, propylene glycol, Polyethylene Glycol.In addition, also need to add antibacterial (as benzyl alcohol, butyl hydroxybenzoate, thimerosal), isoosmotic adjusting agent (as sodium chloride, glucose), suspending agent (as sodium carboxymethyl cellulose, methylcellulose), solubilizing agent (tween 80, lecithin), antioxidant (as vitamin E, vitamin C, sodium pyrosulfite) and filler (as lactose, mannitol).
The inhibitory action of table 4 17-hydroxyjolkinolide B acetic acid ester to kinds of tumor cells growth
The inhibitory action of table 5 17-hydroxyjolkinolide B benzoic acid ester to kinds of tumor cells growth
Experimental result: as shown in table 2,3,4,5, in various tumor cell culture liquid, add after tested medicine, the OD value of medication group, all lower than blank group, has significant inhibitory action to the growth of S180,293, HepG2, MDA-MB-468, MDA-MB-231, MDA-MB-453, HGC, MCF-7, Jurkat, U937, Hela cell.Illustrate that above four kinds of tested medicines all have very strong inhibitory action to mice sarcoma cell, human embryo kidney (HEK) cancerous cell, hepatoma carcinoma cell, human breast cancer cell, stomach cancer cell, human leukemia cell, cervical cancer cell in vitro, antitumor spectra is wide.
The inhibitory action of embodiment 4 17-hydroxy-jolkinolide B to S180 tumor-bearing mice tumor growth
Laboratory animal: female SPF KM mice, provided by Shanghai Slac Experimental Animal Co., Ltd., body weight is 18-22g, and SPF level Animal House is raised, and 12h illumination/12h dark, freely absorbs feedstuff and water.
Experimental drug: compound 17-hydroxy-jolkinolide B (shown in II) is extracted by this laboratory, cyclophosphamide is purchased from Changzhou Xin Li medication chemistry company limited.
Experimental technique: get the inoculation S180 ascites mice of 7 days, extract ascites under aseptic condition, with normal saline adjustment cell concentration to 5 106/ml.S180 cell suspension is seeded in to mice right fore armpit with 0.2ml/ amount only subcutaneous.After inoculation 24h, mice is divided into respectively to 3 groups (10 every group) at random: medication group, with distilled water dissolving 17-hydroxy-jolkinolide B (formula II), dosage is 100mg/kg; Cyclophosphamide group, dosage is 20mg/kg; Matched group gives distilled water, and administration volume is 0.1ml/10g, above each group equal every day gastric infusion 1 time, continuous 7 days.Next day is put to death mice in drug withdrawal, strips tumor piece and weighs, and calculates every cell mean, carries out t check.Calculate tumour inhibiting rate, tumour inhibiting rate=(matched group tumor weight-administration group tumor weight)/matched group tumor heavy × 100%.
The inhibitory action of table 3 17-hydroxy-jolkinolide B to S180 tumor-bearing mice tumor growth
* represent p < 0.01, compared with matched group, there is significant difference.
Experimental result: the data show of table 3,17-hydroxy-jolkinolide B successive administration is after 10 days, medication group mouse tumor weigh less than matched group, difference has significance (p < 0.01), the tumour inhibiting rate of medicine reaches respectively 71.43%, illustrates that 17-hydroxy-jolkinolide B can obviously suppress the growth of S180 tumor-bearing mice tumor in the time of 100mg/kg dosage.Meanwhile, compared with cyclophosphamide group, the body weight of medication group does not decline, and illustrates that this drug toxicity is low.
The preparation of embodiment 5 tablets
Utilize routine techniques, mix following component, then direct compression, prepares the pharmaceutical composition of tablet form, and its formula is as follows:
The preparation of embodiment 6 injections
1. sodium sulfite is added in 500ml water for injection, adds sodium carboxymethyl cellulose, mix, soaked overnight (24 hours), complete molten after, with 210 order nylon cloths filtrations;
2. by 1. heating in water bath of solution, add tween 80, mix;
3. to water-bath boiling, add 17-hydroxy-jolkinolide B, mix, continue heating 30 minutes, take out and be cooled to room temperature, G3 sintered glass funnel filters;
4. inject water to 1000ml, mix, embedding, with 100 ℃ of sterilizings in 30 minutes.
Scope of the present invention is not subject to the restriction of described specific embodiments, and described embodiment is only wanted, as the single example of illustrating various aspects of the present invention, also to comprise method and the component of functional equivalent in the scope of the invention.In fact,, except content as herein described, those skilled in the art can easily grasp multiple improvement of the present invention with reference to description and accompanying drawing above.Within described improvement also falls into the scope of appended claims.Every piece of list of references mentioned above is listed in herein as a reference all in full.
Claims (1)
1. the purposes of diterpene ginkgolide in preparation treatment cancer drug, is characterized in that described diterpene ginkgolide is 17-hydroxyl rock Radix Euphorbiae Pekinensis lactone B or 17-hydroxyl rock Radix Euphorbiae Pekinensis lactone B benzoate; Described cancer is sarcoma, renal carcinoma, hepatocarcinoma, gastric cancer, breast carcinoma, lymphatic cancer or cervical cancer.
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| CN102558288A (en) * | 2010-12-29 | 2012-07-11 | 中国药科大学 | Preparation method of jolkinolide compound and application thereof |
| CN102846596A (en) * | 2011-07-01 | 2013-01-02 | 苏州沪云肿瘤研究中心有限公司 | Application of Jolkinolide B in preparing cellular immunosuppressive drug |
| CN102603765A (en) * | 2012-02-02 | 2012-07-25 | 齐齐哈尔医学院 | Method for extracting active ingredients of Euphorbia fischeriana and diterpenoid medicament prepared by active ingredients |
| CN102653543A (en) * | 2012-04-13 | 2012-09-05 | 中国药科大学 | Preparation method, biological activity and application of 3-substituted type Jolkinolide compound |
| EP2690094A1 (en) * | 2012-07-24 | 2014-01-29 | Centro Atlantico del Medicamento S.A (Ceamed, S.A) | Fused quinonic compounds |
| CN103860546A (en) * | 2014-03-20 | 2014-06-18 | 同济大学 | Application of abietane derivative in medicament for diseases caused by inflammatory mediators |
| CN104672251B (en) * | 2015-02-02 | 2018-04-24 | 齐齐哈尔大学 | A kind of semisynthesis of 17- hydroxyls-jolkinolide B |
| CN105712878A (en) * | 2016-01-20 | 2016-06-29 | 温州统益生物医药科技有限公司 | Diterpene compound and preparation method thereof |
| CN106279081B (en) * | 2016-08-23 | 2018-06-12 | 大连医科大学 | Diterpene class compound and preparation method in euphorbia fischeriana |
| CN107998124A (en) * | 2018-01-09 | 2018-05-08 | 吉林大学 | Application of the jolkinolide B derivatives in chronic obstructive pulmonary disease is treated |
| CN108272806B (en) * | 2018-03-13 | 2019-02-05 | 南京惠正干细胞生物科技有限公司 | Jolkinolide B and derivative are used as the purposes of miR-21 activator and mesenchymal stem cell Osteoblast Differentiation promotor |
| CN108210485A (en) * | 2018-04-08 | 2018-06-29 | 王长国 | A kind of TLR7 agonists are in enhancing CIK cell to the application in terms of tumor cell killing potential |
| CN110393723B (en) * | 2019-09-05 | 2022-10-25 | 北京中医药大学 | Application of abietane derivative in preparing medicine for preventing and treating cerebral ischemic diseases |
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| CN115721643A (en) * | 2021-09-01 | 2023-03-03 | 烟台资生元生物科技开发有限公司 | Application of jolkinolide B in preparation of medicine for treating tumors |
| CN115611720B (en) * | 2022-12-04 | 2023-03-31 | 中日友好医院(中日友好临床医学研究所) | Novel ent-strobane alkane diterpenoid compound, preparation method thereof, pharmaceutical composition and application |
| CN115626932B (en) * | 2022-12-08 | 2023-04-07 | 中日友好医院(中日友好临床医学研究所) | Novel diterpene compound, preparation method thereof, pharmaceutical composition and application thereof in antitumor drugs |
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