CN106478447B - Carboxylic acid derivates and its application as FXR antagonists - Google Patents
Carboxylic acid derivates and its application as FXR antagonists Download PDFInfo
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- RBANCBBZMMCWSQ-UHFFFAOYSA-N CC(C)(C(OC)=O)Oc(cc1)ccc1C(c(cc1)ccc1N)=O Chemical compound CC(C)(C(OC)=O)Oc(cc1)ccc1C(c(cc1)ccc1N)=O RBANCBBZMMCWSQ-UHFFFAOYSA-N 0.000 description 1
- MAXLUOBUENWCMM-UHFFFAOYSA-N CC(C)(C(OCc(cc1)ccc1C(O)=O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O Chemical compound CC(C)(C(OCc(cc1)ccc1C(O)=O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O MAXLUOBUENWCMM-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)(C(Oc1ccc(*)cc1)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O Chemical compound CC(C)(C(Oc1ccc(*)cc1)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O 0.000 description 1
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Abstract
The present invention relates to the preparation of carboxylic acid derivant and its as the application of FXR antagonists, compound or its pharmaceutically acceptable salt and preparation method thereof as shown in formula (I) are specifically provided,Wherein：R1Selected from hydrogen, methyl, methoxyl group, halogen, nitro, carboxyl；X is selected from NH or O；N1 is 0 or 1；N2 is 0 or 1；R1AndGroup is located at arbitrary the position of substitution on phenyl ring.Compound or its pharmaceutically acceptable salt shown in formula (I) have the pharmacological action of reducing blood lipid, are a kind of FXR antagonists.
Description
Technical field
The invention belongs to new drug design and synthesis field, and in particular to a new class of carboxylic acid derivates, preparation method and
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 (patent CN 102093II6 A) two patents and confirm drop in vivo
Blood fat, the present invention is directed to being furtherd investigate on above-mentioned existing Research foundation, to disclosed compound structure into
Row further modification；And a new class of carboxylic acid derivative has been synthesized, experimental study shows that such new carboxylic acid derivates have
FXR antagonisms and effect for reducing blood fat.
Invention content
To open up the resource of clinical medicine, the present invention has selected suitable fenofibrate similar to chemical constitution and amino/hydroxyl
The benzoic acid and its derivative of the benzoic acid and its derivative or aminomethyl of base substitution/methylol substitution are contracted by acylation reaction
It closes, is connected in the form of amido bond or ester bond, to provide a kind of novel FXR antagonists, for opening for blood lipid-lowering medicine
Hair.
The first aspect of the present invention there is provided compound or its pharmaceutically acceptable salt as shown in following formula (I),
Wherein：R1Selected from hydrogen, methyl, methoxyl group, halogen, nitro, carboxyl；X is selected from NH or O；
N1 is 0 or 1；N2 is 0 or 1；R1AndGroup is located at arbitrary the position of substitution on phenyl ring.
A kind of preferred embodiment, in compound shown in above-mentioned formula (I), the halogen is selected from fluorine, chlorine, bromine or iodine.
A kind of preferred embodiment, in compound shown in above-mentioned formula (I), n1 0.
A kind of preferred embodiment, in compound shown in above-mentioned formula (I), n2 0.
A kind of preferred embodiment, in compound shown in above-mentioned formula (I), n1 0, n2 0.
In the present invention, the pharmaceutically acceptable salt of compound as shown in formula (I) is preferably the carboxylic of the compounds of this invention
The salt that base and alkali compounds reaction generate.The alkali compounds is preferably selected from sodium hydroxide, potassium hydroxide, hydroxide
Calcium, sodium carbonate, potassium carbonate, sodium bicarbonate or saleratus etc..Above-mentioned pharmaceutically acceptable salt can be easily separated, shown in formula (I)
Compound can be purified through column chromatography, and compound shown in formula (I) can be through recrystallization purifying at salt with alkali compounds.
In the first aspect of the present invention, formula (I) compound represented is preferably：
Second aspect of the present invention, the present invention provide the synthetic method of the above-mentioned compound as shown in formula (I), including following step
Suddenly：1), compound shown in formula (II) is dissolved in after appropriate solvent, obtained formula (III) institute of oxalyl chloride is added dropwise at the DMF of catalytic amount
Show chloride compounds, 2), by compound is under base catalysis shown in compound shown in formula (III) and formula (IV), in appropriate solvent
Compound shown in formula (I) is obtained by the reaction, reaction equation is shown in following：
Wherein：R in compound shown in compound and formula (I) shown in formula (IV) in reaction equation1, n1, n2 definition it is consistent, and with
R in compound shown in the formula (I) in the above claim1, n1, n2 definition it is consistent.
Appropriate solvent described in step 1) is selected from dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetone；
Alkali described in step 2) is selected from triethylamine, N, N- diisopropylamines, pyridine, sodium hydroxide；
Appropriate solvent described in step 2) is selected from dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, pyrrole
Pyridine, dioxane/water or its mixed solvent.
A kind of preferred embodiment, wherein the alkali described in step 2) is selected from triethylamine or sodium hydroxide.
A kind of preferred embodiment, wherein appropriate solvent described in step 2) be selected from dichloromethane, dioxane/
Water.
The preparation method of compound shown in above-mentioned formula (I), this field those having ordinary skill in the art can empirically choose specifically
Operating procedure, such as：
Compound shown in formula (II) is dissolved in after dichloromethane, the obtained formula (III) of oxalyl chloride is added dropwise at the DMF of catalytic amount
Shown compound.Compound shown in formula (III) is dissolved in spare in the first solvent, it is molten that compound shown in formula (IV) is added on second
In agent, alkali is added and stirs at room temperature 30-60 minutes, compound shown in formula (III) is added dropwise under stirring condition under ice bath
Stock solution, is added dropwise rear stirring at normal temperature and stays overnight, and is extracted after acidification through column chromatography and obtains target compound；Wherein：First is molten
Agent is selected from dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, pyridine, dioxane；Second solvent be selected from dichloromethane,
Chloroform, tetrahydrofuran, dimethylformamide, pyridine, dioxane：Water/1-10:The mixed solution of 1-10；The alkali of addition is three
Ethamine, N, N- diisopropylethylamine, pyridine, dilute solution of sodium hydroxide (such as：2mol/L, abbreviation 2N).
In the third aspect of the present invention, the present invention provides Antilipidemic pharmaceutical compositions, described in first aspect
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 by described in first aspect compound or its is pharmaceutically acceptable
Application of the salt as FXR antagonists.
In addition, the present invention provides by described in first aspect compound or its pharmaceutically acceptable salt adjust blood fat
In application.
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 7.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,
7623 (compounds 5 in 102838505 A of patent CN), determine reducing blood lipid drug effect of the compound 7 for High fat diet rats.Figure
1, Fig. 2, Fig. 3 and Fig. 4 are respectively illustrated using the cholesterol in 7080 determination experiment rat blood serum of Hitachi's automatic biochemistry analyzer
(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：Compound 2- methyl -2- shown in formula (III) (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride
It prepares
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionic acid 31.8g is dissolved in dichloromethane 200mL, is added
Enter n,N-Dimethylformamide 1mL stirrings, oxalyl chloride 19.0g is added dropwise at 0 DEG C, is reacted 3 hours under room temperature, screws out dichloromethane
Alkane obtains 2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 30.8g, yield 91.4%.
Embodiment 2：The preparation of compound 1
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, P-hydroxybenzoic acid 1.38g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, under the conditions of 0 DEG C
2N sodium hydroxide 10mL are added, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continue stirring 10 hours, acid
Change, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.51g, yield 80.1%.mp:183.1-
185.2℃,ESI-MS m/z:437[M-H]+,439[M+H]+.1H NMR(400MHz,DMSO)δ13.08(s,1H),8.01(d,
J=8.4Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 7.74 (d, J=8.4Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.29
(d, J=8.4Hz, 2H), 7.09 (d, J=8.4Hz, 2H), 1.82 (d, 6H)
Embodiment 3：The preparation of compound 2
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, p-aminobenzoic acid 1.37g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, under the conditions of 0 DEG C
2N sodium hydroxide 10mL are added, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continue stirring 10 hours, acid
Change, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.78g, yield 86.3%.ESI-MS m/
z:436[M-H]+.1H NMR (400MHz, DMSO) δ 10.33 (s, 1H), 7.87 (d, J=8.4Hz, 2H), 7.79 (d, J=
8.4Hz, 2H), 7.74-7.68 (m, 4H), 7.59 (d, J=8.4Hz, 2H), 7.03 (d, J=8.4Hz, 2H), 1.65 (s, 6H)
Embodiment 4：The preparation of compound 3
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino -5- methyl benzoic acids 1.51g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0
2N sodium hydroxide 10mL are added under the conditions of DEG C, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continues stirring 10
Hour, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 4.03g, yield 89.2%.
ESI-MS m/z:450[M-H]+.1H NMR (400MHz, DMSO) δ 12.43 (s, 1H), 8.53 (d, J=8.4Hz, 1H), 7.80
(s, 1H), 7.79-7.65 (m, 5H), 7.60 (d, J=8.4Hz, 2H), 7.41 (d, J=11.9Hz, 1H), 7.12 (d, J=
10.8Hz,2H),2.29(s,3H),1.64(s,6H).
Embodiment 5：The preparation of compound 4
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino-5-fluorobenzoic acids 1.55g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C
Under the conditions of 2N sodium hydroxide 10mL are added, stir 30 minutes, spare solution be added dropwise under the conditions of 0 DEG C, it is 10 small to continue stirring
When, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 4.15g, yield 91.2%.ESI-
MS m/z:454[M-H]+.1H NMR (400MHz, DMSO) δ 12.10 (s, 1H), 8.68 (dd, J=9.3,5.2Hz, 1H),
7.73-7.69 (m, 5H), 7.58 (d, J=8.4Hz, 2H), 7.51 (td, J=9.1,3.1Hz, 1H), 7.15 (d, J=8.7Hz,
2H), 6.93 (d, J=8.7Hz, 1H), 1.65 (s, 3H), 1.60 (s, 3H)
Embodiment 6：The preparation of compound 5
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino -5- methoxy benzoic acids 1.67g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in
2N sodium hydroxide 10mL are added under the conditions of 0 DEG C, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continues stirring 10
Hour, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 4.20g, yield 89.7%.
ESI-MS m/z:466[M-H]+,1H NMR(400MHz,CDCl3) δ 11.62 (s, 1H), 8.73 (d, J=9.3Hz, 1H), 7.74
(d, J=8.4Hz, 2H), 7.68 (d, J=8.4Hz, 2H), 7.55 (d, J=2.9Hz, 1H), 7.42 (d, J=8.4Hz, 2H),
7.22 (dd, J=9.3,2.6Hz, 1H), 7.07 (d, J=8.6Hz, 2H), 3.83 (s, 3H), 1.74 (s, 6H)
Embodiment 7：The preparation of compound 6
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino -5- chlorobenzoic acids 1.71g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C
Under the conditions of 2N sodium hydroxide 10mL are added, stir 30 minutes, spare solution be added dropwise under the conditions of 0 DEG C, it is 10 small to continue stirring
When, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 4.33g, yield 91.9%.ESI-
MS m/z:470[M-H]+,ESI-MS m/z:472[M+H]+.1H NMR(400MHz,CDCl3)δ11.86(s,1H),8.79(d,
J=8.8Hz, 1H), 8.02 (s, 1H), 7.71 (dd, J=21.2,8.8Hz, 4H), 7.58 (d, J=8.8Hz, 1H), 7.43 (d,
J=8.4Hz, 2H), 7.06 (d, J=8.4Hz, 2H), 1.73 (s, 6H)
Embodiment 8：The preparation of compound 7
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino -4- chlorobenzoic acids 1.71g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C
Under the conditions of 2N sodium hydroxide 10mL are added, stir 30 minutes, spare solution be added dropwise under the conditions of 0 DEG C, it is 10 small to continue stirring
When, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 4.15g, yield 88.1%.ESI-
MS m/z:470[M-H]+,ESI-MS m/z:472[M+H]+.1H NMR(400MHz,CDCl3)δ12.09(s,1H),8.85(s,
1H), 7.92 (s, 1H), 7.65 (s, 4H), 7.41 (d, J=8.8Hz, 2H), 7.29 (s, 2H), 7.01 (s, 3H), 1.68 (s,
6H).
Embodiment 9：The preparation of compound 8
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino -4- bromobenzoic acids 2.16g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C
Under the conditions of 2N sodium hydroxide 10mL are added, stir 30 minutes, spare solution be added dropwise under the conditions of 0 DEG C, it is 10 small to continue stirring
When, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 4.40g, yield 85.4%.ESI-
MS m/z:516[M-H]+.1H NMR (400MHz, DMSO) δ 12.32 (s, 1H), 8.92 (s, 1H), 7.91 (d, J=8.5Hz,
1H), 7.73-7.69 (m, 4H), 7.60 (d, J=8.0Hz, 2H), 7.38 (d, J=8.9Hz, 1H), 7.15 (d, J=8.7Hz,
2H), 6.93 (d, J=8.8Hz, 1H), 1.65 (s, 6H)
Embodiment 10：The preparation of compound 9
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- Amino-4-nitrobenzoic Acids 1.82g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0
2N sodium hydroxide 10mL are added under the conditions of DEG C, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continues stirring 10
Hour, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 4.14g, yield 85.9%.
ESI-MS m/z:450[M-H]+.1H NMR(400MHz,CDCl3) δ 12.76 (s, 1H), 9.64 (s, 1H), 8.22 (d, J=
8.8Hz, 1H), 7.89 (d, J=8.8Hz, 1H), 7.72 (d, J=8.8Hz, 5H), 7.46 (d, J=8.8Hz, 2H), 7.06 (d,
J=8.8Hz, 2H), 1.77 (s, 6H)
Embodiment 11：The preparation of compound 10
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino terephthalic acid (TPA)s 1.81g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C of item
2N sodium hydroxide 20mL are added under part, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continue stirring 10 hours,
Acidification, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography obtain target compound 3.98g, yield 82.7%.ESI-MS
m/z:480[M-H]+.
Embodiment 12：The preparation of compound 11
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino -6- methyl benzoic acids 1.51g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0
2N sodium hydroxide 10mL are added under the conditions of DEG C, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continues stirring 10
Hour, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.86g, yield 85.6%.
ESI-MS m/z:450[M-H]+.1H NMR(400MHz,CDCl3) δ 10.78 (s, 1H), 8.33 (d, J=8.3Hz, 1H), 7.71
(dd, J=11.1,8.6Hz, 4H), 7.43 (d, J=8.3Hz, 3H), 7.28 (s, 1H), 7.04 (d, J=8.7Hz, 3H), 2.50
(s,3H),1.72(s,6H).
Embodiment 13：The preparation of compound 12
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 2- amino -6- fluobenzoic acids 1.55g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C
Under the conditions of 2N sodium hydroxide 10mL are added, stir 30 minutes, spare solution be added dropwise under the conditions of 0 DEG C, it is 10 small to continue stirring
When, acidification, ethyl acetate extracts, and anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.79g, yield 83.3%.ESI-
MS m/z:454[M-H]+.1H NMR(400MHz,CDCl3) δ 11.86-11.51 (m, 1H), 8.43 (s, 1H), 7.66 (d, J=
8.4Hz, 4H), 7.41 (d, J=8.4Hz, 4H), 7.02 (s, 2H), 6.78 (s, 1H), 1.67 (s, 6H)
Embodiment 14：The preparation of compound 13
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 4- hydroxyl phenylacetic acids 1.52g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, under the conditions of 0 DEG C
2N sodium hydroxide 10mL are added, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continue stirring 10 hours, acid
Change, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.42g, yield 75.7%.ESI-MS m/
z:451[M-H]+.
Embodiment 15：The preparation of compound 14
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 4- aminophenyl acetic acids 1.51g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, under the conditions of 0 DEG C
2N sodium hydroxide 10mL are added, stirs 30 minutes, spare solution is added dropwise under the conditions of 0 DEG C, continue stirring 10 hours, acid
Change, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.84g, yield 85.0%.ESI-MS m/
z:450[M-H]+,ESI-MS m/z:452[M+H]+.1H NMR(400MHz,DMSO)δ12.37(s,1H),10.03(s,1H),
7.72 (dd, J=14.5,8.5Hz, 4H), 7.58 (dd, J=13.4,8.4Hz, 4H), 7.18 (d, J=8.4Hz, 2H), 7.04
(d, J=8.7Hz, 2H), 3.51 (s, 2H), 1.64 (s, 6H)
Embodiment 16：The preparation of compound 15
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, 4- hydroxymethyl-benzoic acids 1.52g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C of condition
Lower addition 2N sodium hydroxide 10mL stir 30 minutes, spare solution are added dropwise under the conditions of 0 DEG C, continue stirring 10 hours, acid
Change, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.25g, yield 71.9%.ESI-MS m/
z:451[M-H]+.
Embodiment 17：The preparation of compound 16
2- methyl -2- (4- (4- chlorobenzene formacyls)-phenoxy group)-propionyl chloride 3.37g is dissolved in 1,4- dioxane 25mL
In it is spare, Aminomethylbenzoic Acid 1.52g is added on Isosorbide-5-Nitrae-dioxane:Water/1:1 20mL in the mixed solvents, in 0 DEG C of condition
Lower addition 2N sodium hydroxide 10mL stir 30 minutes, spare solution are added dropwise under the conditions of 0 DEG C, continue stirring 10 hours, acid
Change, ethyl acetate extraction, anhydrous magnesium sulfate drying, column chromatography obtains target compound 3.75g, yield 83.0%.ESI-MS m/
z:450[M-H]+,ESI-MS m/z:452[M+H]+.1H NMR (400MHz, DMSO) δ 12.90 (s, 1H), 8.83 (t, J=
5.9Hz, 1H), 7.84 (d, J=8.2Hz, 2H), 7.69 (dd, J=8.6,4.6Hz, 4H), 7.63 (d, J=8.5Hz, 2H),
7.28 (d, J=8.2Hz, 2H), 6.97 (d, J=8.8Hz, 2H), 4.35 (s, 2H), 1.59 (d, J=11.3Hz, 6H)
Embodiment 18：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. (referred to as control compound Z-guggulsterone：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.
3. the preparation of 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：
In-vitro screening the results show that control compounds SIPI-7623 IC50It it is 52 μM, the compound of the present invention has quite
A part of external antagonism FXR activity is better than SIPI-7623.Wherein compound 7 and 9 external activity of compound is up to SIPI-7623
4 times.
Embodiment 19：The preparation of tablet
| Prescription： | Dosage |
| Compound 7 | 50mg |
| Microcrystalline cellulose | 250mg |
| Crosslinked polyvinylpyrrolidone | 50mg |
| Pregelatinized starch | 100mg |
| Magnesium stearate | 5mg |
Preparation method：According to above-mentioned formula, compound 7, microcrystalline cellulose, pregelatinized starch and friendship after pulverizing and sieving
Connection polyvinylpyrrolidone uniformly mix, then mix with 5% ethanol solution, granulation, dry, later again with mix lubricant,
Tabletting.Wherein, the compound 7 pulverizes and sieves to cross 60 mesh sieve；Microcrystalline cellulose, pregelatinized starch and the friendship
Connection polyvinylpyrrolidone pulverizes and sieves to cross 80 mesh sieve；The grain diameter size of the granulation is 20 mesh；The drying
Temperature be preferably within 90 DEG C of control biodiversity percentages 3%.
Embodiment 20：The preparation of capsule
Preparation method：According to upper table formula, by drug and each raw material mixing of auxiliary material, in filling to capsule shells.
Embodiment 21：It is prepared by injection
Preparation method：It is using mortar, compound or its salt and wetting agent ground and mixed is uniform according to above-mentioned formula, so
It uniformly mixes, then grinds with suspending agent, preservative and water for injection afterwards.Wherein, the granular size of the grinding is 0.5
μm。
Embodiment 22：Compound 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
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.
The rat of all hyperlipidemia model groups (Model), positive drug group and administration group continues simultaneously during test is administered
Gavage fat emulsion, meanwhile, positive drug group gives Simvastatin (Sim, 10mg/kg) and SIPI-7623 (80mg/kg), administration
Group dosage is respectively 80mg/kg and 20mg/kg, and hyperlipidemia model group gives isometric solvent.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 situation.Successive administration 14 days, Rat Fast 12
Hour, 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 7.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 patent CN 102838505A) that fat-reducing medicament-, which is numbered, determines compound 7 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.Drop TG and LDL-C levels and control compounds SIPI-7623 oral agents when oral dose is 20mg/kg
Amount is that 80mg/kg is suitable；When oral dose is 80mg/kg, drop TC and TG levels and control compounds SIPI-7623 are oral
Dosage is that 80mg/kg is suitable, but drops LDL-C effects and be better than SIPI-7623.
Claims (13)
1. compound or its pharmaceutically acceptable salt, shown in structural formula such as formula (I),
Wherein：R1Selected from hydrogen, methyl, methoxyl group, halogen, nitro, carboxyl；X is selected from NH；
N1 is 0 or 1；N2 is 0 or 1；R1AndGroup is located at arbitrary the position of substitution on phenyl ring.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, which is characterized in that the halogen be selected from fluorine,
Chlorine, bromine or iodine.
3. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, which is characterized in that n1 0.
4. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, which is characterized in that n2 0.
5. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, which is characterized in that n1 0, n2 0.
6. compound as claimed in claim 1 or 2 has structural formula below：
7. according to the synthetic method of compound described in one claim of any of the above, include the following steps：1), by formula (II) institute
Show and chloride compounds shown in the obtained formula (III) of oxalyl chloride are added dropwise after compound is dissolved in appropriate solvent at the DMF of catalytic amount, 2),
By compound shown in compound shown in formula (III) and formula (IV) under base catalysis, it is obtained by the reaction in appropriate solvent shown in formula (I)
Compound, reaction equation are shown in following：
Wherein：R in compound shown in compound and formula (I) shown in formula (IV) in reaction equation1, n1, n2 definition it is consistent, and with it is above
R in compound shown in the formula (I) in claim1, n1, n2 definition it is consistent；
Appropriate solvent described in step 1) is selected from dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetone,
Alkali described in step 2) is selected from triethylamine, N, N- diisopropylamines, pyridine, sodium hydroxide,
Appropriate solvent described in step 2) is selected from dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, pyridine, two
Six rings of oxygen/water or its mixed solvent.
8. synthetic method according to claim 7, wherein the alkali described in step 2) is selected from triethylamine or sodium hydroxide.
9. synthetic method according to claim 7, wherein the appropriate solvent described in step 2) is selected from dichloromethane, dioxy six
Ring/water.
10. including compound or its pharmaceutically acceptable salt and pharmaceutically acceptable described in claim 1-6 any one
The pharmaceutical composition of carrier.
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 as claimed in any one of claims 1 to 6 or its pharmaceutically acceptable salt are used to prepare FXR antagonists
Using.
13. compound as claimed in any one of claims 1 to 6 or its pharmaceutically acceptable salt are preparing serum regulating drug
In application.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1539897A (en) * | 1975-02-12 | 1979-02-07 | Orchimed Sa | Phenoxypropionic acid derivatives |
| WO2004009533A1 (en) * | 2002-07-24 | 2004-01-29 | Ptc Therapeutics, Inc. | Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease |
| CN102093246A (en) * | 2009-12-15 | 2011-06-15 | 上海医药工业研究院 | Ester compound, preparation method and application thereof |
| 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 |
| CN103232348A (en) * | 2013-04-09 | 2013-08-07 | 吉林化工学院 | Fibrate-natural antioxidant twin drug used for treating hyperlipidemia, and preparation method thereof |
| CN104292120A (en) * | 2013-01-29 | 2015-01-21 | 上海医药工业研究院 | Amide compound and preparation method, medicinal composition and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7247741B2 (en) * | 2005-01-21 | 2007-07-24 | Ptc Therapeutics, Inc. | Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease |
-
2015
- 2015-09-01 CN CN201510552009.8A patent/CN106478447B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1539897A (en) * | 1975-02-12 | 1979-02-07 | Orchimed Sa | Phenoxypropionic acid derivatives |
| WO2004009533A1 (en) * | 2002-07-24 | 2004-01-29 | Ptc Therapeutics, Inc. | Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease |
| CN102093246A (en) * | 2009-12-15 | 2011-06-15 | 上海医药工业研究院 | Ester compound, preparation method and application thereof |
| 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 |
| CN104292120A (en) * | 2013-01-29 | 2015-01-21 | 上海医药工业研究院 | Amide compound and preparation method, medicinal composition and application thereof |
| CN103232348A (en) * | 2013-04-09 | 2013-08-07 | 吉林化工学院 | Fibrate-natural antioxidant twin drug used for treating hyperlipidemia, and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 具有降压和降血脂活性的二氢吡啶衍生物的合成;张三奇等;《药学学报》;19981231;第33卷(第10期);第789-792页 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4038052B1 (en) * | 2019-10-02 | 2024-02-07 | Domain Therapeutics | Prostaglandin e2 (pge2) ep4 receptor antagonists |
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