CN108392478A - Application of the andrographolide class compound in terms of preparing for radioactive damage drug - Google Patents
Application of the andrographolide class compound in terms of preparing for radioactive damage drug Download PDFInfo
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- CN108392478A CN108392478A CN201710068116.2A CN201710068116A CN108392478A CN 108392478 A CN108392478 A CN 108392478A CN 201710068116 A CN201710068116 A CN 201710068116A CN 108392478 A CN108392478 A CN 108392478A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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Abstract
The invention discloses a kind of application of andrographolide class compound in terms of preparing radioactive damage drug；The andrographolide class compound of the present invention includes andrographolide class compound, its isomers, prodrug, solvate or pharmaceutically acceptable salt；The andrographolide class compound of the present invention has the function of good therapeutic radiation damage.
Description
Technical field
The present invention relates to medicinal application field, more particularly to a kind of andrographolide class compound and its isomers, prodrug,
The application of solvate or pharmaceutically acceptable salt in terms of preparing radioactive damage drug.
Background technology
Effect of the radiation treatment in treating malignant tumour very significantly unquestionably, but will also see radioreaction
With the presence of damage.High dose ray has also damaged normal cell killing cancer cell simultaneously, patient just will appear it is certain not
Good reaction.Radiation treatment can only kill tumour cell to the maximum extent in the case where normal structure is resistant to.To radiation
The tumour of line sensitivity, killing the dosage of cancer cell will not make tumour normal surrounding tissue be damaged, and radiotherapy can make to swell
Tumor is effected a radical cure, but the radioactive ray lethal dose for the tumour cell having is similar to the lethal or damage dose of normal surrounding tissue cell,
It also can major injury normal structure while killing cancer cell.Radiation treatment is one of effective treatment means of entity tumor,
The tumor patient of 50%-60% needs to carry out radiotherapy over the course for the treatment of.However, normal tissue injury caused by radiation
It is the major issue that clinical radiation therapy faces, is mainly reflected in radioactive inflammation, radiation fibrosis etc..
Radioactive inflammation, including：Radiation esophagitis, radiation thyroiditis, radioactivity osteitis, is put at radiation enteritis
Penetrating property stomatitis, radiation_induced pleurisy, radiodermatitis, radiation pneumonitis, radioactivity vaginitis, radiocystitis.
Radiation fibrosis is after normal structure raying damages, and extracellular matrix (ECM) synthesis is lost with degradation
Balance leads to the process that collagen and other ECM ingredients are built up.Receive cell factor TGF.Bl, matrix in the tissue after irradiation
The expression such as metalloproteinases (MMPs) change and then fibrosis forms GAP-associated protein GAP such as collagen, fiber in induced tissue
The expression such as albumen and other glycoprotein are connected to increase, it is unbalance so as to cause ECM synthesis and degradation.ECM reconstructions will lead to blood vessel
Inner membrance, the fibrosis in middle level, arteries were narrow, the weary oxygen of ischemic occurs for organ and then atrophy, hollow organ are narrow and organ
The pathological changes such as function reduction.Especially with the late lesions that fibrosis is main pathological change, organ structure and work(are often resulted in
It can change.The late lesions for particularly occurring in important organ, as radiation fibrosis of lung, radioactivity myocardial fibrosis,
Radioactivity rectum fibrosis, radioactivity kidney fibrosis etc. seriously affect the life quality or even threat to life of patient.
Andrographolide (andrographolide) is one of highest ingredient of content in Andrographis Paniculata.It has
Therefore multiple target effect mechanism has extensive pharmacological activity, such as antipyretic, anti-inflammatory, analgesia, antibacterial, hypoglycemic etc., with
The research that deepens continuously to andrographolide pharmacological action finds it in immunological regulation, antiviral and antitumor etc. have
It is widely used and (wears Gui Fu etc., Chinese patent drug, 2006,28 (7):1032).Andrographolide concrete structure is as follows：
Currently, having document and patent report (Lin HQ, et al.Biol.Pharm.Bull.2006,29 (2):220,
CN101012211B, CN1666985A, US20050215628A1), andrographolide and its derivative can inhibit LPS to induce
TNF-α, IL1 β and IL-6 expression, to inhibit the inflammatory reaction of body.TNF-α is a kind of precursor inflammatory cytokine,
Participate in many inflammatory reaction processes.By inhibiting TNF-α to can be used for treating various autoimmune disease (rheumatoid joint
Inflammation, Crohn disease, systemic loupus erythematosus, psoriasis etc.), the nervous system disease (Alzheimer's disease, Parkinson's disease, AIDS
Dementia, depression), (Ogata H, the Hibi T.et al.Curr Pharm such as cancer and respiratory virus infection
Des.2003,9(14):1107；Sack M.et al.Pharmacol Ther.2002,94(1-2):123-135；Barnes
PJ.Et al.Annu Rev Pharmacol Toxicol.2002,42:81；Goldring MB.Et al.Expert Opin
Biol Ther.2001Sep；1(5):817).IL1 β are by generations such as mononuclear macrophage, dendritic cells and fibroblasts
Cell factor can stimulate proliferation and the differentiation of T cell and B cell, participate in inflammatory reaction.It includes disease to inhibit IL1 β to can be used for treating
Various inflammatory reactions (Taylor PC.et al.Curr Pharm Des.2003 including poison infection；9(14):1095；
Dellinger RP et al Clin Infect Dis.2003 May 15；36(10):1259).IL-6 is also known as B cell thorn
Swash the factor, various kinds of cell can be spontaneous or generate IL-6 under other stimulations, periphery and development of central nervous system, differentiation,
It plays an important role in regeneration and denaturation.
In addition, found that andrographolide and its derivative had certain effect in terms of viral infection resisting in recent years,
It is had made some progress in terms for the treatment of and preventing AIDS, hepatitis and the infection of hand-foot-and-mouth disease virus.Such as CN103739575A and
CN103739597A discloses the anti-HBV effect of andrographolidume derivative.CN104042621A is disclosed in Herba Andrographitis
Esters medicine-Xiyanping has the serious consequence prevented and mitigated caused by the infection of hand-foot-and-mouth disease virus.
In summary, andrographolide class use of a compound is extensive, be mainly manifested in antiviral, anti-inflammatory, antibacterial, antibechic and
In terms of strengthen immunity, but there is no document reports for the purposes in terms of radioactive damage drug.
Invention content
The present invention provides the new application of andrographolide class compound, i.e. andrographolide class compound is used in preparation
Application in terms of radioactive damage drug.
In the preferred embodiment of the present invention, andrographolide class compound be formula (I) and its isomers, prodrug,
Solvate or pharmaceutically acceptable salt.
Wherein,
A and b is separately singly-bound or double bond, and is double bond when a with b differences；
R1And R2Separately it is selected from hydrogen, alkyl ,-Si (R ')3、-C(O)R’、-SO3M；Alternatively, R1And R2It is connected with each other
5-8 membered heterocycloalkyls are formed, the Heterocyclylalkyl can also further contain 1~2 and be selected from Si, S (O)0-2Or the hetero atom of N
Or group；The Heterocyclylalkyl is unsubstituted or is further replaced by 1~4 substituent group selected from alkyl or oxo base in office
Meaning position；
R3For following any structure：
R4For hydrogen, halogen, amino, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl or-ORa；
R5For hydrogen, halogen, amino, alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl；
R6For hydrogen；R6aFor substituted or unsubstituted aryl, the aryl can be replaced in office by 1~2 halogen when substituted
Meaning position；
R7And R7aIt is separately selected from substituted or unsubstituted alkyl, the alkyl can be by 1~2 hydroxyl when substituted
Or amino substitution is at an arbitrary position；
X, a key and b keys are respectively selected from following combination：
1) X is CR8, a keys are double bond, and b keys are singly-bound；
2) X is CR8, a keys are singly-bound, and b keys are double bond；
3) X is C=CH2Or CR9R9a, a keys and b keys are singly-bound；
R8For connecting key ,-ORbOr substituted or unsubstituted C1-3Alkyl, as the C1-3It, can be by 1 when alkyl is substituted
Hydroxyl replaces at an arbitrary position；R9For connecting key or C1-3Alkyl；R9aFor C1-3Alkyl；Alternatively, R9And R9aIt is connect jointly with it
C atoms form 3~6 yuan of naphthenic base together；
Y and Z is separately CHR10；R10For hydrogen, connecting key, halogen, amino, alkyl, naphthenic base, Heterocyclylalkyl, virtue
Base, heteroaryl, hydroxyl, alkoxy or-OSO3M；
Alternatively, the R8And R10For connecting key when, can be by-CH2It is interconnected to form 7 yuan of naphthenic base；
Alternatively, the R9And R10For connecting key when, 5 membered heterocycloalkyls can be interconnected to form by-O-；
R ' is hydrogen, C1-6Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl,
C3-6Naphthenic base, 3-6 membered heterocycloalkyls, phenyl or 5-6 unit's heteroaryls.
RaFor hydrogen ,-SO3M, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
Base, substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, generation or unsubstituted cycloalkyl-alkyl, substitution or
Unsubstituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl or substitution or
Unsubstituted C2-6Alkenyl；When the substituted alkyl, substituted naphthenic base, substituted Heterocyclylalkyl, substituted aryl, substitution
Heteroaryl, substituted cycloalkyl-alkyl, substituted hetercycloalkylalkyl, substituted aryl alkyl, substituted heteroaryl alkyl
Or the C of substitution2-6Alkenyl can be by 1~3 selected from halogen, C when substituted1-4Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogen
For C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base, 3-6 membered heterocycloalkyls, phenyl, 5-6 unit's heteroaryls ,-NO2、-
CN、-ORc、-SRc、-OC(O)Rc、-OC(O)NRcRd、-NRcRd、-N(Rc)C(O)Rd、-N(Rc)S(O)2Rd、-S(O)0-2Rc、-C
(O)Rc、-C(O)ORcOr-C (O) NRcRdSubstituent group substitution at an arbitrary position；
RbFor hydrogen or-SO3M；
RcAnd RdSeparately it is selected from hydrogen, C1-6Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, C2-6
Alkenyl, C2-6Alkynyl, C3-6Naphthenic base, 3-6 membered heterocycloalkyls, phenyl or 5-6 unit's heteroaryls；
M is hydrogen, Na+、K+Or NH4 +。
The andrographolide class compound (I) and its isomers, prodrug, solvate or pharmaceutically acceptable salt,
Its general formula is more preferably such as lower structure：
Wherein, * is expressed as R configurations or S configurations；
R1、R2、R4、R9a、R10Definition with M is as described above.
Application of the andrographolide class compound in terms of preparing for radioactive damage drug, wherein described to wear
Heart lotus lactone compound (I) is most preferably the combination of following any compound or any number of compounds：
The preferred embodiment of the present invention, the andrographolide class compound are Xiyanping.
The preferred embodiment of the present invention, the radioactive damage are the disease caused by radioactive ray, including but
It is not limited to radioactive inflammation disease, radiation fibrosis disease.
One of which preferred embodiment, the radioactive inflammation disease are the inflammation caused by radioactive ray, including but
It is not limited to radioactivity digestive system inflammation, radioactivity inflammation in respiratory system, radioactivity Urinary system inflammation, radioactivity reproductive system
Inflammation or radioactive skin inflammation.
One of which preferred embodiment, the radioactive inflammation disease is including but not limited to radiation esophagitis, radiation
Property enteritis, radiation thyroiditis, radioactivity osteitis, Inflammation of Radioactive Oral Cavity, radiation_induced pleurisy, radiodermatitis, radioactivity
Pneumonia, radioactivity vaginitis, radiocystitis.
One of which preferred embodiment, the radiation fibrosis disease are the fibrosis caused by radioactive ray, packet
Contain but be not limited to radiation fibrosis of lung, radioactivity myocardial fibrosis, radioactivity rectum fibrosis, radioactivity kidney fibrosis.
The present invention also provides a kind of pharmaceutical compositions for therapeutic radiation damage comprising the work of therapeutically effective amount
Property component and pharmaceutically acceptable auxiliary material；The active component includes andrographolide class compound and its isomers, preceding
It is one or more in medicine, solvate and pharmaceutically acceptable salt.
In described pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include pharmaceutically acceptable carrier, dilution
Agent and/or excipient.
The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and can be the form of solid, semisolid or liquid.This
Outside, pharmaceutical preparation of the invention can be administered by vein, subcutaneous and other suitable approach.One kind is it is preferable that oral have
Effect.Another kind is such as injected intravenously it is preferable that parenterai administration mode, can shorten the time that drug works in vivo in this way.
Pharmaceutical composition can be made to various types of administration unit dosage forms, as tablet, pill, pulvis, liquid, suspension, lotion,
Granula, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, lotion, suppository and injection (solution and outstanding
Supernatant liquid) etc..
In the present invention, content of the composition in pharmaceutical composition is without specifically limited, wherein in the Herba Andrographitis
Ester type compound and its isomers, prodrug, solvate or pharmaceutically acceptable salt can be selected in a wide range
It selects, safely, effectively dosage is determined according to concrete conditions such as the age for the treatment of object, weight, the state of an illness, the course of disease, administration routes,
The content of usual andrographolide class compound is 0.01-99.99wt%, preferably 5-95wt%, more preferably 30-80wt%.
In the present invention, the medication of described pharmaceutical composition is not particularly limited.Can according to patient age, gender and its
Its condition and symptom select the preparation of various dosage forms to be administered.For example, tablet, pill, solution, suspension, lotion, granule or
Capsule oral is administered；Injection can be administered alone, or mixed with injection conveying liquid (such as glucose solution and amino acid solution)
Conjunction is injected intravenously；Suppository is to be administered into rectum.
Can be mammal with the object of the pharmaceutical composition of the present invention and method treatment, especially people.
Further, when treating injury of lungs, pharmaceutical composition of the invention contains pharmaceutically acceptable carrier and punching
Lotus lactone compound (such as Xiyanping, Lian Bizhi, andrographolide active constituent).
In order to make the pharmaceutical composition of tablet form shape, it can be used this field any known and widely used figuration
Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon
Acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose
Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, such as dried starch, mosanom, agar powder and sea
Band powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid monoglycerides,
Starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as season
Amine base and lauryl sodium sulfate etc.；Wetting agent, such as glycerine, starch；Adsorbent, such as starch, lactose, kaolin, bentonite
With colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..It can also be according to need
Select common coated material be made sugar coated tablet, apply gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and
Multilayer tablet.
In order to make the pharmaceutical composition of pill shape, it can be used this field any of and widely used figuration
Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum powder etc.；Adhesive, such as Arabic tree
Rubber powder, tragacanth gum powder, gelatin and ethyl alcohol etc.；Disintegrant, such as agar and Kelp Powder.
In order to make the pharmaceutical composition of suppository form shape, it can be used this field any known and widely used inborn nature
Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
In order to prepare the pharmaceutical composition of injection form, (suitable chlorine can will be preferably added after solution or suspension liquid disinfectant
Change sodium, glucose or glycerine etc.), it is made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any
Common carrier.For example, water, ethyl alcohol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy
The aliphatic ester etc. of anhydro sorbitol.In addition, common lytic agent, buffer and analgesic etc. can also be added.
The present invention provides a kind of method of therapeutic radiation damage.This method includes to the disease for needing to carry out radiation treatment
People or patient with radioactive damage apply a effective amount of andrographolide class compound formulation.
One of preferred embodiment, the andrographolide class compound are Xiyanping, andrographolide or Lian Bizhi.
Age and the state of an illness of the dose therapeutically effective of the Xiyanping according to treated patient, but daily agent of being commonly grown up
Amount is 2-500mg/kg, preferably 5-300mg/kg, more preferable 5-50mg/kg, and children cut down according to the circumstance or follow the doctor's advice, and administration number of times can be
Once a day, or for several times.
The present invention has following advantageous effects：
1, the present invention overcomes the prejudice of the prior art, that is, think that " andrographolide class compound is only that application is general
Inflammation or the purposes such as antiviral, do not have the application conditions in radioactive damage drug still at present " technology prejudice.
2, the present invention by experimental data, further by taking Xiyanping as an example, applicant using IR induction mouse pneumonia and
Pulmonary fibrosis model, integrated use flow cytometry, PCR, western blot and the methods of H＆E dyeing, immunohistochemistry,
The therapeutic effect investigated and compare Xiyanping to lung inflammation and pulmonary fibrosis.Experimental result is shown through the small of Xiyanping
The level of mouse, lung inflammation infiltration and inflammatory factor is decreased obviously, and lung tissue's inflammation damnification mitigates, and pulmonary fibrosis situation is
Improve.
Unless otherwise indicated, the following term occurred in description of the invention and claims has following meanings：
Term " alkyl " refers to the saturated straight chain or branched hydrocarbyl for including 1-20 carbon atom, preferably 1-10 carbon atom,
The representative example of more preferable 1-8,1-7,1-6,1-5,1-4,1-3 carbon atom, alkyl includes but not limited to：Methyl, ethyl,
N-propyl, isopropyl, normal-butyl, sec-butyl, tertiary butyl, isobutyl group, amyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-
Dimethyl amyl group, 2,2,4- tri-methyl-amyls, undecyl, dodecyl and their various isomers etc..
Term " naphthenic base " refers to the saturation or part unsaturation (including 1 or 2 double bond) for including 3-20 carbon atom
One or more cyclic groups.It is preferred that 3-12 member naphthenic base." monocyclic cycloalkyl " preferably 3-10 unit monocycle alkyl, more preferable 3-8 members are single
Naphthenic base, such as：Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, cyclo-dodecyl, hexamethylene
Alkenyl." polycyclic naphthene base " includes " bridged ring base ", " fused cycloalkyl " and " spiro cycloalkyl group ", the representative example packet of " bridged ring base "
It includes but is not limited to：It is bornyl, bicyclic [2.2.1] heptenyl, bicyclic [3.1.1] heptane base, bicyclic [2.2.1] heptane base, bicyclic
[2.2.2] octyl, bicyclic [3.2.2] nonyl, bicyclic [3.3.1] nonyl, bicyclic [4.2.1] nonyl and adamantyl
Deng." fused cycloalkyl " includes to be fused to cycloalkyl ring on phenyl, naphthenic base or heteroaryl, and fused cycloalkyl includes but not
It is limited to：Benzocyclobutene, 2,3- dihydro -1-H- indenes, 2,3- cyclopenta pyridines, 5,6- dihydro -4H- cyclopenta [B] thiophene, ten
Hydrogen naphthalene etc..The representative example of " spiro cycloalkyl group " includes but not limited to：Spiral shell [2,4] heptane base, spiral shell [4,5] decyl etc..Monocycle
Naphthenic base or polycyclic naphthene base can be connected to by arbitrary carbon atom chain on ring on parent molecule.
Term " Heterocyclylalkyl " refers to by carbon atom and the saturation formed selected from hetero atoms such as nitrogen, oxygen or sulphur or part insatiable hunger
The non-aromatic cyclic radical of (including 1 or 2 double bond), this cyclic group can be one or more cyclic groups, in the present invention, miscellaneous
Hetero atom number preferably 1,2,3 or 4 in naphthenic base, nitrogen, carbon or sulphur atom in Heterocyclylalkyl are optionally aoxidized.Nitrogen-atoms
It can optionally further be replaced by other groups and form tertiary amine or quaternary ammonium salt." monocyclic heterocycloalkyl " preferably 3-10 unit monocycle heterocycles
Alkyl, more preferable 3-8 unit monocycles Heterocyclylalkyl.Such as：'-aziridino, tetrahydrofuran -2- bases, morpholine -4- bases, thiomorpholine -
4- bases, thiomorpholine-S-oxide -4- bases, piperidin-1-yl, N- Alkylpiperidine -4- bases, pyrrolidin-1-yl, N- alkyl pyrroles
Alkane -2- bases, piperazine -1- bases, 4- alkyl piperazine -1- bases etc.." polycyclic Heterocyclylalkyl " includes " annelated heterocycles alkyl ", " spiroheterocyclic
Base " and " bridge Heterocyclylalkyl "." annelated heterocycles alkyl " includes the monocycle for being fused to phenyl, naphthenic base, Heterocyclylalkyl or heteroaryl
Heterocycloalkyl ring, annelated heterocycles alkyl include but not limited to：2,3- dihydro benzo furyls, 1,3- dihydroisobenzofurans base,
Indolinyl, 2,3- dihydrobenzos [b] thienyl, dihydrobenzo piperazine are muttered base, 1,2,3,4- tetrahydric quinoline groups etc..Monocyclic heterocycles
Alkyl and polycyclic Heterocyclylalkyl can be linked to by arbitrary annular atom on ring on parent molecule.Above-mentioned annular atom refers in particular to form
The carbon atom and/or nitrogen-atoms of ring skeleton.
Term " cycloalkyl-alkyl " refers to being connected by alkyl between naphthenic base and mother nucleus structure." naphthenic base alkane as a result,
Base " includes the definition of abovementioned alkyl and naphthenic base.
Term " hetercycloalkylalkyl " refers to being connected by alkyl between Heterocyclylalkyl and mother nucleus structure." heterocycle alkane as a result,
Base alkyl " includes the definition of abovementioned alkyl and Heterocyclylalkyl.
Term " alkoxy " refers to has the carbon atom number purpose cyclic annular or acyclic alkyl groups by what oxygen bridge connected, packet
Containing alkyl oxy, cycloalkyl oxy and Heterocyclylalkyl oxygroup." alkoxy " includes abovementioned alkyl, Heterocyclylalkyl and cycloalkanes as a result,
The definition of base.
Term " alkenyl " refers to the straight chain containing at least one carbon-carbon double bond, branch or cyclic annular non-aromatic alkyl.It wherein can be with
There are 1-3 carbon-carbon double bonds, preferably there is 1 carbon-carbon double bond.Term " C2-4Alkenyl " refers to the alkenyl for having 2-4 carbon atom,
Term " C2-6Alkenyl " refers to the alkenyl for having 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2- methyl butene bases
And cyclohexenyl group.The alkenyl can be substituted.
Term " aryl " refers to the 6-10 unit monocycles or bicyclic aromatic groups of any stabilization, such as：Phenyl, naphthalene, four
Hydrogen naphthalene, indanyl or xenyl etc..
Term " heteroaryl " refers to that the carbon atom at least one ring is formed by the hetero atom displacement selected from nitrogen, oxygen or sulphur
Aromatic group, can be 5-7 unit monocycles structure or 7-12 membered bicyclic structures, preferably 5-6 unit's heteroaryls.In the present invention,
Hetero atom number preferably 1,2 or 3, including:Pyridyl group, pyrimidine radicals, (2H) -one of pyridazine -3 base, furyl, thienyl, thiazolyl,
Pyrrole radicals, imidazole radicals, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, tri- nitrogen of 1,2,4-
Oxazolyl, 1,2,3- triazol radicals, tetrazole base, indazolyl, iso indazolyl, indyl, isoindolyl, benzofuranyl, benzo
Thienyl, benzo [d] [1,3] dioxolanyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl
Deng.
Term " aryl alkyl " refers to being connected by alkyl between aryl and mother nucleus structure." aryl alkyl " includes as a result,
The definition of abovementioned alkyl and aryl.
Term " heteroaryl alkyl " refers to being connected by alkyl between Heterocyclylalkyl and mother nucleus structure." heteroaryl alkane as a result,
Base " includes the definition of abovementioned alkyl and heteroaryl.
Term " halogen " indicates fluorine, chlorine, bromine or iodine.
Term " halogenated alkyl " refers to the alkyl arbitrarily replaced by halogen.As a result, " halogenated alkyl " include the above halogen and
The definition of alkyl.
Term " halogenated alkoxy " refers to the alkoxy arbitrarily replaced by halogen.More than " halogenated alkoxy " include as a result,
The definition of halogen and alkoxy.
Term " amino " refers to-NH2。
Symbol "=" indicates double bond.
" prodrug " refers to being converted into original activity compound after compound is metabolized in vivo.Typically say, it is preceding
Medicine is that either specific activity parent compound activity is small but can provide convenient operation, is administered or improve generation for inert matter
Thank to characteristic.
" solvate " of the present invention refers to the solvent addition form comprising stoichiometry or non-stoichiometry solvent.
Some compounds tend to capture under crystalline solid state the solvent molecule of fixed molar ratio example, therefore form solvation
Object.If solvent is water, the solvate of formation is " hydrate ", if solvent is ethyl alcohol, the solvate of formation is
For alcoholate.Hydrate is to be combined to form hydrate with the substance by one or more hydrones, wherein hydrone
State is H2O, such combination can form the hydrate for including one or more hydrones.
" pharmaceutically acceptable salt " of the present invention is in Berge, et al., " Pharmaceutically
Acceptable salts ", J.Pharm.Sci., 66,1-19 are discussed in (1977), and for Pharmaceutical Chemist be it is aobvious and
Be clear to, the salt is substantially avirulent, and pharmacokinetic property needed for capable of providing, palatability, absorption, distribution,
Metabolism or excretion etc..Compound of the present invention can have acidic-group, basic group or amphiprotic group, typically pharmaceutically
Acceptable salt includes the salt that compound and acid reaction are prepared through the invention, such as：Hydrochloride, hydrobromate, sulfuric acid
Salt, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphoric acid
Salt, pyrophosphate, nitrate, acetate, propionate, caprate, caprylate, formates, acrylates, isobutyrate, caproic acid
Salt, enanthate, oxalates, malonate, succinate, suberate, benzoate, methyl benzoic acid salt, phthalic acid
Salt, maleate, mesylate, tosilate, (D, L)-tartaric acid, citric acid, maleic acid, (D, L)-malic acid are rich
Horse acid, succinic acid, succinate, lactate, fluoroform sulphonate, naphthalene -1- sulfonate, mandelate, acetonate, stearic acid
Salt, ascorbate, salicylate.When the compounds of this invention contains acidic-group, pharmaceutically acceptable salt can be with
Including：Alkali metal salt, such as sodium or sylvite；Alkali salt, such as calcium or magnesium salts；Organic alkali salt, for example, with ammonia, alkyl ammonia
The salt of the formation such as class, hydroxy alkyl Ammonia, amino acid (lysine, arginine), N-METHYL-ALPHA-L-GLUCOSAMINE.
" isomers " of the present invention refer to the present invention formula (I) compound can have asymmetric center and racemic modification,
Racemic mixture and single diastereoisomer, all these isomers, including stereoisomer, geometric isomer include
In the present invention.Wherein, " isomers " of the present invention is preferably " stereoisomer ".In the present invention, formula (I) compound or
Its salt is in the form of stereomeric in the presence of (for example, it contains one or more asymmetric carbon atoms), individual alloisomerism
Body (enantiomter and diastereoisomer) and their mixture are included within the scope of the invention.The invention also includes
The independent isomers of compound or salt that formula (I) indicates, and the isomers with the reversion of wherein one or more chiral centres
Mixture.The scope of the present invention includes：The mixture of stereoisomer, and purifying enantiomter or enantiomter/
The mixture of diastereoisomer enrichment.The present invention includes all enantiomters and all possible difference of non-corresponding isomers
The mixture of the stereoisomer of combination.The present invention includes whole groups of the stereoisomer of all specific groups defined above
Conjunction and subset.The invention also includes the geometric isomer of formula (I) compound or its salt, the geometric isomer includes cis-trans isomerism
Body.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention
Example.
The reagents and materials used in the present invention are commercially available.
Description of the drawings
Fig. 1：Mouse radio exposure process；
Fig. 2：The visual condition of 7th week mouse after irradiation；
Fig. 3：4th week each group mouse lung inflammatory cell infiltration situation after irradiation；
Fig. 4：Inflammatory factor is horizontal in 4th week each group mouse bronchoalveolar lavage fluid and serum；
Fig. 5：4th week each group mouse lung tissue form；
Fig. 6：4th week each group mouse lung inflammatory factor mRNA expression；
Fig. 7：Each group mouse lung fibrosis associated genes mRNA expression in 4th week；
Fig. 8：8th week each group mouse lung inflammatory cell infiltration situation；
Fig. 9：Inflammatory factor is horizontal in 8th week each group mouse bronchoalveolar lavage fluid and serum；
Figure 10：8th week each group mouse lung inflammatory factor mRNA expression；
Figure 11：Each group mouse lung fibrosis associated genes mRNA expression in 8th week；
Figure 12：0-40 weeks mouse survival curve after radiation insult.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
Product specification selects.
Various soluble derivatives can be prepared into after general extraction andrographolide, such as sodium sulfite, sulfuric acid or sulfuric acid
Addition reaction, water-soluble sulfonate obtained, Andrographolidi Natrii Bisulfis (LIANBIZHI ZHUSHEYE), succinic acid occur for hydrogen sodium
Andrographolide sulfonate and its mixture is made (such as in half ester k-na salt (' Tanhuning ' injection) or sulfonation：Xiyanping).
The present invention can refer to method disclosed in the prior art and prepare its compound and preparation, and following experiments are with Jiangxi Qing Feng
The Camptotheca acuminata leaves that pharmaceutcal corporation, Ltd provides are that representative is tested.
Embodiment 1
1, modeling method
Female (20g) C57/BL6 mouse, are injected intraperitoneally 1% yellow Jackets, with homemade organic glass mouse cage after anesthesia
It is fixed, it is arranged in order in therapeutic bed, 10 mouse are irradiated in disposable collective.It is complete that single is carried out with 6MV-X lines linear accelerator
Chest irradiation (the double lungs of mouse) 18Gy, absorbs dosage rate 200cGy/min, SSD=100cm, irradiation field 30cm X1.8cm, 1.8cm
For mouse neck to chest segment distance (such as Fig. 1).Mouse conventinal breeding after irradiation.
Blank control group mouse during the experiment, Non Apparent Abnormality symptom.Simple irradiation group mouse the 7th week after irradiation
Start to occur apathetic, diet, activity are reduced, and weight do not increase, and excrement is stiff, and fur starts to bleach in chest irradiation open country, and
Have in some animals irradiation field and lose hair or feathers, fur all bleaches in irradiation field at 10 weeks, continues to 12 weeks.BAL infiltrates 4 weeks
It now obviously increases, irrigating solution cytokine levels highest.There are significant changes in 6 weeks in lung tissue, continues to 12 weeks.
2, Testing index
Above-mentioned model is detected：
2.2.1 changes of weight
It is primary that mouse weight is weighed weekly.
2.2.2 Lung Exponent changes
Lung Exponent=lung weight in wet base/weight × 100%
2.2.3 bronchoalveolar lavage and cell count
Mouse is taken to lie on the back within the 4th week after irradiation, with 22G remaining needle promoting the circulation of qi cannulas.Cold PBS lavations, 0.3ml × 1 time.4℃
Refrigerated centrifuge 500g × 5min.Collect supernatant, -20 DEG C of cell factors to be checked.Cell precipitation is resuspended in 300 μ l PBS, inhales 20 μ l and adds
80 μ l fixer fixed counts.Remaining is divided into two parts fluidic cell dyeing identification of cell classification and ratio (CD3-FITC, CD11b-
APC,Gr1+-PE)。
2.2.4 it is horizontal to detect inflammatory factor in mice serum and bronchoalveolar lavage by ELISA
It takes within the 4th week after irradiation.Mouse extract right side eyeball take blood, with 3000r/min centrifuge 15min, take serum according to
ELISA kit specification operates, and detection serum IL -1b, TNF-a and IFN-γ, IL-17 are horizontal.
2.2.5 pathologic is sliced
It is taken within the 8th, 15,20 week after irradiation and administration.Cervical dislocation puts to death mouse, its inferior lobe of right lung is taken, with 10% formaldehyde
Fixed, dehydration of alcohol, routine paraffin wax embedding, slice carry out H＆E and Mason dyeing.
2.2.6 lung tissue immunohistochemical staining
It is taken within the 8th, 15,20 week after irradiation and administration.It is sliced using pathologic, the expression to a-SMA and collagen
It is detected.
2.2.7 the mRNA of lung tissue inflammation and fibrosis correlation factor is expressed
It is taken within the 8th, 15,20 week after irradiation and administration.It extracts lung tissue RNA, RT-PCR and detects inflammatory factor IL-1b, TNF-a
With IFN-γ, IL-17 and fibrosis correlation factor such as a-SMA, vimentin, E-cadherin, the mRNA tables of collagen etc.
Up to level.
2.2.8 survival rate
It irradiates and to observation post administration mouse survival rate to 20 weeks or so.
2.3 dosage regimen
Start to be administered for 24 hours after irradiation, according in experimental program sampling time point put to death mouse (take blood and BAL within the 4th week,
Tissue is taken within 8th, 15,20 week to be pathological section and extraction RNA.Observed survival rate was to 20-30 weeks or so).
Xiyanping uses two kinds of administering modes, and (1 time a day, 5mg/kg, 10mg/kg and 20mg/kg) is injected intraperitoneally and fills
Stomach (1 time a day, 30mg/kg), administration are for 4 weeks.
2.4 test cell line
The pathogenesis of radiation pneumonitis is not fully aware of at present, clinical manifestation be mainly early stage inflammatory reaction and
The pulmonary fibrosis in late period, therefore intend investigating its mechanism of action in terms of following two：
2.4.1 regulation and control of the Xiyanping (andrographolide class compound) to NF-kB signal paths in pulmonary epithelial cells
Using the pulmonary epithelial cells A549 cell strains of people, LPS stimulations, Western blot and Immunofluorescence test Xiyanping
The mRNA level in-site of the influence and downstream inflammatory factor of (andrographolide class compound) to NF-kB phosphorylations.
2.4.2 Xiyanping (andrographolide class compound) mediates pulmonary epithelial cells fibrosis signal logical TGF-b-Smad
Road regulation and control detect Xiyanping (in Herba Andrographitis using the pulmonary epithelial cells A549 cell strains of people, TGF-b stimulations, Western blot
Ester type compound) influence (p-Smad2, p-Smad3) to TGF-b-Smad signal pathway activateds and TGF-b inductions a-SMA,
The mRNA expressions of vimentin, E-cadherin, collagen etc..
3. experimental result
3.1 mouse weights and cosmetic variation
The 3.2 each group mouse lung inflammatory conditions of modeling 4 weeks
Such as Fig. 3, in the Pneumonia Mice bronchoalveolar lavage fluid (BALF) caused by IR, the total cell digital display of model group (IR) mouse
It writes and is higher than normal group, after injection gavage gives Xiyanping (Andro), can obviously reduce the total cell number in BALF.Into one
After the streaming Coloration experiment of step is the results show that give Xiyanping, the CD3T+ cells infiltrated in lung tissue, macrophage CD11b+
And the infiltration of neutrophil cell (Gr1+) is all decreased obviously.
Lung perfusion is carried out after putting to death mouse, collect the cell in irrigating solution and carries out fluidic cell staining analysis, is counted.
Each group mouse irrigating solution and serum are acquired, ELISA measures each inflammatory factor level, as shown in figure 4, after IR inductions, model group
The level of IL-1 β in mouse lung irrigating solution and serum, IL-6, TNF-α are significantly raised.Xiyanping can inhibit IL-1 in irrigating solution
The level of β；Xiyanping is to the IL-1 β in serum, and IL-6, TNF-α has good inhibiting effect, to disease in pulmonary lavage liquid inflammation
The level of the factor has different degrees of reduction to act on.
4th week each group mouse lung tissue form, as shown in figure 5, H＆E coloration results are shown, normal lung tissue's alveolar wall is thin,
It is clear in structure.4 weeks after irradiation, lung tissue alveolar septum is thickened after IR, alveolar space reduces, and inflammatory exudation occurs and changes, fills
Blood and edematous fluid.After giving Xiyanping, there is more apparent improvement in above-mentioned symptom.
Continue the inflammatory Cytokines Expression situation of investigation lung tissue, each group mouse lung inflammatory factor mRNA expresses feelings within the 4th week
Condition, acquire each group mouse lung tissue, extract RNA, Q-PCR measure index of correlation mRNA level in-site, such as Fig. 6, Q-PCR the results show that
The gene expression of model group mouse lung tissue inflammatory factor il-1b, tnf-a, il-6 are significantly raised, and Xiyanping administration can be notable
Improve their expression.
After IR, fibrosis can occur for lung tissue.Each group mouse lung fibrosis associated genes mRNA expression in 4th week, acquisition
Each group mouse lung tissue extracts RNA, and Q-PCR measures index of correlation mRNA level in-site, and such as Fig. 7, Q-PCR are the results show that model group is small
The mRNA level in-site of the marker gene a-SMA and Vimentin of mouse lung tissue interstitial cells rise notable, the mark of epithelial cell
The expression of gene E-cadhetin is remarkably decreased, and after administration, the expression of corresponding gene all obtains a degree of reverse, illustrates to like
The flat administration of inflammation has certain mitigation to lung tissue's fibrosis caused by IR.
The 3.3 each group mouse lung inflammatory cell infiltration situations of modeling 8 weeks
8th week each group mouse lung inflammatory cell infiltration situation carries out lung perfusion after putting to death mouse, collects in irrigating solution
Cell and carry out fluidic cell staining analysis, count, such as Fig. 8,9,10,11, the feelings of each administration group after comprehensive analysis modeling 8 weeks
Condition：The inhibition inflammation of intraperitoneal injection and the effect of pulmonary fibrosis are preferable, the effect that also has some improvement of gastric infusion group.
0-40 weeks mouse survival situation after 3.4 radiation insults
It can be recognized from fig. 12 that control group starts death in 30 weeks or so, and the death rate persistently rises；Camptotheca acuminata leaves group
It can reduce to dose-dependant the death rate of radioactive damage mouse, extend life span.
Lung cancer is that current incidence is high, and therapeutic effect is poor, one of highest malignant tumour of cancer related mortality rate.Radiation is controlled
Treatment is the important means of lung cancer therapy, and induced lung injury (Radiation-induced lung injury, RILI) is lung cancer
The most common complication of radiotherapy, incidence is up to 10%~20%.Induced lung injury early stage shows as radiation pneumonitis, the later stage into
Exhibition is radiation fibrosis of lung, and death is caused when serious.Currently, RILI still lacks effective means of prevention, adrenal cortex
Hormone, broad-spectrum antibiotic, bronchodilator and immunosuppressor are still the main means for the treatment of acute radiation pneumonitis,
And to the radiation fibrosis of lung in late period, in the prior art without effective remedy measures, and the present invention provides a kind of effective
Method is of great significance for treating or alleviating RILI for improving the effect of radiotherapy of lung cancer.
Early stage injury of lungs (radiation pneumonitis) is often happened in Patients During Radiotherapy, can usually be led to grave consequences, less serious case causes
The course for the treatment of interrupts and influences oncotherapy curative effect, and severe one can directly result in death；Pulmonary infection also aggravates the fibrosis of lung, and one
Denier pulmonary fibrosis generates, and treatment will be a complexity, very long process.
This group experiment using IR induction mouse pneumonia and pulmonary fibrosis model, integrated use flow cytometry, PCR,
The methods of western blot and H＆E dyeing, immunohistochemistry are investigated and compare Xiyanping (injection and gastric infusion) to lung
Portion's inflammation and the therapeutic effect of pulmonary fibrosis.Experimental result shows the mouse through Xiyanping, lung inflammation infiltration and inflammation
The level of the factor is decreased obviously, and lung tissue's inflammation damnification mitigates, and pulmonary fibrosis situation makes moderate progress, and the effect of drug administration by injection is excellent
In gastric infusion.
Andrographolide class compound of the present invention include andrographolide and its derivative, isoandrographolide and its
Derivative.Preparation prepared by andrographolide class compound of the present invention, such as containing there are many andrographolide sulfonates
Xiyanping preparation, lung tissue inflammation damnification is mitigated, pulmonary fibrosis situation makes moderate progress；But andrographolidume derivative or
Isoandrographolide derivative compares andrographolide or isoandrographolide, water-soluble more preferable, and administration works faster, right
Preparation is answered to become apparent lung tissue's inflammation damnification, pulmonary fibrosis improvement.
In conclusion the preparation of andrographolide class compound has radioactive damage certain therapeutic effect, including put
Penetrating property inflammation, radiation fibrosis and normal tissue injury.
Claims (10)
1. application of the andrographolide class compound in terms of preparing for radioactive damage drug.
2. application according to claim 1, which is characterized in that the andrographolide class compound is formula (I) and its different
Structure body, prodrug, solvate or pharmaceutically acceptable salt.
Wherein,
A and b is separately singly-bound or double bond, and is double bond when a with b differences；
R1And R2Separately it is selected from hydrogen, alkyl ,-Si (R ')3、-C(O)R’、-SO3M；Alternatively, R1And R2It is interconnected to form
5-8 membered heterocycloalkyls, the Heterocyclylalkyl can also further contain 1~2 and be selected from Si, S (O)0-2Or the hetero atom or base of N
Group；The Heterocyclylalkyl is unsubstituted or is further substituted in arbitrary position by 1~4 substituent group selected from alkyl or oxo base
It sets；
R3For following any structure：
R4For hydrogen, halogen, amino, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl or-ORa；
R5For hydrogen, halogen, amino, alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl；
R6For hydrogen；R6aFor substituted or unsubstituted aryl, the aryl can be substituted in arbitrary position when substituted by 1~2 halogen
It sets；
R7And R7aSeparately be selected from substituted or unsubstituted alkyl, when the alkyl is substituted can by 1~2 hydroxyl or
Amino replaces at an arbitrary position；
X, a key and b keys are respectively selected from following combination：
1) X is CR8, a key mapping double bonds, b key mapping singly-bounds；
2) X is CR8, a key mapping singly-bounds, b key mapping double bonds；
3) X is C=CH2Or CR9R9a, a keys and b keys are singly-bound；
R8For connecting key ,-ORbOr substituted or unsubstituted C1-3Alkyl, as the C1-3It, can be by 1 hydroxyl when alkyl is substituted
Substitution is at an arbitrary position；R9For connecting key or C1-3Alkyl；R9aFor C1-3Alkyl；Alternatively, R9And R9aIt is former with the C that it connect jointly
Son forms 3~6 yuan of naphthenic base together；
Y and Z is separately CHR10；R10For hydrogen, connecting key, halogen, amino, alkyl, naphthenic base, Heterocyclylalkyl, aryl, miscellaneous
Aryl, hydroxyl, alkoxy or-OSO3M；
Alternatively, the R8And R10For connecting key when, can be by-CH2It is interconnected to form 7 yuan of naphthenic base；
Alternatively, the R9And R10For connecting key when, 5 membered heterocycloalkyls can be interconnected to form by-O-；
R ' is hydrogen, C1-6Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Ring
Alkyl, 3-6 membered heterocycloalkyls, phenyl or 5-6 unit's heteroaryls.
RaFor hydrogen ,-SO3M, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, take
Generation or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, generation or unsubstituted cycloalkyl-alkyl, substitution or unsubstituted
Hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl or substitution or it is unsubstituted
C2-6Alkenyl；When the substituted alkyl, substituted naphthenic base, substituted Heterocyclylalkyl, substituted aryl, substituted heteroaryl
Base, substituted cycloalkyl-alkyl, substituted hetercycloalkylalkyl, substituted aryl alkyl, substituted heteroaryl alkyl take
The C in generation2-6Alkenyl can be by 1~3 selected from halogen, C when substituted1-4Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkane
Oxygroup, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base, 3-6 membered heterocycloalkyls, phenyl, 5-6 unit's heteroaryls ,-NO2、-CN、-ORc、-
SRc、-OC(O)Rc、-OC(O)NRcRd、-NRcRd、-N(Rc)C(O)Rd、-N(Rc)S(O)2Rd、-S(O)0-2Rc、-C(O)Rc、-C
(O)ORcOr-C (O) NRcRdSubstituent group substitution at an arbitrary position；
RbFor hydrogen or-SO3M；
RcAnd RdSeparately it is selected from hydrogen, C1-6Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, C2-6Alkene
Base, C2-6Alkynyl, C3-6Naphthenic base, 3-6 membered heterocycloalkyls, phenyl or 5-6 unit's heteroaryls；
M is hydrogen, Na+、K+Or NH4 +。
3. application according to claim 2, which is characterized in that the andrographolide class compound is selected from：
Wherein, * is expressed as R configurations or S configurations；
R1、R2、R4、R9a、R10Definition with M is the same as described in claim 2.
4. application according to claim 2, which is characterized in that the andrographolide class compound is selected from：
5. application according to claim 1, which is characterized in that the andrographolide class compound is Xiyanping.
6. application according to claim 1, which is characterized in that the radioactive damage is selected from radioactive inflammation disease, puts
Penetrating property fibrotic disease.
7. according to the application described in claim 6, which is characterized in that the radioactive inflammation disease is selected to disappear caused by radioactive ray
Change system inflammation, inflammation in respiratory system, Urinary system inflammation, genital disease or scytitis.
8. application according to claim 6, which is characterized in that the radioactive inflammation disease is selected from：Radiation esophagitis,
Radiation enteritis, radioactivity osteitis, Inflammation of Radioactive Oral Cavity, radiation_induced pleurisy, radiodermatitis, is put at radiation thyroiditis
Penetrating property pneumonia, radioactivity vaginitis, radiocystitis.
9. application according to claim 6, which is characterized in that the radiation fibrosis disease is selected from：Lung radiation injury is fine
Dimensionization, radioactivity myocardial fibrosis, radioactivity rectum fibrosis, radioactivity kidney fibrosis.
10. a kind of pharmaceutical composition for therapeutic radiation damage, including the treatment of claim 1-5 any one of them are effective
The andrographolide class compound and its isomers of amount, prodrug, solvate and one kind or more in pharmaceutically acceptable salt
Kind and pharmaceutically acceptable auxiliary material.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112500376A (en) * | 2020-06-08 | 2021-03-16 | 南开大学 | Radioactive element modified andrographolide derivative and application thereof |
| CN112778168A (en) * | 2019-11-08 | 2021-05-11 | 江西青峰药业有限公司 | Method for preparing andrographolide-19-sulfate-16-sodium carboxylate |
| CN113087618A (en) * | 2019-12-23 | 2021-07-09 | 江西青峰药业有限公司 | Method for preparing andrographolide derivatives by using industrial chromatography |
| IT202000002146A1 (en) * | 2020-02-04 | 2021-08-04 | Foodar Advanced Res S R L | COMPOSITION FOR THE PREVENTION AND TREATMENT OF MUCOSITES |
| CN113582951A (en) * | 2020-04-30 | 2021-11-02 | 江西青峰药业有限公司 | 10- (S) -17-hydrogen-7-dehydro-andrographolide and industrial chromatographic preparation method and application thereof |
| CN113620914A (en) * | 2020-05-08 | 2021-11-09 | 江西青峰药业有限公司 | Andrographolide derivative and industrial chromatographic preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145657A (en) * | 2012-04-12 | 2013-06-12 | 江西青峰药业有限公司 | 17-hydro-9-dehydroandrographolide compound and its preparation method and use in drug preparation |
| CN103224492A (en) * | 2013-04-15 | 2013-07-31 | 南京工业大学 | 14-aryl-ether andrographolide derivative and preparation method and application thereof |
-
2017
- 2017-02-07 CN CN201710068116.2A patent/CN108392478A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145657A (en) * | 2012-04-12 | 2013-06-12 | 江西青峰药业有限公司 | 17-hydro-9-dehydroandrographolide compound and its preparation method and use in drug preparation |
| CN103224492A (en) * | 2013-04-15 | 2013-07-31 | 南京工业大学 | 14-aryl-ether andrographolide derivative and preparation method and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| 何宁一: "中药内服联合喜炎平注射液治疗放射性肺炎19例", 《河南中医》 * |
| 刘桂舫等: "莲必治注射液静脉应用与超声雾化辅助治疗放射性肺炎疗效观察", 《河北医药》 * |
| 康亚辉等: "穿心莲内酯对小鼠放射性肺损伤的防护作用", 《中华放射医学与防护杂志》 * |
| 彭爽: "穿心莲内酯改善放射性肺损伤的作用及机制研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 邹亚峰等: "莲必治注射液辅助治疗放射性肺炎疗效观察", 《现代中西医结合杂志》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778168A (en) * | 2019-11-08 | 2021-05-11 | 江西青峰药业有限公司 | Method for preparing andrographolide-19-sulfate-16-sodium carboxylate |
| CN113087618A (en) * | 2019-12-23 | 2021-07-09 | 江西青峰药业有限公司 | Method for preparing andrographolide derivatives by using industrial chromatography |
| IT202000002146A1 (en) * | 2020-02-04 | 2021-08-04 | Foodar Advanced Res S R L | COMPOSITION FOR THE PREVENTION AND TREATMENT OF MUCOSITES |
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| WO2021218148A1 (en) * | 2020-04-30 | 2021-11-04 | 江西青峰药业有限公司 | 10-(s)-17-hydrogen-7-dehydro-andrographolidume, industrial chromatography-based preparation method therefor, and use thereof |
| CN113582951B (en) * | 2020-04-30 | 2024-03-19 | 江西青峰药业有限公司 | 10- (S) -17-hydrogen-7-dehydroandrographolide and industrial chromatographic preparation method and application thereof |
| CN113620914A (en) * | 2020-05-08 | 2021-11-09 | 江西青峰药业有限公司 | Andrographolide derivative and industrial chromatographic preparation method and application thereof |
| CN113620914B (en) * | 2020-05-08 | 2024-03-19 | 江西青峰药业有限公司 | Andrographolide derivative and industrial chromatographic preparation method and application thereof |
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