CN106632294A - Spiro compound and medicinal use thereof - Google Patents

Spiro compound and medicinal use thereof Download PDF

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Publication number
CN106632294A
CN106632294A CN201611159261.3A CN201611159261A CN106632294A CN 106632294 A CN106632294 A CN 106632294A CN 201611159261 A CN201611159261 A CN 201611159261A CN 106632294 A CN106632294 A CN 106632294A
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compound
alkyl
halogen
acid
cyclopropyl
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李小川
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Ningbo Naxi Pharmaceutical Co Ltd
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Ningbo Naxi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a spiro compound serving as a FXR receptor agonist, whose chemical structure is shown in type I, pharmaceutically acceptable salts of the spiro compound, or the enantiomers, diastereomers, tautomers, racemates, solvates, N-oxide or amino acid conjugates and the pharmaceutical compositions of the spiro compound, and the use in preparing drugs for treatment of diseases mediated by the FXR receptor.

Description

A kind of spiro-compound and its medicinal usage
Technical field
The invention belongs to technical field of organic chemistry, and in particular to a kind of spiro-compound and its medicinal usage.
Background technology
Research in recent years shows, farnesoid X receptor (FXR) activator, with anti-silt courage, the effect of anti-fibrosis.FXR is one Kind of nuclear receptor, is a kind of sensor of cholic acid, the flowing of the synthesis of controllable cholic acid and bile in liver, simultaneously in bile Ambient stable, lipid-metabolism, glycometabolism and inflammation/immune response have effect.
Data shows that 6- α-activation of the ethyl chenodeoxycholic acid (6-ECDCA, OCA) for FXR is goose deoxidation 100 times of cholic acid, clinical research shows, OCA can be used for treating PBC (PBC), portal hypertension (Portal hypertension), nonalcoholic steatohepatitis (NASH), acid diarrhoea (the Bile acid of bile Diarrhea), disease (Drrug relevant with choleresis such as alcoholic hepatitis, primary sclerotic cholangitis (PSC) Discovery Today.Volume 17, Numbers 17/18,2012).
However, has clinically there is obvious side effect in Cholic acids compound OCA：One is itch side effect ratio It is more serious, there is 33 (23%) that itch occurs in 141 patients of OCA groups, and have 9 (6%) to go out in 142 patients of placebo Existing itch (P ＜ 0.0001)；Two is to increase low-density lipoprotein courage, and this may bring some unacceptable side effects.
Therefore, a kind of small molecule FXR activator of non-Cholic acids is developed, may be avoided while drug effect is kept The side effects such as itch, the low-density lipoprotein increase of OCA.
Substantial amounts of document is it has been reported that various FXR small molecule agonists：WO2000037077、WO2008025539、 Bioorg.Med.Chem.Lett.19(2009)2595-2598、Bioorg.Med.Chem.Lett.19(2009)4733- 4739、WO2009012125、WO2011020615、WO2012087519、WO2013007387。
Although these FXR activators have shown that some agonist activities, each there are some and lack in these compounds Point, such as FXR activators GW4064, its bioavilability is low, half-life short；Trans stilbene in its structure is potential poison Property group (toxicology, 1981,22 (2), 149-160；Toxicol Appl.Pharmacol.2000,167 (1), 46- 54)；Ethylene linkage in trans stilbene for ultraviolet photo-labile, so as to there is also potential toxicity problem.Therefore, it is necessary to Some new FXR activators are developed, improves patent medicine property.This kind of volution compound that the present invention is provided, its patent medicine property Typically superior to GW4064, its chemical structural formula is as follows.
The content of the invention
The technical problem to be solved be overcome the shortcomings of existing FXR activators druggability in terms of, there is provided a class The new compound that can improve patent medicine property, is more suitable for treating, suppress or improving the disease of farnesoid X receptor mediation.
To solve above technical problem, the present invention is adopted the following technical scheme that：A kind of compound of formula (I), it is pharmaceutically Acceptable salt, or their enantiomter, diastereoisomer, dynamic isomer, raceme, solvate, N- oxygen Compound or amino acid conjugates：
Wherein,
R1Selected from 5-10 unit's aromatic ring yls or 5-10 units heteroaryl ring group, wherein, each group can be by 1-3 R4Replace；
R2Selected from hydrogen, C1-3 alkyl, halogen C1-3 alkyl or C3-6 cycloalkyl, wherein C3-6 cycloalkyl can by C1-3 alkyl, Halogen C1-3 alkyl replaces；
Z is selected from 5-10 unit's aromatic ring yls or 5-10 units heteroaryl ring group, wherein, each group can be by 1-3 R4Replace；
R3Selected from-CO2R5、-CONR5R6、-CONR5SO2R6、-CONR5(CR7)1-4CO2R5、-SO2R5Or tetrazolium；
R4Selected from halogen, C1-6 alkyl, halogen C1-6 alkyl, C1-6 alkoxyls, halogen C1-6 alkoxyls or C3-6 cycloalkyl；
R5、R6、R7Independently selected from hydrogen, C1-6 alkyl, halogen C1-6 alkyl, C3-6 cycloalkyl or halogen C3-6 cycloalkyl.
According to the present invention, R2Preferably cyclopropyl.
According to the present invention, R1Preferably can be by 1-3 R4Substituted phenyl；Wherein, R4Selected from halogen, C1-6 alkyl, halogen C1-6 alkyl, C1-6 alkoxyls, halogen C1-6 alkoxyls or C3-6 cycloalkyl.
According to the present invention, Z is preferably phenyl, pyridine radicals, pyrazinyl, pyrimidine radicals, furyl, oxazolyl, thienyl, thiazole Base, pyrazoles, benzothienyl, benzofuranyl, benzimidazolyl, narrow azoles [1,2-a] pyridine radicals, pyrroles [1,2-b] pyrazinyl, Indyl, benzothiazolyl, benzisothia oxazolyl, benzoxazolyl, naphthyl, quinolyl, isoquinolyl, wherein, each base Group can be by 1-3 R4Replace；Described R4Selected from halogen, C1-6 alkyl, halogen C1-6 alkyl, C1-6 alkoxyls, halogen C1-6 alkoxyls Or C3-6 cycloalkyl.
According to the present invention, R3Preferably-CO2R5, wherein, R5Selected from hydrogen or C1-6 alkyl, it is highly preferred that R5Solely it is selected from hydrogen.
According to the present invention, typical compound is exemplified below：
3- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H)-position) benzoic acid
4- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H)-position) benzoic acid
6- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H)-position) nicotinic acid
2- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H)-position) benzo [d] thiazole -6- formic acid
5- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H)-position) -1- isopropyl -1H- pyrazoles -3- formic acid
5- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H)-position) -1- naphthoic acids
6- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H)-position) -1- Methyl-1H-indole -2- formic acid
And its pharmaceutically acceptable salt, or they enantiomter, diastereoisomer, dynamic isomer, disappear Rotation body, solvate, N- oxides or amino acid conjugates.
The present invention further provides the glycine of the compound, taurine or acyl group glucuronide conjugate.
The present invention furthermore provides the compound, its pharmaceutically acceptable salt, or they enantiomter, One or more in diastereoisomer, dynamic isomer, raceme and solvate is preparing bile regulation regulation of secretion Application in agent or FXR nuclear receptor activities conditioning agents.
The present invention further provides the compound, its pharmaceutically acceptable salt, or their enantiomter, non- One or more in enantiomter, dynamic isomer, raceme and solvate is preparing prevention and/or is treating cholesterol Property gall stone, PBC, portal hypertension, nonalcoholic steatohepatitis, the acid diarrhoea of bile, Alcoholic Hepatitis, primary sclerotic cholangitis or atherosclerotic, or have the application in the medicine of related disorders with choleresis.
The present invention further provides a kind of pharmaceutical composition, it includes the first therapeutic agent and pharmaceutically acceptable matrix, wherein First therapeutic agent is or its pharmaceutically acceptable salt selected from compound of the present invention, or they enantiomter, The combination of one or more in diastereoisomer, dynamic isomer, raceme and solvate.
Further, described pharmaceutical composition can also include second therapeutic agent, and the second therapeutic agent is selected from treatment The combination of one or more in the medicines such as cholestasis.
The present invention also provides a kind of composition and prevents and/or treat CGS disease, primary biliary Property cirrhosis, portal hypertension, nonalcoholic steatohepatitis, bile acidity diarrhoea, alcoholic hepatitis, primary sclerotic bile duct Scorching or atherosclerotic, or the method for having related disorders with choleresis.
In the present invention, if without explanation in addition, for the present patent application, including the art in specification and claims Language, is defined as follows.It has to be noticed that in the specification and the appended claims, if nothing is clearly dictated otherwise in text, odd number Form " one " includes plural references.If without explanation in addition, using mass spectrum, nuclear-magnetism, HPLC, protein chemistry, biochemistry, weight The conventional method of group DNA technique and pharmacology.
Term " alkyl " refers to straight or branched saturation, containing 1～10 carbon atom (preferably 1～6 carbon atom) Aliphatic hydrocarbon group；C1～Cn alkyl then represents the aliphatic group of the saturation of 1～n carbon atom, including straight chain and branched group (example Such as " C1～C10 alkyl ", refer to that the group is alkyl, and the carbochain amount of carbon atom of alkyl is between 1～10, i.e., containing 1 carbon Atom, 2 carbon atoms or 3 carbon atoms etc., until including the alkyl of 10 carbon atoms.And 1～10 restriction does not include Substituted carbon number on alkyl, such as replaces " alkyl " in alkylamino, when its carbon number is not particularly limited, only refers to The carbon number of the moieties for wherein indicating is 1～10, and does not include the carbon number and ammonia of the substituent on alkyl The carbon number of other substituents on base.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " yuan of rings " includes any circulus.Term " unit " means the quantity for representing the skeletal atom for constituting ring.This Sample, e.g., cyclohexyl, pyridine radicals, pyranose and thiapyran base are hexatomic rings；Cyclopenta, pyrrole radicals, furyl and thienyl are five yuan Ring.
Term " optionally substituted " or " replacement " refer to can be replaced with reference to group by one or more extra groups, extra base Group is individually and independently selected from one or more in following groups：C1～C10 alkyl, C3～C20 cycloalkyl, C5～ C10 aryl, C5～C10 heteroaryls, C2～C20 heterolipid cyclic hydrocarbon, hydroxyl, C1～C5 alkoxyls, alkylthio group, arylthio, alkane sulfoxide Base, fragrant sulfoxide group, alkane sulfuryl, fragrant sulfuryl, cyano group, halogen, carbonyl, thiocarbonyl, nitro, alkylhalide group, fluoroalkyl or amino (bag Include monosubstituted and disubstituted amine groups and its protected derivative), when substituent is multiple, described substituent phase It is same or different.Illustrate, optionally substituted can be halide ,-CN ,-NO2 or LsRs, wherein each Ls independence is selected from A following key：- O- ,-C (=O)-,-C (=O) O- ,-S- ,-S (=O)-,-S (=O) 2- ,-NH- ,-NHC (=O)-,-C (=O) NH-, S (=O) 2NH- ,-NHS (=O) 2 ,-OC (=O) NH- ,-NHC (=O) O- or-(C1～C10 alkyl)；Each Rs Selected from hydrogen, alkyl, fluoroalkyl, miscellaneous alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl.Above substituent can be formed The protection group of protection derivative may be referred to Greene and Wuts.On the one hand, optionally substituted base selected from halogen, trifluoromethyl, Hydroxyl, cyano group, nitro ,-SO3H ,-SO2NH2 ,-SO2Me ,-NH2 ,-COOH ,-CONH2, C1～C5 alkoxyls, the Hes of-N (CH3) 2 C1～C10 alkyl.
In some specific embodiments, the compound has one or more three-dimensional structure centers, and each center with R or S types are individually present.As mentioned herein compound includes all diastereomers, and enantiomer is differed to structure body and their mixture.It is vertical Body isomers can be obtained by such as chiral chromatographic column to the method for Enantiomer separation.
Method described herein and molecular formula include using N- oxide (if appropriate)s, and crystal form is (also referred to as more Crystal formation) or compound of Formula I pharmaceutically acceptable salt, with it is identical activity these compounds active metabolite. In some cases, compound exists possibly as dynamic isomer.All of dynamic isomer includes changing as mentioned herein Within the scope of compound.In certain specific embodiment, the compound is pharmaceutically acceptable with solvate forms presence Solvent such as water or ethanol etc..In other specific embodiments, the compound is with nonsolvated forms presence.
Term " prodrug " refers to the bioconversion derivative of a drug molecule, and it is in vivo through the conversion of enzyme or chemistry Active mother's medicine is discharged, then activity mother medicine plays desired drug effect.Also there are other descriptions, such as J.Rautio with regard to prodrug Deng document (Nat Rev Drug Discov., 2008Mar；7(3)：255-70), it is accordingly by quoting that above-mentioned document is complete Be incorporated to.
As the term is employed herein " salt " refers to the compound of cation and anion, and it can be by being subjected to proton portion The protonation of position and/or it is available for the deprotonation at proton position to produce.It should be noted that the proton at acceptable proton position Change results in cationic species, and its electric charge is balanced by the presence of physiology anion, and be available for proton position go matter Sonization results in anionic species material, and its electric charge is balanced by the presence of physiology cation.
Term " pharmaceutically acceptable salt " refers to that salt is pharmaceutically acceptable.The example of pharmaceutically acceptable salt includes But it is not limited to：(1) acid-addition salts, form with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid；Or and organic acid Formed, such as hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3- (4- hydroxyls Base benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1,2- ethane-disulfonic acid, 2- hydroxyethanesulfonic acids, Benzene sulfonic acid, 4- chlorobenzenesulfonic acids, 2- naphthalene sulfonic acids, 4 p-methyl benzenesulfonic acid, camphoric acid, dodecyl sulphate, gluconic acid, glutamic acid, water Poplar is sour, cis-muconic acid etc.；Or (2) base addition salts, and the conjugate base of any one of above-mentioned inorganic acid formed, wherein Conjugate base is comprising selected from Na+, K+, Mg2+、Ca2+, NHgR " ' cationic componentses in 4-g+, wherein R " ' be C1-3 alkyl, g is Selected from 0,1,2,3 or 4 integer.It should be understood that related to pharmaceutically acceptable salt is all including the sheet of identical acid-addition salts Solvent addition form (solvate) or crystal form (polymorph) defined in text.
Terms " formulation " or " formulation " refer in particular to include the solid of reactive compound and liquid formulations and those skilled in the art Member will be appreciated that active component can exist with different dosage forms, and this depends on required dosage and pharmacokinetic parameter.
Term " acceptable ", as used herein, refers to that a prescription component or active component are good for general treatment target Health does not have undue adverse effect.
Term " experimenter " or " patient " include mammal and nonmammalian.Mammal includes but is not limited to, and feeds Newborn class：People, non-human primates such as orangutan, ape and monkey class；Agricultural animal such as ox, horse, goat, sheep, pig；Domestic animal such as rabbit, dog；It is real Animal is tested including rodent, such as rat, mouse and cavy.Animal includes but is not limited to non-mammalian, bird, fish etc..It is excellent one In selecting example, selected mammal is people.
" nuclear receptor " refers to and one or more genes in nucleus is generally activated or suppressed together with other transcription factors The acceptor of transcription (but also can act on second messenger's signal transduction).Nuclear receptor by acceptor native homologous ligand activation.Core Acceptor is commonly found in cytoplasm or nucleus, rather than film combination.
Farnesoid X receptor (FXR) is a member of nuclear receptor superfamily, and it is mainly expressed among intestinal tract, participates in courage The important step such as juice acid metabolic and cholesterol metabolic.Its part includes primary bile acid chenodeoxycholic acid, secondary in natural environment Level cholic acid lithocholic acid, deoxycholic aicd etc..
" therapeutically effective amount " refers to the chemical combination that effectively treatment disease as herein described or illness are enough to when experimenter is given The amount of thing.According to compound, illness and its severity and will be intended to treat although constituting the amount of the compound of " therapeutically effective amount " The age of experimenter and change, but can in a usual manner be determined by those skilled in the art.
" adjusting (modulating/modulate) " refers to treatment, prevention, suppression, enhancing or inducing function, the patient's condition or disease Disease.
" treat (treating/treatment) " as used herein and cover in treatment experimenter (the preferred mankind) herein Described disease or illness, and including：
I. disease or illness are suppressed, i.e. prevent it from developing；Or
Ii. disease or illness are alleviated, i.e. cause illness to disappear.
" experimenter " refers to or may suffer from the warm-blooded animal of one or more disease as herein described and illness, such as Mammal, the preferred mankind or human child.
" biliary cirrhosis " is referred to because of biliary obstruction, cholestasis and the cirrhosis that causes, point primary biliary liver Hardening (PBC) and secondary biliary cirrhosis.It is generally acknowledged that PBC is a kind of autoimmune disease.
" portal hypertension " refers to that is persistently increased the syndrome for causing by portal venous pressure.Great majority are drawn by cirrhosis Rise, minority is secondary to the not clear other factors of main portal vein or hepatic venous obstruction and reason.When portal vein can not be smooth Passing back into inferior caval vein by liver will cause portal venous pressure to increase.
" non-alcohol fatty liver " refers to a kind of and insulin resistance (insulin resistance, IR) and heredity Susceptible closely related metabolic stress hepar damnification, its pathological change and AML (alcoholic liver Disease, ALD) it is similar, but patient, without excessive drinking history, spectrum of disease includes non-alcoholic simple fatty liver (nonalcoholic simple fatty liver, NAFL), nonalcoholic fatty liver disease (nonalcoholic Steatohepatitis, NASH) and its related liver cirrhosis and hepatocellular carcinoma.
When " the acid diarrhoea of bile " refers to ileal absorption bile acid obstacle, a large amount of bile acids reach the abdomen caused by colon Rush down.
" alcoholic hepatitis " refers to a kind of liver diseases caused by long-term excessive consumption of alcohol.Its main clinical characteristics be nausea, Vomiting, jaundice, liver enlargement and tenderness, can concurrently liver failure and UGB etc..
" primary sclerotic cholangitis " refers to chronic cholestatic disease, it is characterized by extrahepatic duct inflammation and fibre Dimensionization, and then cause multifocal stenosis of bile duct.Most patients finally develop into cirrhosis, portal hypertension and liver function and lose generation Repay.
Term " including ", " ", " such as " etc. mean exemplary and do not limit the scope of the invention.
As used herein, a certain compound or pharmaceutical composition, after administration, obtain can a certain disease, symptom or situation To improvement, espespecially its severity is improved, delayed onset, slows down disease progression, or reduces the state of an illness duration.No matter fix Administration or interim administration, continued administration or interrupted continuous administration, can be attributed to or the situation relevant with administration.
The all features (including any described claim, summary and figure) being described in this manual, and/or appoint Where method or during all steps for being related to, be possible to exist with any one combination, unless some features or step exist Exclude each other in same combination.
On the basis of common sense in the field is met, above-mentioned each optimum condition can be combined, and obtain final product each preferable reality of the present invention Example.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：The FXR receptor agonist activities of the present invention are high, and metabolic stability is more applicable In treating, suppress or improve farnesoid X receptor.
Specific embodiment
Below example is used to be provided on how to implement and use the present invention for those skilled in the art Full disclosure and description, and the invention scope that these examples are not intended to think inventor limits, also non-meaning Refer to that experiment hereafter is all experimentss that are carried out and is only enforceable experiment.The reality of unreceipted actual conditions in experimental example Proved recipe method, generally according to normal condition or according to the condition proposed by manufacturer, chemical reagent used is and analyzes pure in embodiment Reagent, buys from Chinese medicines group.
Embodiment 1. prepares 3- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro rings Penta [c] pyrroles -2 (1H)-position) benzoic acid (01)
Compound 01 is prepared according to following scheme：
Ketone (1.000g, 0.0044mol, 1eq) is dissolved under 10mL methyl alcohol, ice bath and is dividedly in some parts sodium borohydride (0.503g, 0.0133mol, 3eq), finishes and 30min is reacted under ice bath, and TLC shows that raw material conversion is finished, and concentration is dry, instills water It is quenched with watery hydrochloric acid, ethyl acetate is extracted three times, organic layer merges washing, saturated sodium bicarbonate solution is washed, brine It, Off-white powder 0.990g is done to obtain in anhydrous sodium sulfate drying, concentration.
Intermediate 1-3：
1-2 (0.990g, 0.0044mol, 1.5eq) is added into 10mL anhydrous tetrahydro furans, 18- crown-s 6 are added under ice bath (1.305g, 0.0049mol, 1.7eq) and potassium tert-butoxide (550mg, 0.0049mol, 1.7eq), under ice bath 30min is stirred.Will This solution is added dropwise to the 10mL anhydrous THF solutions of compound 1-1 (0.949g, 0.0029mol, 1.0eq), and ice bath is kept for 0 degree, drop Bi Ziran is warmed to room temperature and is stirred overnight.TLC shows that raw material conversion is finished, and adding water is quenched ethyl acetate and extracts to obtain crude product, silicagel column Chromatography (PE/EA=4/1) obtains white solid 0.930g.
Intermediate 1-4：
Intermediate 1 (0.930g, 0.0019mol) is dissolved in 5ml dichloromethane, 5ml trifluoroacetic acids is added under room temperature, Stir 2 hours under room temperature, TLC shows that raw material conversion is finished, and reduced pressure concentration is done, and adds saturated sodium carbonate to be quenched, ethyl acetate extraction Take three times, organic layer merge after respectively with water and brine It one time, concentration is dry after being dried to obtain pale yellow oil 635mg, It is directly used in next step.
Intermediate 1-6：
Intermediate 1-4 (150mg, 0.381mmol) and 5ml acetonitriles are added in vexed tank, addition intermediate 1-5 (200mg, 0.762mmol, 2eq) and triethylamine (77mg, 0.762mmol, 2eq) and copper acetate (76mg, 0.381mmol, 1eq).By system It is heated to 80 degree to be stirred overnight.TLC shows that intermediate 2 is converted completely, adds water and is quenched, and ethyl acetate is extracted three times, organic laminated And, successively with water and brine It one time, concentration is dry after being dried, silica gel column chromatography (PE/EA=10/1,5/1) it is faint yellow Grease 105mg.
Compound 01：
By intermediate：1-6 (105mg, 0.199mmol, 1.0eq), is dissolved in 5ml THF and 5ml MeOH, adds hydrogen-oxygen Change potassium (0.034mg, 0.597mmol, 3.0eq), and 1ml water, be heated to 90 degree and stir 4 hours, TLC shows that raw material has been converted Finish.Concentration goes methyl alcohol and THF, residue to be dissolved in water, and water layer adjusts PH=2, EA extractions after being washed twice with MTBE with 1N hydrochloric acid Take (20ml*2), brown solid 48mg is done to obtain in concentration after being dried.
1H NMR (400MHz, CD3Cl)δ：7.44-7.42 (m, 1H), 7.39-7.20 (m, 5H), 6.78 (d, J=7.2, 1H), 4.21 (s, 2H), 3.91-3.88 (m, 1H), 3.44-3.40 (m, 2H), 3.14-3.11 (m, 2H), 2.66-2.60 (m, 2H), 2.10-2.03 (m, 3H), 1.40-1.20 (m, 4H), 1.08-1.05 (m, 2H) .ESI-MS m/z：511.3(M-H)-。
The preparation of intermediate 1-1：
Intermediate 1-8：
At 0 DEG C, the sodium hydroxide solution (21ml, 0.063mol, 1.1eq) of 3mol/L is instilled the 3.3ml water for suspending Hydroxylamine hydrochloride (4.37g, 0.063mol, 1.1eq) solution in.Again the mixed solution is instilled into 50ml ethanol and 2,6- dichloro-benzenes In the mixed solution of formaldehyde (10g, 0.057mol, 1.0eq), drop finishes, and is heated to 90 DEG C overnight.Reaction is finished, reactant liquor concentration It is dry, the solution that dry solid adds 29.3ml (H2O: EtOH=10: 1) is concentrated, filter after beating crystallization, filter cake is drained, with 45 DEG C vacuum drying, obtain intermediate 1-8, white solid 10.48g, yield 96.5%.
Intermediate 1-9
During 2,6- dichloro-benzenes first azanol (10.48g, 0.055mol, 1.0eq) is dissolved in into 63mlDMF, N- chloros are dividedly in some parts Succimide (7.36g, 0.28mol, 1.0eq).Finish, at 40 DEG C 1h is stirred.Reactant liquor reaction is finished, and is cooled to room temperature, In 0 DEG C of frozen water for pouring 200ml into, extracted once with the methyl tertiary butyl ether(MTBE) of 200ml, water layer is abandoned.Organic layer salt is washed, nothing Aqueous sodium persulfate is dried, and form is evaporated at 30 DEG C into solid oil, and with 6ml n-hexanes crystallization is smashed to pieces, forms solid and filters, and filter cake is true Empty dry intermediate 8-1-2, yellow solid 12.10g, yield is 97.7%.
Intermediate 1-10
By triethylamine (10.91g, 0.11mol, 2.0eq) be added to 3- cyclopropyl -3- propionic acid methyl esters (7.66g, 0.054mol, 1.0eq) mixture in, be stirred at room temperature 30min, then be as cold as 10 DEG C.By intermediate 1-9 (12.10g, 0.054mol, 1.0eq) dissolved with 24.2mL ethanol, in being slow added into above-mentioned reactant liquor, interior temperature does not surpass 24 DEG C.Additionally, this is anti- Should be stirred at room temperature overnight.
After having reacted, reactant liquor is diluted with 45mlEA, is washed with 15ml, and point liquid, aqueous layer with ethyl acetate is extracted once, is closed And organic layer, use salt water washing, anhydrous sodium sulfate drying to filter, filtrate is concentrated to the 10% of total amount, forms precipitation, uses ether Smash beating to pieces, filter, filter cake vacuum draws dry, obtains intermediate 1-10, and white solid 8.48g, yield is 54%.
Intermediate 1-11：
The toluene solution of the diisobutyl aluminium hydride (38ml, 0.057mol, 2.1eq) of 1.5mol/L is added dropwise to into intermediate In the solution of the mixed dissolution of 1-10 (8.48g, 0.027mol, 1.0eq) and 54mlTHF, temperature control is at 0 DEG C or so.Finish, room temperature Stirring 2h.
Reaction finishes the methyl alcohol for adding 1.8g, stirs 10min, then is added dropwise to 27ml water and 54mlEA.The precipitation of formation is led to Diatomite filtration is crossed, mother liquor vacuum is drawn dry.Solid adds n-hexane to smash to pieces, filters, dry intermediate 1-11 under filter cake vacuum, White solid 8.46g.
Intermediate 1-1：
The intermediate 1-11 (8.46g, 0.030mol, 1.0eq) of 8.46g and 60mlDCM is dissolved, triphenylphosphine is added (11.71g, 0.045mol, 1.5eq), mixed liquor is cooled to 0-10 DEG C, be dividedly in some parts carbon tetrabromide (14.82g, 0.045mol, 1.5eq).Reactant liquor is stirred at room temperature 2h.Reaction is finished, and reactant liquor mixes sample, column chromatography purifying PE: EA=10: 1, in obtaining Mesosome 1-1, white crystal 7.35g, yield is 71.2%.
Embodiment 2.
Prepared by the step of compound 2～7 is described with reference to embodiment 1, only reaction raw materials are replaced accordingly, to obtain Target compound.Compound number, compound structure and HNMR/MS details are listed in table 1：
The compound number of table 1, compound structure and HNMR/MS results
Farnesoid X receptor (FXR) activation experiment of embodiment 3
The Activation Activity of the compounds of this invention is tested using FXR reporter genes, method is as follows：
I. cell culture
A. trypsinized, with appropriate density inoculating cell in the complete matrix of 10ml.
B. cultured cells 24 hours under the conditions of 37 DEG C, 5%CO2.
II. cell inoculation and transfection
With FuGENE HD as transfection reagent.
A. transfection mixture is prepared according to following table.
pBIND-FXR(ng/well) 25
pG5Luc(ng/well) 25
FuGENE HD(ul/well) 0.15
No FBS media(ul/well) 1.85
Total mix(ul/well) 2.5
B. acutely pat pipe to mix, be incubated 15 minutes under room temperature.
C. trypsinized, determines cell density.
D. with 600,000 cells/ml density diluting cells liquid to volume required.
E. volume required transfection mixture (previously prepared into two parts of cell liquid) is added, the cell liquid in 100ul/ holes is hanged Float on breadboard.
F. it is incubated breadboard 24 hours under the conditions of 37 DEG C, 5%CO2.
III. compound is processed
A. prepare compound liquid storage is used for FXR to 10mM working concentrations, is then diluted successively with 3 times with 100%DMSO.
B. addition 10ul compounds are in the complete matrix of 90ul.
C. addition 5ul compound solutions are in each hole.
D. it is incubated breadboard 18 hours under the conditions of 37 DEG C, 5%CO2.
IV. luciferase reporter gene method
Firefly and ocean coelenteron luciferase signal by the luciferase reporter gene detecting system of Promega come Analysis.EnVision multiple labeling micropores board detector is used as Chemiluminescence Apparatus.
V. result is calculated
A. the standardization of numerical value is realized by the way that firefly fluorescence signal is divided into into renilla signals." F/R " means “Firefly/Renilla”.Standardization eliminates the difference of different cell quantities and transfection efficiency in each hole.
B. % activation numbers (%Activation value) are calculated
% activation numbers are calculated by following equation,
X is each concentration point " F/R " value.Min is without medicine control group " F/R " mean value.Max is with reference to control group " F/R " mean value.
C. EC50 is calculated with GraphPrism 5.0.
VI. result is as shown in table 2.
The experimental result of table 2
Compound EC50, (nM) Compound EC50, (nM)
01 1983 05 890
02 988 06 563
03 5000 07 479
04 321 GW4064 308
Conclusion, the compounds of this invention shows good FXR receptor activation activities, or even has some compound Activation Activities It is suitable with positive reference compound GW4064.
The medicine of the compound of embodiment 4 is for property
The medicine of compound of formula I can be proved for property by the test of hepatomicrosome metabolic stability：
1st, buffer：Buffer A：1.0L 0.1M potassium phosphate buffers (EDTA containing 1.0mM)；Buffer B： 1.0L 0.1M dipotassium hydrogen phosphate buffer solutions (EDTA containing 1.0mM)；Buffer solution C：0.1M kaliumphosphate buffers (contain 1.0mM EDTA), pH 7.4, buffer A is added in 700mL buffer Bs, is stopped when pH reaches 7.4.
2nd, compound administration solution：500 μM of solution：10 μ L 10mM DMSO storing liquids are added in 190 μ L ACN； 1.5 μM of administrations solution (being dissolved in hepatomicrosome, hepatomicrosome final concentration 0.75mg/mL)：By 1.5 μ L, 500 μM of solution and 18.75 μ L 20mg/mL hepatomicrosomes are added in 479.75uL buffer solution C.
3rd, NADPH solution (6mM, in being dissolved in buffer solution C).
The 4th, 1.5 μM of administration solution of 30L are added in 96 orifice plates the position for being set to different time points.37 DEG C of preheatings 10 Minute.
5th, 15L NADPH solution (6mM) is added to and is set to the position of 45 minutes points, and start timing.
6th, at 30 minutes, 15 minutes, 5 minutes, 15LNADPH solution (6mM) is added to into the position of corresponding time point.
7th, at the end of cultivating (0 minute), 135L ACN (containing the internal standard) are added to and are set in the position of all time points. 15L NADPH solution (6mM) is then added to the position for being set to 0 minute.
8th, it is centrifuged：3220 g are centrifuged 10 minutes.
9th, 50 μ L of supernatant liquid are taken out, is mixed with 50 μ L ultra-pure waters (Millipore), sample presentation to LC/MS is analyzed.
The experimental result of compound is listed in table 3 in embodiment.
The compound experimental result of table 3
Compound t1/2(minute)
01 55
03 73
04 105
GW4064 30
As a result show, the invention provides the novel ratio positive reference compound GW4064 metabolism of a class formation is more stable Compound.
It should be understood that after the above for having read the present invention, those skilled in the art can make various to the present invention Change or change, these equivalent form of values equally fall within the application appended claims limited range.

Claims (12)

1. a kind of compound of formula (I), its pharmaceutically acceptable salt, or they enantiomter, diastereoisomer, Dynamic isomer, raceme, solvate, N- oxides or amino acid conjugates：
Wherein,
R1Selected from 5-10 unit's aromatic ring yls or 5-10 units heteroaryl ring group, wherein, each group can be by 1-3 R4Replace；
R2Selected from hydrogen, C1-3 alkyl, halogen C1-3 alkyl or C3-6 cycloalkyl, wherein C3-6 cycloalkyl can be by C1-3 alkyl, halogen C1-3 Alkyl replaces；
Z is selected from 5-10 unit's aromatic ring yls or 5-10 units heteroaryl ring group, wherein, each group can be by 1-3 R4Replace；
R3Selected from-CO2R5、-CONR5R6、-CONR5SO2R6、-CONR5(CR7)1-4CO2R5、-SO2R5Or tetrazolium；
R4Selected from halogen, C1-6 alkyl, halogen C1-6 alkyl, C1-6 alkoxyls, halogen C1-6 alkoxyls or C3-6 cycloalkyl；
R5、R6、R7Independently selected from hydrogen, C1-6 alkyl, halogen C1-6 alkyl, C3-6 cycloalkyl or halogen C3-6 cycloalkyl.
2. compound as claimed in claim 1, it is characterised in that R2Selected from cyclopropyl.
3. the compound as described in claim 1-2, it is characterised in that R1Selected from can be by 1-3 R4Substituted phenyl；Wherein, R4 Selected from halogen, C1-6 alkyl, halogen C1-6 alkyl, C1-6 alkoxyls, halogen C1-6 alkoxyls or C3-6 cycloalkyl.
4. the compound as described in claim 1-3, it is characterised in that Z is selected from phenyl, pyridine radicals, pyrazinyl, pyrimidine radicals, furan Mutter base, oxazolyl, thienyl, thiazolyl, pyrazoles, benzothienyl, benzofuranyl, benzimidazolyl, imidazoles [1,2-a] pyrrole Piperidinyl, pyrroles [1,2-b] pyrazinyl, indyl, benzothiazolyl, benzisothia oxazolyl, benzoxazolyl, naphthyl, quinolyl, Isoquinolyl, wherein, each group can be by 1-3 R4Replace；Described R4Selected from halogen, C1-6 alkyl, halogen C1-6 alkyl, C1-6 alkoxyls, halogen C1-6 alkoxyls or C3-6 cycloalkyl.
5. the compound that such as claim 1-4 is stated, it is characterised in that R3Selected from-CO2R5, wherein, R5Selected from hydrogen or C1-6 alkyl.
6. the compound as described in claim 1-5, it is characterised in that the compound is selected from：
3- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H) - Position) benzoic acid
4- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H) - Position) benzoic acid
6- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H) - Position) nicotinic acid
2- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H) - Position) benzo [d] thiazole -6- formic acid
5- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H) - Position) -1- isopropyl -1H- pyrazoles -3- formic acid
5- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H) - Position) -1- naphthoic acids
6- (5- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- positions) methoxyl group) hexahydro ring penta [c] pyrroles -2 (1H) - Position) -1- Methyl-1H-indole -2- formic acid
And its pharmaceutically acceptable salt, or they enantiomter, diastereoisomer, dynamic isomer, raceme, Solvate, N- oxides or amino acid conjugates.
7. the compound as described in claim 1-6, it is characterised in that the compound is its glycine, taurine or acyl group Glucuronide conjugate.
8. a kind of compound, its pharmaceutically acceptable salt as described in any one of claim 1～7, or their mapping One or more in isomers, diastereoisomer, dynamic isomer, raceme and solvate is preparing bile regulation point Secrete conditioning agent or the application in FXR nuclear receptor activities conditioning agents.
9. a kind of compound, its pharmaceutically acceptable salt as described in any one of claim 1～7, or their mapping One or more in isomers, diastereoisomer, dynamic isomer, raceme and solvate prepare prevention and/or Treatment CGS disease, PBC, portal hypertension, nonalcoholic steatohepatitis, bile are acid Diarrhoea, alcoholic hepatitis, primary sclerotic cholangitis or atherosclerotic, or have the medicine of related disorders with choleresis In application.
10. a kind of pharmaceutical composition, it is characterised in that the chemical combination as described in any one of claim 1～7 comprising effective dose Thing, or its pharmaceutically acceptable salt, or they enantiomter, diastereoisomer, dynamic isomer, raceme and One or more in solvate, and the pharmaceutical composition of at least one pharmaceutically acceptable carrier or excipient.
A kind of 11. pharmaceutical compositions as claimed in claim 10, it is characterised in that：Described pharmaceutical composition can also include the Two therapeutic agents, the second therapeutic agent is the combination of one or more in the medicines such as treatment cholestasis.
A kind of 12. pharmaceutical compositions as described in claim 10-11, it is characterised in that：Described pharmaceutical composition is pre- to prepare Anti- and/or treatment CGS disease, PBC, portal hypertension, nonalcoholic steatohepatitis, courage Juice acidity diarrhoea, alcoholic hepatitis, primary sclerotic cholangitis or atherosclerotic, or have related disorders with choleresis Medicine.
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