CN105037477B - Sodium taurocholate cotransporting polypeptide (NTCP) inhibitor - Google Patents
Sodium taurocholate cotransporting polypeptide (NTCP) inhibitor Download PDFInfo
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 21
- 108091006611 SLC10A1 Proteins 0.000 title claims description 36
- 102100021988 Sodium/bile acid cotransporter Human genes 0.000 title claims description 35
- 108010003524 sodium-bile acid cotransporter Proteins 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 12
- 239000004380 Cholic acid Substances 0.000 claims description 10
- 229960002471 cholic acid Drugs 0.000 claims description 10
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 7
- 235000019416 cholic acid Nutrition 0.000 claims description 7
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 7
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 claims description 6
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 claims description 6
- 229960001661 ursodiol Drugs 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 239000003613 bile acid Substances 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000033228 biological regulation Effects 0.000 abstract description 3
- 230000002155 anti-virotic effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 230000002503 metabolic effect Effects 0.000 abstract 1
- 210000004185 liver Anatomy 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960002685 biotin Drugs 0.000 description 6
- 239000011616 biotin Substances 0.000 description 6
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940099352 cholate Drugs 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 206010008635 Cholestasis Diseases 0.000 description 3
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229910001415 sodium ion Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- -1 ursodeoxycholic acid compound Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108091006671 Ion Transporter Proteins 0.000 description 1
- 102000037862 Ion Transporter Human genes 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 108091006172 SLC21 Proteins 0.000 description 1
- 102100032846 Solute carrier organic anion transporter family member 1A2 Human genes 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000010235 enterohepatic circulation Effects 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000031142 liver development Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000003041 virtual screening Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Steroid Compounds (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
Abstract
The invention relates to synthesis of a novel sodium taurocholate cotransporting polypeptide (NTCP) inhibitor and inhibiting effects of the inhibitor on the NTCP. The experimental research indicates that the compound has high inhibition activity for NTCP and indicates directions for antivirus, anti-bile siltation and metabolic regulation effects of anti-bile acid transporting drugs. The compound or composition thereof is hopeful to be developed into a novel NTCP inhibitor with great potential.
Description
Technical field:
The present invention relates to the synthesis of biotin-cholic acid/ursodeoxycholic acid compound and its inhibitory action to NTCP.
Background technology:
The sodium ion taurocholic acid found on hepatocyte cotransports polypeptide (sodium-taurocholate co-
Transporting polypeptide, NTCP), it is that surface of hepatocytes basement membrane is distributed in by SLC10A1 gene codes
Transport protein, is the important channel albumen in sodium salt enterohepatic circulation of bile acid.People's NTCP albumen contains 349 aminoacid, molecular weight
56KDa, the homology for having 77% with rat NTCP albumen, containing 9 transmembrane regions.The NTCP albumen overwhelming majority expression of people is in liver
It is dirty, it is positioned at hepatocyte substrate side.NTCP has very high transhipment affinity to conjunction type cholate, is that liver is absorbed from blood
The main thoroughfare albumen of cholate, while the cholate in can making blood maintains very low level.
Multiple researchs show that the suppression of NTCP can affect the hepato-enteric circulation of cholic acid, suppress cholic acid to enter enter liver from blood
It is dirty, so as to alleviate cholestasis, reduce metaboilic level.The case for reporting a NTCP point mutation in 2015, involved girl baby by
In the mutain NTCP for carrying NTCPR252H, cause bile acid transport activity to reduce, the Bile acid concentrations in serum have reached 445 μM
It is (normal<16 μM), and occur in that various metabolism associated adjustment factor contents are low and the symptom such as growth retardation, but liver development is just
Often.Therefore, the suppression of NTCP can block cholic acid reclaim enter liver, can play latent in anti-cholestasis and Metabolism regulation
Using value.
2012, Li Wenhui seminar also found that NTCP is that hepatitis b virus hbv enters hepatocellular receptor, and this is also
The important breakthrough of HBV researchs.Follow-up research shows that NTCP inhibitor can suppress HBV infection hepatocyte, is treating hepatitis B
Medicament research and development provides good theoretical basiss.
And, in liver in addition to NTCP, also a large amount of sodium ion dependent/non-dependent cholate transport proteins, such as organic the moon
Ion transporter family (OATPs), can perform the function similar with NTCP, cholate is transported to liver from blood
In, therefore the disappearance of NTCP does not result in pathological changes clinically.Based on this, suppress NTCP cause in theory significantly
Side effect.
James E.Polli carry out research discovery to chlolic acid derivatives, and such compound has NTCP inhibitory activity
(International Journal of Pharmaceutics 396(2010)111–118;Journal of
Pharmaceutical Sciences, 2011.100 (3), 1184-1195), James E.Polli in 2013 and its team into
Member adopts Pharmacophore Model and Bayesian model, carries out the virtual screening of NTCP inhibitor to chlolic acid derivatives, as a result finds 31
Individual drug molecule is used as lead compound molecule, wherein 27 inhibitor do not report the chemical combination for suppressing NTCP activity before being
Thing, and several inhibitor therein are through surveying discovery living, respectively with curative effects such as antifungal, lipidemia, resisting hypertension
(Mol Pharm.2013,10(3):1008–1019)。
New bio element-cholic acid/ursodeoxycholic acids compound according to the present invention, suppresses to live with very strong NTCP
Property, and such compound is used as NTCP inhibitor, so far there is not yet relevant report both domestic and external.It is according to the present invention new
NTCP inhibitor, is that antiviral, anti-cholestasis and the Metabolism regulation effect of anti-bile acid transport medicine specifies direction.
The content of the invention:
It is an object of the invention to provide new bio element-cholic acid/ursodesoxycholic acid Na-like ions taurocholic acid corotation
Fortune peptide inhibitor.
The second object of the present invention is to provide the method for preparing the compound.
The third object of the present invention is to provide application of the compound in NTCP is suppressed.
The fourth object of the present invention is to provide the compound for active ingredient and pharmaceutically acceptable carrier composition
Pharmaceutical composition and its inhibitory action to NTCP.
Shown in the structure of compound of the present invention such as formula (1):
The synthetic method of compound (I) of the present invention is, by the contracting of bis- replacement diethylamine of biotin (II) and N, N-
Reaction prepare compound (IV) is closed, compound (IV) is dissolved in dichloromethane, be passed through the de- Boc protection groups of HCl gas, be obtained
Compound (V), compound (V) prepare corresponding target compound (I) with cholic acid or ursodeoxycholic acid reaction.
Description of the drawings:
Fig. 1:Compound is to NTCP Activity determination results
Wherein:BCA:Compound I-1;BUDCA:Compound I-2
Specific embodiment:
Following examples only help those skilled in the art to more fully understand the present invention, but limit this never in any form
Invention.
《Embodiment 1》The synthesis of N-Boc-N- methyl ethylenediamines-biotin (IV)
Biotin (II, 11.68g, 47.82mM), 1.5eq HOBt (9.69g), 2.0eq EDCI (18.34g) are added
In the DMF of 25mL dried over anhydrous, electromagnetic agitation 2h.It is subsequently adding 2.0eq DIEA (15.78mL) and N-Boc-N- methyl second two
Amine (III, 10.0g, 57.38mM), is stirred overnight.500ml water quenchings are added to go out.Reactant liquor is extracted with DCM (3 × 150mL), 1N
HCl (3 × 100mL), 1N NaOH (3 × 100mL) and saturated aqueous common salt (2 × 100mL) washing.The anhydrous Mg of organic layer2SO4It is dry
It is dry, filter, be spin-dried for, obtain white solid IV (14.52g), yield:75.82%.
《Embodiment 2》(V) synthesis of N- methyl ethylenediamines-biotin
IV (10.01g, 25mM) is dissolved in dichloromethane (60mL), is led to dry hydrogen chloride gas 2.5h at room temperature, is continued
Stirring 1.5h.Reactant liquor is spin-dried for, is vacuum dried, is obtained white solid V (8.34g), yield:99.1%.
《Embodiment 3》The synthesis of CA-N- methyl ethylenediamines-biotin (I-1)
Cholic acid (2.04g, 5mM), 1.5eq HOBt (1.08g), 2.0eq EDCI (1.98g) are added into 10mL dried over anhydrous
DMF in, electromagnetic agitation 2h.3.6eq DBU (2.79g) and V (1.52g, 4.51mM) are subsequently adding, are stirred overnight.
500ml water quenchings are added to go out.Reactant liquor is extracted with DCM (3 × 30mL) respectively, 1N HCl (3 × 30mL), 1NNaOH (3
× 30mL), and saturated aqueous common salt (2 × 40mL) washing.The anhydrous Mg of organic layer2SO4It is dried, filters, be spin-dried for, obtain yellow oily
Liquid, obtains I-1 white solids (1.76g), yield with silica column purification:51.2%.
《Embodiment 4》The synthesis of UDCA-N- methyl ethylenediamines-biotin (I-2)
Ursodesoxycholic acid (2.99g, 7.61mM), 1.5eq HOBt (1.64g), 2.0eq EDCI (3.01g) are added
In the DMF of 10mL dried over anhydrous, electromagnetic agitation 2h.3.6eq DBU (4.24g) and V (2.32g, 6.87mM) are subsequently adding, are stirred
Overnight.100mL water quenchings are added to go out.Reactant liquor is extracted with DCM (3 × 30mL) respectively, 1N HCl (3 × 30mL), 1N NaOH (3 ×
30mL), wash with saturated aqueous common salt (2 × 40mL).The anhydrous Mg of organic layer2SO4It is dried, filters, be spin-dried for, obtain yellow oily liquid
Body, obtains white solid I-2 (2.35g), yield with silica column purification:45.8%.
《Embodiment 5》Biological activity assay result
The main Physiological Function of NTCP is transport cholic acid, can be with the bile acid transport efficiency of suppression NTCP come detection compound
Inhibitory action to NTCP.After the high expression NTCP of Mus liver parenchymal cell, suppression of the compound to NTCP is determined using H3 intake methods
Make and use.With the taurocholic acid of buffer H3 labellings to 10 μM, and will be the I-1 or I-2 of variable concentrations mixed, while
Process cell 10 minutes, then discard culture fluid, cells are cleaned 3 times with the taurocholic acid without H3 labellings, then cell lysis
Carry out the measure of H3.As a result see Fig. 1, show that I-1 and I-2 can clearly suppress the activity of NTCP.
Preliminary Results show that there is new bio element-cholic acid/ursodeoxycholic acid compound good NTCP to suppress to live
Property, as a class have potential NTCP inhibitor be worth carrying out deeper into research and development, be anti-bile acid transport medicine
Antivirus action specify research direction.
Claims (5)
1. a Na-like ions taurocholic acid cotransports peptide inhibitor, and its structure is as shown in logical formula (I):
R1=
R2, R3=H, C1-C8Alkyl
N=1-10.
2. the method for preparing inhibitor described in claim 1, is characterized in that, the synthetic route of the inhibitor (I) is, by life
The condensation reaction prepare compound (IV) of thing element (II) and bis- replacement diethylamine of N, N-, compound (IV) are dissolved in dichloromethane
In, the de- Boc protection groups of HCl gas are passed through, compound (V), compound (V) and cholic acid or ursodeoxycholic acid reaction is prepared
Prepare desired inhibitor (I):
Wherein R2、R3, n is as defined in claim 1.
3. application of the inhibitor described in claim 1 in NTCP inhibitor is prepared.
4. the medicine for being constituted with pharmaceutically acceptable one or more carrier with inhibitor described in claim 1 as effective ingredient
Compositionss.
5. application of the compositionss described in claim 4 in NTCP inhibitor is prepared.
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