CN107973764A - Andrographolide class compound, its preparation method, pharmaceutical composition and application - Google Patents
Andrographolide class compound, its preparation method, pharmaceutical composition and application Download PDFInfo
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- CN107973764A CN107973764A CN201710997767.XA CN201710997767A CN107973764A CN 107973764 A CN107973764 A CN 107973764A CN 201710997767 A CN201710997767 A CN 201710997767A CN 107973764 A CN107973764 A CN 107973764A
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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
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a kind of andrographolide class compound, its preparation method, pharmaceutical composition and application.Andrographolide class compound (I), its isomers, prodrug, solvate or the pharmaceutically acceptable salt of the present invention has such as lower structure.The andrographolide class compound of the present invention has the function that good treatment inflammation disease, and the inflammation disease including but not limited to may be caused by the pathogen such as bacterium, virus, or the inflammation disease as caused by autoimmunity.
Description
Technical field
The present invention relates to a kind of andrographolide class compound, its isomers, prodrug, solvate or pharmaceutically acceptable
Salt, its pharmaceutical composition, preparation method and application.
Background technology
Andrographolide (andrographolide) is one of highest component of content in Andrographis Paniculata.It has
Multiple target effect mechanism, therefore, 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:
At present, there are document and patent report (Lin HQ, et al.Biol.Pharm.Bull.2006,29 (2):220,
CN101012211B, CN1666985A, US20050215628A1), andrographolide and its derivative can suppress LPS inductions
TNF-α, IL1 β and IL-6 expression, so as to suppress the inflammatory reaction of body.TNF-α is a kind of precursor inflammatory cytokine,
Participate in many inflammatory reaction processes.It can be used for treatment various autoimmune disease (rheumatoid joint by suppressing TNF-α
Inflammation, Crohn disease, systemic loupus erythematosus, psoriasis etc.), the nervous system disease (Alzheimer's disease, Parkinson's, 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 propagation and the differentiation of T cell and B cell, participate in inflammatory reaction.Suppressing IL1 β can be used for treatment to include disease
Various inflammatory reactions (Taylor PC.et al.Curr Pharm Des.2003 including poison infection;9(14):1095;
Dellinger RP et al Clin Infect Dis.2003May 15;36(10):1259).IL-6 is also known as B cell thorn
Swash the factor, various kinds of cell can be spontaneous or produce IL-6 under other stimulations, its periphery and development of central nervous system, differentiation,
Play 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, its
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 hand-foot-and-mouth disease virus infection, but Xiyanping is to wear
The sulfonated products of heart lotus lactone, not single structure, therefore machine further to define using the micromolecular compound of single structure
Reason, is of great significance its drug effect and its toxicologic study.
In summary, although andrographolide class compound has obtained some developmental achievements, for a variety of diseases, especially
Its anti-inflammatory and antiviral field are still used for clinic without particularly effective andrographolide analog.Through retrieval, find no
By in 17 double-bond rearrangements of andrographolide to diterpene ring, and introduce at 14 hydroxyls ester bond or ehter bond formed it is new similar
Thing, and for anti-inflammatory and the report in antiviral field.
The content of the invention
The technical problems to be solved by the invention are, there is provided a kind of new andrographolide class compound, its preparation
Method, pharmaceutical composition and application.The andrographolide class compound of the present invention has good anti-inflammatory effect, can effectively control
Treat inflammation disease.Signified inflammation disease of the invention includes but not limited to may be caused by the pathogen such as bacterium, virus, by certainly
Caused by body is immunized, or inflammation disease caused by radiation damage.
The present invention provides a kind of andrographolide class compound (I), its isomers, prodrug, solvate or pharmaceutically
Acceptable salt;
Wherein,
A and b is separately singly-bound or double bond, and is double bond or singly-bound during a and b differences;
X is-OR5Or-SR6;
Y and Z is separately selected from-O- or-NH-;
R1And R2Separately it is selected from hydrogen or alkyl;
R3And R4Separately selected from hydrogen, alkyl, haloalkyl ,-Si (Rc)3、-C(O)Rc、-SO3M;M for hydrogen, sodium or
Potassium;Or R3And R45-8 membered heterocycloalkyls are interconnected to form, the Heterocyclylalkyl can also be further selected from containing 1~2
Si、S(O)0-2Or the hetero atom or group of N atoms;The Heterocyclylalkyl is unsubstituted or is further selected from alkane by 1~4
The substituent substitution of base, halogen, haloalkyl, hydroxy alkyl, alkoxyalkyl, alkoxy, amino, aminoalkyl or oxo base
At an arbitrary position;
R5For substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, take
It is generation or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted
Hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl, Ra、-C(O)Rb、-C(O)
NRbRc、-C(O)ORc、-S(O)2Rb、-S(O)2NRcRd、-NRcRd、-(CH2)nORa;
R6For hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle alkane
Base, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substitution or not
Substituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl ,-C (O) Rb、-C
(O)NRbRc、-C(O)ORcOr-(CH2)nORa;
R5Or R6In, when the substituted alkyl, the cycloalkyl of substitution, the Heterocyclylalkyl of substitution, the aryl of substitution, substitution
Heteroaryl, substitution cycloalkyl-alkyl, substitution hetercycloalkylalkyl, substitution aryl alkyl or substituted heteroaryl alkane
Base can be by 1~4 selected from halogen, C when substituted1-4Alkyl, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6
Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, 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、-N(Rc)S(O)2NRcRd、-N(Rc)C(O)
NRcRd、-S(O)2NRcRd、-S(O)0-2Rc、-OP(O)(O-Rc)2、-C(O)Rc、-C(O)ORcOr-C (O) NRcRdSubstituent take
In generation, is at an arbitrary position;N is 1~6 integer;
RaFor glycyl-, L- alanyls-, L- leucyls-, L- valyls-, L- isoleucyl-s-, etc. amino acid residue;
RbFor hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle alkane
Base, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substitution or not
Substituted hetercycloalkylalkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl;When the substitution
Alkyl, substitution cycloalkyl, substitution Heterocyclylalkyl, substitution aryl, substitution heteroaryl, substitution cycloalkyl-alkyl,
Substituted hetercycloalkylalkyl, the aryl alkyl of substitution or substituted heteroaryl alkyl can be selected from halogen when being substituted by 1~4
Element, C1-4Alkyl, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, 3-6
Membered heterocycloalkyl, 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、-N(Rc)S(O)2NRcRd、-N(Rc)C(O)NRcRd、-S(O)2NRcRd、-S(O)0-2Rc、-
OP(O)(O-Rc)2、-C(O)Rc、-C(O)ORcOr-C (O) NRcRdSubstituent substitution at an arbitrary position;
RcAnd RdSeparately selected from hydrogen, C1-6Alkyl, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6
Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocycloalkyls, phenyl or 5-6 unit's heteroaryls.
Alternatively, RcAnd RbOr RdWith forming 3-8 membered heterocycloalkyls, the Heterocyclylalkyl together with the N atoms that they are connected jointly
Also further N, O, S, S (O) can be selected from containing 1~32Hetero atom, the 3-8 membered heterocycloalkyls are unsubstituted or into one
Step is selected from alkyl, halogen, haloalkyl, hydroxy alkyl, alkoxyalkyl, alkoxy, amino, aminoalkyl or oxygen by 1~3
The substituent substitution of Dai Ji is at an arbitrary position.
The R1Preferably hydrogen or C1-6Alkyl;The R1More preferably H.
The R2Preferably hydrogen or C1-6Alkyl;The R2More preferably methyl.
The R3Preferably hydrogen, C1-6Alkyl, halo C1-3Alkyl ,-Si (Rc)3、-C(O)Rc、-SO3M;M is hydrogen, sodium or potassium;
The R3More preferably hydrogen.
The R4Preferably hydrogen, C1-6Alkyl, halo C1-3Alkyl ,-Si (Rc)3、-C(O)Rc、-SO3M;M is hydrogen, sodium or potassium;
The R4More preferably hydrogen.
Or the R3And R45-8 membered heterocycloalkyls are interconnected to form, the Heterocyclylalkyl can also further contain 1-
2 are selected from Si, S (O)0-2Or the hetero atom of N atoms;The Heterocyclylalkyl is unsubstituted or is further selected from C by 1-31-4
Alkyl, halogen, halo C1-3Alkyl, hydroxyl C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkoxy, amino, amino C1-3Alkyl
Or the substitution of one or more of substituent of oxo base is at an arbitrary position.
The R5Preferably substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substitution do not take
It is the 3-8 membered heterocycloalkyls in generation, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryls, substituted or unsubstituted
C3-8Cycloalkyl C1-3Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyls C1-3Alkyl, substituted or unsubstituted phenyl C1-3Alkane
Base, substituted or unsubstituted 5-6 unit's heteroaryls C1-3Alkyl, Ra、-C(O)Rb、-C(O)NRbRc、-C(O)ORc、-S(O)2Rb、-S
(O)2NRcRd、-NRcRdOr-(CH2)nORa。
The R6Preferably substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substitution do not take
It is the 3-8 membered heterocycloalkyls in generation, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryls, substituted or unsubstituted
C3-8Cycloalkyl C1-3Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyls C1-3Alkyl, substituted or unsubstituted phenyl C1-3Alkane
Base, substituted or unsubstituted 5-6 unit's heteroaryls C1-3Alkyl ,-C (O) Rb、-C(O)NRbRc、-C(O)ORcOr-(CH2)nORa。
The RbPreferably substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substitution do not take
It is the 3-8 membered heterocycloalkyls in generation, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryls, substituted or unsubstituted
C3-8Cycloalkyl C1-3Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyls C1-3Alkyl, substituted or unsubstituted phenyl C1-3Alkane
Base or substituted or unsubstituted 5-6 unit's heteroaryls C1-3Alkyl.
Andrographolide class compound, its isomers, prodrug, hydrate, solvate as shown in formula (I) or pharmaceutically
Acceptable salt;
In wherein a kind of preferred embodiment, when a is double bond, b is singly-bound;
In wherein a kind of preferred embodiment, when a is singly-bound, b is double bond.
In a currently preferred embodiment, the andrographolide class compound (I), 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;
R2、R3、R4And R5Definition as described above;
Various situations are included in the definition of structural formula (IA) below:
In wherein a kind of preferred embodiment, R2For CH3;
In wherein a kind of preferred embodiment, R3For H, R4For H.
In a currently preferred embodiment, the andrographolide class compound (I), 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;
A rings are phenyl ring or 5-6 member hetero-aromatic rings;
R7For halogen, C1-4Alkyl, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl,
C3-6Cycloalkyl, 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、-N(Rc)S(O)2NRcRd、-N(Rc)C(O)NRcRd、-S(O)2NRcRd、-S(O)0-2Rc、-OP(O)(O-Rc)2、-C(O)Rc、-C(O)ORcOr-C (O) NRcRd;
T is 1,2 or 3;
R1、R2、R4、RcAnd RdIt is defined as described above.
Various situations are included in the definition of structural formula (IB) below:
In wherein a kind of preferred embodiment, R2For CH3;
In wherein a kind of preferred embodiment, R3For H, R4For H.
In a currently preferred embodiment, the andrographolide class compound (I), 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;
R2、R3、R4、RbAnd RcDefinition as described above;
Various situations are included in the definition of structural formula (IC) or (ID) below:
In wherein a kind of preferred embodiment, R2For CH3;
In wherein a kind of preferred embodiment, R3For H, R4For H.
Andrographolide class compound (I), its isomers, prodrug, solvate or the pharmaceutically acceptable salt are most
It is following any structure goodly:
Present invention also offers andrographolide class compound (I), its isomers, prodrug, solvate or the pharmacy
The preparation method of upper acceptable salt, it is following any method:
Method 1:
Wherein, R ' is phenyl, and R " is H;Or R ' and R " is methyl;*、RbOr RcIt is defined as described above.
Include the following steps in method 1:Step 1, in solvent, by compound 1.2 and the carbamyl chloride or acyl chlorides of substitution
In alkaline conditions, reaction obtains compound I-1 or I-2 in non-protonic solvent;Step 2, in solvent, under acid condition,
I-1 or I-2 obtains compound Ia or Ib by de- double hydroxyl protection bases.
In method 1, the condition and step of the reaction can be the condition and step of this area routine, and the present invention is especially excellent
Select following reaction condition:Step 1, the alkali is preferably triethylamine, the preferred dichloromethane of the non-protonic solvent, described
The dosage of non-protonic solvent preferably 1~50mL/mmol compounds 1.2, temperature preferably 0 DEG C-room temperature, reaction time preferred 0-24
Hour, compound 1.2 and N (Rb)(Rc) COCl or RbThe molar ratio of COCl preferably 1:1~1:3, described 1.2 rub with triethylamine
That ratio preferably 1:1~1:10, to accelerate reaction speed, the 4- dimethylamino pyrroles of 0.1~1 equivalent can be also added in the reaction system
Pyridine (DMAP);Step 2, the deprotection reaction is routinely deprotected condition for this area, for example, can take off in acid condition
Remove, when R ' and R " they are methyl, preferred aqueous acetic acid;The aqueous acetic acid preferred volume percentage is 75~85% vinegar
Aqueous acid;The dosage of the aqueous acetic acid preferably 5~20mL/mmol compound I-2 or I-3, the reaction temperature are preferred
20~50 DEG C, when the reaction time preferably 0.2~2 is small.R ' is phenyl, when R " is H, preferably in ethanol solution, in a hydration pair
Deprotection reaction is carried out in the presence of toluenesulfonic acid, wherein, the dosage of the ethanol be preferably 1~50mL/mmol compounds I-1 or
I-2;The molar ratio of the hydration p-methyl benzenesulfonic acid of compound I-1 or I-2 and one is preferably 1:1~1:3, more preferably 1:2;It is described anti-
Answer preferably 20~70 DEG C of temperature, preferably 1~3 day reaction time.
Method 2:
Wherein, R ' is phenyl, and R " is H;Or R ' and R " is methyl;*, A rings, R7It is defined as described above with t.
Include the following steps in method 2:Step 1, in solvent, by 1.2 He of compoundIt is anti-by Mitsunobu
It should obtain compound I-3;Step 2, in solvent, under acid condition, I-3 is taken off into double hydroxyl protection bases and obtains compound Ic.
In method 2, the condition and step of the reaction can be the condition and step of this area routine, and the present invention is especially excellent
Select following reaction condition:Step 1, Mitsunobu reaction triphenylphosphines and diisopropyl azodiformate
(DIAD) combine, 1.2 He of compoundMolar ratio preferably 1:0.9~1:2;The triphenylphosphine, DIAD andMolar ratio preferably 1:1:1~1:2:2;Reaction temperature preferably 0 DEG C~room temperature;Step 2, the deprotection reaction is
This area is routinely deprotected condition, for example, can remove in acid condition, when R ' and R " are methyl, preferably acetic acid is water-soluble
Liquid;The aqueous acetic acid preferred volume percentage is 75~85% aqueous acetic acid;The dosage of the aqueous acetic acid is excellent
Select 5~20mL/mmol compound I-2 or I-3, preferably 20~50 DEG C of the reaction temperature, when the reaction time preferably 0.2~2 is small.
R ' is phenyl, and when R " is H, preferably in ethanol solution, deprotection reaction is carried out in the presence of a hydration p-methyl benzenesulfonic acid, its
In, the dosage of the ethanol is preferably 1~50mL/mmol compounds I-1 or I-2;The hydrations of compound I-1 or I-2 and one are to first
The molar ratio of benzene sulfonic acid is preferably 1:1~1:3, more preferably 1:2;Preferably 20~70 DEG C of the reaction temperature, the reaction time is excellent
Select 1~3 day.
In method one or two, 1.2 synthetic method of compound is as follows:
Wherein, R ' is phenyl, and R " is H;Or R ' and R " is methyl;
1.2 synthetic method of compound includes the following steps:Step 1, in solvent, by andrographolide in hydrogen bromide
Act on lower 17 double bonds generation rearrangement reaction and obtain compound 1.1;Step 2, by 3 of compound 1.1 and 19 hydroxyl protections,
Generally preferably use acetone and 2,2-dimethoxypropane system, or benzaldehyde dimethyl acetal and para-methylbenzenepyridinsulfonate sulfonate hydrochlorate body
System.
In 1.2 synthetic method of compound, the condition and step of the reaction can be the condition and step of this area routine,
Following reaction condition specifically preferred according to the invention:Step 1, the solvent preferred alcohol, dosage preferably 1~50mL/ of the solvent
Mmol andrographolides, the hydrogen bromide preferred mass percentage, 46~48% aqueous solution of hydrogen bromide, the hydrogen bromide water
The volume ratio of solution and solvent preferably 0.5:1~1:1, the reaction temperature preferably 0 DEG C~room temperature, the reaction time preferably 1~24
Hour;Step 2, the hydroxyl protection reaction is routinely deprotected condition for this area.It is preferred that with acetone and 2,2- dimethoxys third
Alkane system, dosage preferably 0.5~5mL/mmol compounds 1.1 of the acetone, the dosage of the 2,2-dimethoxypropane is excellent
Select 1~10mL/mmol compounds 1.1, preferably 30~60 DEG C of temperature, when the reaction time preferably 2~10 is small;It is preferred that with benzaldehyde two
Dimethoxym ethane and para-methylbenzenepyridinsulfonate sulfonate silicate system, wherein solvent are preferably dichloromethane;The benzaldehyde dimethyl acetal and
The molar ratio of compound 1.1 is preferably 1:1~1:3, more preferably 1:2;The dosage of the para-methylbenzenepyridinsulfonate sulfonate hydrochlorate is
Catalytic amount, and the molar ratio of compound 1.1 is preferably 1:0.02~1:0.1, the preferred room temperature of temperature, the reaction time preferably 10~24
Hour;
The pharmaceutically acceptable salt of the andrographolide class compound (I) can be chemically synthesized by general.
Under normal circumstances, the preparation of salt can by free alkali or acid with etc. chemical equivalent or excess acid (inorganic acid or
Organic acid) or alkali (inorganic base or organic base) reacted in suitable solvent or solvent compositions be made.
Present invention also offers a kind of pharmaceutical composition, it includes the active component of therapeutically effective amount and can pharmaceutically connect
The auxiliary material received;The active component includes andrographolide class compound (I), its isomers, prodrug, solvate and pharmaceutically
One or more in acceptable salt.
In described pharmaceutical composition, the active component may also include the other treatments for suppressing inflammation or virus infection etc.
Agent.
In described pharmaceutical composition, the pharmaceutically acceptable auxiliary material may include pharmaceutically acceptable carrier, dilution
Agent and/or excipient.
According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as tablet, pill, powder
Agent, liquid, suspension, lotion, granule, capsule, suppository and injection (solution and suspension) etc., preferred liquid, suspension, breast
Liquid, suppository and injection (solution and suspension) etc..
In order to shape the pharmaceutical composition of tablet form, it can be used this area 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, ethanol, 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 acid carbonate, calcium carbonate, the fatty acid 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..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 shape the pharmaceutical composition of pill, it can be used this area 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 ethanol etc.;Disintegrant, such as agar and Kelp Powder.
In order to shape the pharmaceutical composition of suppository form, it can be used this area 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, ethanol, propane diols, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy
Fatty acid ester of anhydro sorbitol etc..In addition, it can also add common lytic agent, buffer and anodyne etc..
In the present invention, content of the composition in pharmaceutical composition is without specifically limited, wherein in the Herba Andrographitis
Ester type compound (I), its isomers, prodrug, solvate or pharmaceutically acceptable salt can be selected in a wide range
To select, safely, effectively dosage is determined according to concrete conditions such as the age for the treatment of target, weight, the state of an illness, the course of disease, methods of administration for it,
The 5~95% of mass percent are generally can be, are preferably mass percent 30~80%.
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 formulations 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 Freamine Ⅲ)
Conjunction is injected intravenously;Suppository is to be administered into rectum.
Present invention also offers andrographolide class compound (I), its isomers, prodrug, solvate or the pharmacy
Upper acceptable salt, or described pharmaceutical composition, inflammation is treated preparing, including is caused by pathogenic infections such as bacterium, viruses
Inflammation, the purposes in inflammation disease caused by autoimmune response, and the medicine of inflammation caused by radiation damage etc..Its
Described in virus include:The various viruses of hand-foot-and-mouth disease are (for example, cause most common enterovirus EV71, Ke Sa of hand-foot-and-mouth disease
Strange virus CA16 etc.), various hepatitis viruses (for example, hepatitis A, hepatitis B, hepatitis C virus), AIDS virus etc..
Inflammation disease caused by the autoimmune response, including:Rheumatoid arthritis, systemic lupus erythematosus,
Mixed connective tissue disease (MCTD), system chorionitis (including:CREST syndromes), dermatomyositis, nodular vasculitis, nephrosis
(including:Empsyxis nephrotic syndrome, acute glomerulonephritis, primary membranoproliferative glomerulonephtitis etc.), primary biliary
Property hepatic sclerosis, autoimmune cholangitis, oneself immunity hepatitis, primary sclerotic cholangitis, inflammatory bowel disease (IBD) (bag
Include:Crohn disease (CD) and ulcerative colitis (UC)), chronic obstructive pulmonary disease etc..
The radioactive inflammation disease, including:Radiation esophagitis, radiation enteritis, radiation thyroiditis, radioactivity
Osteitis, Inflammation of Radioactive Oral Cavity, radiation_induced pleurisy, radiodermatitis, radiation pneumonitis, radioactivity vaginitis, radioactivity bladder
Inflammation etc..
Present invention also offers andrographolide class compound (I), its isomers, prodrug, solvate or the pharmacy
Upper acceptable salt and one or more other species therapeutic agents are used to treat inflammation, virus infection, autoimmune disease
Disease, and/or radioactivity damage.
Present invention also offers andrographolide class compound (I), its isomers, prodrug, solvate or the pharmacy
Upper acceptable salt and one or more other species therapeutic agents are used to prepare treatment inflammation, virus infection, autoimmunity
Application in the medicine of property disease or radiation damage.
The therapeutic agent of other species can with the andrographolide class compound (I), its isomers, prodrug,
Solvate or pharmaceutically acceptable salt, or described pharmaceutical composition, make the therapeutic dosage forms of single administration, or respectively
The therapeutic dosage forms of consecutive administration.
In the present invention, unless otherwise indicated, do not referred both to not labeled with what " substituted or unsubstituted " defined before substituent title
Substituted situation, such as:" alkyl " refers to unsubstituted alkyl, and " cycloalkyl " refers to unsubstituted cycloalkyl.
Unless otherwise indicated, the following term occurred in description of the invention and claims has following implications:
Term " alkyl " refers to saturated straight chain or branched hydrocarbyl comprising 1-20 carbon atom, preferably 1-10 carbon atom,
More preferably 1-8,1-6,1-4,1-3 carbon atoms, the representative example of alkyl include but not limited to:Methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, sec-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, 4,4- dimethyl-pentens
Base, 2,2,4- tri-methyl-amyls, undecyl, dodecyl, and their various isomers etc..When " alkyl " is used as other bases
During the linking group of group, such as-(CH2)m-, it can be straight or branched, and example includes but not limited to-CH2-、-CH2CH2-、-
CH2CH(CH3)-。
Term " cycloalkyl " refers to the saturation comprising 3-20 carbon atom or part unsaturation (including 1 or 2 double bond)
One or more cyclic groups.It is preferred that 3-12 member cycloalkyl." monocyclic cycloalkyl " preferably 3-10 unit monocycle alkyl, more preferably 3-8 members are single
Cycloalkyl, 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 bag of " bridged ring base "
Include but be 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 ", which includes, is fused to cycloalkyl ring on phenyl, cycloalkyl or heteroaryl, and fused cycloalkyl is included 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..It is monocyclic
Cycloalkyl or polycyclic naphthene base can be connected on parent molecule by arbitrary carbon atom chain on ring.
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 cycloalkyl, nitrogen, carbon or sulphur atom in Heterocyclylalkyl are optionally aoxidized.Nitrogen-atoms
It optionally can further be substituted by other groups and form tertiary amine or quaternary ammonium salt." monocyclic heterocycloalkyl " preferably 3-10 unit monocycle heterocycles
Alkyl, more preferably 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 and is fused to the monocyclic of phenyl, cycloalkyl, 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 on parent molecule by arbitrary annular atom on ring.Above-mentioned annular atom refers in particular to form
The carbon atom and/or nitrogen-atoms of ring skeleton.
Term " cycloalkyl-alkyl " refers to connect by alkyl between cycloalkyl and mother nucleus structure.Thus, " cycloalkyl alkane
Base " includes the definition of abovementioned alkyl and cycloalkyl.
Term " hetercycloalkylalkyl " refers to connect by alkyl between Heterocyclylalkyl and mother nucleus structure.Thus, " heterocycle alkane
Base alkyl " includes the definition of abovementioned alkyl and Heterocyclylalkyl.
Term " alkoxy " refers to has the carbon number purpose ring-type or acyclic alkyl groups, bag by what oxygen bridge connected
Containing alkyl oxy, cycloalkyl oxy and Heterocyclylalkyl epoxide.Thus, " alkoxy " includes abovementioned alkyl, Heterocyclylalkyl and cycloalkanes
The definition of base.
Term " alkoxyalkyl " refers to that any one hydrogen atom is substituted by alkoxy on alkyl.Thus, " alkoxy alkane
Base " includes the definition of abovementioned alkyl and alkoxy.
Term " hydroxy alkyl " refers to that any one hydrogen atom is substituted by hydroxyl on alkyl, includes but not limited to:-
CH2OH、-CH2CH2OH、-CH2CH2C(CH3)2OH。
Term " alkenyl " refers to the straight chain containing at least one carbon-carbon double bond, side chain or the non-aromatic alkyl of ring-type.Wherein can be with
There are 1-3 carbon-carbon double bond, and preferably there are 1 carbon-carbon double bond.Term " C2-4Alkenyl " refers to the alkenyl with 2-4 carbon atom,
Term " C2-6Alkenyl " refers to the alkenyl with 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2- methyl butene bases
And cyclohexenyl group.The alkenyl can be substituted.
Term " alkynyl " refers to the straight chain containing at least one triple carbon-carbon bonds, side chain or cyclic hydrocarbon group.Wherein there may be
1-3 triple carbon-carbon bonds, preferably there are 1 triple carbon-carbon bonds.Term " C2-6Alkynyl " refers to the alkynyl with 2-6 carbon atom, including
Acetenyl, propinyl, butynyl and 3- methylbutynyls.
Term " aryl " refers to the 6-10 unit monocycles or bicyclic aromatic groups of any stabilization, such as:Phenyl, naphthyl, four
Hydrogen naphthyl, 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, it 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:Pyridine radicals, 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 connect by alkyl between aryl and mother nucleus structure.Thus, " aryl alkyl " includes
The definition of abovementioned alkyl and aryl.
Term " heteroaryl alkyl " refers to connect by alkyl between Heterocyclylalkyl and mother nucleus structure.Thus, " heteroaryl alkane
Base " includes the definition of abovementioned alkyl and heteroaryl.
Term " halogen " represents fluorine, chlorine, bromine or iodine.
Term " haloalkyl " refers to the alkyl arbitrarily substituted by halogen.Thus, " haloalkyl " include above halogen and
The definition of alkyl.
Term " halogenated alkoxy " refers to the alkoxy arbitrarily substituted by halogen.Thus, more than " halogenated alkoxy " includes
The definition of halogen and alkoxy.
Term " amino " refers to-NH2, term " alkylamino " refers to that at least one hydrogen atom is substituted by alkyl on amino,
Including but not limited to:-NHCH2、-NHCH2CH3.Term " aminoalkyl " refers to that any one hydrogen atom is taken by amino on alkyl
In generation, include but not limited to:-CH2NH2、-CH2CH2NH2.Thus, " aminoalkyl " and " alkylamino " includes abovementioned alkyl and amino
Definition.
Term " amino acid residue " refers to that the carboxylic acid fragment containing amino is mutual by carboxyl and parent molecule formation acyl group
Connection, the amino acid residue include natural or non-naturally occurring amino acid residue.It is preferred that naturally occurring amino acid residue,
The amino acid includes but not limited to:Alanyl-, valyl-, L- alanyls-, L- leucyls-, L- isoleucyl-s-, dried meat ammonia
Acyl-, phenylalanyl-, tryptophanyl-, methinyl-, glycyl-, seryl-, threonyl-, cysteinyl-, tyrosyl-, asparagus fern
Acyl acyl --, glutamy acyl-, lysyl-, arginyl-, histidyl--, aspartoyl-or glutamy-.
Symbol "=" represents double bond;
" room temperature " of the present invention refers to 15-30 DEG C.
" prodrug " refers to that compound is converted into original activity compound after being metabolized in vivo.Typically say, it is preceding
Medicine is inert matter, and either specific activity parent compound activity is small but can provide convenient operation, is administered or improve generation
Thank to characteristic.
" solvate " of the present invention refers to the solvent addition form comprising stoichiometry or non-stoichiometry solvent.
Some compounds tend to catch the solvent molecule of fixed molar ratio example under crystalline solid state, therefore form solvation
Thing.If solvent is water, the solvate of formation is " hydrate ", if solvent is ethanol, the solvate of formation is
For alcoholate.Hydrate is to combine to form hydrate by one or more hydrones and the material, 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 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 being prepared by the compounds of this invention and acid reaction, 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, its 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 formula (I) compound of the present invention 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), single alloisomerism
Body (enantiomter and diastereoisomer) and their mixture are included within the scope of the invention.Present invention additionally comprises
The compound or the independent isomers of salt that formula (I) represents, and the isomers inverted with wherein one or more chiral centres
Mixture.The scope of the present invention includes:The mixture of stereoisomer, and the enantiomter or enantiomter purified/
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.Present invention additionally comprises 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, each preferably up to the present invention
Example.
The reagents and materials used in the present invention are commercially available.
Brief description of the drawings
Fig. 1:The BV2 cells that andrographolide and the compounds of this invention suppress LPS inductions train IL6 and TNF α level in liquid,
The compounds of this invention can reduce the generation of IL6 and TNF α to a certain degree under 10 μM of concentration, and effect is better than andrographolide.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
Apply among a scope.The experimental method of actual conditions is not specified in the following example, according to conventional methods and conditions, or according to business
Product specification selects.
The structure of all compounds of the present invention can by nuclear magnetic resonance (1H NMR) and/or Mass Spectrometer Method (MS) identification.
1H nmr chemicals displacement (δ) records (10 with PPM-6).NMR is carried out by Bruker AVANCE-400 spectrometers.Close
Suitable solvent is deuterochloroform (CDCl3), deuterated methanol (CD3OD), deuterated dimethyl sulfoxide (DMSO-d6), tetramethylsilane conduct
Internal standard (TMS).
Algorithm (MS) is measured by Agilent 1200HPLC/6120 mass spectrographs, using XBridge C18,4.6
× 50mm, 3.5 μm, condition of gradient elution one:80-5% solvent orange 2 As1With 20-95% solvents B1(1.8 minutes), then 95% solvent
B1With 5% solvent orange 2 A1(more than 3 minutes), percentage account for the percentage by volume of total solvent volume for a certain solvent.Solvent orange 2 A1:
The aqueous solution of 0.01% trifluoroacetic acid (TFA);Solvent B1:The acetonitrile solution of 0.01% trifluoroacetic acid;Percentage accounts for molten for solute
The percentage by volume of liquid.Condition of gradient elution two:80-5% solvent orange 2 As2With 20-95% solvents B2(1.5 minutes), then 95% is molten
Agent B2With 5% solvent orange 2 A2(more than 2 minutes), percentage account for the percentage by volume of total solvent volume for a certain solvent.Solvent orange 2 A2:
The aqueous solution of the ammonium hydrogen carbonate of 10mM;Solvent B2:Acetonitrile.
The purifying of the compounds of this invention can use conventional silica gel plate, silica gel column chromatography or use high performance liquid chromatography
(prep-HPLC) isolated and purified.
High performance liquid chromatograph (prep-HPLC) uses Shimadzu LC-20 preparative liquid chromatographies, and chromatographic column is:waters
Xbridge Pre C18,10um, 19mm*250mm.Mobile phase A:(percentage is volume basis to 0.05% trifluoroacetic acid aqueous solution
Number), Mobile phase B:Acetonitrile;Detection wavelength:214nm&254nm;Flow velocity:15.0mL/ minutes.
Thin layer silica gel plate (TLC) is Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates.Silica gel column chromatography generally uses
Yantai Huanghai Sea 200-300 mesh silica gel is as carrier.
Embodiment 1:The synthesis of compound 1-1
Step 1:Andrographolide (40g, 0.11mol) and ethanol (100mL) are added in there-necked flask (500mL), stirred
Mix to dissolving clear state, be cooled to 0-10 DEG C, add hydrogen bromide (70mL, w/w:48%), keep under the temperature conditionss, react
24 it is small when, stop reaction, add sodium hydrate aqueous solution (6.0M) and adjust pH value between 6-7, add ethyl acetate
(350mL), when stirring 12 is small, separates out a large amount of white solids, filters, and filter cake is recrystallized with ethyl acetate (100mL), filters, filter
Compound 1.1 (35g, yield are obtained after biscuit is dry:88%) it is white solid.
Step 2:Compound 1.1 (35g, 0.10mol), acetone (70mL) and 2,2-dimethoxypropane (175mL) are added
Enter into there-necked flask (500mL), be heated to 40-50 DEG C, keep at this temperature, when stirring 5-6 is small, TLC monitoring (just oneself
Alkane/ethyl acetate=1/1), until raw material disappears, after reaction, reaction solution is transferred in single port bottle (500mL), is concentrated into
It is dry;Ethyl acetate (175mL) is added into residue, 50~60 DEG C is heated to and dissolves, under heat-retaining condition, n-hexane is added dropwise
(175mL), after being added dropwise, is cooled to 20~30 DEG C, separates out a large amount of white solids, filtering, and compound is obtained after filtration cakes torrefaction
1.2 (20g, yields:51%) it is white solid powder.
Step 3:By compound 1.2 (390mg, 1.00mmol), triethylamine (303mg, 3.00mmol) and DMAP (122mg,
1.00mmol) be dissolved in dichloromethane (4mL), reaction system be stirred at room temperature 0.5 it is small when after, add N- ethyl-N-methyl formyls
Chlorine (242mg, 2.00mmol), reaction system be stirred at room temperature 3 it is small when, reaction solution is concentrated to give crude Compound 1.3, is directly used in down
One step.
Step 4:Compound 1.3 is mixed in the in the mixed solvent of acetic acid (4mL) and water (1mL), and reaction system is stirred at room temperature 20
Minute, reaction solution concentration, purifies to obtain compound 1-1 (35mg, two step yields with prep-HPLC:8%) it is white solid.
1H NMR(400MHz,CD3OD):δ 6.81 (td, J=6.8,1.6Hz, 1H), 5.97 (d, J=5.6Hz, 1H),
4.80-4.86 (m, 2H, overlapped with water signal), 4.58 (dd, J=11.0,6.0Hz, 1H), 4.31
(d, J=11.2Hz, 1H), 4.11 (d, J=11.2Hz, 1H), 3.33-3.42 (m, 2H), 3.02-3.19 (m, 2H), 2.91 (d,
J=8.6Hz, 3H), 1.98-2.16 (m, 2H), 1.68-1.88 (m, 4H), 1.58 (s, 3H), 1.43-1.53 (m, 1H), 1.22-
1.32(m,2H),1.20(s,3H),1.08-1.16(m,3H),0.98(s,3H)。
m/z:[M+NH4]+453.1
Embodiment 2:The synthesis of compound 1-2
Using the synthetic method of 1 compound 1-1 of embodiment, the N- ethyl-N-methyl formyl chlorides in step 1 are replaced with into 4-
Morpholine formyl chloride obtains compound 1-2:
1H NMR(400MHz,CD3OD):δ 6.82 (td, J=6.8,1.6Hz, 1H), 6.00 (d, J=5.8Hz, 1H),
4.58 (dd, J=11.2,5.8Hz, 1H), 4.34 (dd, J=11.1,1.8Hz, 1H), 4.11 (d, J=11.2Hz, 1H),
3.60-3.70(m,4H),3.35-3.50(m,6H),3.00-3.19(m,2H),2.05-2.11(m,2H),1.74-1.83(m,
4H),1.57(s,3H),1.30-1.53(m,3H),1.21(s,3H),0.97(s,3H)。
m/z:[M-H]-462.2
Embodiment 3:The synthesis of compound 2-1
Step 1:By compound 1.2 (390mg, 1.00mmol), triphenylphosphine (393mg, 1.50mmol) and to formic acid uncle
Butyl ester phenol (291mg, 1.50mmol) is dissolved in dry tetrahydrofuran (4mL), be cooled to 0 DEG C be added dropwise DIAD (303m g,
1.50mmol), reaction system is stirred overnight at room temperature, and reaction solution concentration, residue purifies (petroleum ether with silica gel column chromatography:Acetic acid
Ethyl ester=3:1) compound 2.1 (410mg, yield are obtained:72%) it is faint yellow solid.
Step 2:Compound 2.1 (200mg, 0.353mmol) is mixed in the in the mixed solvent of acetic acid (2mL) and water (0.5mL),
Reaction system is stirred at room temperature 20 minutes, and reaction solution concentration, purifies to obtain compound 2-1 (15mg, yield with prep-HPLC:6%) it is
White solid.
1H NMR(400MHz,CD3OD):δ 7.96 (d, J=8.8Hz, 2H), 7.02 (d, J=8.8Hz, 2H), 6.88 (td,
J=6.4,1.2Hz, 1H), 5.85 (d, J=5.2Hz, 1H), 4.71 (dd, J=10.8,5.6Hz, 1H), 4.38 (dd, J=
10.8,1.3Hz, 1H), 4.08 (d, J=11.2Hz, 1H), 3.32-3.40 (m, 2H), 2.94-3.12 (m, 2H), 1.98-2.10
(m,2H),1.72-1.83(m,4H),1.59(s,9H),1.56(s,3H),1.38-1.50(m,1H),1.12-1.26(m,5H),
0.89(s,3H)。
m/z:[M+NH4]+543.9
Embodiment 4:The synthesis of compound 2-2
Using the synthetic method of 3 compound 2-1 of embodiment, t-butyl formate phenol will be replaced with to cyanogen in step 1
Base phenol obtains compound 2-2:
1H NMR(400MHz,CD3OD):δ 7.74 (d, J=6.8Hz, 2H), 7.12 (d, J=6.8Hz, 2H), 6.90 (t, J
=6.8Hz, 1H), 5.87-5.91 (m, 1H), 4.68-4.75 (m, 1H), 4.37 (d, J=10.8Hz, 1H), 4.09 (d, J=
10.4Hz,1H),3.48-3.32(m,2H),2.95-3.14(m,2H),2.04(s,2H),1.72-1.88(m,4H),1.56(s,
3H),1.40-1.52(m,1H),1.15-1.25(m,5H),0.90(s,3H)。
m/z:[M+NH4]+468.9
Embodiment 5:The synthesis of compound 3.2
Step 1:Add successively into n,N-Dimethylformamide (50mL) solution of 4- 4-hydroxy-benzonitriles (2.0g, 0.02mol)
Enter ammonium chloride (9.0g, 0.16mol) and sodium azide (2.2g, 0.03mol), reaction system is stirred overnight at 120 DEG C.Will
Reaction system is cooled to room temperature, and is then poured into frozen water, and pH to 2.5, obtained mixture acetic acid second are adjusted with hydrochloric acid (1M)
Ester (50mL × 2) extracts, and merges organic phase, respectively with water and saturated common salt water washing, separates organic phase, is done with anhydrous sodium sulfate
It is dry, filter, be concentrated to give compound 3.1 (2.3g, yield:72%) it is buff white solid.
Step 2:Triethylamine is separately added into dichloromethane (20mL) solution of compound 3.1 (2.0g, 12.3mmol)
(2.5g, 24.7mmol) and Boc2O (3.0g, 13.7mmol), by reaction system be stirred at room temperature 12 it is small when.Then water is used
(10mL × 2) washing reaction system, separates organic phase, with anhydrous sodium sulfate drying, filtering, concentration, residue silica gel column layer
Analysis (petrol ether/ethyl acetate=1/1) purifies to obtain compound 3.2 (1.6g, yield:50%) it is buff white solid.
Embodiment 6:The synthesis of compound 2-3
Step 1:By compound 1.1 (8.0g, 22.8mmol), benzaldehyde dimethyl acetal (6.95g, 45.6mmol) and to first
Benzene sulfonic acid pyridine hydrochloride (PPTS) (0.29g, 1.4mmol) is dissolved in dichloromethane (80mL), and reaction system is at room temperature
Stir 18 it is small when.Then reaction solution is washed with water, separates organic phase, and with anhydrous sodium sulfate is dry, filtering, concentration.Residual
Thing silica gel column chromatography (petrol ether/ethyl acetate=3/1) purifying obtains compound 3.3 (5.1g, yield:51%) it is solid for white
Body.
Step 2:By compound 3.3 (200mg, 0.46mmol), triphenylphosphine (181mg, 0.69mmol) and compound 3.2
(180mg, 0.69mmol) is dissolved in dry tetrahydrofuran (5mL), is cooled to 0 DEG C, states in mixture be added dropwise then up
DIAD (139.5mg, 0.69mmol), reaction system is stirred overnight at room temperature, and then concentrates reaction solution, residue silica gel column layer
Analysis (petrol ether/ethyl acetate=3/1) purifies to obtain compound 3.4 (124mg, yield:36%) it is pale yellow oil.
m/z:[M+H2O]+699.8
Step 3:Compound 3.4 (20mg, 0.029mmol) and a hydration p-methyl benzenesulfonic acid (11mg, 0.06mmol) is molten
In ethanol, 70 DEG C of reaction system stirs 3 days solution, then concentrates reaction solution, and residue purifies to obtain compound with prep-HPLC
2-3 (0.8mg, yield:6%) it is white solid.
m/z:[M+H2O]+512.4
Biological test embodiment:
Embodiment 1:Anti-inflammatory activity in the BV2 microglia inflammatory models of LPS inductions
First, cell is handled
For gene expression detection and ELISA:In advance~16h paving cells, 24 orifice plates, 200,000/hole;Experimental group:100ng/
MlLPS+DMSO or respective compound processing cell;Control group:DMSO same amount of with experimental group handles cell;Train liquid product:
400 μ l/ holes;
2nd, RNA extractings and RT-PCR
1. after compound processing cell 6h, old training liquid is sucked, adds trizol cell lysis, 500 μ l/ holes are blown even, are transferred to
EP is managed;
2. adding 100 μ l CHCl3, mixing 30 times of turning upside down, is stored at room temperature 10min;
3. centrifugation, 4 DEG C, 12000rpm, 15min;
4. taking 200 μ l supernatants into new EP pipes, add 350 μ l isopropanols respectively, mixing 20 times of turning upside down, -20 DEG C quiet
Put 20min;
5. centrifugation, 4 DEG C, 12000rpm, 15min;
6. abandoning supernatant, 75% ethanol of 1ml is added, is turned upside down several times, washing precipitation;
7. centrifugation, 4 DEG C, 12000rpm, 5min;
8. abandoning supernatant, inversion is dried;
9. adding the piping and druming of 30 μ l DEPC water to mix, dissolving precipitation on ice is placed in, surveys RNA concentration;
10.RT-PCR:
(1) RT-PCR is formulated
Reagent | Volume |
oligo dN6(0.1μg/μl) | 1μl |
10mM dNTP | 1μl |
Template RNA | 1μg |
DEPC H2O | 13μl-V(RNA) |
It is total | 15μl |
(2) 70 DEG C, 5min;1min is placed on ice;
(3) 4 μ 5 × RT of l buffer, 1 μ l M-MLVR are added;Mix;25 DEG C of placement 10min;
(4) 42 DEG C, 50min;
(5) 95 DEG C, 5min.
3rd, qPCR
1.qPCR is formulated:
2×PCR mix | 12.5μl |
Template (20 times of RT product dilutions) | 4μl |
Primers F/R(2.5μM/2.5μM) | 4μl |
Water | 4.5μl |
It is total | 25μl |
2. response procedures:
4th, ELISA (being up to section)
1. after compound processing cell 24h, transfer training liquid to EP is managed;
2. centrifugation, 12000rpm, 5min, supernatant are transferred to new EP pipes;
3. subsequent operation is carried out for IL6 and TNF α ELISA kit specifications according to up to section.
Experimental result:LPS processing can cause BV2 (microglia system), and be inflamed reaction, one of them typical table
It is now the generation increase of inflammatory factor (IL1 β, IL6 etc.).Therefore, the BV2 inflammatory models induced first with LPS, pass through qPCR
To evaluate, the suppression of the compounds of this invention is scorching to be acted on the expression of detection IL1 β and IL6.On this basis, it is further with ELISA
The effect that the compounds of this invention generates IL6 and TNF α at 10 μM is demonstrated, the results are shown in Table 1 and Fig. 1.
Table 1:Percentage is the expression of compound treatment group inflammatory factor compared with reference group;" ++ " is to inflammatory
Factor inhibition is best, and secondly, "-" is not detect positive effect to "+".
Table 1
Embodiment 2:Cell toxicity test
Detected for ATP-GLO:BV2 cells:16h spreads cell, 96 orifice plates, 30,000/hole in advance;Experimental group:Respective compound
Handle cell;Control group:DMSO same amount of with experimental group handles cell;Train liquid product:200 μ l/ holes
ATP-GLO is tested:
1. after compound processing cell 24h, old training liquid is sucked, adds ATP-GLO lysates, 100 μ l/ holes;
2. lysis at room temperature cell 10min;
3. lysate is shifted into white 96 orifice plates, microplate reader detection Cell titer glo luminescence.
Experimental result:Influence of the compounds of this invention to BV2 cytoactives have detected by ATP-GLO experiments, as a result show
Show that all test-compounds have not significant impact cytoactive in 10 μM and lower concentration and show that compound is not bright in itself
Aobvious cytotoxicity.
Claims (18)
1. a kind of andrographolide class compound (I), its isomers, prodrug, solvate or pharmaceutically acceptable salt;
Wherein,
A and b is separately singly-bound or double bond, and is double bond or singly-bound during a and b differences;
X is-OR5Or-SR6;
Y and Z is separately selected from-O- or-NH-;
R1And R2Separately it is selected from hydrogen or alkyl;
R3And R4Separately selected from hydrogen, alkyl, haloalkyl ,-Si (Rc)3、-C(O)Rc、-SO3M;M is hydrogen, sodium or potassium;Or
Person R3And R45-8 membered heterocycloalkyls are interconnected to form, the Heterocyclylalkyl further can also be selected from Si, S containing 1~2
(O)0-2Or the hetero atom or group of N atoms;The Heterocyclylalkyl is unsubstituted or further by 1~4 selected from alkyl, halogen
Element, haloalkyl, hydroxy alkyl, alkoxyalkyl, alkoxy, amino, the substituent substitution of aminoalkyl or oxo base are in office
Meaning position;
R5For substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substitution or
Unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted heterocycle
Alkyl-alkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl, Ra、-C(O)Rb、-C(O)
NRbRc、-C(O)ORc、-S(O)2Rb、-S(O)2NRcRd、-NRcRd、-(CH2)nORa;
R6For hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substitution
It is or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted miscellaneous
Cycloalkyl-alkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl ,-C (O) Rb、-C(O)
NRbRc、-C(O)ORcOr-(CH2)nORa;
R5Or R6In, when the substituted alkyl, substitution cycloalkyl, substitution Heterocyclylalkyl, substitution aryl, substitution it is miscellaneous
Aryl, the cycloalkyl-alkyl of substitution, the hetercycloalkylalkyl of substitution, the aryl alkyl of substitution or substituted heteroaryl alkyl quilt
Can be by 1~4 selected from halogen, C during substitution1-4Alkyl, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6Alkenyl,
C2-6Alkynyl, C3-6Cycloalkyl, 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、-N(Rc)S(O)2NRcRd、-N(Rc)C(O)NRcRd、-S
(O)2NRcRd、-S(O)0-2Rc、-OP(O)(O-Rc)2、-C(O)Rc、-C(O)ORcOr-C (O) NRcRdSubstituent substitution it is in office
Meaning position;
RaFor glycyl-, L- alanyls-, L- leucyls-, L- valyls-, L- isoleucyl-s-, etc. amino acid residue;
RbFor hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substitution
It is or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl-alkyl, substituted or unsubstituted miscellaneous
Cycloalkyl-alkyl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted heteroaryl alkyl;When the substituted alkyl,
Substituted cycloalkyl, the Heterocyclylalkyl of substitution, the aryl of substitution, the heteroaryl of substitution, the cycloalkyl-alkyl of substitution, substitution it is miscellaneous
Can be by 1~4 selected from halogen, C when cycloalkyl-alkyl, the aryl alkyl of substitution or substituted substituted heteroaryl alkyl1-4Alkane
Base, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 circle heterocycles alkane
Base, 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、-N(Rc)S(O)2NRcRd、-N(Rc)C(O)NRcRd、-S(O)2NRcRd、-S(O)0-2Rc、-OP(O)(O-
Rc)2、-C(O)Rc、-C(O)ORcOr-C (O) NRcRdSubstituent substitution at an arbitrary position;
RcAnd RdSeparately selected from hydrogen, C1-6Alkyl, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6Alkene
Base, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocycloalkyls, phenyl or 5-6 unit's heteroaryls.
Alternatively, RcAnd RbOr RdWith forming 3-8 membered heterocycloalkyls together with the N atoms that they are connected jointly, the Heterocyclylalkyl may be used also
Further N, O, S, S (O) are selected from containing 1~32Hetero atom, the 3-8 membered heterocycloalkyls for it is unsubstituted or further by
1~3 is selected from alkyl, halogen, haloalkyl, hydroxy alkyl, alkoxyalkyl, alkoxy, amino, aminoalkyl or oxo base
Substituent substitution at an arbitrary position;
N is 1~6 integer.
2. andrographolide class compound (I) as claimed in claim 1, its isomers, prodrug, solvate or pharmaceutically
Acceptable salt, it is characterised in that:R1For hydrogen or C1-6Alkyl;
And/or R2For hydrogen or C1-6Alkyl;
And/or R3For hydrogen, C1-6Alkyl, halo C1-3Alkyl ,-Si (Rc)3、-C(O)Rc、-SO3M;M is hydrogen, sodium or potassium;
And/or R4For hydrogen, C1-6Alkyl, halo C1-3Alkyl ,-Si (Rc)3、-C(O)Rc、-SO3M;M is hydrogen, sodium or potassium;Or R3
And R45-8 membered heterocycloalkyls are interconnected to form, the Heterocyclylalkyl further can also be selected from Si, S (O) containing 1-20-2、
Or the hetero atom or group of N atoms;The Heterocyclylalkyl is unsubstituted or is further selected from C by 1-31-4Alkyl, halogen,
Halo C1-3Alkyl, hydroxyl C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkoxy, amino, amino C1-3Alkyl or oxo base
One or more of substituent substitutes at an arbitrary position.
3. andrographolide class compound (I) as claimed in claim 1, its isomers, prodrug, solvate or pharmaceutically
Acceptable salt, it is characterised in that:R5For substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substitution
Or unsubstituted 3-8 membered heterocycloalkyls, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryls, substitution or not
Substituted C3-8Cycloalkyl C1-3Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyls C1-3Alkyl, substituted or unsubstituted phenyl
C1-3Alkyl, substituted or unsubstituted 5-6 unit's heteroaryls C1-3Alkyl, Ra、-C(O)Rb、-C(O)NRbRc、-C(O)ORc、-S(O)2Rb、-S(O)2NRcRd、-NRcRd、-(CH2)nORa;
R6For substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 circle heterocycles
Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryls, substituted or unsubstituted C3-8Cycloalkyl C1-3
Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyls C1-3Alkyl, substituted or unsubstituted phenyl C1-3Alkyl, substitution do not take
The 5-6 unit's heteroaryls C in generation1-3Alkyl ,-C (O) Rb、-C(O)NRbRc、-C(O)ORcOr-(CH2)nORa;
RbFor hydrogen, substituted or unsubstituted C1-6Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-8 members are miscellaneous
Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 unit's heteroaryls, substituted or unsubstituted C3-8Cycloalkyl
C1-3Alkyl, substituted or unsubstituted 3-8 membered heterocycloalkyls C1-3Alkyl, substituted or unsubstituted phenyl C1-3Alkyl or substitution or
Unsubstituted 5-6 unit's heteroaryls C1-3Alkyl;
Ra、RcAnd RdDefinition it is as claimed in claim 1.
4. as claims 1 to 3 any one of them andrographolide class compound (I), its isomers, prodrug, solvate,
Or pharmaceutically acceptable salt, it is characterised in that:When a is double bond, b is singly-bound.
5. as claims 1 to 3 any one of them andrographolide class compound (I), its isomers, prodrug, solvate,
Or pharmaceutically acceptable salt, it is characterised in that:When a is singly-bound, b is double bond.
6. as claims 1 to 3 any one of them andrographolide class compound (I), its isomers, prodrug, solvate,
Or pharmaceutically acceptable salt, it is characterised in that:Its general structure is:
Wherein, * is expressed as R configurations or S configurations;
R2、R3、R4And R5Definition as described in any one of claims 1 to 3.
7. as claims 1 to 3 any one of them andrographolide class compound (I), its isomers, prodrug, solvate,
Or pharmaceutically acceptable salt, it is characterised in that:Its general structure is:
Wherein, * is expressed as R configurations or S configurations;
A rings are phenyl ring or 5-6 member hetero-aromatic rings;
R7For halogen, C1-4Alkyl, halo C1-3Alkyl, C1-3Alkoxy, halo C1-3Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Ring
Alkyl, 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、-N(Rc)S(O)2NRcRd、-N(Rc)C(O)NRcRd、-S(O)2NRcRd、-S
(O)0-2Rc、-OP(O)(O-Rc)2、-C(O)Rc、-C(O)ORcOr-C (O) NRcRd;
T is 1,2 or 3;
R1、R2、R4、RcAnd RdDefinition as described in any one of claims 1 to 3.
8. andrographolide class compound (I) as claimed in claim 7, its isomers, prodrug, solvate or pharmaceutically
Acceptable salt, it is characterised in that:R2For CH3;
And/or R3For H, R4For H.
9. as claims 1 to 3 any one of them andrographolide class compound (I), its isomers, prodrug, solvate,
Or pharmaceutically acceptable salt, it is characterised in that:Its general structure is:
Wherein, * is expressed as R configurations or S configurations;
R2、R3、R4、RbAnd RcDefinition as described in any one of claims 1 to 3.
10. andrographolide class compound (I) as claimed in claim 9, its isomers, prodrug, solvate or pharmaceutically
Acceptable salt, it is characterised in that:R2For CH3;
And/or R3For H, R4For H.
11. andrographolide class compound (I) as claimed in claim 1, its isomers, prodrug, solvate or pharmaceutically
Acceptable salt, it is characterised in that:The compound as shown in formula (I) is following any compound:
12. such as claim 1~11 any one of them andrographolide class compound (I), its isomers, prodrug, solvation
The preparation method of thing or pharmaceutically acceptable salt, it is following either method:
Method one:The preparation method includes the following steps:1) in solvent, under the action of alkali, by compound I.2 with N (Rb)
(Rc) COCl or RbCOCl carries out nucleophilic substitution;2) in solvent, in acid condition, the compound I-1 that step 1) is obtained
Or I-2 carries out deprotection reaction and obtains Ia or Ib;
Wherein, R ' is phenyl, and R " is H;Or R ' and R " is methyl;
Method two:The preparation method includes the following steps:1) in solvent, by compound 1.2 withCarry out
Mitsunobu reacts;2) in solvent, in acid condition, the compound I-3 that step 1) obtains is subjected to deprotection reaction and is obtained
To Ic;
Wherein, R ' is phenyl, and R " is H;Or R ' and R " is methyl.
13. preparation method as claimed in claim 12, it is characterised in that:It is described as described in formula 1.2 in method one or method two
Compound can be prepared by the following method:
Wherein, the preparation method includes the following steps:1) in solvent, by andrographolide aqueous solution of hydrogen bromide effect
Lower 17 generations rearrangement reaction;2) 3 of compound 1.1 that step 1) obtains and 19 hydroxyls are obtained into compound by protection
1.2;
Wherein, R ' is phenyl, and R " is H;Or R ' and R " is methyl.
14. a kind of pharmaceutical composition, it includes the active component of therapeutically effective amount and pharmaceutically acceptable auxiliary material;The work
Property component include such as claim 1~11 any one of them andrographolide class compound (I), its isomers, prodrug, solvent
Compound or pharmaceutically acceptable salt.
15. pharmaceutical composition as claimed in claim 14, it is characterised in that:It is described pharmaceutically in described pharmaceutical composition
The auxiliary material of receiving includes pharmaceutically acceptable carrier, diluent and/or excipient.
16. as claim 1~11 any one of them compound shown in formula I, its isomers, prodrug, solvate or
Pharmaceutically acceptable salt, or pharmaceutical composition as described in claims 14 or 15 is in preparing and treating inflammation disease medicine
Using.
17. application as claimed in claim 16, it is characterised in that:The inflammation disease is included by cause of diseases such as bacterium, viruses
Inflammation, inflammation disease or the inflammation disease as caused by radiation damage as caused by autoimmune response caused by body-sensing contaminates.
18. application as claimed in claim 17, it is characterised in that:The virus includes the various viruses of hand-foot-and-mouth disease
(include but not limited to:Enterovirus EV71, Coxsackie virus CA16 etc.), hepatitis viruse (include but not limited to:Hepatitis A, hepatitis B, third
Hepatovirus), AIDS virus etc.;Inflammation disease caused by the autoimmune response includes:It is rheumatoid arthritis, systemic
Lupus erythematosus, dermatomyositis, nodular vasculitis, empsyxis nephrotic syndrome, acute glomerulonephritis, primary film proliferative kidney
Bead ephritis, primary biliary cirrhosis, autoimmune cholangitis, oneself immunity hepatitis, primary sclerotic bile duct
Inflammation, Crohn disease, ulcerative colitis, chronic obstructive pulmonary disease etc.;Inflammation caused by the radioactive damage includes:Radioactivity
Esophagitis, radiation enteritis, radiation thyroiditis, radioactivity osteitis, Inflammation of Radioactive Oral Cavity, radiation_induced pleurisy, radioactivity
Dermatitis, radiation pneumonitis, radioactivity vaginitis, radiocystitis etc..
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112645937A (en) * | 2020-12-28 | 2021-04-13 | 深圳湾实验室 | Aza spiro ring and polycyclic andrographolide compound, preparation method thereof, pharmaceutical composition and application thereof |
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 (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020016363A1 (en) * | 2000-05-05 | 2002-02-07 | Dr. Reddy's Research Foundation | Novel anticancer compounds : process for their preparation and pharmaceutical compositions containing them |
US20060106098A1 (en) * | 2004-11-18 | 2006-05-18 | Advanced Gene Technology, Corp. | Andrographolide and its derivatives as TNF-alpha antagonists |
CN101012211A (en) * | 2007-02-06 | 2007-08-08 | 中国药科大学 | Substituted andrographolide derivative, preparing method and pharmaceutical compound thereof |
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 derivatives and preparation method and application thereof |
CN104856987A (en) * | 2015-01-22 | 2015-08-26 | 南京工业大学 | Application of 14-aryl ether andrographolide derivative in antibacterial field |
-
2017
- 2017-10-24 CN CN201710997767.XA patent/CN107973764B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020016363A1 (en) * | 2000-05-05 | 2002-02-07 | Dr. Reddy's Research Foundation | Novel anticancer compounds : process for their preparation and pharmaceutical compositions containing them |
US20060106098A1 (en) * | 2004-11-18 | 2006-05-18 | Advanced Gene Technology, Corp. | Andrographolide and its derivatives as TNF-alpha antagonists |
CN101012211A (en) * | 2007-02-06 | 2007-08-08 | 中国药科大学 | Substituted andrographolide derivative, preparing method and pharmaceutical compound thereof |
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 derivatives and preparation method and application thereof |
CN104856987A (en) * | 2015-01-22 | 2015-08-26 | 南京工业大学 | Application of 14-aryl ether andrographolide derivative in antibacterial field |
Non-Patent Citations (6)
Title |
---|
MAYUR M.UTTEKAR等: "Anti-HIV activity of semisynthetic derivatives of andrographolide and computational study of HIV-1 gp120 protein binding", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
MAYUR M.UTTEKAR等: "Anti-HIV activity of semisynthetic derivatives of andrographolide and computational study of HIV-1 gp120 protein binding", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 56, 24 July 2012 (2012-07-24), pages 4 * |
W.R.CHAN等: "THE STRUCTURE AND STEREOCHEMISTRY OF NEOANDROGRAPHOLIDE, A DITERPENE GLUCOSIDE FROM ANDROGRAPHIS PANICULATA NEES", 《TETRAHEDRON》 * |
W.R.CHAN等: "THE STRUCTURE AND STEREOCHEMISTRY OF NEOANDROGRAPHOLIDE, A DITERPENE GLUCOSIDE FROM ANDROGRAPHIS PANICULATA NEES", 《TETRAHEDRON》, vol. 27, 31 December 1971 (1971-12-31), pages 5084 * |
徐顺: "穿心莲内酯衍生物的构效关系的理论研究", 《中国优秀硕士学位论文全文数据库》, no. 02, pages 1 - 65 * |
马长沙等: "穿心莲内酯及其衍生物药理活性研究", 《吉林中医药》, pages 77 - 81 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
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 |
CN112645937A (en) * | 2020-12-28 | 2021-04-13 | 深圳湾实验室 | Aza spiro ring and polycyclic andrographolide compound, preparation method thereof, pharmaceutical composition and application thereof |
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