CN106478447A - Carboxylic acid derivates and its application as FXR antagonist - Google Patents
Carboxylic acid derivates and its application as FXR antagonist Download PDFInfo
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- 0 CC([C@](C)CC(C(C)(C)Oc(cc1)ccc1C(c(cc1)ccc1N)=O)=*)c(cccc1CC=CC2*C2)c1O Chemical compound CC([C@](C)CC(C(C)(C)Oc(cc1)ccc1C(c(cc1)ccc1N)=O)=*)c(cccc1CC=CC2*C2)c1O 0.000 description 2
- WAZXGTTWCAQSDV-UHFFFAOYSA-N CC(C)(C(Cl)=O)Oc(cc1)ccc1C(C1C=CC(Cl)=CC1)=O Chemical compound CC(C)(C(Cl)=O)Oc(cc1)ccc1C(C1C=CC(Cl)=CC1)=O WAZXGTTWCAQSDV-UHFFFAOYSA-N 0.000 description 1
- LTKLYBGALOALDZ-UHFFFAOYSA-N CC(C)(C(Nc(cc(cc1)Cl)c1C(O)=O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O Chemical compound CC(C)(C(Nc(cc(cc1)Cl)c1C(O)=O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O LTKLYBGALOALDZ-UHFFFAOYSA-N 0.000 description 1
- CYSVOVIMIFPIQW-UHFFFAOYSA-N CC(C)(C(O)=[U])Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O Chemical compound CC(C)(C(O)=[U])Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O CYSVOVIMIFPIQW-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to the preparation of carboxylic acid derivant and its application as FXR antagonist, specifically provide compound or its pharmaceutically acceptable salt and preparation method thereof as shown in 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；R1And group is located at any the position of substitution on phenyl ring.Compound shown in formula (I) or its pharmaceutically acceptable salt have the pharmacological action of blood fat reducing, are class FXR antagonisies.
Description
Technical field
The invention belongs to new drug design and synthesis field are and in particular to the new carboxylic acid derivates of a class, its preparation method and its work
Application for FXR antagonist.
Background technology
Cardiovascular and cerebrovascular disease is current one of disease of harm human life and healthy most serious, be middle-aged and elderly people commonly encountered diseases and
Frequently-occurring disease, is the first place of M ＆ M in many countries.Atherosclerosiss are the bases of many cardiovascular and cerebrovascular diseases,
Substantial amounts of experiment and clinical data prove that atherosclerosiss are closely related with the exception of blood lipid metabolism.Therefore, blood lipid regulation becomes
Key areas for such new drug research current.
By perspective, immediately with comparison clinical research it has proved that some statinses can reduce Atherosclerosis
Change the generation with coronary heart disease, reduce the mortality rate caused by coronary heart disease, reduce the incidence rate of myocardial infarction.Study further
Also confirm that the treatment of fat-reducing medicament can reduce the content of atherosclerotic plaque inner lipid, reinforce ferry grease and stable speckle, subtract
The myocardial infarction lacking plaque rupture and causing and cerebral infarction etc. matters of aggravation.Additionally, lipid regulating agent also can recover damaged blood vessels
The function of endotheliocyte, strengthens fibrinolytic and prevents thrombosiss, and delay the atherosclerotic of people to be in progress and disappear
Established speckle.Therefore, actively treat, using lipid lowering agent, the generation being to mitigate atherosclerosiss and reduce coronary heart disease
Important measures.
The types of drugs of regulation blood fat clinical and conventional at present is more, such as Statins, fibrate, amberlite
Fat or cholic acid chelating agent, nicotinic acid class and other Adjust-blood lipid class medicines.Wherein statinses are particularly noticeable.Statins
Medicine is the inhibitor of cholesterol synthase.3-hydroxy-3-methylglutaric acid list acyl coenzyme A is (referred to as：HMG-CoA) exist
Be changed in the presence of HMG-CoA reductase methoxy dragon acid, statins be chemical constitution open acid moieties and
HMG-CoA is similar, and its contestable suppresses the formation of methoxy dragon acid, thus reducing the synthesis of cholesterol, thus permissible
Reduction Blood Cholesterol and low density lipoprotein, LDL are (referred to as：LDL-C) level.Clinical research proves, patients with coronary heart disease is
Make that the level of cholesterol in serum and low density lipoprotein, LDL is not bery high or normal, statinses can be atherosis with prevention of arterial
The generation of speckle, development and the bad clinical event reducing coronary heart disease.However, long-term taking has upper abdomen except statinses
Outside the gastrointestinal symptoms such as discomfort, considerable part patient also can produce liver function injury, and transaminase raises, myalgia, flesh
Acid kinase rises high side reaction.
Farnesoid X receptor is (referred to as：FXR) be ligand activation transcription factor, adjust target gene expression；Research finds
Bile acid is its native ligand, participates in the metabolism of bile acid, therefore also referred to as Farnesoid X receptor, and chenodeoxy cholic acid is (referred to as：
CDCA) it is its most suitable native ligand.GW4064 is the FXR part of first man work synthesis.FXR removes participation machine
The metabolism of internal bile acid, also plays important adjustment effect to lipid metabolism and carbohydrate metabolism etc..Cholesterol metabolism becomes bile acid master
There are two paths:1. classical path is by cholesterol -7 α-hydroxylase (referred to as：CYP7A1) it is catalyzed, and be subject to bile acid
Negative-feedback regu- lation；2. alternative path is by cholesterol -27 α-hydroxylase (referred to as：CYP27A1) it is catalyzed, account for human body total
The 18% of bile acid biosynthesis, and the supplement as classical path.Classical metabolic pathway process is oxidation product and the liver of cholesterol
X receptor is (referred to as：LXR) combine and induce it with retinoic acid receptor X (referred to as：RXR) form dimer, in conjunction with
To on the reaction original paper of the LXR of DNA, the expression of sharp CYP7A1, then CYP7A1 catalysis cholesterol generation bile acid,
Bile acid is combined with FXR and induces it to form dimer with RXR, is attached on the FXR reaction original paper of DNA, activation is little
The expression of heterodimer part (SHP), and SHP and Liver receptor homolog-1 (LRH-1) combine suppression CYP7A1's
Expression, thus maintain the metabolic balance of cholesterol.FXR is embodied in suppression triglyceride to the regulatory mechanism of Triglyceride Metabolism in Patients
Synthesis：FXR lowers Sterol regulatory element binding protein 1c (referred to as through SHP approach：SREBP-1c), SREBP-1c
It is the central transcription factor participating in lipogenesis gene, the transcription of multiple enzymes participating in fatty acid and triglyceride synthesis can be activated,
Including fatty acid synthetase (referred to as：FAS), acetyl-CoA carboxylase is (referred to as：ACC) etc..Nearest research is sent out
Existing, FXR can be with the differentiation of inducing adipocyte, thus promoting TG in the storage of adipose cell.Also there is document report FXR short of money
The effect that anti-agent reduces triglyceride (TG) is to be realized by way of lowering SREBP-1c.
At present, the FXR antagonist of report is most of is steroid compound, including Z-guggulsterone (abbreviation GS),
CDRI/80-574, Sulfated sterol and Scalarane sesterterpene etc..So far, nonsteroidal FXR antagonist
Isoxazole derivatives including AGN34, replacement.Wherein natural product GS is an efficient antagonist of FXR, and it can subtract
When young in Mus body the level of low density lipoprotein, LDL (LDL) and triglyceride (TG) but the blood plasma of hypercholesterolemia patient can not be improved
Lipid density.FXR, as the novel targets adjusting the appearance of blood fat field in recent years, by the regulation blood fat mechanism of its uniqueness, inhales
Draw the sight of numerous researchers.Therefore, develop the effective medicine to combined hyperlipidemia familial for FXR to have very
Big meaning.
The amides compound of early stage, its preparation method and application (patent CN 102838505 A) and ester type compound, its
Invent a large amount of compounds in two patents of preparation method and application (patent CN 102093II6 A) and confirm to drop in vivo blood
Fat acts on, it is contemplated that furtheing investigate on above-mentioned existing Research foundation, disclosed compound structure is carried out
Modify further；And having synthesized the new carboxylic acid derivative of a class, experimentation shows that such new carboxylic acid derivates have
FXR antagonism, and effect for reducing blood fat.
Content of the invention
For opening up the resource of clinical medicine, the present invention have selected suitable fenofibrate and is similar to chemical constitution and amino/hydroxyl replacement
Benzoic acid and its benzoic acid that replaces of derivant or aminomethyl/methylol and its derivant be condensed by acylation reaction, with acyl
The form of amine key or ester bond connects, thus providing the new FXR antagonist of a class, for the exploitation of blood lipid-lowering medicine.
A 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；R1AndAny the position of substitution that group is located on phenyl ring.
Preferred embodiment, in compound shown in above-mentioned formula (I), described halogen is selected from fluorine, chlorine, bromine or iodine to one kind.
Preferred embodiment, in compound shown in above-mentioned formula (I), n1 is 0 to one kind.
Preferred embodiment, in compound shown in above-mentioned formula (I), n2 is 0 to one kind.
Preferred embodiment, in compound shown in above-mentioned formula (I), n1 is 0, n2 is 0 to one kind.
In the present invention, as shown in formula (I) pharmaceutically acceptable salt of compound be preferably the compounds of this invention carboxyl and
The salt that alkali compoundss reaction generates.Described alkali compoundss preferably be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide,
Sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate etc..Above-mentioned pharmaceutically acceptable salt can be easily separated, shown in formula (I)
Compound can be through column chromatography purification, and the salt become with alkali compoundss of compound shown in formula (I) can be through recrystallization purifying.
In a first aspect of the present invention, the compound shown in formula (I) is preferably：
Second aspect present invention, the present invention provides the synthetic method of compound shown in above-mentioned (I) as formula, comprises the following steps：
1), compound shown in formula (II) is dissolved in after appropriate solvent Deca oxalyl chloride under the DMF of catalytic amount and formula (III) is obtained
Shown chloride compounds, 2), by compound shown in formula (III) and compound shown in formula (IV) under base catalysiss, suitable
In solvent, reaction obtains compound shown in formula (I), and reaction equation is shown in following：
Wherein：R in compound shown in formula (IV) and compound shown in formula (I) in reaction equation1, n1, n2 definition consistent, and with
R in compound shown in described formula (I) in above claim1, n1, n2 definition consistent.
Step 1) described in appropriate solvent be selected from dichloromethane, chloroform, ethyl acetate, oxolane, acetone；
Step 2) described in alkali be selected from triethylamine, N, N- diisopropylamine, pyridine, sodium hydroxide；
Step 2) described in appropriate solvent be selected from dichloromethane, chloroform, oxolane, N,N-dimethylformamide, pyrrole
Pyridine, dioxane/water or its mixed solvent.
One kind preferred embodiment, wherein, step 2) described in alkali be selected from triethylamine or sodium hydroxide.
One kind preferred embodiment, wherein, step 2) described in appropriate solvent be selected from dichloromethane, dioxane/water.
The preparation method of compound shown in above-mentioned formula (I), this area those having ordinary skill in the art can empirically choose specific behaviour
Make step, for example：
Compound shown in formula (II) is dissolved in after dichloromethane Deca oxalyl chloride under the DMF of catalytic amount formula (III) is obtained
Shown compound.Compound shown in formula (III) is dissolved in standby in the first solvent, compound shown in formula (IV) is added on
In two solvents, alkali is added to stir 30-60 minute at room temperature, Deca formula (III) shownization under stirring condition under ice bath
The stock solution of compound, after completion of dropping, stirring at normal temperature overnight, extracts after acidifying through column chromatography and obtains target compound；Wherein：
First solvent is selected from dichloromethane, chloroform, oxolane, dimethylformamide, pyridine, dioxane；Second solvent choosing
From dichloromethane, chloroform, oxolane, dimethylformamide, pyridine, dioxane：Water/1-10:The mixed solution of 1-10；
The alkali adding is triethylamine, N, and N- diisopropylethylamine, pyridine, dilute solution of sodium hydroxide are (for example：2mol/L, abbreviation 2N).
In a third aspect of the present invention, the invention provides Antilipidemic pharmaceutical compositions, including the change described in first aspect
Compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
According to therapeutic purposes, pharmaceutical composition can be made various types of administration unit dosage forms, such as tablet, pill, powder,
Liquid, suspension, emulsion, granule, capsule, suppository and injection (solution and suspension) etc..
In a fourth aspect of the present invention, the invention provides by the compound described in first aspect or its pharmaceutically acceptable salt
Application as FXR antagonist.
Additionally, the invention provides the compound described in first aspect or its pharmaceutically acceptable salt are being adjusted in blood fat
Application.
Content in pharmaceutical composition for the compound and its pharmaceutically acceptable salt as shown in formula (I) of the present invention is no special
Limit, 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 described pharmaceutical composition is not particularly limited.Can according to patient age, sex and its
Its condition and symptom, select the preparation administration of various dosage forms.For example, tablet, pill, solution, suspension, emulsion,
Granule and capsule are oral administrations；Injection can be administered alone, or with injection conveying liquid (as glucose solution and amino
Acid solution) it is mixed into row vein injection, muscle, Intradermal, injection in subcutaneous or abdomen can be carried out merely if necessary with injection；
Suppository is to be administered into rectum.
In the present invention, medication can be properly selected according to method of administration, patient age, sex and other condition and symptom
Dosage.Common dosage can be：About 0.1～300mg active constituents of medicine/kg body weight/day.In general, each
Administration unit dosage forms can contain the active constituents of medicine of 1～200mg.
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.Not
On the premise of departing from present inventive concept, those skilled in the art can be made to preparation method with using instrument within the scope of the claims
Go out to improve, 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 power
Profit requires to be defined.
Brief description
Fig. 1-4 display is the experimental result of the blood fat reducing pharmacodynamic study of compound 7 of the present invention.Experiment has been selected normally big
Mus, as blank, select High fat diet rats model as comparison simultaneously；Positive drug chooses lipid lowerers-simvastatin
The candidate's fat-reducing medicament-number finding in (Simvastatin, abbreviation Sim) and this seminar early-stage Study is
SIPI-7623 (compound 5 in patent CN 102838505 A), determines the hypolipidemic for High fat diet rats for the compound 7
Effect.Fig. 1, Fig. 2, Fig. 3 and Fig. 4 respectively illustrate using Hitachi's automatic biochemistry analyzer 7080 determination experiment rat blood serum
In cholesterol (referred to as：TC), triglyceride is (referred to as：TG), high density lipoprotein (abbreviation HDL-C) and low close
The test result of degree lipoprotein (abbreviation LDL-C).
Specific embodiment
Embodiment 1：The preparation of compound 2- methyl -2- shown in formula (III) (4- (4- chlorobenzene formacyl)-phenoxy group)-propionyl chloride
2- methyl -2- (4- (4- chlorobenzene formacyl)-phenoxy group)-propanoic acid 31.8g is dissolved in dichloromethane 200mL, adds N, N-
Dimethylformamide 1mL stirs, Deca oxalyl chloride 19.0g at 0 DEG C, reacts 3 hours under room temperature, screws out dichloromethane,
Obtain 2- methyl -2- (4- (4- chlorobenzene formacyl)-phenoxy group)-propionyl chloride 30.8g, yield 91.4%.
Embodiment 2：The preparation of compound 1
2- methyl -2- (4- (4- chlorobenzene formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
P-hydroxybenzoic acid 1.38g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, add under the conditions of 0 DEG C
2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10 hours,
Acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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=8.4
Hz, 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
Para-amino benzoic acid 1.37g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, add under the conditions of 0 DEG C
2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10 hours,
Acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino -5- ar-Toluic acid 1.51g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, in 0 DEG C of condition
Lower addition 2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10
Hour, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino-5-fluorobenzoic acid 1.55g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, under the conditions of 0 DEG C
Add 2N sodium hydroxide 10mL, stir 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continue stirring 10 little
When, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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=8.7
Hz, 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino -5- methoxybenzoic acid 1.67g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, in 0 DEG C of bar
Add 2N sodium hydroxide 10mL under part, stir 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continue stirring
10 hours, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino -5- chlorobenzoic acid 1.71g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, under the conditions of 0 DEG C
Add 2N sodium hydroxide 10mL, stir 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continue stirring 10 little
When, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino -4- chlorobenzoic acid 1.71g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, under the conditions of 0 DEG C
Add 2N sodium hydroxide 10mL, stir 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continue stirring 10 little
When, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino -4- bromobenzoic acid 2.16g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, under the conditions of 0 DEG C
Add 2N sodium hydroxide 10mL, stir 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continue stirring 10 little
When, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- Amino-4-nitrobenzoic Acid 1.82g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, in 0 DEG C of condition
Lower addition 2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10
Hour, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino p-phthalic acid 1.81g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, add under the conditions of 0 DEG C
Enter 2N sodium hydroxide 20mL, stir 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continue stirring 10 hours,
Acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and column chromatography obtains 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino -6- ar-Toluic acid 1.51g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, in 0 DEG C of condition
Lower addition 2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10
Hour, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
2- amino -6- fluobenzoic acid 1.55g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, under the conditions of 0 DEG C
Add 2N sodium hydroxide 10mL, stir 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continue stirring 10 little
When, acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and column chromatography obtains target compound 3.79g, yield 83.3%.
ESI-MS m/z:454[M-H]+.1H NMR(400MHz,CDCl3)δ11.86–11.51(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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
4- hydroxyl phenylacetic acid 1.52g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, add under the conditions of 0 DEG C
2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10 hours,
Acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
4- aminophenyl acetic acid 1.51g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, add under the conditions of 0 DEG C
2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10 hours,
Acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL,
4- hydroxymethyl-benzoic acid 1.52g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, add under the conditions of 0 DEG C
2N sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10 hours,
Acidifying, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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 formacyl)-phenoxy group)-propionyl chloride 3.37g is dissolved in standby in Isosorbide-5-Nitrae-dioxane 25mL, will
Aminomethylbenzoic Acid 1.52g is added on 1,4- dioxane:Water/1:In 1 20mL mixed solvent, add 2N under the conditions of 0 DEG C
Sodium hydroxide 10mL, stirs 30 minutes, the standby solution of Deca under the conditions of 0 DEG C, continues stirring 10 hours, is acidified,
Ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and 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=5.9
Hz, 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 activity is 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
Note：Below test in, mM be mmol/L, μM be μm ol/L, nM be μm ol/L.
A. prepare the basic buffer of 20mL 1x, stand-by after mixing.Buffer 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 (referred to as：GS), first it is diluted to 30mM mother solution with 100%DMSO, so
It is diluted to required final concentration by 3 times afterwards.
B. for compound to be detected, first it is diluted to 20mM mother solution with 100%DMSO, be then diluted to by 3 times required dense eventually
Degree.
Then plus 5nL to 384 orifice plate c. for activated compounds GW4064, it is diluted to 520 μM of mother solutions with 100%DMSO,
(low value hole is not included) stand-by, its final concentration reaches 130nM in each hole.
3. the preparation of 1x mixed liquid of protein
A. pressing every hole needs 10 μ L solution to calculate, and prepares 2xFXR-LBD/Eu Anti-GST albumen with the basic buffer of 1x first
Solution, makes GST-FXR-LBD protein solution final concentration reach 3nM.Full edition is as follows：
| Material | Final concentration (mM) |
| GST-FXR-LBD | 3 |
| Eu Anti-GST(nl) | 50nL/ hole |
B. pressing every hole needs 10 μ L solution to calculate, and prepares 2xFXR Biotin-SRC1/SA-APC with the basic buffer of 1x first many
Peptide solution, makes SRC1 polypeptide solution final concentration reach 500nM.Full edition is as follows：
| Material | Final concentration (mM) |
| Biotin-Peptide | 500 |
| SA-APC | 50nL/ hole |
C. both the above 2x GST-ER/Eu Anti-GST solution and 2x peptide/SA-APC solution are pressed volume 1：1 mixing is all
Even, stand-by.
D. 1x protein mixed solution is added each hole of 384 orifice plates, every hole adds 20 μ L.
E. 384 orifice plates are put into centrifuge room temperature 1000 and leave the heart 10 seconds, take out.
F. by 384 orifice plates room temperature place 3 hours after reading.
4.TR-FRET assay reading
384 plates are put into EnVision multi-function microplate reader reading.
5. result treatment
A. reading 665nm and 615nm value, and corrected value is done with 615nm value, final numerical value is expressed as 665nm value/615nm
Value.
B. calculate suppression ratio (%)
Suppression ratio (%) is calculated according to below equation
X is each concentration " 665nm value is than 615nm value ".Min is " the 665nm value ratio of the blank control wells only adding DMSO
615nm value " meansigma methodss.Max be only plus activated compounds and DMSO high RST control wells " 665nm value compares 615nm
Value " meansigma methodss.
Experimental result：
In-vitro screening result shows, the IC of control compounds SIPI-762350For 52 μM, the compound of the present invention has suitable one
Partly external antagonism FXR activity is better than SIPI-7623.Wherein compound 7 and compound 9 external activity are up to SIPI-7623
4 times.
Embodiment 19：The preparation of tablet
| Prescription： | Consumption |
| Compound 7 | 50mg |
| Microcrystalline Cellulose | 250mg |
| Crospolyvinylpyrrolidone | 50mg |
| Pregelatinized Starch | 100mg |
| Magnesium stearate | 5mg |
Preparation method：According to above-mentioned formula, compound 7 after pulverizing and sieving, Microcrystalline Cellulose, Pregelatinized Starch and friendship
Connection Polyvinylpyrrolidone uniformly mixes, and then mixes with 5% ethanol solution, pelletizes, is dried, and mixes with lubricant more afterwards
Close, tabletting.Wherein, described compound 7 pulverizes and sieves as crossing 60 mesh sieves；Described Microcrystalline Cellulose, pre- glue
Change starch and crospolyvinylpyrrolidone pulverizes and sieves as crossing 80 mesh sieves；The grain diameter size of described granulation is 20 mesh；
Within the temperature of described drying is preferably 90 DEG C of control biodiversity percentage ratios 3%.
Embodiment 20：The preparation of capsule
Preparation method：According to upper table formula, medicine and each raw material blending of adjuvant are filled to capsule shells.
Embodiment 21：Prepared by injection
Preparation method：According to above-mentioned formula, using mortar, will compound or its salt with wetting agent ground and mixed uniformly, then with help
Suspension, preservative and water for injection uniformly mix, then grind.Wherein, the granular size of described grinding is 0.5 μm.
Embodiment 22：Compound blood fat reducing pharmacodynamic study
Reagent and lot number：
Adeps Sus domestica 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 Chemical Reagent Co., Ltd., Sinopharm Group lot number：F20090507
1,2- propylene glycol Chemical Reagent Co., Ltd., Sinopharm Group AR lot number：T20070125
Lipomul preparation method：Take Adeps Sus domestica 25g, be placed in the beaker of 200mL, be placed on heating on gas range, treat temperature
When being raised to 100 DEG C, add 10g cholesterol, dissolve, add 1g propylthiouracil, fully stir evenly, be subsequently adding 25mL
Tween 80, makes oil phase.Add 30mL distilled water and 1,2- propylene glycol 20mL in another beaker simultaneously, be placed on water-bath
It is heated to 60 DEG C in pot, be subsequently adding 2g NaTDC, be sufficiently agitated until and be completely dissolved, make aqueous phase.Then by water
It is added to oil phase, fully mix, that is, make lipomul.
Rat adaptability is fed 3 days, is grouped according to body weight, every group 6：Separate 6 and be only used as blank control group (Control),
Remaining rat every morning 9:00-11:00 gavage fat milk, 1mL/100g body weight, continuous gavage 2 weeks.Will further according to body weight
The rat giving lipomul is divided into hyperlipidemia model group (Model), positive drug group and test medicine group.
The rat of all hyperlipidemia model groups (Model), positive drug group and administration group, during administration test, all continues to fill simultaneously
Stomach lipomul, meanwhile, positive drug group gives simvastatin (Sim, 10mg/kg) and SIPI-7623 (80mg/kg), gives
Medicine group dosage is respectively 80mg/kg and 20mg/kg, and hyperlipidemia model group gives equal-volume solvent.Started to be administered orally in the packet same day
Administration, every afternoon 3:00-4:00 is administered once.Weigh on every Mondays, observe rat situation.Successive administration 14 days,
Rat Fast 12 hours, eye socket blood sampling 1mL.Carry out lipid determination.
Using the cholesterol in Hitachi's automatic biochemistry analyzer 7080 determination experiment rat blood serum (referred to as：TC), triglyceride
(referred to as：TG), high density lipoprotein (abbreviation HDL-C) and low density lipoprotein, LDL (abbreviation LDL-C), test result
See Fig. 1, Fig. 2, Fig. 3 and Fig. 4 respectively.In figure, * * represents statistics P<0.01, * * * represents statistics P<0.001.
Fig. 1-4 display is the experimental result of the blood fat reducing pharmacodynamic study of compound 7 of the present invention.Normal rat is selected in experiment
As blank, and by carrying out to rat persistently carrying out gavage with fat milk, set up High fat diet rats model.Positive drug
Choose the candidate finding in lipid lowerers-simvastatin (Simvastatin, abbreviation Sim) and this seminar early-stage Study
Fat-reducing medicament-number is SIPI-7623 (compound 5 in patent CN 102838505A), determines compound 7 for height
The blood fat reducing drug effect of fat rat.The experimental result display compound 7 of Fig. 1, Fig. 2, Fig. 3 and Fig. 4 is in High fat diet rats model
In can significantly reduce rat fat.TG reducing and LDL-C level and control compounds when oral dose is for 20mg/kg
SIPI-7623 oral dose is suitable for 80mg/kg；Fall TC and TG level and contrast when oral dose is for 80mg/kg
Compound SIPI-7623 oral dose is suitable for 80mg/kg, but fall LDL-C effect is better than SIPI-7623.
Claims (13)
1. compound or its pharmaceutically acceptable salt, shown in its structural formula such as 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；R1AndAny the position of substitution that group is located on phenyl ring.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt are it is characterised in that described halogen is selected from fluorine, chlorine, bromine or iodine.
3. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt are it is characterised in that n1 is 0.
4. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt are it is characterised in that n2 is 0.
5. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt are it is characterised in that n1 is 0, n2 is 0.
6. compound as claimed in claim 1 or 2, possesses following structural formula：
7. according to one claim of any of the above compound synthetic method, comprise the following steps：1), compound shown in formula (II) is dissolved in after appropriate solvent Deca oxalyl chloride under the DMF of catalytic amount and formula (III) shown in chloride compounds are obtained, 2), by compound shown in formula (III) and compound shown in formula (IV) under base catalysiss, in appropriate solvent, reaction obtains compound shown in formula (I), and reaction equation is shown in following：
Wherein：R in compound shown in formula (IV) and compound shown in formula (I) in reaction equation1, n1, n2 definition consistent, and with above claim in compound shown in described formula (I) in R1, n1, n2 definition consistent；
Step 1) described in appropriate solvent be selected from dichloromethane, chloroform, ethyl acetate, oxolane, acetone,
Step 2) described in alkali be selected from triethylamine, N, N- diisopropylamine, pyridine, sodium hydroxide,
Step 2) described in appropriate solvent be selected from dichloromethane, chloroform, oxolane, N,N-dimethylformamide, pyridine, dioxane/water or its mixed solvent.
8. synthetic method according to claim 7, wherein, step 2) described in alkali be selected from triethylamine or sodium hydroxide.
9. synthetic method according to claim 7, wherein, step 2) described in appropriate solvent be selected from dichloromethane, dioxane/water.
10. comprise the pharmaceutical composition of compound described in claim 1-6 any one or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
11. pharmaceutical compositions as claimed in claim 10 are it is characterised in that it is tablet, pill, powder, liquid, suspension, emulsion, granule, capsule, suppository or injection form.
12. as described in claim 1-6 any one compound or its pharmaceutically acceptable salt as the application of FXR antagonist.
13. compound or its pharmaceutically acceptable salt applications in preparing serum regulating drug as described in claim 1-6 any one.
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Citations (7)
| 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 |
| US20060167263A1 (en) * | 2005-01-21 | 2006-07-27 | Wilde Richard G | 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 |
-
2015
- 2015-09-01 CN CN201510552009.8A patent/CN106478447B/en active Active
Patent Citations (7)
| 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 |
| US20060167263A1 (en) * | 2005-01-21 | 2006-07-27 | Wilde Richard G | 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 (2)
| Title |
|---|
| L. -F. TIETZE，TH. EICHER: "《精细有机合成 有机化学实践中的反应与合成 》", 31 December 1992 * |
| 张三奇等: "具有降压和降血脂活性的二氢吡啶衍生物的合成", 《药学学报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107602389A (en) * | 2017-08-11 | 2018-01-19 | 扬子江药业集团有限公司 | A kind of Fenofibric Acid analog and preparation method thereof |
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