CN106478453B - Oxime derivatives and its application as FXR antagonists - Google Patents
Oxime derivatives and its application as FXR antagonists Download PDFInfo
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Abstract
A kind of application the present invention relates to oxime derivatives and its as FXR antagonists specifically provides compound or its pharmaceutically acceptable salt and preparation method thereof as shown in formula (I),Wherein：Dotted line Cy indicates uncondensed phenyl ring or fused benzene rings；R1、R2Independently selected from hydrogen, the alkoxy of halogen, phenyl, benzyl, benzyloxy, the alkyl of C1 C3 or C1 C3；R3Selected from hydrogen, methyl；X is selected from O, S.In addition, compound or its pharmaceutically acceptable salt shown in formula (I) have the pharmacological action of reducing blood lipid, it is a kind of FXR antagonists.
Description
Technical field
The invention belongs to new drug design and synthesis fields, and in particular, to a kind of oxime derivatives, preparation method and will
Its application as FXR antagonists.
Background technology
Cardiovascular and cerebrovascular disease is one of the illness for currently endangering human life and healthy most serious, is the common of the middle-aged and the old
Disease and frequently-occurring disease, are the first places of morbidity and mortality in many countries.Atherosclerosis is many cardiovascular and cerebrovascular diseases
Basis, a large amount of experiment and clinical data prove that atherosclerosis and the exception of blood lipid metabolism are closely related.Therefore, blood fat tune
Section becomes the key areas of such current new drug research.
By it is perspective, immediately with the clinical research of control, it has proved that some statins can reduce artery congee
Sample hardens and the generation of coronary heart disease, reduces the death rate caused by coronary heart disease, reduces the incidence of myocardial infarction.Further grind
Study carefully the content for also confirming that the treatment of fat-reducing medicament can reduce atherosclerotic plaque inner lipid, reinforce ferry grease and stablize patch,
Reduce plaque rupture and myocardial infarction and cerebral infarction for causing etc. matters of aggravation.In addition, lipid regulating agent can also restore impaired blood
The function of endothelial cell is reinforced fibrinolytic and prevents thrombosis, and delays the progress of the atherosclerosis of people and disappear
Move back established patch.Therefore, it is the hair for mitigating atherosclerosis and reducing coronary heart disease actively to be treated using lipid lowering agent
Raw important measures.
The clinical at present and common types of drugs for adjusting blood fat is more, such as Statins, fibrate, ion exchange
Resin or cholic acid chelating agent, niacin class and other Adjust-blood lipid class drugs.Wherein statins are particularly noticeable.Statins
Drug is the inhibitor of cholesterol synthase.3-hydroxy-3-methylglutaric acid list acyl coenzyme A is (referred to as：HMG-CoA) in HMG-
It is changed into methoxy dragon acid under the action of CoA reductases, statins are that the opening acid moieties of chemical constitution are similar to HMG-CoA,
Its contestable inhibits the formation of methoxy dragon acid, to reduce the synthesis of cholesterol, thus can reduce Blood Cholesterol
(referred to as with low-density lipoprotein：LDL-C) horizontal.Clinical research proves, even if patients with coronary heart disease cholesterol in serum and low close
Spend lipoprotein level it is not bery high or normal, statins can with the generation of prevention of arterial atherosclerotic plaque, develop and subtract
The bad clinical event of few coronary heart disease.However, take for a long time other than statins have the gastrointestinal symptoms such as epigastric discomfort,
The side reactions such as considerable part patient also will produce hepatic disorder, and transaminase increases, myalgia, and creatine kinase increases.
Farnesoid X receptor is (referred to as：FXR) be ligand activation transcription factor, adjust the expression of target gene；Research finds courage
Juice acid is its native ligand, participates in the metabolism of bile acid, therefore also referred to as Farnesoid X receptor, and chenodesoxycholic acid is (referred to as：
CDCA) it is its most suitable native ligand.GW4064 is the FXR ligands of first man work synthesis.FXR is except bile in participation body
The metabolism of acid, also plays lipid metaboli and glycometabolism etc. important adjustment effect.Cholesterol metabolic mainly has two at bile acid
Access:1. classical access is by -7 α of cholesterol-hydroxylase (abbreviation：CYP7A1 it) is catalyzed, and by the negative-feedback tune of bile acid
Section；2. alternative path is by -27 α of cholesterol-hydroxylase (abbreviation：CYP27A1 it) is catalyzed, accounts for the synthesis of human body total bile acid
18%, and as the supplement of classical access.Classical metabolic pathway process is the oxidation product and liver X receptor (abbreviation of cholesterol：
LXR it) combines and induces itself and retinoic acid receptor X (abbreviation：RXR dimer) is formed, is attached on the reaction original paper of the LXR of DNA,
Swash the expression of CYP7A1, then CYP7A1 is catalyzed cholesterol and generates bile acid, and bile acid is combined with FXR and induces itself and RXR shapes
At dimer, be attached on the FXR reaction original papers of DNA, activate the expression of small heterodimer ligand (SHP), and SHP and liver by
Body analog -1 (LRH-1) combines the expression for inhibiting CYP7A1, to maintain the metabolic balance of cholesterol.FXR is to triglycerides
The regulatory mechanism of metabolism is embodied in the synthesis for inhibiting triglycerides：FXR lowers Sterol regulatory element binding protein 1c through SHP approach
(referred to as：SREBP-1c), and SREBP-1c is the central transcription factor for participating in Fatty synthesis gene, a variety of participation can be activated fatty
The transcription of acid and the enzyme of triglycerides synthesis, including fatty acid synthetase is (referred to as：FAS), acetyl-CoA carboxylase (abbreviation：
ACC) etc..It is nearest the study found that FXR can be with the differentiation of inducing adipocyte, to promote TG in the storage of adipocyte.
It play the role of document report FXR antagonists to reduce triglycerides (TG) being realized by way of lowering SREBP-1c.
Currently, the FXR antagonists of report are largely steroid compound, including Z-guggulsterone (abbreviation GS),
CDRI/80-574, sulfated sterol and scalarane sesterterpene etc..So far, nonsteroidal FXR is short of money
Anti-agent includes AGN34, substituted isoxazole derivatives.Wherein natural products GS is an efficient antagonist of FXR, it can subtract
When young the level of low-density lipoprotein (LDL) and triglycerides (TG) but the blood plasma of high cholesterol patient can not be improved in mouse body
Lipid density.FXR relies on its unique adjusting blood fat mechanism as the novel targets for adjusting the appearance of blood fat field in recent years, attracts
The sight of numerous researchers.Therefore, it is developed to the effective drug of combined hyperlipidemia familial with very careless for FXR
Justice.
The amides compound of early period, preparation method and application (102838505 A of patent CN) and ester type compound,
A large amount of compounds have been invented in preparation method and application (102093246 A of patent CN) two patents and confirm drop in vivo
Blood fat, wherein drug candidate-compound SIPI-7623 (i.e. compounds of patent CN 102838505A specifications page 4
5) preferable effect for reducing blood fat is shown, the invention in this patent has invented a kind of oxime derivatives, emphasis based on early period
Carry out the research of external FXR antagonistic activities, it was demonstrated that there is FXR antagonisms, and rat experiment in vivo confirms there is reducing blood lipid
Effect, and it is better than control compounds SIPI-7623.
Invention content
To open up the resource of clinical medicine, the present invention has synthesized its a series of analog using SIPI-7623 as primer,
By carrying out oximation reaction with corresponding hydroxylamine hydrochloride and its derivative, to provide a kind of oximes FXR antagonists, for dropping
The exploitation of hypolipidemic medicine.
The first aspect of the present invention there is provided compound or its pharmaceutically acceptable salt as shown in formula (I),
Wherein：Dotted line Cy indicates uncondensed phenyl ring or fused benzene rings；
R1、R2Independently selected from hydrogen, the alkoxy of halogen, phenyl, benzyl, benzyloxy, the alkyl of C1-C3 or C1-C3；
R3Selected from hydrogen, methyl；X is selected from O, S.
A kind of preferred embodiment, compound shown in above-mentioned formula (I), R1、R2Independently selected from hydrogen, halogen, phenyl,
Benzyl or benzyloxy.
It is highly preferred that R1、R2Independently selected from halogen, benzyl.
A kind of preferred embodiment, compound shown in above-mentioned formula (I), the halogen are selected from fluorine, chlorine, bromine or iodine.
A kind of preferred embodiment, compound shown in above-mentioned formula (I), dotted line Cy are uncondensed phenyl ring, and structural formula is such as
Formula (I-A),
A kind of preferred embodiment, compound shown in above-mentioned formula (I), dotted line Cy are fused benzene rings, structural formula such as formula
(I-B),
In the first aspect of the present invention, the compound more preferably invented is：
Include phenolic hydroxyl group in the structure of compound shown in above-mentioned formula (I), this phenolic hydroxyl group has faintly acid, can be with
Alkali forming salt appropriate；The alkali appropriate is selected from the hydroxide of alkali or alkaline earth metal；Hydrogen can be preferably selected from
Sodium oxide molybdena, potassium hydroxide or calcium hydroxide etc..Compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) can be easily separated,
Conventional separation methods purification can be used；Such as compound shown in formula (I) can be purified through column chromatography, compound and alkali shown in formula (I)
Salt is through recrystallization purifying formed by property compound.
In second aspect of the present invention, the present invention provides the preparation methods of the compound as shown in above formula (I), including following step
Suddenly：Step a), compound shown in formula (II) and compound shown in formula (III) are reacted into obtain chemical combination shown in formula (IV) in the presence of a base
Object；Step b), finally by compound and R shown in formula (IV)3-NH2HCl reacts to obtain formula under weak basic condition and certain temperature
(I) compound shown in.Reaction equation is shown in following route 1：
Route 1
In the reaction equation of above-mentioned route 1, the dotted line Cy, R1, R2And R3Compound shown in (I) as described above for formula
What is defined is consistent.
In above-mentioned route 1, the alkali described in step a) is selected from sodium carbonate, potassium carbonate, triethylamine, N, N- diisopropyl second
Amine；It is preferred that Anhydrous potassium carbonate.In a kind of preferred mode of operation, step a) selects anhydrous K2CO3As alkali, tetrahydrofuran is made
To be reacted under solvent.
In above-mentioned route 1, weak base used in step b) be triethylamine, n,N-diisopropylethylamine, Anhydrous potassium carbonate, pyridine,
N-methylmorpholine, sodium acetate etc., preferentially select anhydrous sodium acetate.
The synthesis of compound shown in formula (II) can be prepared with pass course 2：Phenolic compounds is in alkali shown in step c), formula (V)
Property under the conditions of and formula (VI) shown in after chloride reaction compound shown in formula (VII)；Step d), by chemical combination shown in formula (VII)
Object hydrolyzed under basic conditions and carboxylic acid compound shown in formula (II-A)；Step e), compound shown in formula (II-A) is passed through H2S
Mercaptan carboxylic acid's compound shown in formula (II-B) is made afterwards；
Route 2
In above-mentioned route 2, the reaction condition of each step is preferably step c) anhydrous Ks2CO3、DMF、80℃；Step d)
.NaOH, alcohols solvent, 80 DEG C；Step e) .H2S、DMF、CDI。
In above-mentioned route 2, alcohols solvent described in the step d) is methanol, ethyl alcohol, isopropanol, n-butanol, isobutanol
Deng preferentially selecting methanol.
In the third aspect of the present invention, the present invention provides Antilipidemic pharmaceutical compositions, described in first aspect
Formula (I) described in compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
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..
In the fourth aspect of the present invention, the present invention provides the compound as shown in formula (I) or its is pharmaceutically acceptable
The application of salt or its pharmaceutical composition as FXR antagonists.
In addition, the present invention provides compound or its pharmaceutically acceptable salts or its pharmaceutical composition as shown in formula (I)
Application of the object in adjusting blood fat.
The present invention as content in pharmaceutical composition of formula (I) compound represented and its pharmaceutically acceptable salt without
It is specifically limited, it can be selected in a wide range, generally can be mass percent 1-70%, preferably mass percent
1-30%.
In the present invention, the medication of the pharmaceutical composition is not particularly limited.Can according to patient age, gender and
Other conditions and symptom select the preparation of various dosage forms to be administered.For example, tablet, pill, solution, suspension, lotion, granule
It is oral medication with capsule；Injection can be administered alone, or (such as glucose solution and amino acid are molten with injection conveying liquid
Liquid) it is mixed into row vein injection, muscle can be carried out with injection, inject in intradermal, subcutaneous or abdomen merely if necessary；Suppository is
It is administered into rectum.
In the present invention, use can be properly selected according to method of administration, patient age, gender and other conditions and symptom
Pharmaceutical quantities.Common dosage can be：About 0.1~300mg active constituents of medicine/kg body weight/days.In general, it each gives
Medicine unit dosage forms can contain the active constituents of medicine of 1~200mg.
Below will by specific embodiment, the present invention is further explained, but the protection domain being not intended to restrict the invention.
Without departing from the inventive concept of the premise, those skilled in the art to preparation method and can use instrument within the scope of the claims
Device makes improvements, these improvement also should be regarded as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended
Subject to claim.
Description of the drawings
Fig. 1-4 displays are the experimental results of the reducing blood lipid pharmacodynamic study of the compound of the present invention 1.Experiment has been selected normal
Rat selects High fat diet rats model as a contrast as blank control；Positive drug chooses lipid-lowering medicine-Simvastatin
It is SIPI- that the candidate fat-reducing medicament-found in (Simvastatin, abbreviation Sim) and this seminar early-stage study, which is numbered,
The compound of 7623 (compounds 5 in 102838505 A of patent CN), determines reducing blood lipid of the compound 1 for High fat diet rats
Drug effect.Fig. 1, Fig. 2, Fig. 3 and Fig. 4 are respectively illustrated using in 7080 determination experiment rat blood serum of Hitachi's automatic biochemistry analyzer
Cholesterol is (referred to as：TC), triglycerides (abbreviation：TG), high-density lipoprotein (abbreviation HDL-C) and low-density lipoprotein (abbreviation
LDL-C test result).
Specific implementation mode
Embodiment 1：It is prepared by-2,2-dimethyl valeric acids of intermediate 5- (2,5- dichlorophenoxies)
By 2,5- chlorophenesic acids (1.63g, 10mmol), anhydrous K2CO3(1.66g, 12mmol), which is added, contains anhydrous DMF
In the 100ml round-bottomed flasks of (25mL), after stirring at normal temperature 0.5h, then by chloro- 2, the 2- dimethyl-pentens acetoacetic esters of 5- (2.32g,
It 12mmol) is added in mixed liquor with tetrabutylammonium iodide (37mg, 0.1mmol), is stirred overnight at 90 DEG C.Toward anti-after cooling
It answers liquid that water (150mL) is added, is extracted with DCM (40mL × 3), merge organic phase, screw out DCM.Ethyl alcohol will be added in concentrate
(40mL) and NaOH (0.8g, 20mmol) are in 80 DEG C of reflux 2h, then screw out ethyl alcohol, water (150mL) are added, with DCM (40mL × 3)
Extraction merges organic phase, screws out DCM ,-2,2-dimethyl valeric acids of intermediate 5- (4- ethyls phenoxy group) are obtained through column chromatography
(2.0g), yield 76.1%.MS(ESI):M/z=315.0 [M+Na]+；1H NMR(400MHz,CDCl3)δ7.28–7.25(m,
1H), 6.86 (dd, J=7.0,2.2Hz, 2H), 3.99 (t, J=6.2Hz, 2H), 1.92-1.70 (m, 4H), 1.26 (s, 6H)
Intermediate 5- (2,5- difluoros phenoxy group)-2,2-dimethyl valeric acids, 5- (2- phenylphenoxies)-2,2-are prepared with method
Dimethyl valeric acid ,-2,2-dimethyl valeric acids of 5- (3- phenylphenoxies) ,-2,2-dimethyl valeric acids of 5- (2- benzyloxyphenoxies),
5- (2- naphthoxys) -2,2- dimethyl valeric acids.
Embodiment 2：It is prepared by-2,2-dimethyl-penten-S- acid of intermediate 5- (2,5- dichlorophenoxies)
CDI (10.0mmol) and-2,2-dimethyl valeric acids (10.0mmol) of 5- (2,5- dichlorophenoxies) are dissolved in DMF
In (20mL), H is passed through after 1h is stirred at room temperature2S reacts 3h.Water (100mL) and ethyl acetate (30mL × 3) extraction is added, through column
Chromatograph to obtain-2,2-dimethyl-penten-S- acid of intermediate 5- (2,5- dichlorophenoxy), 2.41g, MS (ESI):M/z=308 [M+H
]+.
- 2,2-dimethyl-penten-S- acid of intermediate 5- (2- phenylphenoxies), 5- (2- naphthoxys)-2,2- two are prepared with method
The amyl- S- acid of methyl.
Embodiment 3：Intermediate 2- (3,5- dihydroxy phenyls) -2 oxoethyl -5- (2,5- dichlorophenoxies) 2,2- bis-
It is prepared by methylvaleric acid
By 5- (2,5- dichlorophenoxies) -2,2- dimethyl valeric acid (2.91g, 10.0mmol) and K2CO3(1.37g,
It 10.0mmol) is added on after 0.5h is stirred at room temperature in tetrahydrofuran (30mL), alpha-brominated -3,5- dihydroxy benzenes is added dropwise into stirring liquid
The tetrahydrofuran solution (10mL) of ethyl ketone (2.31g, 10.0mmol) continues to stir 12h.Solvent is screwed out, dilute hydrochloric acid acidification is added
Ethyl acetate (25mL × 3) extracts, and organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate detaches through silica gel column chromatography after suction filtration
Purifying, obtains intermediate 3.59g, ESI-MS m/z:442[M+H]+.
Intermediate 2- (3,5- dihydroxy phenyls) -2 oxoethyl -5- (2,5- difluoros phenoxy group) 2,2- bis- is prepared with method
Methylvaleric acid, -2 oxoethyl -5- (2- phenylphenoxies) 2,2- dimethyl valeric acids of 2- (3,5- dihydroxy phenyls), 2- (3,5-
Dihydroxy phenyl) -2 oxoethyl -5- (3- phenylphenoxies) 2,2- dimethyl valeric acid, 2- (3,5- dihydroxy phenyls) -2 oxygen
For ethyl -5- (2- benzyloxyphenoxies) 2,2- dimethyl valeric acid, 2- (3,5- dihydroxy phenyls) -2- oxoethyl -5- (2-
Naphthoxy) -2,2- dimethyl valeric acids.
Embodiment 4：Intermediate S- (2- (3,5- dihydroxy phenyls) -2- oxoethyls) -5- (2,5- dichlorophenoxies) -2,
The preparation of 2- dimethyl thio valeric acids
By 5- (2,5- dichlorophenoxies) -2,2- dimethyl-pentens-S- sour (3.07g, 10.0mmol) and K2CO3(1.37g,
It 10.0mmol) is added on after 0.5h is stirred at room temperature in tetrahydrofuran (30mL), alpha-brominated -3,5- dihydroxy benzenes is added dropwise into stirring liquid
The tetrahydrofuran solution (10mL) of ethyl ketone (2.31g, 10.0mmol) continues to stir 12h.Solvent is screwed out, dilute hydrochloric acid acidification is added
Ethyl acetate (25mL × 3) extracts, and organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate detaches through silica gel column chromatography after suction filtration
Purifying, obtains intermediate 3.46g, ESI-MS m/z:458[M+H]+.
Intermediate S- (2- (3,5- dihydroxy phenyls) -2- oxoethyls) 5- (2- phenylphenoxies) -2,2- is prepared with method
Dimethyl thio valeric acid, S-2- (3,5- dihydroxy phenyls) -2- oxoethyls -5- (2- naphthoxys) -2,2- dimethyl thio penta
Acid.
Embodiment 5：The preparation of compound 1
By 2- (3,5- dihydroxy phenyls) -2 oxoethyl -5- (2,5- difluoros phenoxy group) -2,2- dimethyl valeric acids
(0.408g, 1.0mmol) is dissolved in methanol (15mL), and lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and anhydrous is stirred at room temperature
Sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, it is organic
It is mutually washed with water, anhydrous sodium sulfate drying, filtrate obtains target compound 0.28g, yield through silica gel column chromatography separating purification after suction filtration
66.2%.ESI-MS m/z:422[M-H]+.1H NMR(400MHz,DMSO)δ11.57(s,1H),9.32(s,2H),7.23
(ddd, J=11.1,9.0,5.4Hz, 1H), 7.02 (ddd, J=10.2,6.9,3.0Hz, 1H), 6.74 (td, J=8.4,
3.9Hz, 1H), 6.40 (d, J=2.2Hz, 2H), 6.21 (t, J=2.2Hz, 1H), 5.11 (s, 2H), 3.90 (t, J=7.3Hz,
2H),1.53–1.48(m,4H),1.03(s,6H).
Embodiment 6：The preparation of compound 2
By 2- (3,5- dihydroxy phenyls) -2 oxoethyl -5- (2,5- difluoros phenoxy group) 2,2- dimethyl valeric acids
(0.408g, 1.0mmol) is dissolved in methanol (15mL), and lower addition methoxy amine hydrochlorate (0.100g, 1.0mmol) is stirred at room temperature
With anhydrous sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts
It takes, organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate obtains target compound through silica gel column chromatography separating purification after suction filtration
0.30g, yield 68.6%.ESI-MS m/z:436[M-H]+,438[M+H]+,460[M+Na]+.1H NMR(400MHz,DMSO)
δ 9.37 (s, 2H), 7.23 (ddd, J=11.1,9.0,5.5Hz, 1H), 7.02 (ddd, J=10.2,6.9,3.1Hz, 1H),
6.74 (ddd, J=12.0,6.4,3.2Hz, 1H), 6.40 (d, J=2.2Hz, 2H), 6.24 (t, J=3.2Hz, 1H), 5.09
(s,2H),3.90(s,5H),1.54–1.44(m,4H),1.02(s,6H).
Embodiment 7：The preparation of compound 3
By 2- (3,5- dihydroxy phenyls) -2 oxoethyl -5- (2,5- dichlorophenoxies) -2,2- dimethyl valeric acids
(0.441g, 1.0mmol) is dissolved in methanol (15mL), and lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and anhydrous is stirred at room temperature
Sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, it is organic
It is mutually washed with water, anhydrous sodium sulfate drying, filtrate obtains target compound 0.31g, yield through silica gel column chromatography separating purification after suction filtration
68.0%.ESI-MS m/z:454[M-H]+,478[M+Na]+.1H NMR(300MHz,DMSO)δ11.55(s,1H),9.30(s,
2H), 7.43 (d, J=8.4Hz, 1H), 7.16 (s, 1H), 7.01 (d, J=8.4Hz, 1H), 6.40 (s, 2H), 6.21 (s, 1H),
5.10(s,2H),3.93(s,2H),1.60–1.45(m,4H),1.03(s,6H).
Embodiment 8：The preparation of compound 4
By 2- (3,5- dihydroxy phenyls) -2 oxoethyl -5- (2,5- dichlorophenoxies) 2,2- dimethyl valeric acids
(0.441g, 1.0mmol) is dissolved in methanol (15mL), and lower addition methoxy amine hydrochlorate (0.100g, 1.0mmol) is stirred at room temperature
With anhydrous sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts
It takes, organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate obtains target compound through silica gel column chromatography separating purification after suction filtration
0.26g, yield 55.3%.ESI-MS m/z:468[M-H]+,492[M+Na]+.1H NMR(300MHz,DMSO)δ9.36(s,
2H), 7.43 (d, J=8.4Hz, 1H), 7.16 (s, 1H), 7.01 (d, J=8.4Hz, 1H), 6.40 (s, 2H), 6.24 (s, 1H),
5.08(s,2H),3.93(s,2H),3.89(s,3H),1.62–1.41(m,4H),1.02(s,6H).
Embodiment 9：The preparation of compound 5
By -2 oxoethyl -5- (2- phenylphenoxies) 2,2- dimethyl valeric acids of 2- (3,5- dihydroxy phenyl) (0.448g,
It 1.0mmol) is dissolved in methanol (15mL), lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and anhydrous sodium acetate is stirred at room temperature
(0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, organic phase water
It washes, anhydrous sodium sulfate drying, filtrate obtains target compound 0.27g, yield through silica gel column chromatography separating purification after suction filtration
58.3%.ESI-MS m/z:462[M-H]+,464[M+H]+,486[M+Na]+.1H NMR(300MHz,DMSO)δ11.56(s,
1H), 9.31 (s, 2H), 7.47 (d, J=7.2Hz, 2H), 7.42-7.25 (m, 5H), 7.02 (d, J=7.6Hz, 2H), 6.40
(d, J=2.0Hz, 2H), 6.22 (s, 1H), 5.08 (s, 2H), 3.82 (t, J=4.6Hz, 2H), 1.51-1.32 (m, 4H),
0.96(s,6H).
Embodiment 10：The preparation of compound 6
By -2 oxoethyl -5- (2- phenylphenoxies) 2,2- dimethyl valeric acids of 2- (3,5- dihydroxy phenyl) (0.441g,
It 1.0mmol) is dissolved in methanol (15mL), lower addition methoxy amine hydrochlorate (0.100g, 1.0mmol) and anhydrous second is stirred at room temperature
Sour sodium (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, organic phase
It is washed with water, anhydrous sodium sulfate drying, filtrate obtains target compound 0.35g, yield through silica gel column chromatography separating purification after suction filtration
73.4%.ESI-MS m/z:476[M-H]+,478[M+H]+,500[M+Na]+.1H NMR(300MHz,DMSO)δ9.36(s,
2H), 7.47 (d, J=6.8Hz, 2H), 7.43-7.22 (m, 5H), 7.02 (d, J=7.8Hz, 2H), 6.39 (d, J=2.1Hz,
2H), 6.25 (d, J=4.2Hz, 1H), 5.05 (s, 2H), 3.85 (s, 3H), 3.82 (t, J=5.2Hz, 2H), 1.50-1.26
(m,4H),0.95(s,6H).
Embodiment 11：The preparation of compound 7
By -2 oxoethyl -5- (3- phenylphenoxies) 2,2- dimethyl valeric acids of 2- (3,5- dihydroxy phenyl) (0.448g,
It 1.0mmol) is dissolved in methanol (15mL), lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and anhydrous sodium acetate is stirred at room temperature
(0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, organic phase water
It washes, anhydrous sodium sulfate drying, filtrate obtains target compound 0.30g, yield through silica gel column chromatography separating purification after suction filtration
64.8%.ESI-MS m/z:462[M-H]+,464[M+H]+,486[M+Na]+.1H NMR(400MHz,DMSO)δ11.60(s,
1H), 9.34 (s, 2H), 7.69-7.65 (m, 2H), 7.46 (t, J=7.5Hz, 2H), 7.40-7.33 (m, 2H), 7.21 (d, J=
9.0Hz, 1H), 7.14 (d, J=4.0Hz, 1H), 6.92-6.85 (m, 1H), 6.43 (d, J=2.2Hz, 2H), 6.23 (t, J=
2.1Hz, 1H), 5.12 (s, 2H), 3.89 (t, J=5.2Hz, 2H), 1.59-1.47 (m, 4H), 1.05 (s, 6H)
Embodiment 12：The preparation of compound 8
By -2 oxoethyl -5- (3- phenylphenoxies) 2,2- dimethyl valeric acids of 2- (3,5- dihydroxy phenyl) (0.441g,
It 1.0mmol) is dissolved in methanol (15mL), lower addition methoxy amine hydrochlorate (0.100g, 1.0mmol) and anhydrous second is stirred at room temperature
Sour sodium (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, organic phase
It is washed with water, anhydrous sodium sulfate drying, filtrate obtains target compound 0.30g, yield through silica gel column chromatography separating purification after suction filtration
62.9%.ESI-MS m/z:476[M-H]+,478[M+H]+,500[M+Na]+.1H NMR(400MHz,DMSO)δ9.39(s,
2H), 7.67 (d, J=7.1Hz, 2H), 7.46 (t, J=7.5Hz, 2H), 7.41-7.34 (m, 2H), 7.22 (d, J=9.0Hz,
1H), 7.17-7.12 (m, 1H), 6.89 (dd, J=8.1,2.5Hz, 1H), 6.42 (d, J=2.2Hz, 2H), 6.25 (t, J=
2.1Hz,1H),5.10(s,2H),3.89(s,5H),1.57–1.46(m,4H),1.04(s,6H).
Embodiment 13：The preparation of compound 9
By 2- (3,5- dihydroxy phenyls) -2 oxoethyl -5- (2- benzyloxyphenoxies) 2,2- dimethyl valeric acids
(0.478g, 1.0mmol) is dissolved in methanol (15mL), and lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and anhydrous is stirred at room temperature
Sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, it is organic
It is mutually washed with water, anhydrous sodium sulfate drying, filtrate obtains target compound 0.36g, yield through silica gel column chromatography separating purification after suction filtration
73.0%.ESI-MS m/z:494[M+H]+,516[M+Na]+.1H NMR(400MHz,DMSO)δ11.57(s,1H),9.32(s,
2H), 7.44 (d, J=6.9Hz, 2H), 7.37 (t, J=7.2Hz, 2H), 7.31 (t, J=7.2Hz, 1H), 7.03 (d, J=
7.3Hz, 1H), 6.96-6.84 (m, 3H), 6.41 (d, J=2.2Hz, 2H), 6.23 (t, J=2.1Hz, 1H), 5.11 (s, 2H),
5.07 (s, 2H), 3.83 (t, J=5.5Hz, 2H), 1.63-1.42 (m, 4H), 1.02 (s, 6H)
Embodiment 14：The preparation of compound 10
By 2- (3,5- dihydroxy phenyls) -2- oxoethyls -5- (2- benzyloxyphenoxies) 2,2- dimethyl valeric acids
(0.441g, 1.0mmol) is dissolved in methanol (15mL), and lower addition methoxy amine hydrochlorate (0.100g, 1.0mmol) is stirred at room temperature
With anhydrous sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts
It takes, organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate obtains target compound through silica gel column chromatography separating purification after suction filtration
0.32g, yield 63.1%.ESI-MS m/z:506[M-H]+,508[M+H]+,530[M+Na]+.1H NMR(400MHz,DMSO)
δ 9.37 (s, 2H), 7.45 (d, J=8.4Hz, 2H), 7.37 (t, J=7.2Hz, 2H), 7.32 (d, J=7.2Hz, 1H), 7.03
(d, J=7.2Hz, 1H), 6.89 (dd, J=15.0,8.8Hz, 3H), 6.41 (d, J=2.2Hz, 2H), 6.26 (t, J=
2.2Hz, 1H), 5.08 (s, 2H), 5.07 (s, 2H), 3.88 (s, 3H), 3.83 (t, J=6.1Hz, 2H), 1.54-1.44 (m,
4H),1.00(s,6H).
Embodiment 15：The preparation of compound 11
By 2- (3,5- dihydroxy phenyl) -2- oxoethyls -5- (2- naphthoxys) -2,2- dimethyl valeric acid (0.478g,
It 1.0mmol) is dissolved in methanol (15mL), lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and anhydrous sodium acetate is stirred at room temperature
(0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, organic phase water
It washes, anhydrous sodium sulfate drying, filtrate obtains target compound 0.27g, yield through silica gel column chromatography separating purification after suction filtration
61.8%.ESI-MS m/z:436[M-H]+,438[M+H]+,460[M+Na]+.1H NMR(400MHz,DMSO)δ11.58(s,
1H), 9.34 (s, 2H), 7.81 (t, J=8.0Hz, 3H), 7.46 (t, J=7.4Hz, 1H), 7.34 (t, J=8.0Hz, 1H),
7.24 (s, 1H), 7.13 (d, J=7.4Hz, 1H), 6.43 (d, J=2.2Hz, 2H), 6.25 (t, J=2.2Hz, 1H), 5.12
(s, 2H), 3.92 (t, J=6.4Hz, 2H), 1.66-1.39 (m, 4H), 1.06 (s, 6H)
Embodiment 16：The preparation of compound 12
By 2- (3,5- dihydroxy phenyl) -2- oxoethyls -5- (2- naphthoxys) -2,2- dimethyl valeric acid (0.478g,
It 1.0mmol) is dissolved in methanol (15mL), lower addition methoxy amine hydrochlorate (0.100g, 1.0mmol) and anhydrous second is stirred at room temperature
Sour sodium (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, organic phase
It is washed with water, anhydrous sodium sulfate drying, filtrate obtains target compound 0.27g, yield through silica gel column chromatography separating purification after suction filtration
61.8%.ESI-MS m/z:450[M-H]+,452[M+H]+,474[M+Na]+.1H NMR(400MHz,DMSO)δ9.39(s,
2H), 7.81 (d, J=15.2Hz, 3H), 7.46 (t, J=7.4Hz, 1H), 7.34 (t, J=7.4Hz, 1H), 7.24 (d, J=
2.2Hz, 1H), 7.13 (d, J=7.4Hz, 1H), 6.43 (d, J=2.1Hz, 2H), 6.27 (d, J=4.2Hz, 1H), 5.10 (s,
2H), 3.92 (t, J=4.1Hz, 2H), 3.90 (s, 3H), 1.63-1.41 (m, 4H), 1.05 (s, 6H)
Embodiment 17：The preparation of compound 13
By S- (2- (3,5- dihydroxy phenyls) -2- oxoethyls) 5- (2,5- dichlorophenoxies) -2,2- dimethyl thio
Valeric acid (0.457g, 1.0mmol) is dissolved in methanol (15mL), be stirred at room temperature lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and
Anhydrous sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts,
Organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate obtains target compound 0.29g through silica gel column chromatography separating purification after suction filtration,
Yield 61.4%, ESI-MS m/z:473[M-H]+.
Embodiment 18：The preparation of compound 14
By S- (2- (3,5- dihydroxy phenyls) -2- oxoethyls) 5- (2,5- dichlorophenoxies) -2,2- dimethyl thio
Valeric acid (0.457g, 1.0mmol) is dissolved in methanol (15mL), be stirred at room temperature lower addition methoxy amine hydrochlorate (0.100g,
1.0mmol) with anhydrous sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate is added
(25mL) is extracted, and organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate obtains target through silica gel column chromatography separating purification after suction filtration
Compound 0.32g, yield 65.7%, ESI-MS m/z:487[M-H]+.
Embodiment 19：The preparation of compound 15
By S- (2- (3,5- dihydroxy phenyls) -2- oxoethyls) 5- (2- phenylphenoxies) -2,2- dimethyl thio penta
Sour (0.464g, 1.0mmol) is dissolved in methanol (15mL), and lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and nothing is stirred at room temperature
Water sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, has
Machine is mutually washed with water, anhydrous sodium sulfate drying, and filtrate obtains target compound 0.25g, receive through silica gel column chromatography separating purification after suction filtration
Rate 52.2%, ESI-MS m/z:479[M-H]+.
Embodiment 20：The preparation of compound 16
By S- (2- (3,5- dihydroxy phenyls) -2- oxoethyls) 5- (2- phenylphenoxies) -2,2- dimethyl thio penta
Sour (0.464g, 1.0mmol) is dissolved in methanol (15mL), be stirred at room temperature lower addition methoxy amine hydrochlorate (0.100g,
1.0mmol) with anhydrous sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate is added
(25mL) is extracted, and organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate obtains target through silica gel column chromatography separating purification after suction filtration
Compound 0.28g, yield 56.7%, ESI-MS m/z:494[M-H]+.
Embodiment 21：The preparation of compound 17
By S-2- (3,5- dihydroxy phenyls) -2- oxoethyls -5- (2- naphthoxys) -2,2- dimethyl thio valeric acids
(0.438g, 1.0mmol) is dissolved in methanol (15mL), and lower addition hydroxylamine hydrochloride (0.076g, 1.0mmol) and anhydrous is stirred at room temperature
Sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts, it is organic
It is mutually washed with water, anhydrous sodium sulfate drying, filtrate obtains target compound 0.21g, yield through silica gel column chromatography separating purification after suction filtration
46.3%, ESI-MS m/z:454[M-H]+.
Embodiment 22：The preparation of compound 18
By S-2- (3,5- dihydroxy phenyls) -2- oxoethyls -5- (2- naphthoxys) -2,2- dimethyl thio valeric acids
(0.438g, 1.0mmol) is dissolved in methanol (15mL), and lower addition methoxy amine hydrochlorate (0.100g, 1.0mmol) is stirred at room temperature
With anhydrous sodium acetate (0.090g, 1.2mmol), 60 DEG C of reaction 3h after finishing.Solvent is screwed out, ethyl acetate (25mL) is added and extracts
It takes, organic phase is washed with water, anhydrous sodium sulfate drying, and filtrate obtains target compound through silica gel column chromatography separating purification after suction filtration
0.25g, yield 53.4%, ESI-MS m/z:468[M-H]+.
Embodiment 23：FXR antagonistic activities are tested
Experimentation：
Agents useful for same material supplier is as follows：
| Reagent material | Supplier | Article No. |
| FXR-LBD(GST) | Invitrogen | PV4835 |
| Streptavidin-XL665-5,000tests | cisbio | 610SAXLA |
| MAb Anti GST-K-5,000tests | cisbio | 61GSTKLA |
| SRC1 | GL | - |
| Triton X-100 | Beyotime | ST795 |
| KF | Sigma | 60240-250G |
| Sodium Molybdate | Sigma | M1003-100G |
| Ultrapure 1M Tris-HCl pH7.5 | invitrogen | 15567-027 |
| 0.5M EDTA pH8.0 | invitrogen | 15575-020 |
| Glycerol | FLUKA | 49780-1L |
| DTT | Shenggong | DB0058 |
1. the preparation of basic buffer solution
Note：Below test in, mM mmol/L, μM be μm ol/L, nM be μm ol/L.
A. prepare the basic buffer solutions of 20mL 1x, it is for use after mixing.Buffer solution Verbose Listing is as follows：
| Material | Final concentration (mM) |
| Tris-HCl | 20 |
| EDTA | 1 |
| glycerol | 10% |
| Triton X-100 | 0.0025% |
| KF | 400 |
| BSA | 0.01% |
| Sodium Molybdate | 10 |
| DTT | 5 |
| H2O | Supply 20ml |
2. the preparation of compound solution
A. for control compound Z-guggulsterone (abbreviation GS), 30mM mother liquors first are diluted to 100%DMSO,
Then it is diluted to required final concentration by 3 times.
B. for compound to be detected, 20mM mother liquors first are diluted to 100%DMSO, are then diluted to required end by 3 times
Concentration.
C. for activated compounds GW4064,520 μM of mother liquors are diluted to 100%DMSO, then add 5nL to 384 orifice plates
In each hole for use (including low value hole), final concentration reaches 130nM.
The preparation of 3.1x mixed liquid of protein
A. press needs 10 μ L solution to calculate per hole, prepares 2xFXR-LBD/Eu Anti-GST with the basic buffer solutions of 1x first
Protein solution makes GST-FXR-LBD protein solution final concentrations reach 3nM.Full edition is as follows：
| Material | Final concentration (mM) |
| GST-FXR-LBD | 3 |
| Eu Anti-GST(nl) | The holes 50nl/ |
B. press needs 10 μ L solution to calculate per hole, prepares 2xFXR Biotin-SRC1/SA- with the basic buffer solutions of 1x first
APC polypeptide solutions make SRC1 polypeptide solution final concentrations reach 500nM.Full edition is as follows：
| Material | Final concentration (mM) |
| Biotin-Peptide | 500 |
| SA-APC | The holes 50nl/ |
C. both the above 2x GST-ER/Eu Anti-GST solution and 2x peptide/SA-APC solution are pressed volume 1：1
It is uniformly mixed, for use.
D. each hole of 384 orifice plates is added in 1x protein mixed solutions, adds 20 μ L per hole.
E. 384 orifice plates are put into centrifuge room temperature 1000 and leave the heart 10 seconds, taken out.
F. 384 orifice plates are read after being placed at room temperature for 3 hours.
4.TR-FRET assay readings
384 plates are put into EnVision multi-function microplate readers reading.
5. result treatment
A. 665nm and 615nm values are read, and corrected value is done with 615nm values, final numerical value is expressed as 665nm values/615nm
Value.
B. inhibiting rate (%) is calculated
Inhibiting rate (%) is calculated according to following formula
X is each concentration " 665nm value ratio 615nm value ".Min is " the 665nm value ratios for the blank control wells for only adding DMSO
615nm values " average value.Max is only to add " the 665nm value ratio 615nm values " of activated compounds and the high RST control wells of DMSO flat
Mean value.
Experimental result：
Experimental result is shown in tables, and it is SIPI-7623 that the candidate fat-reducing medicament-that wherein this seminar early-stage study is found, which is numbered,
The IC of (compound 5 in 102838505 A of patent CN) compound50For 52uM, the external antagonism FXR activity of the compounds of this invention
It is better than control compounds.
Embodiment 24：The preparation of tablet
| Prescription： | Dosage |
| Compound 1 | 50mg |
| Microcrystalline cellulose | 250mg |
| Crosslinked polyvinylpyrrolidone | 50mg |
| Pregelatinized starch | 100mg |
| Magnesium stearate | 5mg |
Preparation method：By above-mentioned formula, compound 1, microcrystalline cellulose, pregelatinized starch and crosslinking after pulverizing and sieving
Polyvinylpyrrolidone uniformly mixes, and is then mixed with 5% ethanol solution, and granulation, drying are pressed with mix lubricant again later
Piece.Wherein, the compound pulverizes and sieves to cross 60 mesh sieve；Microcrystalline cellulose, pregelatinized starch and the crosslinking
Polyvinylpyrrolidone pulverizes and sieves to cross 80 mesh sieve；The grain diameter size of the granulation is 20 mesh；The drying
Temperature is preferably within 90 DEG C of control biodiversity percentages 3%.
Embodiment 25：The preparation of capsule
Preparation method：By upper table formula, by drug and each raw material mixing of auxiliary material, in filling to capsule shells.
Embodiment 26：It is prepared by injection
Preparation method：It is using mortar, compound or its salt and wetting agent ground and mixed is uniform by above-mentioned formula, then
It uniformly mixes, then grinds with suspending agent, preservative and water for injection.Wherein, the granular size of the grinding is 0.5 μ
m.Embodiment 27：Reducing blood lipid pharmacodynamic study
Reagent and lot number
Lard is commercially available
Cholesterol Shanghai Blue Season Technology Development Co., Ltd lot number：090720
Propylthiouracil Shanghai Blue Season Technology Development Co., Ltd lot number：090505
Deoxycholic acid Shanghai Blue Season Technology Development Co., Ltd lot number：090615
Tween 80 CP Sinopharm Chemical Reagent Co., Ltd. lot number：F20090507
1,2- propylene glycol Sinopharm Chemical Reagent Co., Ltd. AR lot numbers：T20070125
Method
Fat emulsion preparation method：Lard 25g is taken, is placed in the beaker of 200mL, is placed on gas stove and heats, wait for temperature
When being raised to 100 DEG C, 10g cholesterol is added, dissolves, adds 1g propylthiouracil (PTU)s, fully stir evenly, 25mL tweens are then added
80, oil phase is made.30mL distilled water and 1,2- propylene glycol 20mL is added in another beaker simultaneously, is placed in water-bath and heats
To 60 DEG C, 2g NaTDCs are then added, is sufficiently agitated until and is completely dissolved, water phase is made.Then oil phase is added in water phase,
It mixes well, that is, fat emulsion is made.
Rat adaptable fed 3 days, is grouped according to weight, every group 6：It separates 6 and is only used as blank control group
(Control), remaining rat every morning 9:00-11:00 gavage Fat Emulsion, 1mL/100g weight, continuous gavage 2 weeks.Root again
The rat for giving fat emulsion is divided into hyperlipidemia model group (Model), positive drug group and test medicine group according to weight.
All hyperlipidemia model groups (Model), positive drug group and test medicine group rat be administered test during, simultaneously after
Continuous gavage fat emulsion, meanwhile, positive drug group gives Simvastatin (Sim, 10mg/kg) and SIPI-7623 (80mg/kg), surveys
Reagent group gives the compound of the present invention 1 that dosage is respectively 80mg/kg and 20mg/kg, and hyperlipidemia model group is given isometric molten
Agent.Started to be administered orally in the grouping same day, every afternoon 3:00-4:00 is administered once.It weighs on every Mondays, observes rat feelings
Condition.Successive administration 14 days, Rat Fast 12 hours, eye socket blood sampling 1mL.Carry out lipid determination.
(referred to as using the cholesterol in 7080 determination experiment rat blood serum of Hitachi's automatic biochemistry analyzer：TC), glycerine three
Ester is (referred to as：TG), high-density lipoprotein (abbreviation HDL-C) and low-density lipoprotein (abbreviation LDL-C), test result are shown in figure respectively
1, Fig. 2, Fig. 3 and Fig. 4.In figure, * * represent statistics P<0.01, * * * represent statistics P<0.001.
Fig. 1-4 displays are the experimental results of the reducing blood lipid pharmacodynamic study of the compound of the present invention 1.Experiment is selected normal big
Mouse establishes High fat diet rats model as blank control, and by being continued to carry out gavage with Fat Emulsion to rat.Positive drug
Choose the candidate found in lipid-lowering medicine-Simvastatin (Simvastatin, abbreviation Sim) and this seminar early-stage study
It is SIPI-7623 (compound 5 in 102838505 A of patent CN) that fat-reducing medicament-, which is numbered, determines compound 1 for high in fat
The reducing blood lipid drug effect of rat.The experimental result of Fig. 1, Fig. 2, Fig. 3 and Fig. 4 show that compound 7 can be notable in High fat diet rats model
Reduce rat fat.Experimental result, which is shown, has apparent lipid-lowering effect when 80mg/kg is administered orally in compound 1, be administered
The with obvious effects better than the candidate drop found in this seminar early-stage study of plasma TC, TG and LDL-C is reduced when 80mg/kg
The compound that it is SIPI-7623 that fat drug-, which is numbered,；Reduced when 20mg/kg is administered orally plasma TC, the effect of TG and LDL-C with
It is suitable that 80mg/kg SIPI-7623 are administered orally.
Claims (13)
1. compound or its pharmaceutically acceptable salt as shown in formula (I),
Wherein：
Dotted line Cy expressions are not present or phenyl ring；
R1、R2Independently selected from hydrogen, the alkoxy of halogen, phenyl, benzyl, benzyloxy, the alkyl of C1-C3 or C1-C3；
R3Selected from hydrogen, methyl；
X is selected from O, S.
2. compound or its pharmaceutically acceptable salt shown in formula (I) as described in claim 1, which is characterized in that R1、R2Solely
On the spot it is selected from hydrogen, halogen, phenyl, benzyl or benzyloxy.
3. compound or its pharmaceutically acceptable salt shown in formula (I) as described in claim 1, which is characterized in that R1、R2Solely
On the spot it is selected from halogen, benzyl.
4. compound or its pharmaceutically acceptable salt, feature shown in the formula (I) as described in claim 1-3 any one exist
In the halogen is selected from fluorine, chlorine, bromine or iodine.
5. compound or its pharmaceutically acceptable salt shown in formula (I) as claimed in claim 4, which is characterized in that its structure
Formula such as formula (I-A),
6. compound or its pharmaceutically acceptable salt shown in formula (I) as described in claim 1, including following compound：
7. or more formula (I) compound represented described in claim synthetic method, include the following steps：
Step a), compound shown in formula (II) is reacted into obtain formula (IV) shownization in the presence of a base with compound shown in formula (III)
Close object；Step b), finally by compound and R shown in formula (IV)3-NH2.HCl formula is reacted to obtain under weak basic condition and certain temperature
(I) compound shown in；Reaction equation is shown in following：
In above-mentioned reaction equation, the dotted line Cy, R1, R2And R3Definition with formula (I) shownization described in the above claim
Conjunction object defines consistent.
8. synthetic method according to claim 7, which is characterized in that the alkali described in step a) is selected from sodium carbonate, carbonic acid
Potassium, triethylamine or N, N- diisopropylethylamine.
9. synthetic method according to claim 7, which is characterized in that weak base used in step b) is triethylamine, N, and N- bis- is different
Propylethylamine, Anhydrous potassium carbonate, pyridine, N-methylmorpholine or sodium acetate.
10. including compound or its pharmaceutically acceptable salt and pharmacy shown in the formula (I) described in claim 1-6 any one
The pharmaceutical composition of upper acceptable carriers.
11. pharmaceutical composition as claimed in claim 10, which is characterized in that it is tablet, pill, pulvis, liquid, suspension
Liquid, lotion, granule, capsule, suppository or injection form.
12. compound (I) as claimed in any one of claims 1 to 6 or its pharmaceutically acceptable salt or its pharmaceutical composition
Object is used to prepare the application of FXR antagonists.
13. compound (I) as claimed in any one of claims 1 to 6 or its pharmaceutically acceptable salt or its pharmaceutical composition
Object is used to prepare the application of serum regulating drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101133040A (en) * | 2005-01-27 | 2008-02-27 | 瑟维尔实验室 | Novel heterocyclic oxime derivatives, method for preparing same and use thereof as hypoglycaemic or hypolipidemic agents |
| WO2012080144A1 (en) * | 2010-12-15 | 2012-06-21 | F. Hoffmann-La Roche Ag | Oxime compounds as hdl-cholesterol raising agents |
| CN102838505A (en) * | 2011-06-24 | 2012-12-26 | 上海医药工业研究院 | Amide compound and preparation method as well as application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101133040A (en) * | 2005-01-27 | 2008-02-27 | 瑟维尔实验室 | Novel heterocyclic oxime derivatives, method for preparing same and use thereof as hypoglycaemic or hypolipidemic agents |
| WO2012080144A1 (en) * | 2010-12-15 | 2012-06-21 | F. Hoffmann-La Roche Ag | Oxime compounds as hdl-cholesterol raising agents |
| CN102838505A (en) * | 2011-06-24 | 2012-12-26 | 上海医药工业研究院 | Amide compound and preparation method as well as application thereof |
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