CN103224492A - 14-aryl-ether andrographolide derivative and preparation method and application thereof - Google Patents
14-aryl-ether andrographolide derivative and preparation method and application thereof Download PDFInfo
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- CN103224492A CN103224492A CN2013101469233A CN201310146923A CN103224492A CN 103224492 A CN103224492 A CN 103224492A CN 2013101469233 A CN2013101469233 A CN 2013101469233A CN 201310146923 A CN201310146923 A CN 201310146923A CN 103224492 A CN103224492 A CN 103224492A
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- Prior art keywords
- replacement
- group
- nitro
- rographolide
- alkyl
- Prior art date
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
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- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000005574 norbornylene group Chemical group 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229930006728 pinane Natural products 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 14-aryl-ether andrographolide derivative and preparation method and application thereof, and the structure is shown in the formula (I). The compound, isomer or salt thereof can be applied to medicament for regulating nuclear receptor function or preparation of medicament for preventing or treating diseases related to nuclear receptor FXR.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of 14-aryl ethers andrographolidume derivative, steric isomer, cis-trans-isomer or the preparation of its pharmacy acceptable salt and application pharmaceutically.These compounds by regulating nuclear receptor FXR function or be used for treatment and prophylaxis of tumours, diabetes and obesity and other metabolic disease, cardiovascular pathological changes, reproductive system disease by other identical, the similar or different action target or the mechanism of action, immunological disease, inflammation, comprise senile dementia and Parkinson disease and other neurological disorder class disease, be used for reducing cholesterol and blood fat, and the AIDS that causes of the disease that causes of treatment and prevention yellow fever virus caused singapore hemorrhagic fever, hepatitis C, West Nile Virus infection and HIV.
Background technology
Nuclear receptor (Nuclear receptor or title Nuclear hormone receptor, abbreviation NHR) being that a class is present in tenuigenin or nucleus is interior also can spread and the interior signal protein of ligands specific (ligand) bonded cell, thereby regulate important vital process (the Handschin C of endocellular sugar metabolism, lipid metabolism, energy transformation and immunne response with the transcriptional regulator that is subjected to physical efficiency to combine the formation ligand-dependent with the DNA response element after part combines
S, Roth A, Looser R, Oscarson M, Kaufmann MR, Podvinec M, Gnerre C, Meyer UA Nucl Recept2004,2,7.), therefore they are bringing into play keying action (Evans RM Mol Endocrinol2005 in cell proliferation, cytodifferentiation and cell internal and external equilibrium, 19,1429-1438.), in vital processes such as reproduction, growth and metabolism, play important regulation (Robinson-Rechavi M, Escriva GH, Laudet V J Cell Sci2003,116,585-586.).
(Farnesoid X Receptor is one of nuclear hormone receptor superfamily member FXR) to method Buddhist nun's ester derivative X acceptor, has typical NHR family structure.The present FXR that discovers plays the part of vital role in processes such as regulation and control bile acide, lipoprotein and glucose metabolism, liver regeneration, intestinal bacteria growth and hepatotoxin responsing reaction.In liver, cholesterol is formed bile acide by metabolism, and bile acide not only can be used as the physiology solvent to help absorption, transhipment and the distribution of liposoluble vitamin and fat, can also regulate bile acide and cholesterol metabolic to activate FXR as signaling molecule.Therefore, synthetic and screening can be regulated and control the new drug that the active compound of FXR will help developing the treatment metabolic disease.
Nuclear receptor plays a role jointly with action target COX (cyclooxygenase) enzyme family of non-steroidal anti-inflammatory drugs (NSAID is nonsteroidal anti-inflammatory drug) sometimes, as nuclear receptors PPAR's δ, RAR, RXR and COX-2 the variation of expression (Delage B is arranged all in colorectal carcinoma, Rullier A, Capdepont M, Rullier E, Cassand P Nutrition Journal2007,6,20); Cholic acid in stomach cancer cell (bile acid) can induce COX-2 expression (Park MJ, Kim KH, Kim HY, Kim K, Cheong J Carcinogenesis2008,29 (1), 2385-2393); Nuclear receptor Nur77 suppresses to depend on the inflammatory reaction (Shao Q, Shen LH, Hu LH, Pu J, Qi MY, Li WQ, Tian FJ, Jing Q, He B J.Molecular Cellular Cardiology2010,49 (2), 304) of COX-2; RXRa mediation Ibuprofen BP/EP class NSAID medicine to the beta amyloid material of Alzheimer disease (effect of β-amyloid) (and You X, Zhang YW J Neurochemistry2009,111,142-149.); Nuclear receptors PPAR's g is activated (Bernardo A, Ajmone-Cat MA, Gasparini L by flurbiprofen class NSAID medicine HCT1026 in the rat microgliacyte, Ongini E, Minghetti L J Neurochem.2005,92 (4), 895-903.).
The reductase enzyme reduction reaction of HMG-CoA reductase enzyme (hydroxymethylglutaryl-coenzyme A reductase, HMG-CoA reductase) is that cholesterol synthetic rate determining step is rapid.On the one hand, consider that from chemical structure rographolide and HMG-CoA reductase inhibitor-fungal metabolite lovastatin (Lovastatin) or its semi-synthetic derivative Simvastatin (Simvastatin), Pravastatin (Pravastatin) have certain space structure similarity, so rographolide and derivative thereof may have the function of inhibition HMG-CoA reductase enzyme; On the other hand, many nuclear receptors and endogenic ligand thereof are participated in the cholesterol biosynthetic process, so rographolide and derivative thereof also may suppress the biosynthesizing of cholesterol by other mechanism.
Summary of the invention
The objective of the invention is on the basis of existing technology, provide a class to have corresponding active 14-aryl ethers Herba Andrographis Inner ester derivative, steric isomer, cis-trans-isomer or its pharmacy acceptable salt.
Another object of the present invention provides a kind of preparation method of above-claimed cpd.
The 3rd purpose of the present invention provides the purposes of a kind of above-claimed cpd aspect pharmacy.
Purpose of the present invention can reach by following measure:
14-aryl ethers Herba Andrographis Inner ester derivative, isomer or its pharmacy acceptable salt shown in the formula (I),
Wherein,
The Z ring is phenyl ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, furan nucleus, thiazole ring, pyrrole ring, oxazole ring, thiazole ring, imidazole ring, isozole ring, isothiazole ring or pyrazoles ring;
R
1～R
5Be independently selected from hydrogen, halogen, cyano group, nitro, C respectively
1～6Alkyl, C
1～6Haloalkyl, C
1～6Acyl group, C
1～6Carboxylic acid group, C
1～6The C of amide group, replacement or non-replacement
3～6The C of cycloalkyl, replacement or non-replacement
1～6The C of alkoxyl group, replacement or non-replacement
1～6The C of alkylthio, replacement or non-replacement
2～6The C of the alkylsulfonyl of the amino of carboxylicesters, replacement or non-replacement, replacement or non-replacement, replacement or non-replacement
2～6The C of alkylene, replacement or non-replacement
3～6The C of cycloalkenyl group, replacement or non-replacement
3～6The aromatic alkyl of the aromatic base of heterocyclic radical, replacement or non-replacement, replacement or non-replacement; Described substituting group is selected from halogen, cyano group, nitro, C
1～6Alkyl, C
1～6Haloalkyl, C
1～6Alkoxyl group, C
1～6Alkylthio or C
2～6Alkylene;
Perhaps R
1～R
5In adjacent two groups and Z ring are common constitutes naphthalene, anthracene, phenanthrene, quinoline, isoquinoline 99.9, chromene, benzopyrone, cumarone, thionaphthene, indoles, purine or pteridine radicals group;
R
6Or R
7Be independently selected from hydrogen, C respectively
1～6The C of acyl group, replacement or non-replacement
1～6The C of alkyl, replacement or non-replacement
3～6The C of the heterocyclic radical of cycloalkyl, replacement or non-replacement, replacement or non-replacement
2～6The C of alkylene, replacement or non-replacement
3～ 6The aromatic alkyl of the aromatic base of cycloalkenyl group, replacement or non-replacement, replacement or non-replacement or replacement or non-substituted heterocycle thiazolinyl; Described substituting group is selected from halogen, cyano group, nitro, C
1～6Alkyl, C
1～6Haloalkyl, C
1～6Alkoxyl group, C
1～6Alkylthio or C
2～6Alkylene;
Perhaps R
6And R
7Link to each other and constitute C
1～6Alkylidene group or C
3～6Cycloalkyl;
Do not replace or arbitrarily the substituted aroma alkyl, do not replace or arbitrarily the substituted heterocycle aryl radical, do not replace or arbitrarily the substituted aroma alkyl, do not replace or arbitrarily the substituted heterocycle aromatic alkyl, do not replace or arbitrarily the substituted aroma alkylene, do not replace or substituted heterocycle aromatic alkenyl arbitrarily
* be expressed as R configuration or S configuration.
Preferably, compound of the present invention is suc as formula the compound shown in (II), isomer or its pharmacy acceptable salt,
Wherein,
R
1, R
2, R
3, R
4Or R
5Be independently selected from hydrogen, nitro, halogen, C respectively
1～6Alkyl, C
1～6Haloalkyl, C
3～6Cycloalkyl, C
1～6Alkoxyl group, C
2～6Carboxylic acid group or C
2～6Carboxylic acid ester groups;
R
6Or R
7Be independently selected from hydrogen, C respectively
1～6Acyl group, C
1～6Alkyl, C
1～6Haloalkyl, perhaps R
6And R
7Link to each other and constitute C
1～6Alkylidene group;
* be expressed as R configuration or S configuration.
Further preferred, compound of the present invention is suc as formula the compound shown in (III), isomer or its pharmacy acceptable salt,
R
1, R
2, R
3, R
4Or R
5Be independently selected from hydrogen, nitro, halogen, C respectively
1～3Alkyl, C
1～3Haloalkyl, C
1～3Alkoxyl group, C
3～6Cycloalkyl, C
2～6Carboxylic acid group or C
2～6Carboxylic acid ester groups;
R
6Or R
7Be independently selected from hydrogen, C respectively
1～3Acyl group, C
1～3Alkyl, C
1～3Haloalkyl, perhaps R
6And R
7Link to each other and constitute C
1～6Alkylidene group;
* be expressed as R configuration or S configuration.
In formula (I), formula (II) and formula (III), preferred, R
1Or R
5Be independently selected from hydrogen, nitro, C respectively
1～3Alkyl, C
1～3Haloalkyl, C
1～3Alkoxyl group, halogen, C
2～6Carboxylic acid group or C
2～6Carboxylic acid ester groups;
In formula (I), formula (II) and formula (III), preferred, R
2Or R
4Be independently selected from hydrogen, nitro, C respectively
1～3Alkyl, C
1～3Haloalkyl, C
2～6Carboxylic acid group, C
2～6Carboxylic acid ester groups or halogen;
In formula (I), formula (II) and formula (III), preferred, R
3Be selected from hydrogen or nitro.
In formula (I), formula (II) and formula (III), preferred, R
1, R
2, R
3, R
4Or R
5Be independently selected from hydrogen, nitro, methyl, methoxyl group, chlorine, fluorine or group-4 ethyl formate respectively.
In formula (I), formula (II) and formula (III), preferred, R
6Or R
7Be independently selected from hydrogen or ethanoyl respectively, perhaps R
6And R
7Link to each other and constitute isopropylidene.
Compound of the present invention can adopt the method for being prepared as follows:
The present invention further provides a kind of preparation method of preferred compound, it comprises the steps:
A) rographolide 14-α configuration OH introduces ethanoyl by Mitsunobu reaction, simultaneously the configuration of 14-position change (from α-configuration to beta configuration).In the reaction there-necked flask, add andrographolidume derivative-pure 14-α-OH(1 equivalent successively under rare gas element existence and the ice bath), triphenyl phosphorus (1～10 equivalent), behind acetic acid (1～10 equivalent) and the anhydrous THF, slowly add diisopropyl azodiformate (DIAD then, 1～10 equivalent) THF solution, ice bath stirred after 1 hour, and room temperature reaction spends the night.Steam most of THF, remove most of by product hydrazine with ethyl acetate/water (1/1～1/5) extracted several times after, the anhydrous sodium sulfate drying organic layer is after column chromatography or recrystallization obtain 14-β-OAc product.
B) 14-β-OAc product is dissolved in the methyl alcohol, the tosic acid that adds catalytic amount, solvent evaporated behind the stirring at room reaction 30min, the ethyl acetate dilution, after respectively washing once with saturated sodium bicarbonate solution, water, saturated nacl aqueous solution successively, the organic phase anhydrous sodium sulfate drying gets rographolide 14-OAc epimer or 14-epimer through column chromatography or recrystallization.
C) with 14-epimer, catalytic amount tosic acid pyridinium salt (PPTS), add a certain amount of methylene dichloride that dewaters again, add 2 at last, 2-Propanal dimethyl acetal (1-200 equivalent), slowly be heated to 40 ℃, it is complete substantially to react 3-12 hour afterreaction, stop heating and be cooled to after the room temperature with the ethyl acetate dilution, the saturated sodium bicarbonate solution washing, organic phase with anhydrous sodium sulfate drying after column chromatography or recrystallization get 14-β-OH product.
D) in reaction flask, add andrographolidume derivative-alcohol (1 equivalent) successively under rare gas element existence and the ice bath, triphenyl phosphorus (1～10 equivalent), behind phenol (1～10 equivalent) and the anhydrous THF, slowly add diisopropyl azodiformate (DIAD then, 1～10 equivalent) THF solution, ice bath stirred after 1 hour, and room temperature-80 a ℃ reaction is spent the night.Steam most of THF, remove most of by product hydrazine with ethyl acetate/water (1/1～1/5) extracted several times after, the anhydrous sodium sulfate drying organic layer obtains A or D series product through column chromatography.
E) A or D series product are dissolved in the methyl alcohol, the tosic acid that adds catalytic amount, solvent evaporated behind the stirring at room reaction 3Omin, the ethyl acetate dilution, after respectively washing once with saturated sodium bicarbonate solution, water, saturated nacl aqueous solution successively, the organic phase anhydrous sodium sulfate drying gets B or E series product through column chromatography.
F) add B or E series product (1 equivalent) in the reaction flask successively, zinc chloride (0.5～20 equivalent), aceticanhydride (1～100 equivalent) was in 30-90 ℃ of reacting by heating 5 hours.Add entry, ethyl acetate after being cooled to room temperature, the saturated sodium bicarbonate solution thorough washing, organic phase anhydrous sodium sulfate drying after water, saturated nacl aqueous solution washing gets C or F series product through column chromatography again.
Another technical issues that need to address of the present invention provide above-mentioned 14-aryl ethers andrographolidume derivative, steric isomer, cis-trans-isomer or the application of its pharmacy acceptable salt in medicine:
14-aryl ethers andrographolidume derivative compound, steric isomer, cis-trans-isomer or its pharmacy acceptable salt are used for regulating the application of the function of nuclear receptor FXR (Farnesoid X receptor) and the prevention disease medicament relevant with FXR with treatment.
14-aryl ethers andrographolidume derivative, steric isomer, cis-trans-isomer or its pharmacy acceptable salt are used for the treatment of with prophylaxis of tumours and are used for cholesterol and dysbolism of blood fat, as reducing cholesterol and blood fat.
14-aryl ethers andrographolidume derivative, steric isomer, cis-trans-isomer or its pharmacy acceptable salt are used for the treatment of and prevent diabetes and obesity and other metabolic disease, cardiovascular pathological changes, reproductive system disease, immunological disease, inflammation, senile dementia and Parkinson disease and other neurological disorder class disease
A kind of pharmaceutical composition, it is mainly formed as activeconstituents and at least a pharmaceutically acceptable carrier with 14-aryl ethers andrographolidume derivative of the present invention, steric isomer, cis-trans-isomer or its pharmacy acceptable salt.
Definition
Constituting a part of the present invention is pharmaceutically acceptable solvate, can make crystalline hydrate or with other solvent crystallization thing, as ethanol etc.
Constituting a part of the present invention is pharmacy acceptable salt:
If The compounds of this invention is an alkalescence, then suitable " pharmacy acceptable salt " comprises the conventional non-toxic salt of the The compounds of this invention that The compounds of this invention and mineral acid or organic acid reaction form.For example, comprise deriving from for example salt of hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid etc. of mineral acid, also comprise deriving from for example salt of acetate, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid etc. of organic acid.
If The compounds of this invention is a tart, then suitable " pharmacy acceptable salt " is meant that The compounds of this invention comprises the salt of mineral alkali and organic bases preparation by pharmaceutically acceptable nontoxic alkali.The salt that derives from mineral alkali comprises aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc.Derive from the salt of pharmaceutically acceptable organic nontoxic alkali, described alkali comprises the salt of primary amine, secondary amine and tertiary amine, and the amine of replacement comprises that natural existence and synthetic replace amine, cyclic amine and deacidite.For example arginine, trimethyl-glycine, caffeine, choline, diethylamine, 2-DEAE diethylaminoethanol, 2-dimethylaminoethanol, monoethanolamine, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, Histidine, isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane etc.
Compound of the present invention can have asymmetric center, chiral axis and chirality face, and racemoid, racemoid mixture and single diastereomer and all possible isomers and composition thereof of existing comprise that optically active isomer includes in the present invention.In addition, compound disclosed by the invention can tautomer exists, and two kinds of tautomeric forms all comprise within the scope of the invention, even only described wherein a kind of tautomeric structure.For example, any claimed following compounds A is interpreted as and comprises tautomeric structure B, and vice versa, comprises its mixture equally.
When there is two key cis-trans-isomer in the present invention, exist with individual isomer, or the mixture of cis-isomeride and trans-isomer(ide), even only described wherein a kind of heterogeneous structure.
Term used herein " alkyl " means and comprises C1-C18 alkyl, C2-C18 thiazolinyl, C2-C18 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic radical, Heterocyclylalkyl.The line that puts loop systems from substituting group under represents that the key of indication can be connected on the atom of any ring that can replace.If loop systems is many rings, it means that this key only is connected on any suitable carbon atom of adjacent loops.
Term " replace arbitrarily " is appreciated that those of ordinary skills can select the substituting group of The compounds of this invention and substitution pattern and provide chemically stable and can the synthetic compound from the raw material that can obtain by art technology and method.Replace if substituting group self is exceeded a group, should understand these groups can be on the identical carbon atoms or on the different carbon atom, as long as make Stability Analysis of Structures.
Term used herein " alkyl " means and comprises side chain, straight chain or the cyclic saturated fatty alkyl with particular carbon atom number.The definition of " C1-C18 " comprises the group of arranging with straight or branched with 1,2,3,4,5,6,7,8～18 carbon atom main chain in " C1-C18 alkyl ".For example, " C1-C18 alkyl " specifically comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, heptyl, octyl group, cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl etc.
Term " thiazolinyl " refers to straight chain, side chain or cyclic, and main chain contains the non-aromatic hydrocarbon base of 12～18 carbon atoms and at least one carbon-to-carbon double bond.Therefore, " C12-C18 thiazolinyl " refers to that main chain has the thiazolinyl of 12～18 carbon atoms.Thiazolinyl comprises vinyl, propenyl, butenyl, 2-methyl butene base and cyclohexenyl etc.If the straight chain of thiazolinyl, side chain or circular part can contain two keys and indicate the thiazolinyl that replaces then this part can be substituted.
Term " alkynyl " refers to straight chain, side chain or cyclic, and main chain contains 12～18 carbon atoms and at least one carbon carbon triple-linked non-aromatic hydrocarbon base.Therefore, " C12-C18 alkynyl " refers to have the alkynyl of 12～18 carbon atoms.Alkynyl comprises ethynyl, proyl, butynyl, 3-methyl butynyl etc.If the straight chain of alkynyl, side chain or circular part can contain triple bond and indicate the alkynyl that replaces then this part can be substituted.
Term " aryl " is 3-10 atom bicyclic carbocyclic nearly in any stable monocycle of 3-10 atom or each ring nearly in the finger ring, wherein at least one to encircle be aromatic nucleus.The example of aryl comprises phenyl, naphthyl, anthryl and xenyl.
Term " aralkyl " comprises the group that wherein above-mentioned " alkyl " replaced by above-mentioned " aryl ".The example of aralkyl comprises benzyl, styroyl, naphthyl methylene radical, anthryl methylene radical.
3-10 atom bicyclic carbocyclic nearly in the stable monocycle of 3-10 atom or each ring nearly in term " heteroaryl " the representative ring, wherein at least one ring is aromatic nucleus and contains the individual heteroatoms that is selected from O, N and S of 1-4.Heteroaryl in this range of definition includes but not limited to acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl.
Term " heteroaralkyl " comprises the group that wherein above-mentioned " alkyl " replaced by above-mentioned " heteroaryl ".The example of heteroaryl comprises furfurylidene, pyridine ethyl, pyrroles's methylene radical.
Term " heterocyclic radical " is meant that containing 1-4 is selected from heteroatomic 3-12 unit's aromaticity such as O, N and S or non-aromaticity heterocycle, and comprises bicyclic radicals." heterocyclic radical " therefore comprises above mentioned heteroaryl, also comprises its dihydro and tetrahydro-analogue." heterocyclic radical " further example includes but not limited to benzimidazolyl-; benzofuryl; benzopyranyl; the benzopyrazoles base; the benzotriazole base; benzothienyl benzoxazolyl; carbazyl; carbolinyl; the cinnolines base; furyl; imidazolyl; indolinyl; indyl; indazolyl; isobenzofuran-base; pseudoindoyl; isoquinolyl; isothiazolyl isoxazolyl oxadiazole base oxazolyl oxazoline isoxazoline; oxetanyl (oxetanyl); pyranyl; pyrazinyl; pyrazolyl; pyridazinyl; the pyridopyridine base; pyridazinyl; pyridyl; pyrimidyl; pyrryl; quinazolyl; quinolyl quinoxalinyl; THP trtrahydropyranyl; tetrazyl; the tetrazolo pyridyl; thiadiazolyl group; thiazolyl; thienyl; triazolyl; azetidinyl; l, the 4-alkyl dioxin; azepan base (hexallydroazepinyl); piperazinyl; piperidyl; the pyridin-2-ones base; pyrrolidyl; morpholinyl; thio-morpholinyl (thiomorpholinyl); the dihydrobenzo imidazolyl; dihydro benzo furyl; the dihydrobenzo thienyl; Er hydrogen benzoxazolyl; the dihydrofuran base; the glyoxalidine base; indolinyl; the dihydro-isoxazole base; dihydro isothiazolyl Er Qing oxadiazole base dihydro-oxazole base; the dihydro pyrazinyl; the pyrazoline base; the dihydropyridine base; the dihydro-pyrimidin base; the pyrrolin base; the dihydroquinoline base; the dihydro tetrazyl; the thiodiazoline base; dihydro-thiazolyl; the dihydro-thiophene base; the dihydro triazolyl; the dihydro azetidinyl; the methylenedioxyphenyl formyl radical; tetrahydrofuran base and tetrahydro-thienyl and N-oxide compound thereof.The connection of heterocyclic substituent can realize by carbon atom or by heteroatoms.
Term " ring-type " shows the ring compound that contains more than 3 carbon or other atom in the ring.
Term " many rings " comprises the structure that wherein forms at least 2 rings, has at least volution or also (closing) of at least 2 common atoms that 1 common atom is arranged between two rings to encircle or bridge (striding) ring structure among these rings.The basic structure of typical structure such as diamantane, norborneol, norbornylene, pinane, (different) camphane, carane etc.Can contain or not contain substituent structure on these rings, these polynuclear planes can be mixed to be encircled more.
Term " heterocyclic radical " comprises the group that wherein above-mentioned " alkyl " replaced by above-mentioned " heterocyclic radical ".The heterocyclic radical example comprises imidazoles methylene radical, tetramethyleneimine ethyl, tetrazolium methylene radical.
Term " halogen " means and comprises fluorine, chlorine, bromine and iodine.
Term " separately " is meant that the variable of independent utility is being applied to independent variation between the application.
Andrographolidume derivative of the present invention can be configured to medicinal compositions, gives patient's medication according to the mode that gives of multiple suitable selection, and these approach comprise for example oral or parenteral of whole body, by intravenously, muscle, transdermal or subcutaneous etc.
The administering mode of preferred andrographolidume derivative is oral, but need according to the concrete physics of compound and chemical characteristic and stable different, and the drug formulation and the administering mode of the difference of therapeutic purpose decision use, include but not limited to the application method that slowly-releasing is controlled.
Embodiment
Embodiment 1: rographolide 14-beta comfiguration derivative synthetic
Rographolide 14-α configuration OH introduces ethanoyl by Mitsunobu reaction, simultaneously the configuration of 14-position change (from α-configuration to beta configuration).In the reaction there-necked flask, add andrographolidume derivative-pure 14-α-OH(1 equivalent successively under rare gas element existence and the ice bath), triphenyl phosphorus (1～10 equivalent), behind acetic acid (1～10 equivalent) and the anhydrous THF, slowly add diisopropyl azodiformate (DIAD then, 1～10 equivalent) THF solution, ice bath stirred after 1 hour, and room temperature reaction spends the night.Steam most of THF, remove most of by product hydrazine with ethyl acetate/water (1/1～1/5) extracted several times after, the anhydrous sodium sulfate drying organic layer is after column chromatography or recrystallization obtain 14-β-OAc product, yield～70%.
14-β-OAc product is dissolved in the methyl alcohol, the tosic acid that adds catalytic amount, solvent evaporated behind the stirring at room reaction 30min, the ethyl acetate dilution, after respectively washing once with saturated sodium bicarbonate solution, water, saturated nacl aqueous solution successively, the organic phase anhydrous sodium sulfate drying gets rographolide 14-OAc epimer or 14-epimer through column chromatography or recrystallization, and yield is～90%.
With 14-epimer, catalytic amount tosic acid pyridinium salt (PPTS), add a certain amount of methylene dichloride that dewaters again, add 2 at last, 2-Propanal dimethyl acetal (1-200 equivalent), slowly be heated to 40 ℃, it is complete substantially to react 3-12 hour afterreaction, and with the ethyl acetate dilution, saturated sodium bicarbonate solution washs after stopping heating and being cooled to room temperature, after column chromatography or recrystallization get 14-β-OH product, yield is～82% with anhydrous sodium sulfate drying for organic phase.
Synthesizing of embodiment 2:A or D series compound
In reaction flask, add andrographolidume derivative-alcohol (1 equivalent) successively under rare gas element existence and the ice bath, triphenyl phosphorus (1～10 equivalent), behind phenol (1～10 equivalent) and the anhydrous THF, slowly add diisopropyl azodiformate (DIAD then, 1～10 equivalent) THF solution, ice bath stirred after 1 hour, and room temperature-80 a ℃ reaction is spent the night.Steam most of THF, remove most of by product hydrazine with ethyl acetate/water (1/1～1/5) extracted several times after, the anhydrous sodium sulfate drying organic layer obtains A or D series product through column chromatography or recrystallization, productive rate is 30～80%.Above-claimed cpd
1H NMR,
13C NMR, high resolution mass spectrum data see Table lattice 1.
Synthesizing of embodiment 3:B or E series compound
A or D series product are dissolved in the methyl alcohol, the tosic acid that adds catalytic amount, solvent evaporated behind the stirring at room reaction 3Omin, the ethyl acetate dilution, after respectively washing once with saturated sodium bicarbonate solution, water, saturated nacl aqueous solution successively, the organic phase anhydrous sodium sulfate drying gets B or E series product through column chromatography or recrystallization, and yield is～90%.Above-claimed cpd
1H NMR,
13C NMR, high resolution mass spectrum data see Table lattice 1.
Synthesizing of embodiment 4:C or F series compound
Add B or E series product (1 equivalent) in the reaction flask successively, zinc chloride (0.5～20 equivalent), aceticanhydride (1～100 equivalent) was in 30-90 ℃ of reacting by heating 5 hours.Add entry, ethyl acetate after being cooled to room temperature, the saturated sodium bicarbonate solution thorough washing, organic phase anhydrous sodium sulfate drying after water, saturated nacl aqueous solution washing gets C or F series product, productive rate 40～90% through column chromatography or recrystallization again.Above-claimed cpd
1H NMR,
13C NMR, high resolution mass spectrum data see Table lattice 1.
Form 1 part of compounds
1H NMR,
13C NMR, high resolution mass spectrum data
Embodiment 5: nuclear receptor method Buddhist nun ester X acceptor (FXR) ligand screening general planning
Use can be simulated the in-vitro screening model of intravital biological aspect, according to disclosed screening method, screens 14-aryl ethers andrographolidume derivative of the present invention and regulates nuclear receptor FXR activity.
Common compound dissolution to be determined is made into gradient solution in DMSO, be diluted to the working solution that contains 2%DMSO with PBS before use, the contrast working solution that does not contain medicine is the PBS that contains 2%DMSO, pastille working solution and the contrast working solution that does not contain medicine join in the experimental port diluted 20 times, and the concentration of final DMSO is 0.1% in all experimental ports.Compound activity is measured the control group that blank group, positive drug or positive compound are set simultaneously.
The 293T cell that will be in logarithmic phase is with 2x10
4Go down to posterity in 96 porocyte culture plates in/hole, overnight incubation, length are used for transfection when 80～90% expire.
With optimizing nutrient solution DMEM dilution Lipofectamine2000 reagent (0.5 μ l/100 μ l) and plasmid DNA.Optimizing nutrient solution dilution back plasmid concentration is pCMV-Gal4-FXR-LBD, 25ng/ hole, pFR-Luci, 50ng/ hole, pFRTlaczeo plasmid, 50ng/ hole.The Lipofectamine2000 dilution after 5 minutes mixes liposome after the dilution and plasmid DNA equal-volume, pipettes liposome/DNA mixture again after room temperature is placed 20min.
Rapidly above-mentioned cell is changed the DMEM100 μ l that liquid becomes to contain 10% foetal calf serum.The sample injector head is goed deep into dropwise adding liposome/DNA mixture under the liquid level, and jiggle mixing.
Testing compound is dissolved among the DMSO, at cell transient transfection plasmid after 6 hours, adds the compound of different concns respectively and with the DMSO contrast of concentration.Be put in 5%CO
2Continue in the incubator to cultivate 24 hours.Utilize VERITAS according to Promega company Steady-Glo kit specification sheets
TMMicroplateluminometer (Turner Biosystems) measures the fluorescent value of cell, and fluorescent value reacts the FXR activity, and proofreaies and correct as interior mark with Gal.Get 20 μ l cell lysates and place 96 orifice plates, add 100 * Mg solution, 1.5 μ l, 1 * ONPG solution, 33 μ l, 0.1mol/L sodium phosphate (pH7.5) 95.5 μ l.37 ℃ of temperature are bathed to yellow occurring, add 50 μ l, 0.1mol/L Na
2CO
3Termination reaction reads OD
405
Activity research for antagonist need add the corresponding endogenous agonist of acceptor gallodesoxycholic acid (chenodoxycholic acid, CDCA) (final concentration 25 μ M) simultaneously.
The activity of the antagonist of part of compounds sees Table lattice 2.At present bibliographical information mainly is the FXR agonist or has partial agonist simultaneously and the conditioning agent of partial antagonist feature (as GW4064, MFA-1 etc., is seen PNAS2008,105 (14): 5337 – 5342; The 04th phase of J.Surgery Concepts﹠Practice2010).The compound of the FXR antagonist of this patent report has better activity (J.Med.Chem.2012,55, the IC of the best FXR inhibitor of 7037-7053 than the FXR agonist compounds of another piece bibliographical information
50At 8.9 μ M, in this patent form 2 before B2, A3, A2,14-α-OH, A4, A6, A8, A9, A10, A11 totally 10 compound activity IC
50Be lower than 5.0 μ M, 14-β-OAc, E1, B1, B3, D2, B9, B10, B11 be the IC of totally 8 compounds
50Less than or near 8.9 μ M).
The activity of the FXR antagonist of form 2 part of compounds
Claims (10)
1. the compound shown in the formula (I), isomer or its pharmacy acceptable salt,
Wherein,
The Z ring is phenyl ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, furan nucleus, thiazole ring, pyrrole ring, oxazole ring, thiazole ring, imidazole ring, isozole ring, isothiazole ring or pyrazoles ring;
R
1～R
5Be independently selected from hydrogen, halogen, cyano group, nitro, C respectively
1～6Alkyl, C
1～6Haloalkyl, C
1～6Acyl group, C
1～6Carboxylic acid group, C
1～6The C of amide group, replacement or non-replacement
3～6The C of cycloalkyl, replacement or non-replacement
1～6The C of alkoxyl group, replacement or non-replacement
1～6The C of alkylthio, replacement or non-replacement
2～6The C of the alkylsulfonyl of the amino of carboxylicesters, replacement or non-replacement, replacement or non-replacement, replacement or non-replacement
2～6The C of alkylene, replacement or non-replacement
3～6The C of cycloalkenyl group, replacement or non-replacement
3～6The aromatic alkyl of the aromatic base of heterocyclic radical, replacement or non-replacement, replacement or non-replacement; Described substituting group is selected from halogen, cyano group, nitro, C
1～6Alkyl, C
1～6Haloalkyl, C
1～6Alkoxyl group, C
1～6Alkylthio or C
2～6Alkylene;
Perhaps R
1～R
5In adjacent two groups and Z ring are common constitutes naphthalene, anthracene, phenanthrene, quinoline, isoquinoline 99.9, chromene, benzopyrone, cumarone, thionaphthene, indoles, purine or pteridine radicals group;
R
6Or R
7Be independently selected from hydrogen, C respectively
1～6The C of acyl group, replacement or non-replacement
1～6The C of alkyl, replacement or non-replacement
3～6The C of the heterocyclic radical of cycloalkyl, replacement or non-replacement, replacement or non-replacement
2～6The C of alkylene, replacement or non-replacement
3～ 6The aromatic alkyl of the aromatic base of cycloalkenyl group, replacement or non-replacement, replacement or non-replacement or replacement or non-substituted heterocycle thiazolinyl; Described substituting group is selected from halogen, cyano group, nitro, C
1～6Alkyl, C
1～6Haloalkyl, C
1～6Alkoxyl group, C
1～6Alkylthio or C
2～6Alkylene;
Perhaps R
6And R
7Link to each other and constitute C
1～6Alkylidene group or C
3～6Cycloalkyl;
Do not replace or arbitrarily the substituted aroma alkyl, do not replace or arbitrarily the substituted heterocycle aryl radical, do not replace or arbitrarily the substituted aroma alkyl, do not replace or arbitrarily the substituted heterocycle aromatic alkyl, do not replace or arbitrarily the substituted aroma alkylene, do not replace or substituted heterocycle aromatic alkenyl arbitrarily
* be expressed as R configuration or S configuration.
2. compound according to claim 1, isomer or its pharmacy acceptable salt, described compound be suc as formula shown in (II),
Wherein,
R
1, R
2, R
3, R
4Or R
5Be independently selected from hydrogen, nitro, halogen, C respectively
1～6Alkyl, C
1～6Haloalkyl, C
3～6Cycloalkyl, C
1～6Alkoxyl group, C
2～6Carboxylic acid group or C
2～6Carboxylic acid ester groups;
R
6Or R
7Be independently selected from hydrogen, C respectively
1～6Acyl group, C
1～6Alkyl, C
1～6Haloalkyl, perhaps R
6And R
7Link to each other and constitute C
1～6Alkylidene group;
* be expressed as R configuration or S configuration.
3. compound according to claim 2, isomer or its pharmacy acceptable salt, described compound be suc as formula shown in (III),
R
1, R
2, R
3, R
4Or R
5Be independently selected from hydrogen, nitro, halogen, C respectively
1～3Alkyl, C
1～3Haloalkyl, C
1～3Alkoxyl group, C
3～6Cycloalkyl, C
2～6Carboxylic acid group or C
2～6Carboxylic acid ester groups;
R
6Or R
7Be independently selected from hydrogen, C respectively
1～3Acyl group, C
1～3Alkyl, C
1～3Haloalkyl, perhaps R
6And R
7Link to each other and constitute C
1～6Alkylidene group;
* be expressed as R configuration or S configuration.
4. compound according to claim 3, isomer or its pharmacy acceptable salt, wherein
R
1Or R
5Be independently selected from hydrogen, nitro, C respectively
1～3Alkyl, C
1～3Haloalkyl, C
1～3Alkoxyl group, halogen, C
2～6Carboxylic acid group or C
2～6Carboxylic acid ester groups;
R
2Or R
4Be independently selected from hydrogen, nitro, C respectively
1～3Alkyl, C
1～3Haloalkyl, C
2～6Carboxylic acid group, C
2～6Carboxylic acid ester groups or halogen;
R
3Be selected from hydrogen or nitro.
5. compound according to claim 3, isomer or its pharmacy acceptable salt, wherein
R
1, R
2, R
3, R
4Or R
5Be independently selected from hydrogen, nitro, methyl, methoxyl group, chlorine, fluorine or group-4 ethyl formate respectively;
R
6Or R
7Be independently selected from hydrogen or ethanoyl respectively, perhaps R
6And R
7Link to each other and constitute isopropylidene.
6. compound according to claim 1, isomer or its pharmacy acceptable salt, wherein said compound is selected from:
14-(R)-phenoxy group-3,19-isopropylidene rographolide,
14-(R)-(4 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-phenoxy group-rographolide,
14-(R)-(4 '-nitro-phenoxy)-rographolide,
14-(R)-(2 '-methoxyl group-4 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(2 '-methoxyl group-4 '-nitro-phenoxy group)-rographolide,
14-(R)-(2 '-methyl-4 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(2 '-methyl-4 '-nitro-phenoxy group)-rographolide,
14-(R)-(2 '-chloro-4 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(2 '-chloro-4 '-nitro-phenoxy group)-rographolide,
14-(R)-(2 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(2 '-nitro-phenoxy group)-rographolide,
14-(R)-(3 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(3 '-nitro-phenoxy group)-rographolide,
14-(R)-(3 '-methyl-4 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(3 '-methyl-4 '-nitro-phenoxy group)-rographolide,
14-(R)-(2 '-group-4 ethyl formate-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(2 '-group-4 ethyl formate-phenoxy group)-rographolide,
14-(R)-(2 '-fluoro-4 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(2 '-fluoro-4 '-nitro-phenoxy group)-rographolide,
14-(R)-(3 '-fluoro-4 '-nitro-phenoxy group)-3,19-isopropylidene-rographolide,
14-(R)-(3 '-fluoro-4 '-nitro-phenoxy group)-rographolide,
14-(R)-(2 '-methoxyl group-4 '-nitro-phenoxy group)-3,19-diacetyl-rographolide,
14-(S)-phenoxy group-3,19-isopropylidene-rographolide,
14-(S)-phenoxy group-rographolide,
14-(S)-(4 '-nitro-phenoxy)-3,19-isopropylidene-rographolide,
14-(S)-(4 '-nitro-phenoxy)-rographolide.
7. the preparation method of the described compound of claim 1 is characterized in that comprising the steps:
8. the described compound of claim 1, isomer or its salt are used for regulating the application of medicine or prevention or the treatment and the nuclear receptor FXR relative disease medicine of nuclear receptor FXR function in preparation.
The described compound of claim 1, isomer or its salt preparation be used for the treatment of or the preventing disease medicine in application, wherein said disease is tumour, cholesterol or dysbolism of blood fat, diabetes, obesity, cardiovascular pathological changes, reproductive system disease, immunological disease, inflammation, senile dementia, Parkinson disease or neurological disorder class disease.
10. a pharmaceutical composition is characterized in that said composition is a main active ingredient with the compound in the claim 1, isomer or its salt, is aided with pharmaceutically acceptable carrier and forms.
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| EP2897608A4 (en) * | 2013-04-22 | 2016-04-13 | Innobioscience Llc | Treatment of alzheimer's and cognitive impairment with andrographolides |
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| CN108392478A (en) * | 2017-02-07 | 2018-08-14 | 江西青峰药业有限公司 | Application of the andrographolide class compound in terms of preparing for radioactive damage drug |
| CN111568896A (en) * | 2019-05-14 | 2020-08-25 | 南京工业大学 | Application of 14-substituted andrographolide in preparing antiviral drug |
| CN115487189A (en) * | 2021-10-29 | 2022-12-20 | 南京工业大学 | Application of andrographolide derivative |
| CN115487189B (en) * | 2021-10-29 | 2024-02-23 | 南京工业大学 | Application of andrographolide derivative |
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