CN102153610B - Nitric oxide donor type bile acid derivatives as well as preparation methods and medicinal application thereof - Google Patents

Nitric oxide donor type bile acid derivatives as well as preparation methods and medicinal application thereof Download PDF

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CN102153610B
CN102153610B CN2011100473317A CN201110047331A CN102153610B CN 102153610 B CN102153610 B CN 102153610B CN 2011100473317 A CN2011100473317 A CN 2011100473317A CN 201110047331 A CN201110047331 A CN 201110047331A CN 102153610 B CN102153610 B CN 102153610B
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oxygen
oxadiazole
benzenesulfonyl
beta
cholestane
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CN102153610A (en
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赖宜生
刘文清
张之昊
季晖
张奕华
崔冉
叶小磊
李月珍
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention relates to the field of biomedicine, in particular to nitric oxide donor type bile acid derivatives shown as general formulas (I) and (II) or medicinally acceptable salts, preparation methods and medicinal application of the compounds, and particularly application to preparation of anti-tumor medicaments. Pharmacological experiment results show that the nitric oxide donor type bile acid derivatives have good anti-tumor activity and can be used for preparing the anti-tumor medicaments in clinic.

Description

Nitric oxide donator type bile acid derivative, its preparation method and medicinal use
Technical field
The present invention relates to biomedicine field; Be specifically related to one type of nitric oxide donator type bile acid derivative or its medically acceptable salt; Their preparation method contains the medicinal compsns of these verivates and their medicinal use, particularly the application in the preparation antitumor drug.
Background technology
Nitrogen protoxide (NO) is courier's material and an effector molecule important in the mammalian body, intravital multiple physiology of participation machine and pathologic process.In recent years, the effect of NO in generation, development and the death of tumour become one of oncotherapy hot research fields.Big quantity research shows that the NO that continues lower concentration in the body can promote the growth of cell to suppress apoptosis; The NO of high density then produces cytotoxicity, inducing apoptosis of tumour cell, the diffusion of prevention tumour cell and transfer (Nitric Oxide, 2008,19,192-198).Yet,, be easy to see through microbial film because NO is a kind of active hydroxyl radical gas molecule; And the transformation period is short; Add that its effect in vivo is extremely extensive, and possibly produce toxic side effect in some cases, therefore use NO treatment tumour and exist shortcomings such as poor controllability and shortage target property.People have carried out the research of NO donator type antitumor drug for this reason.
Bile acide is present unique orally active small molecules hepatic targeting drug carrier, its have in vivo special movement system (Mol Pharm, 2010,7,291-298).The bile acid transport system has following characteristics: 1. become interior liver sausage circulation every day of human body 6-15 time, heavily absorbed in circulation greater than 95% bile acide, therefore have high efficiency; 2. bile acide carries out the liver sausage circulation through the special translocator of expressing on liver/intestinal cells film, has embodied the specificity of bile acid transport; 3. the translocator on bile acide and the liver plasma membrane has special identification and binding ability, can be transported to liver effectively, therefore has organotropism; 4. bile acide has good bio-compatibility (Cell Mol Life Sci, 2008,65,2461-2483 as endogenic natural aglucon; Molecules, 2007,12,1859-1889).
Figure BSA00000440844000011
Ursodesoxycholic acid (UDCA) is a kind of endogenous wetting ability bile acide in the human body bile pond, have protect the liver, cholagogic, chemotherapy sensitizing and multiple biological activity such as antitumor (Biochim Biophys Acta, 2009,1788,507-513).Chenodiol (CDCA) is a kind of hydrophobicity bile acide, and it has good solvency action to the SUV gallbladdergallstonecholetithiasis, in addition CDCA have also that stronger cholagogic is antibiotic, anti-inflammatory and biological activity such as apoptosis-induced (Nutr Cancer, 1998,31,111-8).
Multinomial research shows, helps improving the liver picked-up and the bioavailability of medicine with bile acide as pharmaceutical carrier, improves curative effect, reduce toxicity (Molecules, 2007,12,1859-1889).
Summary of the invention
The invention discloses nitric oxide donator type bile acid derivative, its preparation method and medicinal use.Compound disclosed by the invention is the nitric oxide donator type bile acid derivative shown in general formula (I), (II) or its medically acceptable salt:
Figure BSA00000440844000012
Wherein:
R 1Be selected from α-OH or β-OH;
R 2Be selected from OH or C 1-6Alkanoyloxy;
-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein:
X is selected from O or NH;
Y is selected from C 2-6Alkyl, C 2-4OC 2-4Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl;
-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, α-Bing Ansuan, Beta-alanine, leucine; Phenylalanine(Phe), γ-An Jidingsuan, Xie Ansuan, Isoleucine, methionine(Met); Halfcystine, tyrosine, tryptophane, l-arginine, proline(Pro) or Histidine; Described amino acid whose L-or the D-type of being configured as.
Further, the nitric oxide donator type bile acid derivative shown in general formula (I), (II) or its medically acceptable salt is characterized in that:
In the general formula (I), R 1Be selected from α-OH or β-OH; R 2Be selected from OH;-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein, X is selected from O or NH; Y is selected from C 2-6Alkyl, C 2-4OC 2-4Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl;-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, α-Bing Ansuan, Beta-alanine, leucine, phenylalanine(Phe); Described amino acid whose L-or the D-type of being configured as;
In the general formula (II), R 1Be selected from α-OH or β-OH;-CO-L-O-is selected from-CO-X-Y-O-, and wherein, X is selected from O or NH; Y is selected from C 2-4Alkyl, C 2-4OC 2-4Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl.
Further, the nitric oxide donator type bile acid derivative shown in general formula (I), (II) or its medically acceptable salt is characterized in that:
In the general formula (I), work as R 1When being selected from α-OH, R 2Be selected from OH;-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein, X is selected from O or NH; Y is selected from C 2-6Alkyl, C 4Alkynyl;-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, Beta-alanine, L-leucine, L-phenylalanine(Phe); Work as R 1When being selected from β-OH, R 2Be selected from OH;-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein, X is selected from O or NH; Y is selected from C 2-6Alkyl, C 2OC 2Alkyl, C 4Alkynyl;-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, Beta-alanine, L-L-Ala, L-phenylalanine(Phe);
Among the general formula I I, work as R 1When being selected from α-OH ,-CO-L-O-is selected from-CO-X-Y-O-, and wherein, X is selected from O or NH; Y is selected from C 2-4Alkyl; Work as R 1When being selected from β-OH ,-CO-L-O-is selected from-CO-X-Y-O-, and wherein, X is selected from O; Y is selected from C 3-4Alkyl.
Specifically, general formula (I) and (II) shown in the nitric oxide donator type bile acid derivative preferably from following compounds:
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] ester (compound number: I 1, down together)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester (I 2)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester (I 3)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl] ester (I 4)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[2-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl] ester (I 5)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne base] ester (I 6)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] amyl group] ester (I 7)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] hexyl] ester (I 8)
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acyl group-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] amine (I 9)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester (I 10)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 11)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 12)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester (I 13)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester (I 14)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester (I 15)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester (I 16)
Own ester (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 17)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine (I 18)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester (I 19)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 20)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 21)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester (I 22)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester (I 23)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester (I 24)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester (I 25)
Own ester (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 26)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine (I 27)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 28)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester (I 29)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester (I 30)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester (I 31)
Own ester (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 32)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-β-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine (I 33)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 34)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 35)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester (I 36)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester (I 37)
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine (I 38)
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] ester (I 39)
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester (I 40)
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester (I 41)
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl] ester (I 42)
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne base] ester (I 43)
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] hexyl] ester (I 44)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 45)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 46)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester (I 47)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester (I 48)
Own ester (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 49)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine (I 50)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 51)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester (I 52)
Own ester (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 53)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 54)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine (I 55)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propylamine (I 56)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 57)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester (I 58)
Own ester (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 59)
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine (I 60)
3 α-[4-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 beta-hydroxy-5 β-cholestane-24-acid (II 1)
3 α-[4-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butoxy]-1,4-dioxo butoxy]-7 beta-hydroxy-5 β-cholestane-24-acid (II 2)
3 α-[4-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butoxy]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid (II 3)
3 α-[4-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid (II 4)
3 α-[4-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] oxyethyl group]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid (II 5)
3 α-[4-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid (II 6)
3 α-[4-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethylamino-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid (II 7)
The code name of compound is equal to the pairing compound of code name here in the following pharmacological evaluation.
Described compound comprises all conformers, optically active isomer and the racemic modification of general formula (I), (II) compound, diastereomer and tautomer and steric isomer, and the mixtinite of any above-mentioned form.
Another purpose of the present invention is to provide the formula of the present invention (I) and (II) preparation method of compound, and wherein, the preparation method of formula (I) compound comprises the steps:
Step I: under the alkaline reagents effect, 3,4-two benzenesulfonyls-2-oxygen-1,2,5-oxadiazole and corresponding diol or hydramine (HX-Y-OH) reaction makes the compound shown in the formula (a):
Figure BSA00000440844000041
Wherein, the definition of X and Y as previously mentioned;
Compound is characterised in that shown in the preparation formula (a); Alkaline reagents is selected from one or more in sodium hydroxide, Pottasium Hydroxide, yellow soda ash or the salt of wormwood; Solvent is methylene dichloride, chloroform, THF, ETHYLE ACETATE, 1; Among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF one or more, temperature of reaction are room temperature, and the reaction times is 1-24 hour;
Step I i: under condensing agent and 4-Dimethylamino pyridine (DMAP) effect, formula (a) compound and Boc-amino acid (Boc-NH-A-CO 2H) condensation makes formula (b), takes off Boc-protection base through trifluoroacetic acid (TFA) again and makes the compound shown in the formula (c):
Figure BSA00000440844000051
Wherein, the definition of NH-A-CO, X and Y as previously mentioned;
Compound is characterised in that shown in the preparation formula (c); Condensing agent is selected from 1,3-NSC 57182 (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) or N, N-DIC (DIC); Solvent is selected from methylene dichloride, chloroform, THF, ETHYLE ACETATE, ethyl formate, methyl acetate, 1; Among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF one or more, temperature of reaction are-10-30 ℃, and the reaction times is 1-48 hour;
Step I ii: under the condensing agent effect, formula (a) compound or formula (c) compound and the condensation of bile acide parent make the compound shown in the formula (I):
Figure BSA00000440844000052
Wherein, R 1, R 2, NH-A-CO, L, X and Y definition as previously mentioned;
Preparation formula (I) compound is characterised in that; Condensing agent is selected from 1; 3-NSC 57182 (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl), N; N-DIC (DIC), Vinyl chloroformate or methyl-chloroformate, solvent are selected from methylene dichloride, chloroform, THF, ETHYLE ACETATE, ethyl formate, methyl acetate, 1, one or more among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF; Temperature of reaction is-10-50 ℃, and the reaction times is 1-48 hour;
The preparation method of formula (II) compound comprises the steps:
Step I v: (bile acid) is raw material with bile acide, under the trifluoroacetic acid effect, makes the compound shown in the formula (d) with trimethyl carbinol generation esterification:
Wherein, R 1Definition as previously mentioned;
Preparation formula (d) compound is characterised in that, trimethyl carbinol charging capacity be the bile acide molar weight 5-20 doubly, temperature of reaction is-10-50 ℃, the reaction times is 10-48 hour;
Step v: formula (d) compound makes the compound shown in the formula (e) with the Succinic anhydried reaction under the DMAP effect:
Figure BSA00000440844000061
Wherein, R 1Definition as previously mentioned;
Preparation formula (e) compound is characterised in that; The charging capacity of Succinic anhydried is 1-20 a times of formula (d) compound molar weight; Solvent is selected from methylene dichloride, chloroform, THF, 1; Among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF one or more, temperature of reaction are reflux temperature, and the reaction times is 12-48 hour;
Step vi: formula (e) compound room temperature makes the compound shown in the formula (f) with formula (a) compound condensation under DCC and DMAP effect:
Figure BSA00000440844000062
Wherein, R 1, L, X and Y definition as previously mentioned;
Preparation formula (f) compound is characterised in that solvent is selected from one or more in methylene dichloride, chloroform or the THF, and the reaction times is 1-48 hour;
Step vii: formula (f) compound removes tertiary butyl protection and makes the compound shown in the formula (II) under the trifluoracetic acid effect:
Figure BSA00000440844000063
Wherein, R 1, L, X and Y definition as previously mentioned.
Preparation formula (I) compound is characterised in that, condensing agent is preferred 1,3-NSC 57182 (DCC) or Vinyl chloroformate, and preferred anhydrous methylene chloride of solvent or anhydrous tetrahydro furan, temperature of reaction is-10-25 ℃, the reaction times is 24 hours.
Preparation formula (d) compound is characterised in that trimethyl carbinol charging capacity is 10 times of bile acide molar weight, temperature of reaction is-and 10-25 ℃, the reaction times is 25 hours.
Further purpose of the present invention is to provide a kind of pharmaceutical composition that contains invention general formula (I), (II) compound or its medically acceptable salt and the pharmaceutically acceptable carrier of effective dosage.
A purpose more of the present invention provides general formula of the present invention (I), the application of (II) compound in the preparation antitumor drug, especially treats liver cancer, kidney, lung cancer, mammary cancer, the cancer of the brain, the application in the tumour medicines such as cancer of the stomach and colorectal carcinoma.
The pharmacological experimental method and the result of the anti-tumor activity of The compounds of this invention are following:
(1) anti tumor activity in vitro of nitric oxide donator type ursodeoxycholic acid derivative test
Adopt the antiproliferative activity of blue colourimetry (MTT) evaluation objective of tetramethyl-nitrogen azoles compound to 8 kinds of human cancer cell strains and people's normal liver cell.Mtt assay has been widely used in the responsive mensuration of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy etc.Positive control drug is Zorubicin (ADR) and UDCA, and ADR is widely used clinically at present antitumor drug.
Cell strain: human liver cancer cell Hep 3B, human breast cancer cell MCF7, MDA-MB-231, human renal carcinoma cell 786-O, OS-RC-2, human lung cancer cell A549, H460, people's brain cancer cell U251 and people's normal liver cell LO2.
Experimental technique: compound is dissolved with DMSO, be diluted to concentration with PBS and be respectively 1 * 10 -7, 1 * 10 -6, 1 * 10 -5Mol/L receives test solution.Get and be in one bottle of exponential phase of growth, growth conditions good cell, add 0.25% tryptic digestion, attached cell is come off, process every milliliter and contain 2 * 10 4-4 * 10 4The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L put constant temperature CO 2Cultivated 24 hours in the incubator.Change liquid, adding receives test solution, and every hole 20 μ L cultivated 48 hours.In the blue adding of tetramethyl-nitrogen azoles 96 orifice plates, every hole 20 μ L, reaction is 4 hours in the incubator.Supernatant is removed in suction, adds DMSO, every hole 150 μ L, and jolting is 5 minutes on the dull and stereotyped shaking table.Use enzyme-linked immunosorbent assay instrument in the optical density of wavelength, calculate cell inhibitory rate as the every hole of mensuration, 570nm place.Part of test results is as shown in table 1.
Figure BSA00000440844000071
Table 1 part of compounds of the present invention is to tumor cell proliferation inhibition rate % (10 μ mol/L)
Figure BSA00000440844000072
Figure BSA00000440844000081
Annotate: ADR: Zorubicin; UDCA: ursodesoxycholic acid.
(2) anti tumor activity in vitro of nitric oxide donator type chenodeoxycholic acid derivatives test
Cell strain: human colon cancer cell Caco2, human breast cancer cell MCF7, gastric carcinoma cells MGC803, human liver cancer cell HepG2, SMC7721 and Bel7402.
Experimental technique: adopt mtt assay (operation is the same) to measure the restraining effect of nitric oxide donator type chenodeoxycholic acid derivatives to above-mentioned 6 kinds of human cancer cell strains growth, and calculate its tumor cell proliferation half-inhibition concentration, wherein compound concentration is: 5 * 10 -5μ M, 2.5 * 10 -5μ M, 1.25 * 10 -5μ M, 6.25 * 10 -6μ M, 3.13 * 10 -6μ M; Positive control drug is 5 FU 5 fluorouracil (5-FU) and CDCA, and 5-FU is widely used clinically at present antitumor drug, and wherein the positive control concentration is: 2 * 10 -4μ M, 1 * 10 -4μ M, 5 * 10 -5μ M, 2.5 * 10 -5μ M, 1.25 * 10 -5μ M.Part of test results is as shown in table 2.
Table 2 part of compounds of the present invention is to the half-inhibition concentration (IC of tumor cell proliferation 50, μ mol/L)
Figure BSA00000440844000082
Annotate: the 5-FU:5-Fluracil; CDCA: Chenodiol.
The pharmacological results shows; The nitric oxide donator type bile acid derivative has restraining effect to some extent to human tumor cell's propagation; All antitumor activity of compound all obviously are better than parent ursodesoxycholic acid and Chenodiol, and most antitumor activity of compound is superior to positive control drug Zorubicin and 5 FU 5 fluorouracil.
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative fully, they only are used to come the specific descriptions to the present invention, are not to be understood that to be limitation of the present invention.Used ursodesoxycholic acid of the present invention and Chenodiol are purchased the crystalline substance pure reagent ltd in Shanghai, content＞98.5%.
Embodiment 1
2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] alcoholic acid preparation (a 1)
With 0.56mL (10mmol) terepthaloyl moietie and 0.92g (2.5mmol) 3,4-two benzenesulfonyls-2-oxygen-1,2, the 5-oxadiazole is dissolved among the 10mLTHF; Splash into 0.5mL 25%NaOH solution, stirring at room reaction 2 hours, in the reaction solution impouring 20mL water, ETHYLE ACETATE (3 * 20mL) extractions; The saturated common salt water washing, anhydrous sodium sulfate drying filters concentrating under reduced pressure; The methanol-water recrystallization gets white solid 0.5g, yield 69%, m.p.118-120 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] ester 1)
With 0.35g (0.89mmol) ursodesoxycholic acid, 0.28g (0.98mmol) a 1, 0.24g (1.14mmol) DCC, 40mg (0.30mmol) DMAP and 15mL anhydrous methylene chloride add in the reaction flask successively, stirring at room reaction 24 hours, the filtering insolubles, concentrating under reduced pressure, column chromatography get white solid 0.29g, yield 49.6%, m.p.68-70 ℃.
ESI-MS：660.5[M+NH 4] +；
IR(KBr)v：3737，3390，2929，2860，1739，730，678cm -1；
1HNMR(300MHz，CDCl 3)δ：0.68(s，3H，CH 3)，1.93-2.02(t，2H，COCH 2)，3.58(br?s，2H，2×OH)，4.50-4.51(t，J＝3.0Hz，2H，OCH 2)，4.62-4.65(t，J＝4.5Hz，2H，OCH 2)，7.60-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.06-8.09(d，2H，ArH)ppm.
Embodiment 2
Preparation (a of 3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl alcohol 2)
With reference to a 1The preparation method, by 1, ammediol makes white solid, yield 77.3%, m.p.100-102 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester 2)
With reference to I 1The preparation method, by a 2Make white solid, yield 55.7%, m.p.74-76 ℃.
ESI-MS：674.5[M+NH 4] +；
IR(KBr)v：3394，2931，2862，1733，731，687cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66-0.68(d，3H，C 21-CH 3)，0.95(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，4.25-4.29(t，J＝6.0Hz，2H，OCH 2)，4.50-4.54(t，J＝6.0Hz，2H，OCH 2)，7.62-7.67(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 3
Preparation (a of 1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl alcohol 3)
With reference to a 1The preparation method, make white solid by 1,3 butylene glycol, yield 83%, m.p.101-103 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester 3)
With reference to I 1The preparation method, by a 3Make white solid, yield 19.4%, m.p.66-68 ℃.
ESI-MS：688.5[M+NH 4] +；
IR(KBr)v：3735，3390，2929，2860，1728，731，680cm -1；
1HNMR(300MHz，CDCl 3)：δ0.64-0.66(d，3H，C 21-CH 3)，0.94(s，6H，C 10，13-CH 3)，1.92-2.07(t，2H，COCH 2)，3.58(br?s，2H，2×OH)，4.45-4.50(t，J＝6.0Hz，2H，OCH 2)，5.10-5.16(m，1H，OCH)，7.62-7.67(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.07-8.09(d，2H，ArH)ppm.
Embodiment 4
Preparation (a of 4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butanols 4)
With reference to a 1The preparation method, by 1, the 4-butyleneglycol makes white solid, yield 82.8%, m.p.70-72 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl] ester 4)
With reference to I 1The preparation method, by a 4Make white solid, yield 58%, m.p.60-62 ℃.
ESI-MS：688.5[M+NH 4] +；
IR(KBr)v：3739，3394，3086，2923，2856，1749，729，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，0.95(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，4.14-4.18(t，J＝6.0Hz，2H，OCH 2)，4.45-4.49(t，J＝6.3Hz，2H，OCH 2)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.06-8.08(d，2H，ArH)ppm.
Embodiment 5
2-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] oxyethyl group] alcoholic acid preparation (a 5)
With reference to a 1The preparation method, make white solid by glycol ether, yield 73.3%, m.p.57-59 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[2-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl] ester 5)
With reference to I 1The preparation method, by a 5Make white solid, yield 39.8%, m.p.44-46 ℃.
ESI-MS：704.5[M+NH 4] +；
IR(KBr)v：3386，2931，2864，1733，727，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，3.79-3.82(t，J＝4.5Hz，2H，OCH 2)，3.92-3.94(t，J＝3.0Hz，2H，OCH 2)，4.26-4.29(t，J＝4.5Hz，2H，OCH 2)，4.56-4.59(t，J＝4.5Hz，2H，OCH 2)，7.60-7.66(t，2H，ArH)，7.74-7.77(t，1H，ArH)，8.06-8.10(d，2H，ArH)ppm.
Embodiment 6
Preparation (a of 4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne-1-alcohol 6)
With reference to a 1The preparation method, by 2-butyne-1, the 4-glycol makes white solid, yield 60%, m.p.110-112 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne base] ester 6)
With reference to I 1The preparation method, by a 6Make white solid, yield 68%, m.p.76-78 ℃.
ESI-MS：684.5[M+NH 4] +；
IR(KBr)v：3448，3419，2935，2864，1739，731，680cm -1；
1HNMR(300MHz，CDCl 3)：δ0.68(s，3H，C 21-CH 3)，1.92-2.07(t，2H，COCH 2)，3.58(br?s，2H，2×OH)，4.74(s，2H，OCH 2)，5.11(s，2H，OCH 2)，7.62-7.67(t，2H，ArH)，7.76-7.81(t，1H，ArH)，8.07-8.10(d，2H，ArH)ppm.
Embodiment 7
Preparation (a of 5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] amylalcohol 7)
With reference to a 1The preparation method, by 1, the 5-pentanediol makes white solid, yield 24%, m.p.110-112 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] amyl group] ester 7)
With reference to I 1The preparation method, by a 7Make white solid, yield 45.5%, m.p.55-57 ℃.
ESI-MS：702.5[M+NH 4] +；
IR(KBr)v：3388，2935，2864，1731，732，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.10-4.14(t，J＝6.3Hz，2H，OCH 2)，4.41-4.46(t，J＝6.3Hz，2H，OCH 2)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 8
Preparation (a of 6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] hexanol 8)
With reference to a 1The preparation method, by 1, the 6-pinakon makes white solid, yield 25.7%, m.p.109-112 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acid-[6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] hexyl] ester 8)
With reference to I 1The preparation method, by a 8Make white solid, yield 21.8%, m.p.79-82 ℃.
ESI-MS：716.5[M+NH 4] +；
IR(KBr)v：3739，3390，2925，2856，1737，727，682cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.0-4.11(t，J＝6.0Hz，2H，OCH 2)，4.40-4.44(t，J＝6.0Hz，2H，OCH 2)，7.60-7.65(t，2H，ArH)，7.74-7.79(t，1H，ArH)，8.01-8.07(d，2H，ArH)ppm.
Embodiment 9
Preparation (a of 2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 9)
With reference to a 1The preparation method, make white solid by thanomin, yield 85.8%, m.p.102-104 ℃.
3 α, the preparation (I of 7 beta-dihydroxyies-5 β-cholestane-24-acyl group-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] amine 9)
With reference to I 1The preparation method, by a 9Make white solid, yield 53.3%, m.p.135-137 ℃.
ESI-MS：659.5[M+NH 4] +；
IR(KBr)v：3737，3386，2933，2864，1737，729，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，3.49-3.60(m，2H，NCH 2)，3.58(br?s，2H，2×OH)，4.50-4.53(t，J＝4.8Hz，2H，OCH 2)，5.92-5.93(t，1H，NH)，7.61-7.68(t，2H，ArH)，7.76-7.81(t，1H，ArH)，8.06-8.08(d，2H，ArH)ppm.
Embodiment 10
Preparation (the b of N-Boc-glycocoll-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester 1)
With 0.32g (1.1mmol) a 1Be dissolved in 15mL CH 2Cl 2In, add 0.17g (1.0mmol) Boc-glycocoll successively, 0.26g (1.25mmol) DCC and 40mg (0.4mmol) DMAP, stirring at room reaction 24 hours is filtered, concentrating under reduced pressure, column chromatography for separation gets white solid 0.27g, yield 60%, m.p.90-92 ℃.
Preparation (the c of glycocoll-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester trifluoroacetate 1)
With 0.23g (0.52mmol) b 1Be dissolved in 10mL CH 2Cl 2In, the ice-water bath cooling is slow Dropwise 5 mL trifluoroacetic acid down, drips to finish in stirring at room reaction 2 hours, and concentrating under reduced pressure gets c 1, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester 10)
Get 0.13g (0.32mmol) UDCA and be dissolved in 15mL THF, the ice-water bath cooling adds 90.0mg (0.352mmol) N-methylmorpholine down successively, and 0.13g (0.48mmol) Vinyl chloroformate reacted 15-30 minute, adds 0.12g (0.352mmol) midbody c 1, sodium hydrogencarbonate 26.9mg is dissolved in behind the 3mL water adds in the reaction solution again, reacted 1.5 hours, column chromatography gets white solid 50mg, yield 21.8%, m.p.83-86 ℃.
ESI-MS：717.5[M+NH 4] +；
IR(KBr)v：3739，3394，3407，2931，2862，1745，729，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67-0.68(d，3H，C 21-CH 3)，1.93-2.05(t，2H，COCH 2)，3.58(br?s，2H，2×OH)，4.13-4.15(d，2H，NCH 2)，4.62-4.63(d，4H，2×OCH 2)，5.92-5.93(t，1H，NH)，7.61-7.68(t，2H，ArH)，7.76-7.81(t，1H，ArH)，8.06-8.08(d，2H，ArH)ppm.
Embodiment 11
Preparation (the b of N-Boc-glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 2)
With reference to b 1The preparation method, by a 2Make white solid, yield 76%, m.p.78-80 ℃.
Preparation (the c of glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 2)
With reference to c 1The preparation method by b 2Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 11)
With reference to I 10The preparation method, by c 2Make white solid, yield 41.4%, m.p.84-86 ℃.
ESI-MS：731.5[M+Cl] -；
IR(KBr)v：3735，3390，2929，2860，1743，731，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，0.95(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，4.07-4.08(d，2H，NCH 2)，4.36-4.40(t，J＝6.0Hz，2H，OCH 2)，4.50-4.54(t，J＝6.0Hz，2H，OCH 2)，5.98-6.02(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 12
Preparation (the b of N-Boc-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 3)
With reference to b 1The preparation method, by a 3Make white solid, yield 78.6%, m.p.84-86 ℃.
Preparation (the c of glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 3)
With reference to c 1The preparation method by b 3Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 12)
With reference to I 10The preparation method, by c 3Make white solid, yield 20.8%, m.p.110-113 ℃.
ESI-MS：745.5[M+H] +；
IR(KBr)v：3417，2929，2864，1737，727，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.07-4.08(d，2H，NCH 2)，4.50-4.54(t，J＝6.0Hz，2H，OCH 2)，5.19-5.25(m，1H，OCH)，5.97-6.01(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 13
Preparation (the b of N-Boc-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester 4)
With reference to b 1The preparation method, by a 4Make white solid, yield 78%, m.p.60-62 ℃.
Preparation (the c of glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester trifluoroacetate 4)
With reference to c 1The preparation method by b 4Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester 13)
With reference to I 10The preparation method, by c 4Make white solid, yield 50%, m.p.54-57 ℃.
ESI-MS：745.5[M+H] +；
IR(KBr)v：3737，3409，2933，2864，1743，731，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，0.94(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，4.06-4.08(d，2H，NCH 2)，4.25-4.29(t，J＝6.0Hz，2H，OCH 2)，4.45-4.48(t，J＝6.0Hz，2H，OCH 2)，5.92-5.93(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 14
Preparation (the b of N-Boc-glycocoll-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester 5)
With reference to b 1The preparation method, by a 5Make white solid, yield 45.2%, m.p.89-91 ℃.
Preparation (the c of glycocoll-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester trifluoroacetate 5)
With reference to c 1The preparation method by b 5Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester 14)
With reference to I 10The preparation method, by c 5Make white solid, yield 39.5%, m.p.68-72 ℃.
ESI-MS：761.5[M+H] +；
IR(KBr)v：3739，3392，3072，2931，2864，1749，730，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，0.95(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，3.73-3.76(t，J＝4.5Hz，2H，OCH 3)，3.80-3.83(t，J＝4.5Hz，2H，OCH 3)，4.06-4.10(d，2H，NCH 2)，4.35-4.38(t，J＝4.5Hz，2H，OCH 2)，4.56-4.59(t，J＝4.5Hz，2H，OCH 2)，5.98-6.07(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.07-8.09(d，2H，ArH)ppm.
Embodiment 15
Preparation (the b of N-Boc-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 6)
With reference to b 1The preparation method, by a 6Make white solid, yield 68%, m.p.88-90 ℃.
Preparation (the c of glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester trifluoroacetate 6)
With reference to c 1The preparation method by b 6Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 15)
With reference to I 10The preparation method, by c 6Make white solid, yield 19.6%, m.p.113-116 ℃.
ESI-MS：741.5[M+H] +；
IR(KBr)v：3737，3392，2929，2860，1743，725，680cm -1；
1HNMR(300MHz，CDCl 3)：δ0.68(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.12-4.14(d，2H，NCH 2)，4.82(s，2H，OCH 2)，5.10(s，2H，OCH 2)，5.92-5.93(t，1H，NH)，7.62-7.67(t，2H，ArH)，7.76-7.81(t，1H，ArH)，8.07-8.10(d，2H，ArH)ppm.
Embodiment 16
Preparation (the b of N-Boc-glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 7)
With reference to b 1The preparation method, by a 7Make oily matter, yield 72.2%.
Preparation (the c of glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester trifluoroacetate 7)
With reference to c 1The preparation method by b 7Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 16)
With reference to I 10The preparation method, by c 7Make white solid, yield 42.6%, m.p.83-86 ℃.
ESI-MS：759.5[M+H] +；
IR(KBr)v：3392，2931，2862，1739，729，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67-0.68(d，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.05-4.07(d，2H，NCH 2)，4.20-4.24(t，J＝6.3Hz，2H，OCH 2)，4.42-4.46(t，J＝6.3Hz，2H，OCH 2)，5.95-6.01(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.04-8.07(d，2H，ArH)ppm.
Embodiment 17
Preparation (the b of the own ester of N-Boc-glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 8)
With reference to b 1The preparation method, by a 8Make oily matter, yield 22.4%.
Preparation (the c of the own ester trifluoroacetate of glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 8)
With reference to c 1The preparation method by b 8Make, directly be used for next step reaction.
Preparation (the I of the own ester of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 17)
With reference to I 10The preparation method, by c 8Make white solid, yield 6.9%, m.p.112-115 ℃.
ESI-MS：773.5[M+H] +；
IR(KBr)v：3739，3411，3392，2925，2858，1741，727，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.68(s，3H，C 21-CH 3)，0.95(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，4.05-4.06(d，2H，NCH 2)，4.17-4.21(t，J＝6.3Hz，2H，OCH 2)，4.41-4.45(t，J＝6.3Hz，2H，OCH 2)，5.92-5.97(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 18
Preparation (the b of N-Boc-glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 9)
With reference to b 1The preparation method, by a 9Make oily matter, yield 76.9%.
Preparation (the c of glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine trifluoroacetate 9)
With reference to c 1The preparation method by b 9Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 18)
With reference to I 10The preparation method, by c 9Make white solid, yield 44.5%, m.p.85-87 ℃.
ESI-MS：716.5[M+H] +；
IR(KBr)v：3307，2923，2856，1739，730，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，3.77-3.79(d，2H，NCH 2)，3.98-4.00(d，2H，NCH 2)，4.50-4.53(t，J＝4.8Hz，2H，OCH 2)，6.22-6.28(t，1H，NH)，6.71-6.76(t，1H，NH)，7.63-7.68(t，2H，ArH)，7.76-7.79(t，1H，ArH)，8.07-8.10(d，2H，ArH)ppm.
Embodiment 19
Preparation (the b of N-Boc-L-L-Ala-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester 10)
0.32g (1.1mmol) a1 is dissolved in 15mL CH 2Cl 2In, add 0.2g (1.0mmol) Boc-L-L-Ala successively, 0.26g (1.25mmol) DCC and 40mg (0.4mmol) DMAP, stirring at room reaction 24 hours is filtered, concentrating under reduced pressure, column chromatography for separation gets white solid 0.33g, yield 72%, m.p.101-103 ℃.
Preparation (the c of L-L-Ala-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester trifluoroacetate 10)
With 0.33g (0.72mmol) b 10Be dissolved in 10mL CH 2Cl 2In, the ice-water bath cooling is slow Dropwise 5 mL trifluoroacetic acid down, drips to finish in stirring at room reaction 2 hours, and concentrating under reduced pressure gets c 10, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester 19)
Get 0.25g (0.64mmol) UDCA and be dissolved in 15mL THF, the ice-water bath cooling adds 0.18g (0.70mmol) N-methylmorpholine down successively, and 0.26g (0.96mmol) Vinyl chloroformate reacted 15-30 minute, adds 0.25g (0.70mmol) midbody c 10, the 53.8mg sodium hydrogencarbonate is dissolved in behind the 3mL water adds in the reaction solution again, reacted 1.5 hours, column chromatography gets white solid 60mg, yield 12.8%, m.p.86-89 ℃.
ESI-MS：731.5[M+NH 4] +；
IR(KBr)v：3735，3398，2933，2864，1745，730，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66-0.67(d，3H，C 21-CH 3)，0.94(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，4.56-4.61(t，2H，OCH 2)，4.62-4.66(t，2H，OCH 2)，5.95-6.03(d，1H，NH)，7.62-7.67(t，2H，ArH)，7.76-7.78(t，1H，ArH)，8.06-8.08(d，2H，ArH)ppm.
Embodiment 20
Preparation (the b of N-Boc-L-L-Ala-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 11)
With reference to b 10The preparation method, by a 2Make faint yellow oily thing, yield 70%, ESI-MS:505.9 [M+Cl] -Preparation (the c of L-L-Ala-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 11)
With reference to c 10The preparation method by b 11Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 20)
With reference to I 19The preparation method, by c 11Make white solid, yield 9.8%, m.p.91-93 ℃.
ESI-MS：745.5[M+H] +；
IR(KBr)v：3400，2927，2862，1739，729，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.31-4.35(t，J＝5.4Hz，2H，OCH 2)，4.50-4.54(t，J＝6.0Hz，2H，OCH 2)，4.58-4.62(m，1H，NCH)，5.97-5.99(d，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 21
Preparation (the b of N-Boc-L-L-Ala-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 12)
With reference to b 10The preparation method, by a 3Make white solid, yield 43.3%, m.p.98-101 ℃.
Preparation (the c of L-L-Ala-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 12)
With reference to c 10The preparation method by b 12Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 21)
According to I 19The preparation method, by c 12Make white solid, yield 47.8%, m.p.77-82 ℃.
ESI-MS：759.5[M+H] +；
IR(KBr)v：3735，3392，2927，2860，1739，730，678cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.47-4.51(t，J＝6.0Hz，2H，OCH 2)，4.52-4.58(m，1H，NCH)，5.18-5.31(m，J＝6.0Hz，1H，OCH)，5.96-5.98(d，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.77(t，1H，ArH)，8.04-8.08(d，2H，ArH)ppm.
Embodiment 22
Preparation (the b of N-Boc-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester 13)
With reference to b 10The preparation method, by a 4Make white solid, yield 52%, m.p.107-109 ℃.
Preparation (the c of L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester trifluoroacetate 13)
With reference to c 10The preparation method by b 13Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester 22)
With reference to I 19The preparation method, by c 13Make white solid, yield 43%, m.p.71-73 ℃.
ESI-MS：759.5[M+H] +；
IR(KBr)v：3402，2933，2864，1737，731，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66-0.67(d，3H，C 21-CH 3)，0.94(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，4.19-4.25(t，J＝5.4Hz，2H，OCH 2)，4.45-4.47(t，J＝3.0Hz，2H，OCH 2)，4.59-4.64(m，1H，NCH)，5.99-6.01(d，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.77(t，1H，ArH)，8.04-8.08(d，2H，ArH)ppm.
Embodiment 23
Preparation (the b of N-Boc-L-L-Ala-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] oxyethyl group] ethyl ester 14)
With reference to b 10The preparation method, by a 5Make white solid, yield 64%, m.p.127-129 ℃.
Preparation (the c of L-L-Ala-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] oxyethyl group] ethyl ester trifluoroacetate 14)
With reference to c 10The preparation method by b 14Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester 23)
With reference to I 19The preparation method, by c 14Make white solid, yield 19%, m.p.65-69 ℃.
ESI-MS：775.5[M+H] +；
IR(KBr)v：3739，3394，3319，2923，2856，1741，730，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(d，3H，C 21-CH 3)，0.94(s，6H，C 10，13-CH 3)，3.58(br?s，2H，2×OH)，3.80-3.83(t，J＝4.5Hz，2H，OCH 2)，3.91-3.94(t，J＝3.6Hz，2H，OCH 2)，4.30-4.36(t，J＝4.5Hz，2H，OCH 2)，4.56-4.59(t，J＝3.6Hz，2H，OCH 2)，4.61-4.66(m，1H，NCH)，6.02-6.07(d，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.07-8.09(d，2H，ArH)ppm.
Embodiment 24
Preparation (the b of N-Boc-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 15)
With reference to b 10The preparation method, by a 6Make white solid, yield 60%, m.p.113-115 ℃.
Preparation (the c of L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester trifluoroacetate 15)
With reference to c 10The preparation method by b 15Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 24)
With reference to I 19The preparation method, by c 15Make white solid, yield 16%, m.p.80-83 ℃.
ESI-MS：755.5[M+H] +；
IR(KBr)v：3737，3338，2929，2860，1731，731，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.68(s，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.63-4.67(m，1H，NCH)，4.81(s，2H，OCH 2)，5.11(s，2H，OCH 2)，5.93-5.96(d，1H，NH)，7.62-7.67(t，2H，ArH)，7.76-7.81(t，1H，ArH)，8.07-8.10(d，2H，ArH)ppm.
Embodiment 25
Preparation (the b of N-Boc-L-L-Ala-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 16)
With reference to b 10The preparation method, by a 7Make oily matter, yield 68%, m.p.80-82 ℃.
Preparation (the c of L-L-Ala-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester trifluoroacetate 16)
With reference to c 10The preparation method by b 16Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 25)
With reference to I 19The preparation method, by c 16Make white solid, yield 45.4%, m.p.59-62 ℃.
ESI-MS：773.5[M+H] +；
IR(KBr)v：3737，3388，2927，2860，1737，730，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67-0.68(d，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.19-4.21(t，J＝3.0Hz，2H，OCH 2)，4.43-4.45(t，J＝3.0Hz，2H，OCH 2)，4.59-4.61(m，1H，NCH)，6.02-6.04(d，1H，NH)，7.62-7.66(t，2H，ArH)，7.76-7.78(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 26
Preparation (the b of the own ester of N-Boc-L-L-Ala-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 17)
With reference to b 10The preparation method, by a 8Make oily matter, yield 57%, m.p.62-65 ℃.
Preparation (the c of the own ester trifluoroacetate of L-L-Ala-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 17)
With reference to c 10The preparation method by b 17Make, directly be used for next step reaction.
Preparation (the I of the own ester of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 26)
With reference to I 19The preparation method, by c 17Make white solid, yield 40.8%, m.p.68-73 ℃.
ESI-MS：787.5[M+H] +；
IR(KBr)v：3737，3390，3357，2929，2860，1739，731，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.68(d，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，4.15-4.19(t，J＝6.0Hz，2H，OCH 2)，4.41-4.45(t，J＝6.0Hz，2H，OCH 2)，4.58-4.62(m，1H，NCH)，6.00-6.02(d，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 27
Preparation (the b of N-Boc-L-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 18)
With reference to b 10The preparation method, by a 9Make oily matter, yield 44%, m.p.147-151 ℃.
Preparation (the c of L-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine trifluoroacetate 18)
With reference to c 10The preparation method by b 18Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 27)
With reference to I 19The preparation method, by c 18Make white solid, yield 23.9%, m.p.121-124 ℃.
ESI-MS：730.5[M+H] +；
IR(KBr)v：3737，3290，2923，2856，1739，725，678cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65-0.66(d，3H，C 21-CH 3)，3.58(br?s，2H，2×OH)，3.83-3.85(t，J＝3.0Hz，2H，OCH 2)，3.65-3.69(m，1H，NCH)，5.95-6.01(t，1H，NH)，6.75-6.77(d，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 28
Preparation (the b of N-Boc-Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 19)
With 0.345g (1.1mmol) a 3Be dissolved in 15mL CH 2Cl 2In, add 0.19g (1.0mmol) Boc-Beta-alanine successively, 0.26g (1.25mmol) DCC and 40mg (0.4mmol) DMAP, stirring at room reaction 24 hours is filtered, concentrating under reduced pressure, column chromatography for separation gets oily matter 350mg, yield 72%.
Preparation (the c of Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 19)
With 0.35g (0.72mmol) b 19Be dissolved in 10mL CH 2Cl 2In, the ice-water bath cooling slowly drips the 2mL trifluoroacetic acid down, drips and finishes in stirring at room reaction 2 hours, and concentrating under reduced pressure gets c 19, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 28)
Get 0.44g (1.11mmol) UDCA and be dissolved in 15mL THF, the ice-water bath cooling adds 0.12g (1.22mmol) N-methylmorpholine down successively, and 0.18g (1.66mmol) Vinyl chloroformate reacted 15-30 minute, adds 0.47g (1.22mmol) midbody c 19, add reaction solution after again the 93mg sodium hydrogencarbonate being dissolved in 3mL water, reacted 1.5 hours, column chromatography gets white solid 0.28g, yield 33.3%, m.p.89-92 ℃.
ESI-MS：759.5[M+H] +；
IR(KBr)v：3406，2931，2862，1730，730，690cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，2.50-2.55(t，2H，CH 2CO)，3.58(br?s，2H，2×OH)，4.47-4.50(t，J＝6.0Hz，2H，OCH 2)，5.16-5.18(m，1H，OCH)，6.75-6.77(d，1H，NH)，7.62-7.67(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.07-8.10(d，2H，ArH)ppm.
Embodiment 29
Preparation (the b of N-Boc-Beta-alanine-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester 20)
With reference to b 19The preparation method, by a 5Make oily matter, yield 26%.
Preparation (the c of Beta-alanine-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester trifluoroacetate 20)
With reference to c 19The preparation method by b 20Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester 29)
With reference to I 28The preparation method, by c 20Make white solid, yield 46.2%, m.p.60-65 ℃.
ESI-MS：775.5[M+H] +；
IR(KBr)v：3737，3392，2931，2862，1733，730，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66-0.70(d，3H，C 21-CH 3)，2.57-2.61(t，J＝5.4Hz，2H，CH 2CO)，3.58(br?s，2H，2×OH)，3.73-3.81(t，J＝4.5Hz，2H，OCH 2)，3.91-3.95(t，J＝4.5Hz，2H，OCH 2)，4.29-4.32(t，J＝4.5Hz，2H，OCH 2)，4.57-4.60(t，J＝4.5Hz，2H，OCH 2)，6.20-6.22(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.06-8.09(d，2H，ArH)ppm.
Embodiment 30
Preparation (the b of N-Boc-Beta-alanine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 21)
With reference to b 19The preparation method, by a 6Make oily matter, yield 54%.
Preparation (the c of Beta-alanine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester trifluoroacetate 21)
With reference to c 19The preparation method by b 21Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 30)
With reference to I 28The preparation method, by c 21Make white solid, yield 23.5%, m.p.85-90 ℃.
ESI-MS：755.5[M+H] +；
IR(KBr)v：3737，3409，3398，2931，2864，1741，729，680cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，0.94(s，6H，C 10，13-CH 3)，2.59-2.63(t，2H，CH 2CO)，3.58(brs，2H，2×OH)，4.77(s，2H，OCH 2)，5.11(s，2H，OCH 2)，5.92-5.97(t，1H，NH)，7.62-7.67(t，2H，ArH)，7.76-7.81(t，1H，ArH)，8.07-8.10(d，2H，ArH)ppm.
Embodiment 31
Preparation (the b of N-Boc-Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 22)
With reference to b 19The preparation method, by a 7Make oily matter, yield 66%.
Preparation (the c of Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester trifluoroacetate 22)
With reference to c 19The preparation method by b 22Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 31)
With reference to I 28The preparation method, by c 22Make white solid, yield 15.1%, m.p.76-80 ℃.
ESI-MS：773.5[M+H] +；
IR(KBr)v：3400，2923，2854，1730，727，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66-0.68(d，3H，C 21-CH 3)，2.54-2.58(m，2H，NCH 2)，3.58(br?s，2H，2×OH)，4.13-4.18(t，J＝6.3Hz，2H，OCH 2)，4.44-4.48(t，J＝6.0Hz，2H，OCH 2)，6.02-6.08(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.04-8.07(d，2H，ArH)ppm.
Embodiment 32
Preparation (the b of the own ester of N-Boc-Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 23)
With reference to b 19The preparation method, by a 8Make oily matter, yield 83%.
Preparation (the c of the own ester trifluoroacetate of Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 23)
With reference to c 19The preparation method by b 23Make, directly be used for next step reaction.
Preparation (the I of the own ester of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 32)
With reference to I 28The preparation method, by c 23Make white solid, yield 58.8%, m.p.87-90 ℃.
ESI-MS：787.5[M+H] +；
IR(KBr)v：3664，3396，3375，2931，2864，1728，729，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.67(s，3H，C 21-CH 3)，2.53-2.57(t，2H，CH 2CO)，3.49-3.51(m，2H，NCH 2)，3.58(br?s，2H，2×OH)，4.10-4.15(t，J＝6.3Hz，2H，OCH 2)，4.41-4.45(t，J＝6.0Hz，2H，OCH 2)，6.02-6.08(t，1H，NH)，7.61-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 33
Preparation (the b of N-Boc-β-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 24)
With reference to b 19The preparation method, by a 9Make oily matter, yield 88%.
Preparation (the c of β-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine trifluoroacetate 24)
With reference to c 19The preparation method by b 24Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-β-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 33)
With reference to I 28The preparation method, by c 24Make white solid, yield 30%, m.p.71-73 ℃.
ESI-MS：730.5[M+H] +；
IR(KBr)v：3737，3392，2929，2862，1737，727，688cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，2.50-2.57(t，2H，CH 2CO)，3.49-3.51(m，2H，NCH 2)，3.46-3.56(t，2H，CH 2CO)，3.58(br?s，2H，2×OH)，3.72-3.78(t，2H，NCH 2)，4.48-4.52(t，J＝6.0Hz，2H，OCH 2)，6.35-6.36(br?s，2H，2×NH)，7.63-7.68(t，2H，ArH)，7.77-7.79(t，1H，ArH)，8.08-8.11(d，2H，ArH)ppm.
Embodiment 34
Preparation (the b of N-Boc-L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 25)
With 0.33g (1.1mmol) a 2Be dissolved in 15mLCH 2Cl 2In, add 0.265g (1.0mmol) Boc-L-phenylalanine(Phe) successively, 0.26g (1.25mmol) DCC and 40mg (0.4mmol) DMAP; Concentrating under reduced pressure is filtered in stirring at room reaction 24 hours; Column chromatography for separation gets white solid 0.22g, yield 38.9%, m.p.101-104 ℃.
Preparation (the c of L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 25)
With 0.22g (0.40mmol) b 25Be dissolved in 10mL CH 2Cl 2In, the ice-water bath cooling slowly drips the 2mL trifluoroacetic acid down, drips and finishes in stirring at room reaction 2 hours, and concentrating under reduced pressure gets c 25, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 34)
Get 0.35g (0.9mmol) UDCA and be dissolved in 15mLTHF, the ice-water bath cooling adds 0.1g (0.99mmol) N-methylmorpholine down successively, and 0.15g (1.35mmol) Vinyl chloroformate reacted 15-30 minute, adds 0.47g (1.1mmol) midbody c 25, add reaction solution after again the 76mg sodium hydrogencarbonate being dissolved in 3mL water, reacted 1.5 hours, column chromatography gets white solid 0.43g, yield 58.2%, m.p.87-90 ℃.
ESI-MS：821.5[M+H] +；
IR(KBr)v：3737，3392，2931，2862，1737，731，694cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，3.10-3.12(d，2H，CH 2Ph)，3.58(br?s，2H，2×OH)，4.24-4.28(t，J＝6.0Hz，2H，OCH 2)，4.34-4.38(t，J＝6.0Hz，2H，OCH 2)，4.86-4.94(m，1H，NCH)，5.87-5.90(d，1H，NH)，7.11-7.13(d，2H，ArH)，7.23-7.28(m，3H，ArH)，7.60-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.04-8.07(d，2H，ArH)ppm.
Embodiment 35
Preparation (the b of N-Boc-L-phenylalanine(Phe)-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 26)
With reference to b 25The preparation method, by a 3Make white solid, yield 57%, m.p.60-62 ℃.
Preparation (the c of L-phenylalanine(Phe)-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 26)
With reference to c 25The preparation method by b 26Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 35)
With reference to I 34The preparation method, by c 26Make white solid, yield 29.5%, m.p.96-99 ℃.
ESI-MS：835.5[M+H] +；
IR(KBr)v：3737，3392，3363，2927，2860，1737，732，694cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，3.10-3.11(d，2H，CH 2Ph)，3.58(br?s，2H，2×OH)，4.34-4.44(t，J＝6.3Hz，2H，OCH 2)，4.74-4.83(m，1H，NCH)，5.13-5.15(m，1H，OCH)，5.85-5.87(d，1H，NH)，7.13-7.15(t，2H，ArH)，7.24-7.26(m，3H，ArH)，7.62-7.65(t，2H，ArH)，7.74-7.74(t，1H，ArH)，8.05-8.08(d，2H，ArH)ppm.
Embodiment 36
Preparation (the b of N-Boc-L-phenylalanine(Phe)-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 27)
With reference to b 25The preparation method, by a 6Make white solid, yield 52.2%, m.p.89-91 ℃.
Preparation (the c of L-phenylalanine(Phe)-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester trifluoroacetate 27)
With reference to c 25The preparation method by b 27Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester 36)
With reference to I 34The preparation method, by c 27Make white solid, yield 26.1%, m.p.132-135 ℃.
ESI-MS：831.5[M+H] +；
IR(KBr)v：3398，2931，2862，1747，732，694cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，3.13-3.18(d，2H，CH 2Ph)，3.58(br?s，2H，2×OH)，4.79(s，2H，OCH 2)，5.12(s，2H，OCH 2)，5.59-5.61(m，1H，NCH)，5.79-5.81(d，1H，NH)，7.12-7.15(d，2H，ArH)，7.26-7.31(m，3H，ArH)，7.60-7.66(t，2H，ArH)，7.75-7.80(t，1H，ArH)，8.07-8.09(d，2H，ArH)ppm.
Embodiment 37
Preparation (the b of N-Boc-L-phenylalanine(Phe)-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 28)
With reference to b 25The preparation method, by a 7Make white solid, yield 48.7%.
Preparation (the c of L-phenylalanine(Phe)-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester trifluoroacetate 28)
With reference to c 25The preparation method by b 28Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 37)
With reference to I 34The preparation method, by c 28Make white solid, yield 33%, m.p.69-72 ℃.
ESI-MS：849.5[M+H] +；
IR(KBr)v：3739，3384，2933，2864，1739，729，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，C 21-CH 3)，3.11-3.18(d，2H，CH 2Ph)，3.58(br?s，2H，2×OH)，4.14-4.19(t，J＝6.6Hz，2H，OCH 2)，4.40-4.44(t，J＝6.3Hz，2H，OCH 2)，4.87-4.91(m，1H，NCH)，5.79-5.81(d，1H，NH)，7.12-7.15(d，2H，ArH)，7.26-7.31(m，3H，ArH)，7.60-7.63(t，2H，ArH)，7.66-7.77(t，1H，ArH)，8.07-8.09(d，2H，ArH)ppm.
Embodiment 38
Preparation (the b of N-Boc-L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 29)
With reference to b 25The preparation method, by a 9Make white solid, yield 18.2%, m.p.135-138 ℃.
Preparation (the c of L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine trifluoroacetate 29)
With reference to c 25The preparation method by b 29Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 38)
With reference to I 34The preparation method, by c 29Make white solid, yield 25.5%, m.p.121-123 ℃.
ESI-MS：806.5[M+H] +；
IR(KBr)v：3398，2929，2864，1737，754，698cm -1；
1HNMR(300MHz，CDCl 3)：δ0.64-0.66(d，3H，C 21-CH 3)，3.13-3.15(d，2H，CH 2Ph)，3.58(br?s，2H，2×OH)，4.35-4.37(t，J＝6.0Hz，2H，OCH 2)，4.86-4.97(m，1H，NCH)，6.07-6.10(d，1H，NH)，6.34-6.37(t，1H，NH)，7.20-7.22(d，2H，ArH)，7.23-7.26(m，3H，ArH)，7.62-7.67(t，2H，ArH)，7.76-7.81(t，1H，ArH)，8.04-8.06(d，2H，ArH)ppm.
Embodiment 39
3 α, the preparation (I of 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] ester 39)
With reference to I 1The preparation method, by Chenodiol and a 1Reaction makes white solid, yield 55%, m.p.79-80 ℃.
ESI-MS：695.4[M+Cl] -；
IR(KBr)v：3736，3554，3390，2928，2856，1737，1622，1550，1452，1165，1080，731，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，1.25(s，3H，CH 3)，1.96-2.05(m，2H，COCH 2)，3.85(br?s，1H，OH)，3.42-3.50(m，2H，2×OCH)，4.50(t，J＝3.9Hz，2H，OCH 2)，4.65(t，J＝4.5Hz，2H，OCH 2)，7.62(t，J＝7.2Hz，2H，ArH)，7.75(t，J＝7.5Hz，1H，ArH)，8.09(d，J＝7.5Hz，2H，ArH)ppm.
Embodiment 40
3 α, the preparation (I of 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester 40)
With reference to I 1The preparation method, by Chenodiol and a 2Reaction makes white solid, yield 65%, m.p.74-75 ℃.
ESI-MS：709.3[M+Cl] -；
IR(KBr)v：3734，3406，2929，2862，1732，1618，1552，1454，1371，1255，731，686，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65(s，3H，CH 3)，0.91(s，3H，CH 3)，1.25(s，3H，CH 3)，1.90-2.02(m，2H，COCH 2)，3.85(br?s，1H，OH)，3.42-3.50(m，2H，2×OCH)，4.25(t，J＝6.0Hz，2H，OCH 2)，4.50(t，J＝6.0Hz，2H，OCH 2)，7.62(t，J＝7.5Hz，2H，ArH)，7.75(t，J＝7.5Hz，1H，ArH)，8.10(d，2H，ArH)ppm.
Embodiment 41
3 α, the preparation (I of 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester 41)
With reference to I 1The preparation method, by Chenodiol and a 3Reaction makes white solid, yield 38%, m.p.72-74 ℃.
ESI-MS：723.3[M+Cl] -；
IR(KBr)v：3736，3554，3329，2926，2852，1728，1622，1550，1450，1371，1251，1166，1080，731，678，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.64(s，3H，CH 3)，0.91(s，3H，CH 3)，1.26(s，3H，CH 3)，1.96-2.04(m，2H，COCH 2)，3.85(br?s，1H，OH)，3.42-3.50(m，2H，2×OCH)，4.51(t，J＝3.0Hz，2H，OCH 2)，5.15-5.20(m，1H，OCH)，7.59(t，J＝7.5Hz，2H，ArH)，7.64(t，J＝6.8Hz，1H，ArH)，8.07(d，J＝7.8Hz，2H，ArH)ppm.
Embodiment 42
3 α, the preparation (I of 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl] ester 42)
With reference to I 1The preparation method, by Chenodiol and a 4Reaction makes white solid, yield 64%, m.p.79-81 ℃.
ESI-MS：723.4[M+Cl] -；
IR(KBr)v：3736，3329，2929，2858，1730，1620，1552，1452，1371，1253，1166，1082，731，684，597，555cm -1；
1HNMR(300MHz，CDCl 3)：δ0.59(s，3H，CH 3)，0.85(s，3H，CH 3)，1.25(s，3H，CH 3)，1.80-2.00(m，2H，COCH 2)，3.85(br?s，2H，2×OH)，3.33-3.42(m，2H，2×OCH)，4.11(t，J＝6.0Hz，2H，OCH 2)，4.45(t，J＝6.0Hz，2H，OCH 2)，7.56(t，J＝8.1Hz，2H，ArH)，7.71(t，J＝7.5Hz，1H，ArH)，8.00(m，2H，ArH)ppm.
Embodiment 43
3 α, the preparation (I of 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne base] ester 43)
With reference to I 1The preparation method, by Chenodiol and a 6Reaction makes white solid, yield 62%, m.p.81-83 ℃.
ESI-MS：719.3[M+Cl] -；
IR(KBr)v：3610，3331，3064，2929，2860，1741，1620，1548，1548，1454，1363，1166，1080，729，684，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，1.26(s，3H，CH 3)，1.75-1.85(m，2H，COCH 2)，3.85(br?s，1H，OH)，3.42-3.50(m，2H，2×OCH)，4.75(s，2H，OCH 2)，5.15(s，2H，OCH 2)，7.65(t，J＝7.5Hz，2H，ArH)，7.75(t，J＝6.8Hz，1H，ArH)，8.10(d，J＝6.8Hz，2H，ArH)ppm.
Embodiment 44
3 α, the preparation (I of 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] hexyl] ester 44)
With reference to I 1The preparation method, by Chenodiol and a 8Reaction makes white solid, yield 39%, m.p.73-75 ℃.
ESI-MS：751.4[M+Cl] -；
IR(KBr)v：3734，3410，2931，2860，1728，1618，1550，1452，1371，1255，1166，1082，991，731，688，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，1.25(s，3H，CH 3)，3.50(br?s，2H，2×OH)，4.15(t，J＝5.1Hz，2H，OCH 2)，4.45(t，J＝6.6Hz，2H，OCH 2)，7.65(t，J＝8.1Hz，2H，ArH)，7.75(t，J＝8.1Hz，1H，ArH)，8.10(d，J＝7.8Hz，2H，ArH)ppm.
Embodiment 45
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 45)
With reference to I 10The preparation method, by Chenodiol and c 2Reaction makes white solid, yield 39.5%, m.p.81-83 ℃.
ESI-MS：766.2[M+Cl] -；
IR(KBr)v：3736，3396，2928，2858，1737，1618，1552，1458，1375，1253，1165，1078，1033，729，680，597cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，1.25(s，3H，CH 3)，3.31-3.46(m，1H，OCH)，3.85(br?s，1H，OH)，3.90-4.10(m，2H，NCH 2)，4.36(t，J＝6.0Hz，2H，OCH 2)，4.50(t，J＝6.0Hz，2H，OCH 2)，5.97(br?s，H，NH)，7.60(t，J＝8.4Hz，2H，ArH)，7.75(t，J＝8.4Hz，1H，ArH)，8.05(d，J＝8.4Hz，2H，ArH)ppm.
Embodiment 46
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 46)
With reference to I 10The preparation method, by Chenodiol and c 3Reaction makes white solid, yield 31.5%, m.p.84-85 ℃.
ESI-MS：780.3[M+Cl] -；
IR(KBr)v：3419，2929，2866，1737，1656，1614，1552，1450，1371，1255，1201，1168，1080，731，684，597cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65(s，3H，CH 3)，0.90(s，3H，CH 3)，1.25(s，3H，CH 3)，1.36(d，3H，CH 3)，3.42-3.50(m，1H，OCH)，3.84(br?s，1H，OH)，4.04(d，J＝6.0Hz，2H，NCH 2)，4.09-4.16(m，1H，OCH)，4.49(t，J＝6.0Hz，2H，OCH 2)，5.22(m，1H，COOCH)，5.98(t，1H，NH)，7.64(t，J＝7.5Hz，2H，ArH)，7.76(t，J＝7.5Hz，1H，ArH)，8.06(d，J＝7.5Hz，2H，ArH)ppm.
Embodiment 47
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester 47)
With reference to I 10The preparation method, by Chenodiol and c 4Reaction makes white solid, yield 57%, m.p.74-75 ℃.
ESI-MS：780.3[M+Cl] -；
IR(KBr)v：3732，3410，2931，2862，1743，1658，1616，1550，1452，1369，1255，1166，1080，1035，991，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.93(s，3H，CH 3)，1.25(s，3H，CH 3)，3.42-3.50(m，1H，OCH)，3.85(br?s，1H，OH)，4.07(d，J＝5.1Hz，2H，NCH 2)，4.11-4.16(m，1H，OCH)，4.27(t，J＝6.0Hz，2H，OCH 2)，4.47(t，J＝6.0Hz，2H，OCH 2)，5.97(br?s，1H，NH)，7.64(t，J＝7.5Hz，2H，ArH)，7.78(t，J＝7.5Hz，1H，ArH)，8.05(d，J＝7.2Hz，2H，ArH)ppm.
Embodiment 48
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 48)
With reference to I 10The preparation method, by Chenodiol and c 7Reaction makes white solid, yield 48%, m.p.60-61 ℃.
ESI-MS：794.4[M+Cl] -；
IR(KBr)v：3736，3417，2926，2858，1730，1618，1550，1456，1371，1255，1168，1080，993，729，684，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，1.25(s，3H，CH 3)，3.50(m，1H，OCH)，3.85(br?s，1H，OH)，4.06(d，2H，NCH 2)，4.12(t，H，OCH)，4.22(t，J＝6.0Hz，2H，OCH 2)，4.45(t，J＝6.0Hz，2H，OCH 2)，5.35(br?s，1H，OH)，6.00(br?s，1H，NH)，7.63(t，J＝7.5Hz，2H，ArH)，7.77(t，J＝7.5Hz，1H，ArH)，8.05(d，J＝7.2Hz，2H，ArH)ppm.
Embodiment 49
Preparation (the I of the own ester of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 49)
With reference to I 10The preparation method, by Chenodiol and c 8Reaction makes white solid, yield 21.8%, m.p.69-71 ℃.
ESI-MS：808.5[M+Cl] -；
IR(KBr)v：3738，3414，2931，2862，1741，1656，1614，1550，1452，1367，1257，1166，1080，997，731，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，3.40-3.50(m，2H，2×OCH)，3.85(br?s，1H，OH)，4.05(d，J＝5.1Hz，2H，NCH 2)，4.18(t，J＝6.0Hz，2H，OCH 2)，4.45(t，J＝6.0Hz，2H，OCH 2)，5.65(br?s，1H，NH)，7.63(t，J＝7.8Hz，2H，ArH)，7.77(t，J＝7.5Hz，1H，ArH)，8.05(d，J＝7.5Hz，2H，ArH)ppm.
Embodiment 50
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 50)
With reference to I 10The preparation method, by Chenodiol and c 9Reaction makes light yellow solid, yield 33.2%, m.p.68-70 ℃.
ESI-MS：751.3[M+Cl] -；
IR(KBr)v：3736，3419，2935，2866，1633，1550，1454，1367，1257，1201，1166，1080，1030，723，671，597cm -1；
1HNMR(300MHz，DMSO 6)：δ0.59(s，3H，CH 3)，0.89(s，3H，CH 3)，1.25(s，3H，CH 3)，3.63-3.69(m，2H，NCH 2)，4.05-4.18(m，2H，CH 2CO)，4.42(m，2H，OCH 2)，7.76(t，J＝7.5Hz，2H，ArH)，7.90(t，1H，ArH)，8.04(d，J＝8.1Hz，2H，ArH)ppm.
Embodiment 51
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 51)
With reference to I 28The preparation method, by Chenodiol and c 19Reaction makes white solid, yield 42.6%, m.p.85-86 ℃.
ESI-MS：794.4[M+Cl] -；
IR(KBr)v：3419，2933，2866，1732，1653，1618，1550，1454，1369，1255，1168，1080，1043，731，684，597cm -1；
1HNMR(300MHz，CDCl 3)：δ0.64(s，3H，CH 3)，0.90(s，3H，CH 3)，2.55(t，2H，CH 2CO)，3.40-3.50(m，4H，2×OCH，NCH 2)，3.85(br?s，2H，2×OH)，4.48(t，J＝6.0Hz，2H，OCH 2)，5.13-5.16(m，1H，OCH)，6.00(br?s，1H，NH)，7.63(t，J＝7.2Hz，2H，ArH)，7.77(t，J＝7.8Hz，1H，ArH)，8.05(d，J＝7.2Hz，2H，ArH)ppm.
Embodiment 52
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester 52)
With reference to I 28The preparation method, by Chenodiol and c 22Reaction makes white solid, yield 32.6%, m.p.70-71 ℃.
ESI-MS：808.3[M+Cl] -；
IR(KBr)v：3742，3416，2931，2866，1732，1651，1616，1552，1452，1367，1255，1168，1078，999，731，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65(s，3H，CH 3)，0.90(s，3H，CH 3)，2.55(t，2H，CH 2CO)，3.47-3.55(m，3H，NCH 2，OCH)，3.84(br?s，H，OH)，4.14(t，J＝6.3Hz，2H，OCH 2)，4.44(t，J＝6.3Hz，2H，OCH 2)，6.03(t，1H，NH)，7.63(t，J＝7.5Hz，2H，ArH)，7.77(t，J＝7.5Hz，1H，ArH)，8.05(d，J＝7.5Hz，2H，ArH)ppm.
Embodiment 53
Preparation (the I of the own ester of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 53)
With reference to I 28The preparation method, by Chenodiol and c 23Reaction makes white solid, yield 53.6%, m.p.62-63 ℃.
ESI-MS：822.3[M+Cl] -；
IR(KBr)v：3740，3419，2937，2866，1687，1552，1454，1371，1199，1078，9993，727，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65(s，3H，CH 3)，0.90(s，3H，CH 3)，2.55(t，2H，CH 2CO)，3.85(br?s，1H，OH)，3.40-3.55(m，3H，NCH 2，OCH)，4.09-4.16(m，3H，OCH 2，OCH)，4.44(t，J＝6.3Hz，2H，OCH 2)，6.05(t，1H，NH)，7.63(t，J＝7.5Hz，2H，ArH)，7.77(t，J＝7.5Hz，1H，ArH)，8.06(d，J＝7.2Hz，2H，ArH)ppm.
Embodiment 54
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester (I 54)
With reference to I 34The preparation method, by Chenodiol and c 25Reaction makes white solid, yield 66.1%, m.p.78-80 ℃.
ESI-MS：856.3[M+Cl] -；
IR(KBr)v：3736，3400，2931，2864，1737，1550，1456，1373，1257，1168，1078，1035，729，692，596，553cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，3.10(d，2H，CH 2Ph)，3.46-3.50(m，2H，2×OCH)，3.85(br?s，2H，2×OH)，4.16(t，J＝6.9Hz，2H，OCH 2)，4.37(t，J＝6.0Hz，2H，OCH 2)，4.87-5.90(m，1H，NCH)，5.90(br?s，1H，NH)，7.11(d，J＝7.2Hz，2H，ArH)，7.23-7.27(m，3H，ArH)，7.63(t，J＝7.5Hz，2H，ArH)，7.77(t，J＝7.8Hz，1H，ArH)，8.06(d，J＝7.2Hz，2H，ArH)ppm.
Embodiment 55
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 55)
With reference to I 34The preparation method, by Chenodiol and c 29Reaction makes light yellow solid, yield 20.1%, m.p.85-86 ℃.
ESI-MS：841.4[M+Cl] -；
IR(KBr)v：3466，2929，2862，1735，1639，1548，1080，792，694，596cm -1；
1HNMR(300MHz，DMSO 6)：δ0.58(s，3H，CH 3)，2.90-3.02(m，2H，CH 2Ph)，3.65(m，2H，2×OCH)，4.11(br?s，2H，OCH 2)，4.25(br?s，2H，NCH 2)，4.43(br?s，1H，NCH)，7.25(br?s，5H，ArH)，7.50-7.87(br?s，3H，ArH)，8.04-8.40(br?s，2H，ArH)ppm.
Embodiment 56
Preparation (a of 3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propylamine 10)
With reference to a 1The preparation method, make light yellow oil by the 3-Propanolamine, yield 27%.
Preparation (the b of N-Boc-L-phenylalanyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propylamine 30)
With reference to b 25The preparation method, by a 10Make light yellow oily, yield 23.2%.
Preparation (the c of L-phenylalanyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propylamine trifluoroacetate 30)
With reference to c 25The preparation method by b 30Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propylamine 56)
With reference to I 34The preparation method, by Chenodiol and c 30Reaction makes white solid, yield 35.2%, m.p.96-98 ℃.
ESI-MS：855.4[M+Cl] -；
IR(KBr)v：3742，3414，2931，2858，1737，1647，1550，1454，1367，1166，1080，731，696cm -1；
1HNMR(300MHz，DMSO 6)：δ0.58(s，3H，CH 3)，2.90-3.02(m，2H，CH 2Ph)，3.70(m，2H，2×OCH)，4.15(br?s，2H，NCH 2)，4.63(br?s，2H，OCH 2)，7.20-7.22(d，2H，ArH)，7.15-7.30(m，5H，ArH)，7.75(br?s，2H，ArH)，7.91(brs，1H，ArH)，8.23(br?s，2H，ArH)ppm.
Embodiment 57
Preparation (the b of N-Boc-L-leucine-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 31)
With 0.33g (1.1mmol) a 2Be dissolved in 15mL CH 2Cl 2In, add 0.23g (1.0mmol) Boc-L-leucine, 0.26g (1.25mmol) DCC and 40mg (0.4mmol) DMAP, stirring at room reaction 24 hours is filtered, concentrating under reduced pressure, column chromatography for separation gets white solid 0.36g, yield 71%.
Preparation (the c of L-leucine-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester trifluoroacetate 31)
With 0.36g (0.72mmol) b 31Be dissolved in 10mL CH 2Cl 2In, the ice-water bath cooling slowly drips the 2mL trifluoroacetic acid down, drips and finishes in stirring at room reaction 2 hours, and concentrating under reduced pressure gets c 31, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester 57)
Get 0.44g (1.11mmol) CDCA and be dissolved in 15mL THF, add 0.12g (1.22mmol) N-methylmorpholine under the ice-water bath successively, 0.18g (1.66mmol) Vinyl chloroformate reacted 15-30 minute, added 0.32g (1.22mmol) midbody c 31, add reaction solution after again the 93mg sodium hydrogencarbonate being dissolved in 3mL water, reacted 1.5 hours, column chromatography gets white solid 0.24g, yield 33.3%, m.p.74-75 ℃.
ESI-MS：822.3[M+Cl] -；
IR(KBr)v：3736，3402，2929，2864，1739，1618，1552，1456，1373，1257，1165，1080，1035，731，682，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.94(s，3H，CH 3)，3.13-3.15(d，2H，CH 2Ph)，3.47-3.60(m，2H，2×OCH)，3.85(br?s，1H，OH)，4.35(t，J＝6.0Hz，2H，OCH 2)，4.54(t，J＝6.0Hz，2H，OCH 2)，4.65(m，1H，NCH)，5.75(d，1H，NH)，7.64(t，J＝7.8Hz，2H，ArH)，7.77(t，J＝7.5Hz，1H，ArH)，8.06(d，J＝7.5Hz，2H，ArH)ppm.
Embodiment 58
Preparation (the b of N-Boc-L-leucine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester 32)
With reference to b 31The preparation method, by a 4Make white solid, yield 56.7%.
Preparation (the c of L-leucine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester trifluoroacetate 32)
With reference to c 31The preparation method by b 32Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester 58)
With reference to I 57The preparation method, by Chenodiol and c 32Reaction makes white solid, yield 42%, m.p.62-63 ℃.
ESI-MS：836.3[M+Cl] -；
IR(KBr)v：3742，3402，2929，2864，1737，1654，1616，1552，1452，1369，1255，1165，1080，999，731，555cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.90(s，3H，CH 3)，0.96(s，3H，CH 3)，2.10(s，3H，CH 3)，3.46-3.55(m，1H，OCH)，3.85(br?s，1H，HO)，4.11-4.15(m，1H，OCH)，4.24(t，J＝6.0Hz，2H，OCH 2)，4.47(t，J＝6.3Hz，2H，OCH 2)，4.60-4.70(m，1H，NCH)，5.84(d，1H，NH)，7.64(t，J＝7.5Hz，2H，ArH)，7.77(t，J＝7.5Hz，1H，ArH)，8.06(d，J＝7.8Hz，2H，ArH)ppm.
Embodiment 59
Preparation (the b of the own ester of N-Boc-L-leucine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 33)
With reference to b 31The preparation method, by a 8Make white solid, yield 56.7%.
Preparation (the c of the own ester trifluoroacetate of L-leucine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 33)
With reference to c 31The preparation method by b 33Make, directly be used for next step reaction.
Preparation (the I of the own ester of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] 59)
With reference to I 57The preparation method, by Chenodiol and c 33Reaction makes white solid, yield 31.4%, m.p.50-51 ℃.
ESI-MS：864.5[M+Cl] -；
IR(KBr)v：3738，3398，2931，2864，1737，1616，1550，1452，1369，1255，1165，1080，999，731，686，553cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65(s，3H，CH 3)，0.90(s，3H，CH 3)，0.94(br?s，6H，2×CH 3)，3.47-3.57(m，2H，OCH，OH)，3.85(br?s，1H，OH)，4.11-4.15(m，2H，2×CH)，4.05-4.19(m，3H，OCH 2，OCH)，4.42(m，2H，OCH 2)，4.60-4.71(m，1H，NCH)，5.81(d，1H，NH)，7.64(t，2H，ArH)，7.75(t，1H，ArH)，8.05(d，J＝6.9Hz，2H，ArH)ppm.
Embodiment 60
Preparation (the b of N-Boc-L-leucyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 34)
With reference to b 31The preparation method, by a 9Make light yellow oil, yield 26.9%.
Preparation (the c of L-leucyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine trifluoroacetate 34)
With reference to c 31The preparation method by b 34Make, directly be used for next step reaction.
Preparation (the I of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine 60)
With reference to I 57The preparation method, by c 34Make white solid, yield 11.4%, m.p.88-90 ℃.
ESI-MS：807.3[M+Cl] -；
IR(KBr)v：3740，3410，2931，2864，1734，1653，1548，1456，1369，1257，1166，1082，731cm -1；
1HNMR(300MHz，CDCl 3)：δ0.65(s，3H，CH 3)，0.90(s，3H，CH 3)，0.94(br?s，6H，2×CH 3)，3.46-3.55(m，2H，OCH，OH)，3.85(br?s，1H，OH)，4.19-4.24(m，3H，NCH 2，OCH)，4.45(t，J＝6.0Hz，2H，OCH 2)，4.60-4.71(m，1H，NCH)，5.79(d，1H，NH)，7.64(t，J＝7.8Hz，2H，ArH)，7.77(t，J＝7.8Hz，1H，ArH)，8.05(d，J＝7.8Hz，2H，ArH)ppm.
Embodiment 61
Preparation (the d of 24-ursodeoxycholic tert-butyl acrylate 1)
1.20g (3.1mmol) UDCA is dissolved among the anhydrous THF of 25mL, the ice-water bath cooling slowly splashes into the 5mL trifluoroacetic acid down, drips to finish to remove ice bath, adds 7.5mL (79mmol) anhydrous tertiary butanol; Stirring at room reaction 7 hours, ice-water bath cooling add the ammoniacal liquor of 5mL 35% down, in 0 ℃ of reaction 12 hours, add 2.5mL ammoniacal liquor again; Stirring at room reaction 4 hours adds 25mL water, 50mL extracted with diethyl ether, saturated sodium-chloride washing; Anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography get white solid 1.03g; Productive rate 74%, m.p.51-53 ℃, ESI-MS:448.5 [M+Na] +
Preparation (the e of 3-O-succinyl-24-ursodeoxycholic tert-butyl acrylate 1)
With 1.03g (2.3mmol) d 1, 0.92g (9.2mmol) Succinic anhydried, 0.28g (2.3mmol) DMAP is dissolved in the 20mL chloroform, back flow reaction 36 hours; Concentrating under reduced pressure adds water 100mL stirred overnight at room temperature, dichloromethane extraction, saturated sodium-chloride washing; Anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography get white solid 0.13g; Yield 11.8%, m.p.118-120 ℃, ESI-MS:548.5 [M-H] -
Preparation (the f of 3-O-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-] succinyl-24-ursodeoxycholic tert-butyl acrylate 1)
With 0.2g (0.365mmol) e 1Be dissolved in 15mLCH 2Cl 2In, add 0.11g (0.365mmol) a 2, 0.11g (0.55mmol) DCC and 18mg (0.15mmol) DMAP, stirring at room reaction 24 hours is filtered, concentrating under reduced pressure, column chromatography for separation gets white solid 80mg, yield 26.7%, m.p.45-48 ℃.
Preparation (the II of 3 α-[4-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 beta-hydroxy-5 β-cholestane-24-acid 1)
With 80mg (0.096mmol) f 1Be dissolved in the 4mL anhydrous methylene chloride, the ice-water bath cooling slowly adds the 0.5mL trifluoroacetic acid down, and drip and finish in stirring at room reaction 45 minutes, concentrating under reduced pressure, column chromatography for separation gets white solid 20mg, productive rate 27%, m.p.59-61 ℃.
ESI-MS：774.5[M+NH 4] +；
IR(KBr)v：3386，2925，2856，1731，729，682cm -1；
1HNMR(300MHz，CDCl 3)：δ0.68(s，3H，CH 3，C 21-CH 3)，2.20-2.24(t，J＝6.0Hz，2H，COCH 2)，2.55-2.61(m，4H，2×COCH 2)，3.58(br?s，1H，OH)，4.29-4.33(t，J＝6.0Hz，2H，OCH 2)，4.49-4.53(t，J＝6.0Hz，2H，OCH 2)，7.61-7.66(m，2H，ArH)，7.74-7.77(m，1H，ArH)，8.05-8.08(m，2H，ArH)ppm.
Embodiment 62
Preparation (the f of 3-O-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butoxy] succinyl-24-ursodeoxycholic tert-butyl acrylate 2)
With reference to f 1The preparation method, by e 1And a 4Reaction makes white solid, yield 22.2%, m.p.47-49 ℃, ESI-MS:844.5 [M+NH 4] +
Preparation (the II of 3 α-[4-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butoxy]-1,4-dioxo butoxy]-7 beta-hydroxy-5 β-cholestane-24-acid 2)
With reference to II 1The preparation method, by f 2Make white solid, productive rate 18.2%, m.p.56-58 ℃.
ESI-MS：788.5[M+NH 4] +；
IR(KBr)v：3388，2948，2867，1731，730，686cm -1；
1HNMR(300MHz，CDCl 3)：δ0.68(s，3H，CH 3，C 21-CH 3)，2.41-2.60(m，4H，2×COCH 2)，3.58(br?s，1H，OH)，4.17-4.21(t，J＝6.0Hz，2H，OCH 2)，4.44-4.48(t，J＝6.0Hz，2H，OCH 2)，7.61-7.66(m，2H，ArH)，7.74-7.77(m，1H，ArH)，8.05-8.08(m，2H，ArH)ppm.
Embodiment 63
Preparation (the d of the 24-Chenodiol tert-butyl ester 2)
With reference to d 1The preparation method, make light yellow oil by Chenodiol, yield 35.2%.
Preparation (the e of 3-O-succinyl-24-Chenodiol tert-butyl ester 2)
With reference to e 1The preparation method, by d 2Make light yellow oil, yield 73.5%, ESI-MS:547 [M-H] -
Preparation (the II of 3 α-[4-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butoxy]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid 3)
With reference to II 1The preparation method, by e 2And a 4Reaction also makes white solid, productive rate 71.4%, m.p.40-42 ℃ through the trifluoroacetic acid deprotection.
ESI-MS：823.3[M+Cl] -；
IR(KBr)v：3743，3450，2933，2868，1730，1616，1552，1452，1367，1257，1165，1076，997，731，688，596cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，1.25(s，3H，CH 3)，2.54-2.69(m，4H，2×COCH 2)，3.28(br?s，2H，OCH，OH)，3.85(br?s，1H，OH)，4.17(t，J＝6.0Hz，2H，OCH 2)，4.47(t，J＝6.0Hz，2H，OCH 2)，4.55-4.65(m，1H，COOCH)，7.63(t，J＝7.8Hz，2H，ArH)，7.75(t，J＝7.5Hz，1H，ArH)，8.05(m，2H，ArH)ppm.
Embodiment 64
Preparation (the II of 3 α-[4-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid 4)
With reference to II 1The preparation method, by e 2And a 2Reaction also makes white solid, productive rate 54.3%, m.p.46-48 ℃ through the trifluoroacetic acid deprotection.
ESI-MS：809.4[M+Cl] -；
IR(KBr)v：3738，3394，2935，2870，1737，1616，1550，1454，1165，1076，997，729，678cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，2.65-2.82(m，4H，2×COCH 2)，3.85(br?s，1H，OH)，4.05-4.15(m，1H，OCH)，4.31(t，J＝6.0Hz，2H，OCH 2)，4.55-4.65(m，3H，COOCH，OCH 2)，7.63(t，J＝7.2Hz，2H，ArH)，7.75(t，J＝7.5Hz，1H，ArH)，8.05(m，2H，ArH)ppm.
Embodiment 65
Preparation (the II of 3 α-[4-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] oxyethyl group]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid 5)
With reference to II 1The preparation method, by e 2And a 1Reaction also makes white solid, productive rate 78.2%, m.p.44-46 ℃ through the trifluoroacetic acid deprotection.
ESI-MS：795.3[M+Cl] -；
IR(KBr)v：3740，3448，2933，2866，1732，1620，1550，1456，1165，1078，731，684cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，2.55-2.62(m，4H，2×COCH 2)，3.07(br?s，3H，OH，2×COOCH)3.85(br?s，1H，OH)，4.52(t，J＝4.5Hz，2H，OCH 2)，4.61(t，J＝4.5Hz，2H，OCH 2)，7.63(t，J＝7.5Hz，2H，ArH)，7.75(t，J＝7.5Hz，1H，ArH)，8.05(m，2H，ArH)ppm.
Embodiment 66
Preparation (the II of 3 α-[4-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid 6)
With reference to II 1The preparation method, by e 2And a 3Reaction also makes white solid, productive rate 43.3%, m.p.49-50 ℃ through the trifluoroacetic acid deprotection.
ESI-MS：823.3[M+Cl] -；
IR(KBr)v：3421，2926，2860，1734，1614，1552，1456，1373，1166，1078，995，729，680cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，2.57-2.62(m，4H，2×COCH 2)，3.84(br?s，1H，OH)，4.11-4.13(m，1H，COOCH)，4.32-4.40(m，1H，COOCH)，4.48(t，J＝7.2Hz，2H，OCH 2)，5.20(m，1H，OCH)，7.63(t，J＝7.2Hz，2H，ArH)，7.74(t，1H，ArH)，8.07(d，J＝7.2Hz，2H，ArH)ppm.
Embodiment 67
Preparation (the II of 3 α-[4-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethylamino-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid 7)
With reference to II 1The preparation method, by e 2And a 9Reaction also makes light yellow solid, productive rate 17.9%, m.p.49-51 ℃ through the trifluoroacetic acid deprotection.
ESI-MS：794.2[M+Cl] -；
IR(KBr)v：3743，3392，2937，2870，1735，1643，1452，1348，1163，1085，727，682，611cm -1；
1HNMR(300MHz，CDCl 3)：δ0.66(s，3H，CH 3)，0.91(s，3H，CH 3)，2.56-2.63(m，4H，2×COCH 2)，3.65(m，2H，NCH 2)，4.30(m，J＝5.1Hz，2H，OCH 2)，4.70(br?s，2H，2×COOCH)，5.10(br?s，1H，OH)，6.45(br?s，1H，NH)，7.61(t，J＝7.8Hz，2H，ArH)，7.73(t，J＝7.2Hz，1H，ArH)，8.09(m，2H，ArH)ppm.

Claims (10)

1. the nitric oxide donator type bile acid derivative shown in general formula (I), (II) or its medically acceptable salt:
Figure FSB00000904936900011
Wherein:
R 1Be selected from α-OH or β-OH;
R 2Be selected from OH or C 1-6Alkanoyloxy;
-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein:
X is selected from O or NH;
Y is selected from C 2-6Alkylidene group, C 2-4OC 2-4Alkylidene group, C 2-6Alkenylene or C 2-6Alkynylene;
-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, α-Bing Ansuan, Beta-alanine, leucine or phenylalanine(Phe); Described amino acid whose L-or the D-type of being configured as.
2. nitric oxide donator type bile acide according to claim 1 or its medically acceptable salt is characterized in that:
In the general formula (I), R 1Be selected from α-OH or β-OH; R 2Be selected from OH;-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein, X is selected from O or NH; Y is selected from C 2-6Alkylidene group, C 2-4OC 2-4Alkylidene group, C 2-6Alkenylene or C 2-6Alkynylene;-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, α-Bing Ansuan, Beta-alanine, leucine or phenylalanine(Phe); Described amino acid whose L-or the D-type of being configured as;
In the general formula (II), R 1Be selected from α-OH or β-OH;-CO-L-O-is selected from-CO-X-Y-O-, and wherein, X is selected from O or NH; Y is selected from C 2-4Alkylidene group, C 2-4OC 2-4Alkylidene group, C 2-6Alkenylene or C 2-6Alkynylene.
3. nitric oxide donator type bile acide according to claim 2 and medically acceptable salt thereof is characterized in that:
In the general formula (I), work as R 1When being selected from α-OH, R 2Be selected from OH;-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein, X is selected from O or NH; Y is selected from C 2-6Alkylidene group or C 4Alkynylene;-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, Beta-alanine, L-leucine or L-phenylalanine(Phe); Work as R 1When being selected from β-OH, R 2Be selected from OH;-CO-L-O-is selected from-CO-X-Y-O-or-CO-NH-A-CO-X-Y-O-, wherein, X is selected from O or NH; Y is selected from C 2-6Alkylidene group, C 2OC 2Alkylidene group or C 4Alkynylene;-NH-A-CO-represented amino acid residue, described amino acid is selected from glycocoll, Beta-alanine, L-L-Ala, or L-phenylalanine(Phe);
In the general formula (II), work as R 1When being selected from α-OH ,-CO-L-O-is selected from-CO-X-Y-O-, and wherein, X is selected from O or NH; Y is selected from C 2-4Alkylidene group; Work as R 1When being selected from β-OH ,-CO-L-O-is selected from-CO-X-Y-O-, and wherein, X is selected from O; Y is selected from C 3-4Alkylidene group.
4. according to each described nitric oxide donator type bile acid derivative of claim 1-3 or its medically acceptable salt, it is characterized in that compound is selected from:
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[2-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne base] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] amyl group] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acid-[6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] hexyl] ester;
3 α, 7 beta-dihydroxyies-5 β-cholestane-24-acyl group-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] amine;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester;
The own ester of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen];
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester;
The own ester of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-L-Ala-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen];
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl oxygen] ethyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester;
The own ester of N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen];
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-β-alanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanine(Phe)-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester;
N-(3 α, 7 beta-dihydroxyies-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine;
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethyl] ester;
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester;
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl group] ester;
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl] ester;
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen]-2-butyne base] ester;
3 α, 7 alpha-dihydroxy-s-5 β-cholestane-24-acid-[6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] hexyl] ester;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester;
The own ester of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycocoll-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen];
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-glycyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-5-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] pentyl ester;
The own ester of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-Beta-alanine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen];
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-4-quinone-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-phenylalanyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propylamine;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propyl ester;
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butyl ester;
The own ester of N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucine-6-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen];
N-(3 α, 7 alpha-dihydroxy-s-5 β-24-oxo cholestane-24-yl)-L-leucyl-2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] ethamine;
3 α-[4-[4-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] butoxy]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid;
3 α-[4-[3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid;
3 α-[4-[2-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] oxyethyl group]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid;
3 α-[4-[1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2,5-oxadiazole-3-yl) oxygen] propoxy-]-1,4-dioxo butoxy]-7 Alpha-hydroxy-5 β-cholestane-24-acid.
5. according to the preparation method of the described nitric oxide donator type bile acid derivative of claim 1-4, wherein, the preparation method of formula (I) compound comprises the steps:
Step I: under the alkaline reagents effect, 3,4-two benzenesulfonyls-2-oxygen-1,2,5-oxadiazole and corresponding diol or hydramine (HX-Y-OH) reaction makes the compound shown in the formula (a):
Figure FSB00000904936900051
Wherein, the definition of X and Y such as claim 1-4 are said;
Compound is characterised in that shown in the preparation formula (a); Alkaline reagents is selected from one or more in sodium hydroxide, Pottasium Hydroxide, yellow soda ash or the salt of wormwood; Solvent is methylene dichloride, chloroform, THF, ETHYLE ACETATE, 1; Among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF one or more, temperature of reaction are room temperature, and the reaction times is 1-24 hour;
Step I i: under condensing agent and 4-Dimethylamino pyridine (DMAP) effect, formula (a) compound and Boc-amino acid (Boc-NH-A-CO 2H) condensation makes formula (b), takes off Boc-protection base through trifluoroacetic acid (TFA) again and makes the compound shown in the formula (c):
Figure FSB00000904936900061
Wherein, the definition of NH-A-CO, X and Y such as claim 1-4 are said;
Compound is characterised in that shown in the preparation formula (c); Condensing agent is selected from 1,3-NSC 57182 (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) or N, N-DIC (DIC); Solvent is selected from methylene dichloride, chloroform, THF, ETHYLE ACETATE, ethyl formate, methyl acetate, 1; Among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF one or more, temperature of reaction are-10-30 ℃, and the reaction times is 1-48 hour;
Step I ii: under the condensing agent effect, formula (a) compound or formula (c) compound and the condensation of bile acide parent make the compound shown in the formula (I):
Figure FSB00000904936900062
Wherein, R 1, R 2Said with definition such as the claim 1-4 of L;
Preparation formula (I) compound is characterised in that; Condensing agent is selected from 1; 3-NSC 57182 (DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl), N; N-DIC (DIC), Vinyl chloroformate or methyl-chloroformate, solvent are selected from methylene dichloride, chloroform, THF, ETHYLE ACETATE, ethyl formate, methyl acetate, 1, one or more among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF; Temperature of reaction is-10-50 ℃, and the reaction times is 1-48 hour;
The preparation method of formula (II) compound comprises the steps:
Step I v: (bile acid) is raw material with bile acide, under the trifluoroacetic acid effect, makes the compound shown in the formula (d) with trimethyl carbinol generation esterification:
Figure FSB00000904936900071
Wherein, R 1Definition such as claim 1-4 said;
Preparation formula (d) compound is characterised in that, trimethyl carbinol charging capacity be the bile acide molar weight 5-20 doubly, temperature of reaction is-10-50 ℃, the reaction times is 10-48 hour;
Step v: formula (d) compound makes the compound shown in the formula (e) with the Succinic anhydried reaction under the DMAP effect:
Figure FSB00000904936900072
Wherein, R 1Definition such as claim 1-4 said;
Preparation formula (e) compound is characterised in that; The charging capacity of Succinic anhydried is 1-20 a times of formula (d) compound molar weight; Solvent is selected from methylene dichloride, chloroform, THF, 1; Among 2-ethylene dichloride, benzene, toluene, dioxane or the DMF one or more, temperature of reaction are reflux temperature, and the reaction times is 12-48 hour;
Step vi: formula (e) compound room temperature makes the compound shown in the formula (f) with formula (a) compound condensation under DCC and DMAP effect:
Figure FSB00000904936900073
Wherein, R 1Said with definition such as the claim 1-4 of L;
Preparation formula (f) compound is characterised in that solvent is selected from one or more in methylene dichloride, chloroform or the THF, and the reaction times is 1-48 hour;
Step vii: formula (f) compound removes tertiary butyl protection and makes the compound shown in the formula (II) under the trifluoracetic acid effect:
Figure FSB00000904936900081
Wherein, R 1Said with definition such as the claim 1-4 of L.
6. method according to claim 5, preparation formula (I) compound is characterised in that, condensing agent preferred 1; 3-NSC 57182 (DCC) or Vinyl chloroformate; Preferred anhydrous methylene chloride of solvent or anhydrous tetrahydro furan, temperature of reaction be-10-25 ℃, and the reaction times is 24 hours.
7. method according to claim 5, preparation formula (d) compound are characterised in that trimethyl carbinol charging capacity is 10 times of bile acide molar weight, temperature of reaction is-and 10-25 ℃, the reaction times is 25 hours.
8. pharmaceutical composition is gone up the described general formula of claim 1 (I) of effective dose or (II) compound or its medically acceptable salt and acceptable accessories are formed by treatment.
The described general formula of claim 1 (I) or (II) shown in nitric oxide donator type bile acid derivative or its medically acceptable salt purposes in the preparation antitumor drug.
10. the purposes of claim 9, tumour wherein is a liver cancer, kidney, lung cancer, mammary cancer, the cancer of the brain, cancer of the stomach, colorectal carcinoma.
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