CN108929292A - 2- methylene fundamental mode substituted type splits lignanoids derivative and its medical usage - Google Patents
2- methylene fundamental mode substituted type splits lignanoids derivative and its medical usage Download PDFInfo
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- CN108929292A CN108929292A CN201710387206.8A CN201710387206A CN108929292A CN 108929292 A CN108929292 A CN 108929292A CN 201710387206 A CN201710387206 A CN 201710387206A CN 108929292 A CN108929292 A CN 108929292A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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Abstract
The present invention relates to 2- methylene fundamental mode substituted types to split lignanoids derivative and its medical usage, more particularly to compound or its pharmaceutically acceptable salt with structure shown in Formulas I, pharmaceutical composition containing the compound or its pharmaceutically acceptable salt, the compound or its pharmaceutically acceptable salt are in the purposes for preparing the JAK-STAT signal path related disease of purposes and the compound or its pharmaceutically acceptable salt for preventing and/or treating subject in the drug using JAK-STAT signal path as target spot.
Description
Technical field
The invention belongs to field of medicine and chemical technology, are related to 2- methene substituted type and split Lignanoids compounds, the invention further relates to
The pharmaceutical composition and its medical usage of Lignanoids compounds are split comprising 2- methene substituted type.
Background technique
Lignanoid is a kind of natural products as made of Phenylpropanoid Glycosides oxidation polymerization, and usual meaning is its dimer.Split the wooden rouge
Plain (Duan Lian lignanoid) is uncommon Lignanoids compounds, a C in lignan6-C3After open loop fracture occurs for unit
It reconnects, so that parent nucleus is become the structure type of dibenzylbutyrolactone, Chen CM in 1989 etc. is for the first time from Peperomia
Such compound is separated in japonica.It is known in nature to split Lignanoids compounds according on its gamma-butyrolacton ring
The substitution type of 2-C and carbonyl reduction situation, can be divided into 2- methyl substituted type, 2- methene substituted type, 2- methylol substituted type,
Carbonyl is reduced to the types such as hydroxyl on 2- acetyl-o-methyl substituted type and gamma-butyrolacton ring.Wherein, 2- methene substituted type
Split more rare in lignanoids nature, current only isolated 5 compounds in Herba Peperomiae pellucidae category, Urtica.According to document
Report, splitting Lignanoids compounds Peperomin B and Herba Peperomiae pellucidae element E has strong growth inhibitory activity to kinds of tumor cells.
JAK (Janus kinase) is one of protein tyrosine kinase (PTK), can with mediating cytokine and its by
Signal protein molecule after body combines cascades priming reaction.It is activated after in conjunction with receptor corresponding to its such as cell factor, growth factor
JAK, and then activation signal transductant and transcription activator STAT (signal transducer and activator of
transciription).STAT is a kind of unique protein family that can be incorporated into DNA, has now been found that there are 7 for STAT family
A member, i.e. STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6.JAK-STAT signal path is more
Kind of cell factor and growth factor transmit the common pathway of signal in the cell, participate in body cell proliferation, differentiation, apoptosis and
The various biologicals processes such as immune disorder, inflammation and tumour generation, obtain extensive research both domestic and external in recent decades.JAK-
It includes various entity tumors, lymthoma, leukaemia and inflammation disease that the activation of STAT signal path, which promotes various diseases,
The occurrence and development of disease.For example, gamma interferon (IFN-γ) mainly activates downstream gene transcription by STAT1 signal path, promote
The processes such as cellular immunity, humoral immunity play anti-malignant tumor cell Proliferation, antiviral, immunological surveillance and tumor suppression
Effect.But IFN-γ is the possible pathogenic factor of autoimmune disease.Inhibit the STAT1 of sustained activation may be to itself
Immunity disease, chronic inflammation and the following tissue damage have therapeutic effect.Interleukin-6 (IL-6), epidermal growth factor
Sub (EGF) etc. mainly activates the processes such as the corresponding gene regulation cell Proliferation in downstream, apoptosis by STAT3 signal path.Continue
The STAT3 of activation can also be led to by inhibiting the anti-tumor immune response of body to promote tumor cell proliferation, existence and transfer
Cross promotion NF- κ B, IL-6-GP130-JAK-STAT signal generates inflammation.The STAT3 for inhibiting sustained activation in tumour cell, can
To effectively promote apoptosis of tumor cells, inhibit the development of tumour.In addition, some hepatic injuries and the nervous system disease also with JAK-
STAT signal path to it is related.
So far, it there are no the chemical combination that lignanoids structural framework is split with 2- methylene fundamental mode in domestic and international correlative study
Object has the relevant report of inhibitory activity to JAK-STAT signal path.
Summary of the invention
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology
The normally understood meaning of personnel institute.Also, laboratory operation step involved in herein is to be widely used in corresponding field
Conventional steps.Meanwhile for a better understanding of the present invention, the definition and explanation of relational language is provided below.
As used in this article, term " C1-4Alkoxy " refers to C1-4The group that the mode of alkyl-O- is formed, including but not
It is limited to C1-4Straight or branched alkoxyl, such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, C4Straight or branched alkoxyl.
As used in this article, term " C2-5Alkenyloxy group " refers to C2-4The group that the mode of alkenyl-O- is formed, including but not
It is limited to C2-5Linear chain or branched chain alkenyloxy group, such as ethyleneoxy, allyl oxygroup, acrylic oxygroup, C4-5Linear chain or branched chain alkene oxygen
Base (such as 2- methyl-2-butene base-O-, 2-methyl-1-butene alkenyl-O-, 3-methyl-1-butene base-O).
As used in this article, term " C2-4Alkynyloxy group " refers to C2-4The group that the mode of alkynyl-O- is formed, including but not
It is limited to C2-4Linear chain or branched chain alkynyloxy group, such as acetylene oxygroup, propinyl oxygroup, propargyloxy, C4Linear chain or branched chain alkynes oxygen
Base.
As used in this article, term " C6-8Fragrant oxyl " refers to C6-8The base that the mode of aryl radical-O- is formed
Group, including but not limited to phenoxy group, benzyloxy.
As used in this article, term " C1-12Fat acyloxy " refer to the fatty acid containing 1-12 carbon atom remove to
The group that hydrogen atom in a few carboxyl is formed, the fatty acid are straight chain fatty acid or branched chain fatty acid, saturated fatty acid
Or unsaturated fatty acid, the fatty acid contain one or more carboxyls.The C2-12Fat acyloxy includes but is not limited to first
Acyloxy, acetoxyl group, acryloxy, butyryl acyloxy, isobutyl acyloxy, valeryl oxygroup, isoamyl acyloxy, amber acyl-oxygen
Base, octane acyloxy, laurel acyloxy.
As used in this article, term " C1-4Fat acyloxy ", " C1-5Fat acyloxy ", " C1-8Fat acyloxy ",
“C1-12Fat acyloxy ", " C3-5Fat acyloxy ", " C3-6Fat acyloxy ", " C6-10Fat acyloxy ", " C7-9Fatty acyl-oxygen
Base ", " C9-12Fat acyloxy " respectively refers to C1-12In fat acyloxy, contain 1-5 carbon atom, 1-8 carbon atom, 1-12
The specific reality of carbon atom, 3-5 carbon atom, 3-6 carbon atom, 6-10 carbon atom, 7-9 carbon atom, 9-12 carbon atom
Example.
As used in this article, term " straight chain fatty acyloxy ", " Branched fatty acyloxy ", " saturated fat acyl-oxygen
Base ", " unsaturated fat acyloxy ", " linear saturation fat acyloxy ", " branch saturated fat acyloxy ", " straight chain is unsaturated
The fatty acid that fat acyloxy ", " branch unsaturated fat acyloxy " respectively refer to form fat acyloxy is straight chain fatty acid, branch
Chain fatty acid, saturated fatty acid, unsaturated fatty acid, linear saturated fatty acids, branch chain saturated fatty acid, straight chain unsaturated fat
The specific example of acid, branch unsaturated fatty acid.
As used in this article, term " C6-8Fragrant acyloxy " refer to the aromatic carboxylic acids containing 6-8 carbon atom remove to
The group that hydrogen atom in a few carboxyl is formed, such as benzoyloxy, phenylacetyl oxygroup.
Term " pharmaceutically acceptable salt " in the present invention refers to acidic functionality (example present in the compounds of this invention
Such as-COOH ,-OH ,-SO3H etc.) with appropriate inorganic or organic cation (alkali) formed salt, including with alkali metal or alkaline earth
Salt (such as sodium salt, sylvite, magnesium salts or calcium salt), the ammonium salt of metal formation, and the salt formed with nitrogenous organic base；And this hair
Basic functionality present in bright compound (such as-NH2Deng) with appropriate inorganic or organic anion (acid) formation salt,
Including the salt formed with inorganic acid and the salt formed with organic carboxyl acid.
As used in this article, term " room temperature " refers to 25 ± 5 DEG C.
As used in this article, term " about " should be readily appreciated by one skilled in the art, and will be with the upper of place used in it
Hereafter there is a degree of variation.If to those skilled in the art, used according to the context of term application
It is not clearly, then mean no more than the certain number value or range positive and negative 10% of " about ".
The 2- first with structure shown in Formulas I has successfully been obtained by creative labor and unremitting effort in the present inventor
Alkenyl substituted type splits Lignanoids compounds (as shown in Figure 1)：
Wherein, the Arabic numerals in cyclic structure indicate corresponding mark.The present inventors have additionally discovered that the compound can
The activity for inhibiting intracellular JAK-STAT signal path, thus provides following inventions：
In one aspect, the present invention relates to compound or its pharmaceutically acceptable salt with structure shown in Formulas I,
Wherein,
R1、R2The following groups for each being selected from hydroxyl and being optionally substituted with a substituent：C1-4Alkoxy, C2-5Alkenyloxy group, C2-4
Alkynyloxy group, C6-8Fragrant oxyl, C1-12Fat acyloxy, C6-8Fragrant acyloxy, the substituent group are selected from hydroxyl, halogen (example
Such as fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the number of the substituent group be 1-6 (such as 1,2,3,4,5
It is a or 6)；Alternatively, R1With R2Formation-O- (CH2)n- O- (n=1 or 2)；
R3、R4The following groups for each being selected from hydroxyl and being optionally substituted with a substituent：C1-4Alkoxy, C2-5Alkenyloxy group, C2-4
Alkynyloxy group, the substituent group are selected from hydroxyl, halogen (such as fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the substituent group
Number is 1-6 (such as 1,2,3,4,5 or 6)；
R5、R6The following groups for each being selected from hydroxyl and being optionally substituted with a substituent：C1-4Alkoxy, C2-5Alkenyloxy group, C2-4
Alkynyloxy group, the substituent group are selected from hydroxyl, halogen (such as fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the substituent group
Number is 1-6 (such as 1,2,3,4,5 or 6)；Alternatively, R5With R6Formation-O- (CH2)n- O- (n=1 or
2)；
In certain embodiments, the C1-4Alkoxy is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, C4Directly
Chain or branched alkoxy.
In certain embodiments, the C2-5Alkenyloxy group is selected from ethyleneoxy, allyl oxygroup, acrylic oxygroup, C4-5
Linear chain or branched chain alkenyloxy group.
In certain embodiments, the C2-4Alkynyloxy group is selected from acetylene oxygroup, propinyl oxygroup, propargyloxy, C4Directly
Chain or branched alkynyloxy.
In certain embodiments, the C6-8Fragrant oxyl is selected from phenoxy group, benzyloxy.
In certain embodiments, the C1-12Fat acyloxy is selected from C1-4Fat acyloxy, C1-5Fat acyloxy,
C1-8Fat acyloxy, C1-12Fat acyloxy, C3-5Fat acyloxy, C3-6Fat acyloxy, C6-10Fat acyloxy, C7-9Rouge
Fat acyloxy, C9-12Fat acyloxy.
In certain embodiments, the fat acyloxy is selected from：Straight chain fatty acyloxy, is satisfied at Branched fatty acyloxy
With fat acyloxy, unsaturated fat acyloxy, linear saturation fat acyloxy, branch saturated fat acyloxy, straight chain insatiable hunger
With fat acyloxy, branch unsaturated fat acyloxy.
In certain embodiments, the C1-12Fat acyloxy is selected from：Formyloxy, acetoxyl group, acryloxy,
Butyryl acyloxy, isobutyl acyloxy, valeryl oxygroup, isoamyl acyloxy, octane acyloxy, amber acyloxy, laurel acyloxy.
In certain embodiments, the C1-12Fat acyloxy is replaced by carboxyl or hydroxyl.
In certain embodiments, the C replaced by carboxyl or hydroxyl1-12Fat acyloxy is 3- hydroxylauric acyl-oxygen
Base.
In certain embodiments, the C6-8Fragrant acyloxy is selected from benzoyloxy, phenylacetyl oxygroup.
In certain embodiments, the C6-8Fragrant acyloxy is replaced by halogen, hydroxyl or nitro.
In certain embodiments, the C replaced by halogen, hydroxyl or nitro6-8Fragrant acyloxy is selected from nutgall acyl
Oxygroup, p-nitrophenyl formyloxy, to chlorobenzoyl oxygroup, to fluorobenzoyl oxygroup.
In certain embodiments, R1、R2Each be selected from hydroxyl, methoxyl group, ethyoxyl, isoamyl alkenyloxy group, formyloxy,
Acetoxyl group, acryloxy, butyryl acyloxy, isobutyl acyloxy, valeryl oxygroup, isoamyl acyloxy, amber acyloxy, octane acyl
It is oxygroup, laurel acyloxy, 3- hydroxylauric acyloxy, benzoyloxy, nutgall acyl oxygroup, p-nitrophenyl formyloxy, right
Chlorobenzoyl oxygroup, to fluorobenzoyl oxygroup, alternatively, R1With R2Formation-O- (CH2)n- O- (n=1 or 2)；
R3、R4It each is selected from the C being optionally substituted with a substituent1-3Alkoxy (such as methoxyl group, ethyoxyl, propoxyl group, isopropyl
Oxygroup)；
R5、R6It each is selected from the C being optionally substituted with a substituent1-3Alkoxy (such as methoxyl group, ethyoxyl, propoxyl group, isopropyl
Oxygroup), alternatively, R5With R6Formation-O- (CH2)n- O- (n=1 or 2)；
The substituent group is selected from hydroxyl, halogen (such as fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the substituent group
Number be 1-6 (such as 1,2,3,4,5 or 6).
In certain embodiments, the compound meets the following conditions：
(1)R1-R6It is not simultaneously methoxyl group, and
(2) work as R1、R3、R4Respectively methoxyl group, and R5With R6Formation-O-CH2When-O-, R2It is not hydroxyl.
In certain embodiments, R1、R2Each be selected from hydroxyl, methoxyl group, ethyoxyl, isoamyl alkenyloxy group, acetoxyl group,
Benzoyloxy, nutgall acyl oxygroup, p-nitrophenyl formyloxy；
R3、R4It each is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy；
R5、R6It each is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, alternatively, R5With R6Formation-O- (CH2)n-O-
(n=1 or 2)；
Also, the compound meets the following conditions：
(1)R1-R6It is not simultaneously methoxyl group, and
(2) work as R1、R3、R4Respectively methoxyl group, and R5With R6Formation-O-CH2When-O-, R2It is not hydroxyl.
In certain embodiments, R1For hydroxyl or methoxyl group；
R2Selected from hydroxyl, methoxyl group, ethyoxyl, isoamyl alkenyloxy group, acetoxyl group, benzoyloxy, nutgall acyl oxygroup,
P-nitrophenyl formyloxy；
R3、R4、R5、R6Respectively methoxyl group；Alternatively, R3、R4Respectively methoxyl group, R5With R6Formation-O-CH2-O-；
Also, the compound meets the following conditions：
(1)R1-R6It is not simultaneously methoxyl group, and
(2) work as R1、R3、R4Respectively methoxyl group, and R5With R6Formation-O-CH2When-O-, R2It is not hydroxyl.
In certain embodiments, R1、R3、R4、R5、R6Respectively methoxyl group, R2For hydroxyl.
In certain embodiments, R2、R3、R4、R5、R6Respectively methoxyl group, R1For hydroxyl.
In certain embodiments, R1、R3、R4Respectively methoxyl group, R2For ethyoxyl, R5With R6Formation-O-CH2-O-。
In certain embodiments, R1、R3、R4Respectively methoxyl group, R2For isoamyl alkenyloxy group, R5With R6Formation-O-CH2-
O-。
In certain embodiments, R1、R3、R4Respectively methoxyl group, R2For acetoxyl group, R5With R6Formation-O-CH2-O-。
In certain embodiments, R1、R3、R4Respectively methoxyl group, R2For nutgall acyl oxygroup, R5With R6Formation-O-
CH2-O-。
In certain embodiments, R1、R3、R4Respectively methoxyl group, R2For p-nitrophenyl formyloxy, R5With R6Formed-
O-CH2-O-。
In certain embodiments, R1、R3、R4Respectively methoxyl group, R2For benzoyloxy, R5With R6Formation-O-CH2-
O-。
In one aspect, the present invention relates to a kind of pharmaceutical composition, containing the compound of the present invention or its pharmaceutically may be used
With the salt of receiving, optionally, also contain one or more pharmaceutic adjuvants.
When the pharmaceutic adjuvant of the application refers to production drug and prescription being dispensed, the excipient and additives used refers to and removes
Outside active constituent, reasonable assessment is had been carried out in terms of safety, and includes the substance in pharmaceutical preparation.Pharmaceutic adjuvant
In addition to excipient, serve as carrier, improve stability other than, also there is solubilising, hydrotropy, delay the critical functions such as controlled release, be that possible will affect
To the important component of the quality of drug, safety and validity.Pharmaceutic adjuvant according to source can be divided into natural goods, semisynthetic and
Fully synthetic object；It can be divided into according to its effect with purposes：Solvent, propellant, solubilizer, cosolvent, emulsifier, colorant, bonding
Agent, disintegrating agent, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, corrigent, preservative, suspending
Agent, coating material, aromatic, anti stickness agent, antioxidant, chelating agent, penetration enhancer, pH adjusting agent, buffer, plasticizer,
Surfactant, foaming agent, defoaming agent, thickener, inclusion agents, moisturizer, absorbent, diluent, flocculant and deflocculant,
Filter aid, release retarding agent etc.；According to its administration route can be divided into oral, injection, mucous membrane, percutaneous or local administration, intranasal or
Oral inhalation administration and ophthalmic administration etc..Same pharmaceutic adjuvant can be used for the pharmaceutical preparation of different way of administration, and have different
Effect and purposes.
Various suitable dosage forms can be made in the pharmaceutical composition of the application according to administration route.Administration route can be mouth
Clothes, non-bowel or local administration.
The pharmaceutical composition of the application can be applied in any way, such as：Oral, spraying sucking, rectal application, nasal cavity
Administration, local application, non-bowel medication, as in subcutaneous, vein, intramuscular, peritonaeum, in intrathecal, intra-ventricle, breastbone and intracranial injection
Or input, or by explant memory；Wherein preferred administration mode is to take orally, is in peritonaeum or intravenous.
When oral medication, described pharmaceutical composition can be made into and arbitrarily take orally acceptable dosage form, including but unlimited
In tablet, capsule, granule, pill, syrup, oral solution, oral suspensions and Orally taken emulsion etc..Wherein, tablet
The carrier used generally comprises lactose and cornstarch, and lubricant such as magnesium stearate in addition can also be added.Capsule uses dilute
It releases agent and generally comprises lactose and dried corn starch.Oral suspensions are then usually by active constituent and suitable emulsifier and to hang
Floating agent is used in mixed way.Optionally, some sweeteners, aromatic or colorant can also be added in the above oral dosage form.
When percutaneous or local application, described pharmaceutical composition can be made into ointment, lotion or liniment form appropriate, wherein
Active constituent is suspended or dissolved in one or more carriers.Carrier workable for ointment formulation includes but is not limited to：Mineral
Oil, Albolene, albolene, propylene glycol, polyethylene glycol oxide, polypropylene oxide, emulsifying wax and water；Lotion or liniment can make
Carrier includes but is not limited to：Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene
Fragrant and mellow, 2- octyldodecanol, benzyl alcohol and water.
Described pharmaceutical composition can the medication in the form of injection, including injection, injection sterile powder and injection
Concentrated solution.Wherein, workable carrier and solvent include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterilizing is non-
Volatile oil also is used as solvent or suspension media, such as monoglyceride or two glyceride.
In certain embodiments, the compound of the present invention or its pharmaceutically acceptable salt are deposited in the form of unit dose
It is in pharmaceutical composition.
In certain embodiments, a effective amount of described pharmaceutical composition of subject is given.As used herein, art
Language " effective quantity " refers to the amount for being enough to obtain or at least partly obtaining desired effect.For example, prevention condition effective amount refers to, foot
It with prevention, prevents, or postpones the amount of the generation of disease；Treatment condition effective amount refers to, it is sufficient to cure or at least partly prevent
The disease of patient with disease and the amount of its complication.Such effective quantity is measured completely in the ability of those skilled in the art
Within the scope of.For example, therapeutical uses are effectively measured by depend on the severity of disease to be treated, patient oneself it is immune
Overall status, the ordinary circumstance of patient such as age, weight and the gender of system, the method for application of drug, and be administered simultaneously
Other treatment etc..
In one aspect, the present invention relates to any of the above-described compound, its pharmaceutically acceptable salt or any of the above-described
Pharmaceutical composition is preparing the purposes in the drug using JAK-STAT signal path as target spot.
In one aspect, the present invention relates to any of the above-described compound, its pharmaceutically acceptable salt or any of the above-described
Use of the pharmaceutical composition in the drug for preparing the JAK-STAT signal path related disease for preventing and/or treating subject
On the way.
In one aspect, the present invention relates to it is a kind of prevention and/or treatment JAK-STAT signal path related disease method,
Including to subject with this need application any of the above-described compound, its pharmaceutically acceptable salt or any of the above-described drug
Composition.
In one aspect, the present invention relates to any of the above-described compound, its pharmaceutically acceptable salt or any of the above-described
Pharmaceutical composition is used to prevent and/or treat the JAK-STAT signal path related disease of subject.
In certain embodiments, the JAK-STAT signal path related disease is selected from tumour, inflammation, autoimmune
Disease, hepatic injury and the nervous system disease.
In certain embodiments, the tumour is selected from cancer of pancreas, the cancer of the brain, colorectal cancer, gastric cancer, liver cancer, lung cancer, ovary
Cancer, breast cancer, cervical carcinoma, lymthoma, Human acute promyelocytic leukemia.
In certain embodiments, the inflammation and autoimmune disease be selected from chronic inflammation, rheumatic arthritis and
Rheumatoid arthritis.
In certain embodiments, the hepatic injury is selected from Ischemia-reperfusion Injury in Rat, fatty liver, virus hepatitis, liver
Fibrosis and hepatic failure.
In certain embodiments, the nervous system disease is selected from spinal cord injury, subarachnoid hemorrhage, peripheral nerve
Damage, transverse myelitis and cerebral infarction.
In certain embodiments, the subject be mammal, such as bovid, equid, caprid,
Porcine animals, canid, felid, rodent, primate；For example, described, subject is a human.
On the other hand, the present invention relates to the method for preparation any of the above-described compound or its pharmaceutically acceptable salt, institutes
The method of stating includes the following steps：
(1) dindygulen peperomia herb ethanol total extract is prepared；
(2) dindygulen peperomia herb ethanol total extract is extracted using organic solvent (such as petroleum ether and ethyl acetate), is obtained
To extraction product；
(3) extraction product is separated using vacuum liquid chromatogram, obtains initial gross separation product；
(4) using column chromatography and half preparative high-performance liquid chromatographic to initial gross separation product or in which one or more parts
It is separated.
In certain embodiments, the step (1) includes：Dindygulen peperomia herb is heated to reflux in ethanol solution, mistake
Filter, the solvent removed in filtrate obtain dindygulen peperomia herb ethanol total extract.
In certain embodiments, the step (2) includes：Respectively using petroleum ether and ethyl acetate to dindygulen peperomia herb ethyl alcohol
Total extract is extracted, and three extraction positions are obtained, and merges petroleum ether, Ethyl acetate fraction, is removed solvent and is extracted
Take product.
In certain embodiments, the step (3) includes：Utilize vacuum liquid chromatogram (6 × 9cm, 200~300 mesh silicon
Glue, petroleum ether-ethyl acetate 5:3~0:1) extraction product is separated, is detected, is obtained using thin-layer chromatography (TLC)
Initial gross separation product, including 5 parts, i.e. Fr.A, Fr.B, Fr.C, Fr.D, Fr.E.
In certain embodiments, the step (4) includes：(11 × 21cm, GH-ODS silica gel, methanol-are chromatographed using column
Water 40:60~55:45) Fr.D is separated, is detected with high performance liquid chromatography (HPLC), obtains D1, D2, D3, D4；Use half
Prepare HPLC (5 × 27cm, YMC-ODS silica gel, methanol-water 45:55) D2 is separated, obtains 6 parts, i.e. D2-1, D2-
2,D2-3,D2-4,D2-5,D2-6；Using half prepare HPLC in the D2-1~D2-6 it is one or more partially respectively into
Row separation, obtains the compound of the present invention.
In certain embodiments, the method also includes：A compound of the invention is alkylated or is acylated
Reaction, obtains another compound of the invention.
Beneficial effect
The compound of the present invention is able to suppress the activity of intracellular JAK-STAT signal path, prevent and/or treat with
In terms of the relevant disease of JAK-STAT signal path (such as tumour, inflammation and autoimmune disease), have medicinal well
Potentiality.
Embodiment of the present invention is described in detail below in conjunction with embodiment and attached drawing, still, art technology
Personnel will be understood that, the following example and attached drawing are merely to illustrate the present invention, rather than the restriction to the scope of the present invention.According to excellent
The following detailed description of embodiment is selected, various purposes of the invention and advantageous aspect will become to those skilled in the art
It obtains obviously.
Detailed description of the invention
Fig. 1 shows the structural formula of the compounds of this invention.
Fig. 2 shows in embodiment 1 that the thin-layer chromatography for carrying out reduced pressure chromatography separation to dindygulen peperomia herb ethanol total extract is examined
Survey result (unfolding condition：Petroleum ether-ethyl acetate 1:3).
Fig. 3 is shown in embodiment 1, and the thin-layer chromatography point sample analysis result (exhibition of reversed phase column chromatography separation is carried out to Fr.D
Open condition：Petroleum ether-ethyl acetate 1:3).
Fig. 4 is shown in embodiment 1, and the thin-layer chromatography testing result (unfolding condition of reversed phase column chromatography separation is carried out to D3：
Petroleum ether-acetone 1:2).
Specific embodiment
It will be understood to those of skill in the art that the following examples are merely to illustrate the present invention, and it should not be regarded as limiting this
The range of invention.The person that is not specified actual conditions in embodiment, carries out according to conventional conditions or manufacturer's recommended conditions.Examination used
Production firm person is not specified in agent or instrument, and being can be with conventional products that are commercially available.
In the structural research of following embodiment, specific rotatory power is surveyed with the PolAAr3005 type polarimeter of OA company of Britain
It is fixed.Negative ions ESI-MS and HR-ESI-MS use 3000 type LC-MS instrument of American AB company API and Britain respectively
The measurement of Micromass company LCT type mass spectrograph.Circular dichroism spectra Biologic Science company of France MOS-450 circular dichroism
Spectrometer measurement.Nuclear magnetic resonance map Japan's JEOL company JNM-ECA-400 type and U.S.'s Bruker company INOV600 type superconduction
Nmr determination.Analytic type HPLC uses HP1200 type high performance liquid chromatograph, UV detector, and chromatographic column uses
wondasilTMODS column (5 μm, 4.6 × 150mm)；YMC-PACK-ODS-A column(5μm,4.6×150mm).Half prepares
HPLC use Shimadzu LC-15C type HPLC, SPD-15C detector, chromatographic column using YMC-PACK-ODS-A column (5 μm, 10
×250mm)。
The solvent used in all experiments is the pure rank of analysis, and petroleum ether boiling spread used is 60-90 DEG C.
Embodiment 1：The extraction of dindygulen peperomia herb medicinal material and the preparation of compound 1,2,3,4,5,6
The dry herb 1.3kg of dindygulen peperomia herb (Peperomia blanda Jacq.Kunth) cuts segment, 80% (2 × 12L) second
Alcohol heating and refluxing extraction 2h, filtering.Decompression removal solvent obtains dindygulen peperomia herb ethanol total extract 290g after gained filtrate merges, point
Not Shi Yong petroleum ether (3 × 800mL), ethyl acetate extraction (3 × 800mL) obtain three extraction positions.Merge petroleum ether, acetic acid
Ethyl ester extract position, solvent is removed under reduced pressure and obtains 105g product, through reduced pressure chromatography separation (VLC, repetitive operation 7 times, 6 ×
9cm, 200~300 mesh silica gel, according to petroleum ether-ethyl acetate 5:3→4:3→1:1→1:2→0:1 sequence gradient elution),
According to thin-layer chromatography testing result (unfolding condition：Petroleum ether-ethyl acetate 1:3), merge fraction 1-3 respectively；4-6；7-10；
11-13；14-22 (as shown in Figure 2) is concentrated to get 5 parts (Fr.A~Fr.E).
Take 10g Fr.D, inverted column chromatography for separation (11 × 21cm, YMC-ODS silica gel), methanol-water (40:60,45:
55,50:50,55:45) gradient elution, each gradient elution 2000ml, fraction are evaporated after collecting, the analysis (exhibition of thin-layer chromatography point sample
Open condition：Petroleum ether-ethyl acetate 1:3), according to tomographic results, merge fraction 1-3 respectively；4-6；7-12；13-19 (such as Fig. 3
It is shown), obtain four fraction D1~D4.
D3 is stood after being concentrated into small size, is precipitated impurity (30mg), and mother liquor, which is evaporated, is weighed as 1.4g, inverted column chromatography (5
× 27cm, YMC-ODS silica gel, methanol-water 45:55) it separates, according to thin-layer chromatography (unfolding condition：Petroleum ether-acetone 1:2) it examines
It surveys as a result, merging fraction 12-13 respectively；14-15；16-16Δ；17-18；19；20 (as shown in Figure 4) obtain six fractions
(D3-1~D3-6).
D3-1 separates (methanol-water 40 using half preparation HPLC:60, flow velocity 1.5ml/min, pressure 220bar) obtain chemical combination
Object 2 (2mg).D3-2 separates (methanol-water 40 using half preparation HPLC:60, flow velocity 1.5ml/min) obtain compound 3 (6mg),
Compound 4 (18mg).D3-3 is partly prepared after separating removal low molecular weight impurities through gel filtration chromatography (2 × 100cm, methanol)
HPLC separates (methanol-water 48:52, flow velocity 1.5ml/min, pressure 212bar) obtain compound 1 (10mg), compound 2,5
Mixture, further using half preparation HPLC (acetonitrile-methanol-water 20:23:57, flow velocity 1.5ml/min, pressure 180bar) point
From obtaining compound 2 (2mg), compound 5 (12mg).D3-6 separates (methanol-water 58 through half preparation HPLC:42, flow velocity 1.5ml/
Min, pressure 180bar) obtain compound 6 (5mg).
In addition half preparation HPLC (methanol-water 40 is repeatedly used:60, flow velocity 1.5ml/min, pressure 220bar) it is right
D3-2 remainder is separated, and the sterling 125mg of compound 4 is obtained.
The physicochemical constant and spectral data of compound 1~6
Compound 1：White amorphous powder is soluble in methanol；(c 0.10,MeOH)；(+)HRESI-
MS m/z:431.1699[M+H]+,453.1519[M+Na]+(calculated value m/z 453.1525)；(+)ESI-MS m/z：431.3
[M+H]+, 448.3 [M+NH4]+, 453.2 [M+Na]+, 883.5 [2M+Na]+；ECD(c 1mM,MeOH)：[θ]213- 2450,
[θ]2313825, [θ]245- 2949, [θ]284+9350；1H NMR(400MHz,CDCl3) (being shown in Table 1)；13C NMR(100MHz,
CDCl3) (being shown in Table 1).The NMR data of compound 1 is according to it shown in table 11H spectrum,13C uncouples spectrum and HSQC, HMBC etc. entirely
Two-dimensional spectrum result is belonged to.
Compound 2：White amorphous powder is soluble in methanol；(c 0.60,MeOH)；(+)
HRESI-MS m/z：431.1700[M+H]+(calculated value m/z 431.1706)；(+)ESI-MS m/z：431.17[M+H]+,
448.20[M+NH4]+, 453.16 [M+Na]+；ECD(c 1mM,MeOH)：[θ]213- 2120, [θ]231+ 4253, [θ]243+ 305,
[θ]274.5+9388；1H NMR(400MHz,CDCl3) (being shown in Table 1)；13C NMR(100MHz,CDCl3) (being shown in Table 1).Shown in table 1
The NMR data of compound 2 is according to it1H spectrum,13C uncouples spectrum entirely and the two-dimensional spectrums result such as HSQC, HMBC is belonged to.
NMR data (400/100MHz, the CDCl of 1 compound 1,2 of table3)
Compound 3：White amorphous powder is soluble in methanol；(+)ESI-MS m/z：462.5[M+NH4]+, 467.5 [M+
Na]+, 483.4 [M+K]+；1H NMR(600MHz,CDCl3) (being shown in Table 2).
Compound 4：White amorphous powder is soluble in methanol；(+)ESI-MS m/z：415.4[M+H]+, 432.4 [M+
NH4]+, 438.4 [M+K]+, (-) ESI-MS m/z：413.2[M-H]-；1H NMR(400MHz,CDCl3) (being shown in Table 2).
Compound 5：White amorphous powder is soluble in methanol；(+)ESI-MS：m/z 429.3[M+H]+, 446.6 [M+
NH4]+, 451.3 [M+Na]+, 467.3 [M+K]+, 463.3 [M+Cl]-, 473.5 [M+HCOO]-；1H NMR(400MHz,CDCl3)
(being shown in Table 2).
Compound 6：Light yellow solid is soluble in chloroform；(+)ESI-MS m/z：413.2[M+H]+, 430.3 [M+NH4]+,
435.4[M+Na]+, 451.3 [M+K]+, 847.4 [2M+Na]+；1H NMR(400MHz,CDCl3) (being shown in Table 2).
2 compound 3~6 of table1H NMR data
Note：The determination condition of compound 3 is (600MHz, CDCl3)；The determination condition of compound 4~6 be (400MHz,
CDCl3)。
The structure difference of compound 1-6 is as follows：
Embodiment 2：It is prepared by the derivatization of the compounds of this invention 4a~4f
The about 12mg of compound 4 made from above-described embodiment 1 is weighed, with 0.5ml acetone solution, 50mg anhydrous K is added2CO3It is mixed
It is even, 50 μ l dithyl sulfates are added dropwise under 60 DEG C of magnetic agitations and carry out ethylation reaction 6h.Reaction product is thin using silica gel is prepared
Analysis is isolated and purified layer by layer, and in addition to recycling 4mg raw material compound 4,4a (1.2mg, cation ESI-MS m/z is made：443
[M+H]+, 459 [M+NH4]+)。
The about 12mg of compound 4 made from above-described embodiment 1 is weighed, with 0.5ml acetone solution, 50mg anhydrous K is added2CO3It is mixed
It is even, the bromo- 3- methyl-2-butene of 50 μ l1- is added dropwise under 60 DEG C of magnetic agitations, normal-temperature reaction 12h is filtered, a small amount of acetone washing,
Merging filtrate, evaporated under reduced pressure are prepared silica gel thin-layer chromatography and are isolated and purified, in addition to recycling 3mg raw material compound 4, system
Obtain 4b (1.5mg, cation ESI-MS m/z：483[M+H]+, anion ESI-MS m/z：481[M-H]-)。
The about 12mg of compound 4 made from above-described embodiment 1 is weighed, is dissolved, is rapidly added with 0.25ml anhydrous pyridine
0.25ml aceticanhydride mixes, and avoid light place carries out acetylization reaction for 24 hours.Reaction product prepared silica gel thin-layer chromatography separate it is pure
Change, 4c (3mg, cation ESI-MS m/z is made：457[M+H]+, anion ESI-MS m/z：455[M-H]-)。
The about 12mg of compound 4 made from above-described embodiment 1 is weighed, with 0.25ml acetone solution, 0.25ml galla turcica is added
Acid 10mg/ml acetone soln mix, then be added dropwise 6N hydrochloric acid 1 drop mix after, avoid light place carries out acylation reaction 7 days at room temperature.
Reaction product is isolated and purified through preparing silica gel thin-layer chromatography, and 4d (0.8mg, cation ESI-MS m/z is made：567[M+H
]+, anion ESI-MS m/z：565[M-H]-)。
The about 12mg of compound 4 made from above-described embodiment 1 is weighed, is dissolved with 0.2ml anhydrous pyridine, is rapidly added p- nitro
Chlorobenzoyl chloride 13mg is mixed, and avoid light place 10h carries out acylation reaction.Reaction product prepared silica gel thin-layer chromatography separate it is pure
Change, 4e (3mg, cation ESI-MS m/z is made：564[M+H]+, anion ESI-MS m/z：562[M-H]-)。
The about 12mg of compound 4 made from above-described embodiment 1 is weighed, is dissolved with 0.2ml anhydrous pyridine, is rapidly added benzoyl
8 μ l of chlorine is mixed, and avoid light place 20h carries out acylation reaction.Reaction product is isolated and purified through preparing silica gel thin-layer chromatography, is made
4f (2.2mg, cation ESI-MS m/z：537[M+H]+, anion ESI-MS m/z：535[M-H]-)。
The structure difference of compound 4a-4f is as follows：
Embodiment 3：Test of the formula Compound I to JAK-STAT signal path inhibitory activity
4#/HepG2 cell distinguishes stable transfection STAT1-Luciferase, STAT3-Luciferase plasmid (with a-MEM
Addition 10%FBS is culture medium).After cultivating 4#/HepG2 tumour cell to logarithmic growth phase, cell, 1000rpm centrifugation 5 are collected
Minute, supernatant is abandoned, with the suspension of appropriate culture medium, adjustment cell concentration to 2 × 105/ ml, by cell suspension inoculation to 96 hole cells
In culture plate, every 100 μ l of hole, be placed in cell incubator (37 DEG C, 5%CO2) in.Cell culture to completely it is adherent, grow to
It is random to be grouped after density 60~70%：
Negative control：The culture medium containing 0.5% final concentration DMSO isometric with drug to be measured is added, if 2 secondary orifices, point
Not Jia Ru 11 μ l of agonist (IFN-γ or IL-6), be incubated for 5.5 hours；
Positive control：Three groups of positive controls to be set up, 2 secondary orifices are respectively set, it is respectively 100,50 that 100 μ l concentration, which are added, in every hole,
10,2,0.4,0.08 μM of Pyridone 6 is separately added into 11 μ l of agonist (IFN-γ or IL-6), is incubated for 5.5 hours；
Drug-treated：Drug-treated group respectively sets 2 secondary orifices, is separately added into compound 1-6, (every hole adds compound 4a-4f
Enter the drug that 100 μ l concentration are respectively 250,100,50,10,2,0.4,0.08 μM) after culture 1 hour, it is separately added into agonist
(IFN-γ or IL-6) 11 μ l continues to be incubated for 5.5 hours；
96 orifice plates are taken out, it is careful to draw, culture medium is removed, luciferase cell pyrolysis liquid (CCLR) 30 μ l is added in every hole,
After gently concussion cracks cell sufficiently, 20 μ l are pipetted respectively into 96 orifice plate of enzyme mark, and 30 μ l luciferase substrates, mixing is added
Uniformly, it is placed in fluorescence intensity in microplate reader, calculates IC50.IC is calculated with Prism Graphpad5.0 statistical software50
Value.Inhibitory activity the results are shown in Table 3.
3 the compounds of this invention of table and positive control JAK inhibitor Pyridone 6 are to IFN-γ/STAT1, IL-6/STAT3
Inhibitory activity
As shown in table 3, Pyridone 6 produces IFN-γ/STAT1 signal path and IL-6/STAT3 signal path
Strong inhibiting effect, it was demonstrated that cell model models successfully.The present invention 12 is had detected using luciferase reporter gene detection method
A compound is to IFN-γ/STAT1, IL-6/STAT3 signal path inhibitory activity.12 compounds of the invention are shown pair
The different degrees of inhibitory activity of IFN-γ/STAT1 signal path, the IC of inhibiting effect50Value is 1.35 to 81.47 μM；This 12
A compound also shows the different degrees of inhibitory activity to IL-6/STAT3 signal path, the IC of inhibiting effect50Value is
0.59 arrives>100μM.
Above the experiment results show that the compound of the present invention has JAK-STAT signal path inhibitory activity, can be used for pre-
Anti- and/or treatment disease relevant to JAK-STAT signal path, for example, tumour, inflammation, autoimmune disease, hepatic injury and
The nervous system disease.
Although a specific embodiment of the invention has obtained detailed description, it will be appreciated by those skilled in the art that：Root
According to all introductions having disclosed, details can be carry out various modifications and be changed, and these change in guarantor of the invention
Within the scope of shield.Full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (8)
1. compound or its pharmaceutically acceptable salt with structure shown in Formulas I,
Wherein,
R1、R2The following groups for each being selected from hydroxyl and being optionally substituted with a substituent：C1-4Alkoxy, C2-5Alkenyloxy group, C2-4Alkynes oxygen
Base, C6-8Fragrant oxyl, C1-12Fat acyloxy, C6-8Fragrant acyloxy, the substituent group be selected from hydroxyl, halogen (such as fluorine,
Chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the number of the substituent group is 1-6 (such as 1,2,3,4,5 or 6
It is a)；Alternatively, R1With R2Formation-O- (CH2)n- O- (n=1 or 2)；
R3、R4The following groups for each being selected from hydroxyl and being optionally substituted with a substituent：C1-4Alkoxy, C2-5Alkenyloxy group, C2-4Alkynes oxygen
Base, the substituent group are selected from hydroxyl, halogen (such as fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the number of the substituent group
It is 1-6 (such as 1,2,3,4,5 or 6)；
R5、R6The following groups for each being selected from hydroxyl and being optionally substituted with a substituent：C1-4Alkoxy, C2-5Alkenyloxy group, C2-4Alkynes oxygen
Base, the substituent group are selected from hydroxyl, halogen (such as fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, the number of the substituent group
It is 1-6 (such as 1,2,3,4,5 or 6)；Alternatively, R5With R6Formation-O- (CH2)n- O- (n=1 or 2)；
Preferably, the C1-4Alkoxy is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, C4Straight or branched alkoxyl；
Preferably, the C2-5Alkenyloxy group is selected from ethyleneoxy, allyl oxygroup, acrylic oxygroup, C4-5Linear chain or branched chain alkene oxygen
Base；
Preferably, the C2-4Alkynyloxy group is selected from acetylene oxygroup, propinyl oxygroup, propargyloxy, C4Linear chain or branched chain alkynyloxy group；
Preferably, the C6-8Fragrant oxyl is selected from phenoxy group, benzyloxy；
Preferably, the C1-12Fat acyloxy is selected from C1-4Fat acyloxy, C1-5Fat acyloxy, C1-8Fat acyloxy,
C1-12Fat acyloxy, C3-5Fat acyloxy, C3-6Fat acyloxy, C6-10Fat acyloxy, C7-9Fat acyloxy, C9-12Rouge
Fat acyloxy；
Preferably, the fat acyloxy is selected from：Straight chain fatty acyloxy, Branched fatty acyloxy, saturated fat acyloxy, no
Saturated fat acyloxy, linear saturation fat acyloxy, branch saturated fat acyloxy, straight chain unsaturated fat acyloxy, branch
Chain unsaturated fat acyloxy；
Preferably, the C1-12Fat acyloxy is selected from：Formyloxy, acetoxyl group, acryloxy, butyryl acyloxy, isobutyryl
Oxygroup, valeryl oxygroup, isoamyl acyloxy, octane acyloxy, amber acyloxy, laurel acyloxy；
Preferably, the C1-12Fat acyloxy is replaced by carboxyl or hydroxyl；
Preferably, the C replaced by carboxyl or hydroxyl1-12Fat acyloxy is 3- hydroxylauric acyloxy；
Preferably, the C6-8Fragrant acyloxy is selected from benzoyloxy, phenylacetyl oxygroup；
Preferably, the C6-8Fragrant acyloxy is replaced by halogen, hydroxyl or nitro；
Preferably, the C replaced by halogen, hydroxyl or nitro6-8Fragrant acyloxy is selected from nutgall acyl oxygroup, p-nitrophenyl
Formyloxy, to chlorobenzoyl oxygroup, to fluorobenzoyl oxygroup.
2. the compound of claim 1 or its pharmaceutically acceptable salt, wherein
R1、R2It each is selected from hydroxyl, methoxyl group, ethyoxyl, isoamyl alkenyloxy group, formyloxy, acetoxyl group, acryloxy, fourth
Acyloxy, isobutyl acyloxy, valeryl oxygroup, isoamyl acyloxy, amber acyloxy, octane acyloxy, laurel acyloxy, 3- hydroxyl
Laurel acyloxy, benzoyloxy, nutgall acyl oxygroup, p-nitrophenyl formyloxy, to chlorobenzoyl oxygroup, to fluorobenzoyl
Oxygroup, alternatively, R1With R2Formation-O- (CH2)n- O- (n=1 or 2)；
R3、R4It each is selected from the C being optionally substituted with a substituent1-3Alkoxy (such as methoxyl group, ethyoxyl, propoxyl group, isopropyl oxygen
Base)；
R5、R6It each is selected from the C being optionally substituted with a substituent1-3Alkoxy (such as methoxyl group, ethyoxyl, propoxyl group, isopropyl oxygen
Base), alternatively, R5With R6Formation-O- (CH2)n- O- (n=1 or 2)；
The substituent group is selected from hydroxyl, halogen (such as fluorine, chlorine, bromine, iodine), nitro, carboxyl, benzyloxy, of the substituent group
Number is 1-6 (such as 1,2,3,4,5 or 6)；
Preferably, the compound meets the following conditions：
(1)R1-R6It is not simultaneously methoxyl group, and
(2) work as R1、R3、R4Respectively methoxyl group, and R5With R6Formation-O-CH2When-O-, R2It is not hydroxyl.
3. the compound of claims 1 or 2 or its pharmaceutically acceptable salt, wherein
R1、R2It each is selected from hydroxyl, methoxyl group, ethyoxyl, isoamyl alkenyloxy group, acetoxyl group, benzoyloxy, galla turcica acyl-oxygen
Base, p-nitrophenyl formyloxy；
R3、R4It each is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy；
R5、R6It each is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, alternatively, R5With R6Formation-O- (CH2)n- O- (n=1
Or 2)；
Also, the compound meets the following conditions：
(1)R1-R6It is not simultaneously methoxyl group, and
(2) work as R1、R3、R4Respectively methoxyl group, and R5With R6Formation-O-CH2When-O-, R2It is not hydroxyl.
4. the compound of any one of claim 1-3 or its pharmaceutically acceptable salt, wherein
R1For hydroxyl or methoxyl group；
R2Selected from hydroxyl, methoxyl group, ethyoxyl, isoamyl alkenyloxy group, acetoxyl group, benzoyloxy, nutgall acyl oxygroup, to nitre
Base benzoyloxy；
R3、R4、R5、R6Respectively methoxyl group；Alternatively, R3、R4Respectively methoxyl group, R5With R6Formation-O-CH2-O-；
Also, the compound meets the following conditions：
(1)R1-R6It is not simultaneously methoxyl group, and
(2) work as R1、R3、R4Respectively methoxyl group, and R5With R6Formation-O-CH2When-O-, R2It is not hydroxyl.
5. the compound of any one of claim 1-4 or its pharmaceutically acceptable salt, the compound are selected from：
6. a kind of pharmaceutical composition, containing compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt, appoint
Selection of land also contains one or more pharmaceutic adjuvants.
7. prepared by the pharmaceutical composition of any one of claim 1-5 compound, its pharmaceutically acceptable salt or claim 6
Using JAK-STAT signal path as the purposes in the drug of target spot.
8. prepared by the pharmaceutical composition of any one of claim 1-5 compound, its pharmaceutically acceptable salt or claim 6
Purposes in the drug of JAK-STAT signal path related disease for preventing and/or treating subject；
Preferably, the JAK-STAT signal path related disease be selected from tumour, inflammation, autoimmune disease, hepatic injury and
The nervous system disease；
Preferably, the tumour is selected from cancer of pancreas, the cancer of the brain, colorectal cancer, gastric cancer, liver cancer, lung cancer, oophoroma, breast cancer, uterine neck
Cancer, lymthoma, Human acute promyelocytic leukemia；
Preferably, the inflammation and autoimmune disease are selected from chronic inflammation, rheumatic arthritis and rheumatoid arthritis；
Preferably, the hepatic injury is selected from Ischemia-reperfusion Injury in Rat, fatty liver, virus hepatitis, liver fibrosis and hepatic failure；
Preferably, the nervous system disease is selected from spinal cord injury, subarachnoid hemorrhage, peripheral nerve injury, transverse ridge
Marrow inflammation and cerebral infarction；
Preferably, the subject is mammal, such as bovid, equid, caprid, porcine animals, Canidae
Animal, felid, rodent, primate；For example, described, subject is a human.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981577A (en) * | 1998-06-18 | 1999-11-09 | Development Center For Biotechnology | α-methylene peperomins and halogenated derivatives thereof |
| CN105503786A (en) * | 2015-12-07 | 2016-04-20 | 大连大学 | Secolignan compound-nettle secolignan glucoside E and preparation method thereof |
-
2017
- 2017-05-27 CN CN201710387206.8A patent/CN108929292B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981577A (en) * | 1998-06-18 | 1999-11-09 | Development Center For Biotechnology | α-methylene peperomins and halogenated derivatives thereof |
| CN105503786A (en) * | 2015-12-07 | 2016-04-20 | 大连大学 | Secolignan compound-nettle secolignan glucoside E and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| DARUNEE SOORUKRAM等: "A stereoselective approach to bioactive secolignans: synthesis of peperomin C and its analogues", 《TETRAHEDRON》 * |
| JIAN-LIN WU等: "Bioactive Secolignans from Peperomia dindygulensis", 《JOURNAL OF NATURAL PRODUCTS》 * |
| MATTHEW G. LLOYD等: "Phosphorylated cyclopropanes in the synthesis of α-alkylidene-γ-butyrolactones: total synthesis of (±)-savinin, (±)-gadain and (±)-peperomin E", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
| RUO-FENG SUN等: "Novel secolignans from Peperomia dindygulensis and their inhibitory activities on JAK-STAT signaling pathways", 《FITOTERAPIA》 * |
| SU XU等: "Bioactive Compounds from Peperomia pellucida", 《JOURNAL OF NATURAL PRODUCTS》 * |
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