CN1308534A - Angiogenesis inhibitors - Google Patents
Angiogenesis inhibitors Download PDFInfo
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- CN1308534A CN1308534A CN99808280A CN99808280A CN1308534A CN 1308534 A CN1308534 A CN 1308534A CN 99808280 A CN99808280 A CN 99808280A CN 99808280 A CN99808280 A CN 99808280A CN 1308534 A CN1308534 A CN 1308534A
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- naphthyl
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- 229940121369 angiogenesis inhibitor Drugs 0.000 title description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 title description 3
- 125000004999 nitroaryl group Chemical group 0.000 claims abstract description 15
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- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- AASUFOVSZUIILF-UHFFFAOYSA-N diphenylmethanone;sodium Chemical compound [Na].C=1C=CC=CC=1C(=O)C1=CC=CC=C1 AASUFOVSZUIILF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 108010064365 glycyl- arginyl-glycyl-aspartyl-seryl-prolyl-lysine Proteins 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 description 1
- DASJFYAPNPUBGG-UHFFFAOYSA-N naphthalene-1-sulfonyl chloride Chemical compound C1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 DASJFYAPNPUBGG-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940076372 protein antagonist Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Images
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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- C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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Abstract
RGD mimetics which combine a nitroaryl moiety with an arylether/ alpha -aminoacid/guanidine framework exhibit activity as antagonists toward various integrins and as inhibitors of angiogenesis.
Description
Technical field
The present invention relates to have RGD and simulate active non-peptide compound, also relate to and have the synthetic and biologic activity that RGD simulates active non-peptide compound.Especially relate to the RGD analogies of nitro aryl and their synthetic and biological activity.
Technical background
Integral protein is that a class promotes cell-cell and exoprotein (Cheresh, D.A. that cell-matter is adhered to; Mecham.R.P.Eds.; Academic Press:New York, 1994; Stromblad, S.; Cheresh, D.A.Chem.Bio.1996,3,881).The assorted biglycan albumen of film combination that biology, object was made up of α-subunit and littler β-subunit that these are important.The bonded relative affinity of part and specificity can by different α-and the specific combination of β-subunit determine.In the member of these receptor families, α
IIbβ
3, α
5β
1, α
vβ
3And α
vβ
5Study at most.With the bonded many native ligands of these integral proteins, as Fibronectin (with α
5β
1In conjunction with), Fibrinogen is (with α
IIbβ
3In conjunction with) and crystalline protein (with α
vβ
3In conjunction with), in its native sequences, comprising main peptide sequence Arg-Gly-Asp (RGD), this sequence is approved by most integral proteins.For anticoagulant, α
IIbβ
3Having demonstrated is a good object, and some data disclose design and synthetic (Ojima et al.Bioorg.Med.Chem., 1995,337 of the effective bonding agent that comprises peptide and non-peptide structure; Engleman et al.Ann.Rep.Med.Chem.1996,31,191).
In angiogenesis, α
vβ
3And α
vβ
5Function to have demonstrated be fatal.Ceresh and colleague thereof show, these integral proteins by antibody or cyclic peptide to suppressing to influence angiogenesis in the bonded body that contains the RGD part and induced tumor (the Brooks et al.Science 1994 et al.Rosenfeld et al.Cell 1994 that disappear, 79,1157).Except suitable to angiogenesis, the also known α of people
vβ
3Regulating adhering to and in the transplanting smooth muscle cell, playing an important role of osteoclast and bone matrix.
α thus
vβ
3Antagonist by be thought of as in advance the treatment various diseases (as diabetic retinopathy, cancer, osteoporosis and restenosis) effective therapeutic agent (Van der Pluijm etal.Bone Mineral Res.1994,9,1021; Helfrich et al.J.BoneMineral Res.1992,7,335; Horton et al.Exp.Cell Res.1991,195,368; Robey et al.Ann.Rep.Med.Chem.1993,28,227; Choiet al.Surgery 1994,19,125; Matsuno et al.Circulation 1994,90,2203; Hammes et al.Nature Med.1996,2,529; Friedlanderet al.Proc.Natl.Acad.Sci., USA 1996,93, and 9764).
Kessler et al. has reported α
vβ
3The first micromolecule antagonist (embodiment 1, Fig. 1; Gurrath et al.Eur.J.Biochem.1992,210,911; Mulleret al.Angew.Chem.Int.Ed.Engl.1992,31,326; Aumailleyet al.FEBS Lett.1991,291,50; Pfaff et al.J.Bio.Chem.1994,269,20233; Haubner et al.J.Am.Chem.Soc.1996,118,7461).Then, from Dupont-Merck (embodiment 2, Fig. 1) and SmithKlineBeecham (SKB) (embodiment 3, Fig. 1) published their achievement in research in this field.In addition, other cyclic peptide 4 and 5 (Fig. 1) that contains RGD also has been synthesized by Burgess et al. and Goodman et al. respectively, and they demonstrate very active (Bach et al.J.Am.Chem.Soc.1996,118,293; Peishoff et al.J.Med.Chem.1992,35,3962; Burgess et al.J.Med.Chem.1996,39,4520; Tranet al.Bioorg.Med.Chem.Lett.1997,7,997).
Recently, many research groups are reported their achievement in research, to α
vβ
3The part that structure has a high affinity has changed traditional peptide structure significantly, and (embodiment 6 to 9, Fig. 2).These α
vβ
3Structure comprises center bearing bracket (as benzene, benzodiazepine class or urea skeleton), the appurtenance that has carboxylate and guanidino group (the Duggan et al.Abstracts of Papers that links to each other with center bearing bracket, 21th ACS National Meeting, New Orleans, LA, March 24-28,1996; American Chemical Society:Washington, DC, 1996, MEDI 234; Keenan et al.J.Med.Chem.1997,40,2289; Corbett et al.Bioorg.Med.Chem.Lett.1997,7,1371; Gadeket al.Abstracts of Papers, 21th ACS National Meeting, NewOr1eans, LA, March 24-28,1996; American Chemical Society:Washington, DC, 1996, MEDI 235; Hirschmann et al.J.Am.Chem.Soc.1996,115,12550).
People are needed to be exactly synthetic spendable RGD analogies, and these analogies have the body internal stability and various integral protein objects are had high activity and selectivity; Be exactly effective universal method of developing this compounds of preparation in addition.
Brief summary of the invention
The present invention relates to design, chemosynthesis and a series of RGD analogies that contain the nitro aryl of biological assessment.More specifically, the present invention relates to the chemical compound that disclosed aryl ether/a-amino acid/the guanidine class formation combines in the United States Patent (USP) 5,741,796 with new nitro aryl system and publication on April 21st, 1998, i.e. " Merck chemical compound ", above-mentioned patent documentation is hereby incorporated by reference.
One aspect of the present invention relates to the RGD analogies by following general formula:
In said structure, R
1Be selected from following groups:
Wherein X be selected from sulfur ,-NH-and oxygen.R
2Be selected from-CO
2-the tert-butyl group ,-the CO-aryl and-SO
2-aryl.Preferred aryl groups comprises phenyl, 1-naphthyl and 2-naphthyl.Preferred R
2For-SO
2-aryl.Preferred RGD analogies have following structure to represent:
Other preferred RGD analogies have following one group of structural formula to represent:
The present invention relates to the method for preparing above-mentioned RGD analogies on the other hand.The nitro aryl precursor of being represented by following structural that contains the fluorin radical that links to each other with nitro aryl rings covalency at first is provided:
In said structure, R
3Be acid protecting group.Then, replace, utilize to contain the nucleopilic reagent replacement fluorin radical that is protected guanidine radicals group, generate and protected the RGD analogies by nucleophilic aromatic.At last, utilize acid will be protected RGD analogies deprotection.
Another aspect of the present invention relates to the RGD analogies of being represented by following structural:
In said structure, R
2Be selected from-CO
2-the tert-butyl group and-SO
2-aryl.Preferred aryl groups comprises phenyl, 1-naphthyl and 2-naphthyl.
In order to determine that the present invention has tested above-mentioned RGD analogies to various integral protein (α in conjunction with selectivity
vβ
3, α
IIbβ
3And α
vβ
5) suppress the ability of cell attachment.The chemical compound of selecting has also been tested the ability that suppresses angiogenesis in its body in CAM (chicken chorioallantoid membrane) measures.All chemical compounds all are proved to have above-mentioned object had and suppress activity and selectivity, with its active consistent as angiogenesis inhibitor.
The present invention relates on the other hand to α
IIbβ
3The cell attachment and the α that regulate
vβ
3The differential of the cell attachment of regulating suppresses.Express alpha
IIbβ
3Cell select the solution of RGD analogies to contact with containing.The concentration of this class RGD analogies is enough to suppress α in the solution
IIbβ
3The cell attachment of regulating.The repressed α of result
IIbβ
3The cell attachment of regulating is approximately α at least
vβ
3100 times of the cell attachment of regulating.It is as follows to can be used for these preferred RGD analogies on the one hand of the present invention:
Accompanying drawing is described:
Fig. 1 has illustrated the α based on the RGD peptide sequence
vβ
3The choice structure of antagonist.
Fig. 2 has illustrated to have high α
vβ
3The non-peptide RGD of the selection of affinity analogies.
Fig. 3 has illustrated the target nitro aryl ether (10-21) as RGD analogies and benzimidazole 22.
Fig. 4 has illustrated the general structure and the anti-synthesis analysis of nitro aryl ether RGD analogies.
Fig. 5 has illustrated amino ester 26,29a and 29b synthesizing under following reagent and condition: (a) 1.1 equivalent Boc
2O, 1.0 equivalent Na
2CO
3, 1,4-diox, 25 ℃, 88%; (b) 20%Cs i)
2CO
3Aqueous solution, H
2O: MeOH (1: 2.5), 25 ℃, 4 hours, 100%, ii) 1.1 equivalent BnBr, DMF, 25 ℃, 14 hours, 88%; (c) 1.5 equivalent PhI (OCOCF
3)
2, DMF: H
2O (1: 1), 2.0 equivalent pyridines, 25 ℃, 3.5 hours, 41%; (d) 1.1 equivalent ArSO
2Cl, 2.25 equivalent NaOH , diox: H
2O (1: 2), 0 to 25 ℃, 3 hours, [27a is 71%, and 27b is 66%]; (e) 1.3 equivalent Br
2, 9.2 equivalent NaOH, H
2O, 0 to 99 ℃, [28a is 75%, and 28b is 81%]; (f) isobutene., the dense H of 2.8 equivalents
2SO
4, DME ,-78 to 25 ℃, 48 hours, [29a is 55%, and 29b is 51%].The DME=dimethoxy-ethane; The DMF=dimethyl formamide; The pH=phenyl; The 2-naphthyl.
Fig. 6 has illustrated synthetic compound 10-13:(a under following reagent and condition) 5.0 equivalent MeC (OMe)
3, PhMe, 80 ℃, 8 hours, 98%; (b) 1.1 equivalent N
3(CH
2)
2OTBS, 0.1 equivalent TBAF, 4 MS, DMF, 25 ℃, 4 hours, 73%; (c) 2.0 equivalent LiOHH
2O, 3: 1 dioxs: H
2O (3: 1), 25 ℃, 4 hours, 99%; (d) 1.0 equivalent DCC, 0.2 equivalent 4-DMAP, CH
2Cl
2, 25 ℃, 4 hours, 82%; (e) 50%TFA is in CH
2Cl
2Solution, 25 ℃, 2 hours, 84%; (f) 1.1 equivalent PhSO
2Cl, or 1-Naphso
2Cl, 1.3 equivalent i-Pr
2NEt, CH
2Cl
2, 25 ℃, 4 hours, 38a (78%) or 38b (57%); (g) 2.0 equivalent Ph
3P, 44 equivalent H
2O, THF, 25 ℃, 12 hours, 80%, about 1: 1 35a: 35b; 80%, about 1: 1 39a: 41a; 81%, about 1: 1 39b: 41b; (h) 2.0 equivalent LiOHH
2O, THF: H
2O (3: 1), 25 ℃, 4 hours, 93-99% 36ab, 40ab, 42a; (i) 1.1 equivalent 1H-pyrazoles-1-carboxyl amidine HCl, 1.1 equivalent i-Pr
2NEt, DMF, 25 ℃, 16 hours, 13-15% 10,11,13; 50 ℃, 16 hours, 5% 12, after RP-HPLC.The TFA=trifluoroacetic acid; TBAF=tetra-n-butyl ammonium fluoride; DDC=1, the 3-dicyclohexyl carbodiimide.
Fig. 7 has illustrated synthetic guanidine derivatives 51-56:(a under following reagent and condition) 1.0 equivalent BtBMTP, 2.0 equivalent Et
3N, 1.0 equivalent HgCl
2, DMF, 25 ℃, 4 hours, 98%; (b) 1.0 equivalent BtBMTP, DMF, 25 ℃, 14 hours, 95%; (c) 1.0 equivalent BtBCT, DMF, 25 ℃, 14 hours, 60%; (d) 0.2 equivalent BtBMTP, 0.4 equivalent Et
3N, 0.2 equivalent HgCl
2, DMF, 25 ℃, 4 hours, 51%; (e) 0.66 equivalent o-NH
2C
6H
4NH
2, 5.5N HCl aqueous solution refluxes, and 24 hours, 73%; (f) 1.0 equivalent DmPDHBr, iPr
2NEt, DMF, 25 ℃, 11 hours, 51%.The Boc=tert-butoxycarbonyl; BtBCT=N, N '-two-tert-butoxycarbonyl thiourea; BtBMTP=1,3-two (tert-butoxycarbonyl)-2-methyl-2-sulfur pseudo-urea; DmPDHBr=2-(3 base)-4,5-dehydrogenation imidazoles hydrobromide.
Fig. 8 has illustrated synthetic compound 11 and 14-19:(a under following reagent and condition) 1.2 equivalents (COCl)
2, PhH, DMF, 0 ℃, 6 hours, 99%; (b) 1.0 equivalent 29a or 29b, 1.2 equivalent Et
3N, CH
2Cl
2, 0 ℃, 2 hours, 58 (98%) or 59 (96%); (c) for 60:2.2 equivalent NaH, 2.2 equivalents 51, DMF, 25 ℃, 8 hours, 66%; For 63:4.0 equivalent NaH, 1.2 equivalents 51, DMF, 25 ℃, 4 hours, 69%; (d) 1.1 equivalents 53, DMF, 25 ℃, 4 hours, 73%; For 64:1.9 equivalent 53, NMP, 25 ℃, 99%; (e) for 65:2.2 equivalent NaH, 2.5 equivalents 54, DMF, 25 ℃, 12 hours, 23%; (f) 1.1 equivalents 52, DMF, 25 ℃, 6 hours, 83%; For 66:2.0 equivalent 52, DMF, 25 ℃, 20 hours, 99%; (g) 50%TFA is in CH
2Cl
2, 25 ℃, 30 minutes, 90-99% 11,14-19 were after RP-HPLC.The Boc=tert-butoxycarbonyl; The TFA=trifluoroacetic acid; The NMP=N-N-methyl-2-2-pyrrolidone N-; The DMF=dimethyl formamide.
Fig. 9 has illustrated synthetic compound 20 and 21:(a under following reagent and condition) 1.0 equivalents, 55,2.2 equivalent Et
3N, DMF, 25 ℃, 16 hours, 92%; (b) 50% TFA is in CH
2Cl
2In, 25 ℃, 4 hours, 97%; (c) 1.0 equivalents, 56,2.2 equivalent Et
3N, DMF, 12 hours, 120% (thick yield); (d) 50% TFA is in CH
2Cl
2In, 25 ℃, 4 hours, 83%, after RP-HPLC.The TFA=trifluoroacetic acid; The DMF=dimethyl formamide.
Figure 10 has illustrated synthetic compound 22:(a under following reagent and condition) NH
3, DMF, 25 ℃, 5 hours, 93%; (b) 10% Pd/C, H
2, MeOH, 25 ℃, 8 hours, 90%; (c) 1.1 equivalent PhNCS, EtOH, 14 hours, 69%; (d) 1.0 equivalent HgCl
2, 1.0 equivalent Et
3N, DMF, 4 hours, 81%; (e) 50%TFA is in CH
2Cl
2In, 30 minutes, 88% (yield) was after RP-HPLC.The TFA=trifluoroacetic acid; The DMF=dimethyl formamide.
Figure 11 represents cohersive and integrated data, shows the interaction of nitro aryl ether pair part relevant with RGD and integral protein.The figure shows part in conjunction with the required concentration (IC of half maximum inhibition
50).For reference, peptide GRGDSPK and chemical compound 1 have been comprised.By to α
vβ
3IC
50, stored data.' cQ ' value representation NPE is with respect to the activity of chemical compound 1.'>' expression IC
50Do not reach the Cmax 10 μ M of test.
Figure 12 represents cohersive and integrated data, shows the effect that nitro aryl ether pair cell relevant with RGD and static part adhere to.The figure shows part in conjunction with the required concentration (IC of half maximum inhibition
50).Under the condition that has nitro aryl ether of the present invention as described herein, allow 25000 cell attachment in static part.Figure 12 has represented at half maximum resulting concentration (IC of cell attachment that suppresses
50).By to α
vβ
3IC
50(from low to high), data have been stored.
Describe in detail Embodiment 1: the design of non-peptide integral protein antagonist, synthetic and biological assessment:
In this embodiment, we have described a series of design, chemosynthesis and biological assessments that contain nitro aryl RGD analogies.Fig. 3 has shown target compound (10-22).Cause the consideration of its design to comprise: the Merck that (a) points to the importance of guanidine/arylsulfonyl amine functional group finds (Duggan et al.Abstracts of Papers, 211
ThACSNational Meeting, New Orleans, LA, March 24-28,1996; AmericanChemical Society:Washington, DC, 1996, MEDI 234); And (b) as shown in Figure 4, obtain this class formation from o-nitro-aryl fluoride easily.The molecule of design belongs to general formula (I) structure (Fig. 4), and this molecule can be that II and segment III (nucleopilic reagent) and IV (aminoacid ingredient) derive by coupling center nitro fluoro aromatics.
For synthetic compound 10-22 (Fig. 3), need amino acid derivativges 26,29a and 29b.These intermediate can be obtained by altheine acid (23) shown in Figure 5.Thus, under standard conditions, change into Boc derivant (24,88%) and can generate benzene methyl (Cs 23
2CO
3-BnBr) obtaining 25 (yields 88%) carries out afterwards.Utilize PhI (OCOCF
3)
2The reduction primary amide can obtain derivant 26, and yield is 41%.Sulfonamide 29a and 29b can make by following method: sulfonylation aminoacid, obtain 27a, and then carry out the Hoffmann reorganization, utilize isobutene. esterification gained aminoacid (28a and 28b) (Fig. 5).
Fig. 6 has summarized the initial methods of preparation chemical compound 10-13.Thus, under 80 ℃, utilize trimethyl orthoacetate to handle, 4-fluoro-o-nitrobenzoic acid (30) changed into its methyl ester (31,98%), then, in the presence of catalytic amount TBAF, in DMF with N
3(CH
2)
2The OTBS reaction, the result generates chemical compound 32 (73%; Yield is not best).Saponification 32 (LiOH, yield are 99%) obtains carboxylic acid 33, exists under DCC and the 4-DMAP condition, utilizes building block 26 to concentrate carboxylic acid 33, obtains main intermediate 34 (yield is 82%).In order to synthesize 10, there is H
2Under the O condition, utilize Ph
3 P reducing compound 34 obtains amine 35a and recombinant products 35b (merging yield is 80%), and wherein the side chain hetero atom has transposition (by inner nucleophillic attack, referring to structure 35a).When placing at ambient temperature, primary amine 35a is experiencing and quantitatively is being transformed into primary alconol 36b.But, by basic hydrolysis (LiOH) and amidination reaction (1H-pyrazoles-1-carboxyl amidine HCl), can handle chemical compound rapidly, obtain target compound 10 (yield is 15% behind the RP-HPLC purification) with low yield.
For synthetic sulfonamide compounds 11-13, intermediate 34 deprotections (TFA, 84%) commonly used, unconfined amine (37) obtains chemical compound 38a (78%) and 38b (57%) with suitable that sulfonic acid chloride reacts.Utilize Ph
3P-H
2 O reduction nitrine 38a of functional group and 38b obtain corresponding primary amine (39a and 39b) and reorganization primary alconol (41a and 41b) thereof again, and total recovery is 80%. Basic hydrolysis 39a and 39b generate corresponding carboxylic acid (40a and 40b, yield are 93-99%), carry out the amidination reaction as mentioned, obtain required chemical compound 11 and 13 (yield is 13-15%) respectively.Similarly, hydrolysis 41a (LiOH, yield are 96%) then carries out the amidination reaction, obtains chemical compound 12 by chemical compound 42 with low yield.
In reduction side chain azido group process observed reorganization bootable we seek the another kind of method of synthetic target nitro aryl ether chemical compound.According to new plan, comprise and protect the nucleophilic sample of guanidine part in the nitro aryl system of center, to replace fluoride fully.For this reason, nucleopilic reagent 51-56 (Poss et al.Tetrahedron Lett.1992,33,5933; Iwanowicz et al.Synth.Commun.1993,23,1443; Cherkaoui etal.Bull.Soc.Chim.Fr.1991,255) can be by the initiation material that obtains easily and by standard chemical process preparation shown in Figure 7.By nucleophilic aromatic replace with these fragments be incorporated into the method for molecule main structure and final goal thing synthetic shown in Fig. 8 (11,14-19) and Fig. 9 (21 and 22).Thus, there is Et
3Under the condition of N,, obtain amide 58 (98%) and 59 (99%) respectively with acyl chlorides 57 (derive and get) and amine 29a and 29b coupling by carboxylic acid 30.In DMF, under the condition that has NaH, with 58 with nucleopilic reagent 51 couplings, obtain product 60, yield is 66%.Similarly, by coupling 59 and 51, can obtain 63 (yield is 69%).By at ambient temperature, in DMF,, can be 73% and 99% to obtain amino- compound 61 and 64 respectively with yield by 58 and 59 with amine 53 reactions.Be exposed to (DMF, 25 ℃, yield is 23%) among mercaptan 54 and the NaH with 58, can obtain thioether 62.At room temperature, in CH
2Cl
2In utilize TFA to handle chemical compound 60-64, yield that can be good (being 90-99% RP-HPLC after) obtains guanidine and carboxylic acid group, and the two follows deprotection.By 58 and 59, can prepare diethylenediamine compound 16 and 19 respectively, at first utilize nucleopilic reagent 52 to replace fluoride, then gained derivant 65 and 66 be carried out TFA and induce deprotection as the method for Fig. 8 general introduction by similar mode.
At last, the preparation of chemical compound 22 as shown in figure 10.Thus, in DMF,, obtain nitroaniline 69 with yield 93% with main intermediate 57 and ammonia react.Existing under the 10%Pd/C catalyst condition, in MeOH, utilize H
2Reduction 69 obtains 1, and 2-diamidogen 70 (90%) reacts with the phenyl isothiocyanate in EtOH again, obtains thiourea 71 (yield is 69%).At ambient temperature, in DMF, utilize HgCl
2And Et
3N handles 71, obtains guanidine 72 (yield is 81%).In 72, be used in CH
2Cl
2In the TFA cracking tert-butyl ester, obtain target compound 22 (yield is 80%, after the RP-HPLC purification) then.
Experimental record
General
Except as otherwise noted, respond all and to contain not moisture and under the argon gas atmosphere of the new solvent that steams under the anhydrous condition, to carry out.Oxolane (THF) and ether steam from sodium-benzophenone, dichloromethane (CH
2Cl
2), benzene (PhH) and toluene steams from calcium hydride.Anhydrous solvent also can be by making it by commercial activated alumina post.Unless otherwise indicated, yield be meant utilize chromatographer and spectrographic method (
1H NMR) the homogeneous phase material of purification.Except as otherwise noted, all reagent are all buied with the highest commercial mass, need not in use to be further purified.
Institute responds and all detects by thin layer chromatography.Described thin layer chromatography carries out under the following conditions: 0.25mm E.Merck silica gel plate (60F-254), and utilize UV light as developing agent, 7% alcoholic solution of phosphomolybdic acid or P-methoxybenzal-dehyde is as developing solvent.E.Merck silica gel (60, granularity is 0.040-0.063mm) is used for the flash column chromatography purification.The preparation of lamina chromatographic isolation can 0.25,0.50 or 1mm E.Merck silica gel plate (60F-254) on carry out.Reversed-phase HPLC carries out on Waters Model 600E HPLC instrument, and this instrument uses Vydac 218TP1022 post, in 40 minutes, utilizes 90: 10; 40: 60 H
2O: CH
3CN+0.1% TFA gradient solution detects at the 254nm place.
Utilize Bruker DRX-600, AMX-500, AMX-400 or AC-250 instrument record NMR spectrum, utilize residual not deuterated solvent to carry out verification as internal reference.Following abbreviation is used to explain that multiplicity: s is unimodal; D is bimodal; T is three peaks; Q is four peaks; M is a multiplet; Band is several overlapped signals; B is a broad peak.Utilize Perkin-Elmer 1600 serial FT-IR spectrometer record IR spectrum.Under fast atom bombardment (FAB) condition, utilize VG ZAB-ZSE mass spectrograph record high resolution mass spec.Utilize Perkin Elmer ScienceAPI III mass spectrograph record EFI mass spectrum.As shown in Figure 5, the synthesizing amino acid derivative 25.
Chemical compound 25: to tert-butoxycarbonyl-(L)-agedoite acid (12.6g, 50mol; Aldrich) add entry (20ml) in MeOH (200ml) solution.Utilize 20% Cs
2CO
3Aqueous solution (57ml) neutralization solution is evaporated to dried then.The gained residue is collected among the DMF (50ml), yet does and azeotropic drying by being evaporated to.Cesium salt is collected among the DMF (125ml), then add benzyl bromide a-bromotoluene (6.5ml, 55mol).At room temperature stirred the mixture 6 hours, and be evaporated to driedly, utilize water (500ml) to grind residue.Add solid and be dissolved in the ethyl acetate (150ml), utilize water (75ml) washing organic facies, at Na
2SO
4Last dry, removal of solvent under reduced pressure.Oil ethyl acetate/hexane recrystallization is ester just, obtains 25 (15.1g, 88%), is colorless solid.
IR (KBr): n
Max3401,3349,3204,2982,2935,1741,1688,1657,1524,1293,1169,1055 cm
-1 1HNMR (500MHz, CDCl
3): d 7.36-7.32 (m, 5 hours, Ph), 5.73 (d, J=8.5Hz, 1H, NHCO
2), 5.59 (bs, 1H, CONHH), 5.40 (bs, 1H, CONHH), 5.20 (d, J=12.5Hz, 1H, CHHPh), 5.17 (d, J=12.5Hz, 1H, CHHPh), 4.56 (ddd, J=4.0,5.0,8.5Hz, 1H, CHCH
2), 2.95 (dd, J=5.0,16.5Hz, 1H, CHCHH), 2.76 (dd, J=4.0,16.5Hz, 1H, CHCHH), 1.42 (s, 9H,
tBu);
13C NMR (150MHz, CDCl
3): d 171.9,171.2, and 155.7,135.4,128.5,128.3,128.2,80.1,67.4,50.3,37.4,28.3; FAB-HRMS (M+Na
+) value of calculation 345.1426, measured value 345.1421.
As shown in Figure 5, synthetic compound 26: at room temperature, to two (trifluoroacetyl oxygen base) phenyl-iodide (2.0g, DMF 4.7mmol): H
2Adding chemical compound 25 in O (24ml, 1: the 1 v/v) agitating solution (1.0g, 3.1mmol).After 15 minutes, (0.5ml 6.2mmol), continues to stir 3 hours to add pyridine.Solvent evaporated under reduced pressure is dissolved in residue in the water (30ml).Utilize water washing solution, utilize 1N NaOH alkalization water layer, utilize dichloromethane extraction.Removal of solvent under reduced pressure obtains the oily residue.(10%MeOH is in CH by the flash column chromatography purification
2Cl
2In), obtain amine 26, be yellow oil (0.37g, 41%).R
f=0.11 (2.5% methanol is in ethyl acetate);
IR (thin film
): n
Max3366,3313,3064,2979,2934,1688,1518,1501,1456,1393,1368,1324,1254,1204,1166,1055,1002,838,800,743,692cm
-1 1H NMR (500MHz, CDCl
3): d 7.36-7.28 (m, 5H, Ph), 6.36 (bm, 2H, NH
2), 6.06 (d, J=7.5Hz, 1H, NHCO
2), 5.18 (d, J=12.0Hz, 1H, CHHPh), 5.13 (d, J=12.0Hz, 1H, CHHPh), 4.52-4.43 (bm, 1H, CHCH
3), 3.35 (bdd, J=12.5Hz, 1H, CHCHH), 3.24 (bdd, J=6.5,12.5Hz, 1H, CHCHH), 1.32 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 170.0,155.9, and 134.8,128.5,128.4,128.3,80.6,67.7,52.9,41.6,28.0; FAB-HRMS (M+H
+) value of calculation 295.1658, measured value 295.1650.
As shown in Figure 5, synthetic compound 27a.Under 0 ℃ to (L)-agedoite acid (23) (10.00g, H 75.7mmol)
2O ∶ diox (50ml: add in solution 50ml) NaOH (3.40g, 85.0mmol).At 0 ℃ after following 15 minutes, add the phenyl sulfonic acid chloride (10.6ml, 84.0mmol),, then add NaOH (3.40g, H 85.0mmol) at 0 time
2O (50ml) solution.After 30 minutes, remove cooling bath, decompression concentrated solution is to about 50ml.Utilize ethyl acetate (2 * 50ml) aqueous phase extracted.Under 0 ℃, utilize dense HCl (pH ≈ 1) acidify water, be settled out protected amino acid, collect the gained solid, utilize water (20ml) washing by filtering.Oven dry is spent the night under about 50 ℃, obtains 27a, is colorless solid (14.6g, 71%).Crude product can need not to be further purified use down.
IR (KBr): n
Max3495,3338,3260,1723,1648,1578,1449,1325,1261,1202,1166,1086cm
-1 1H NMR (500MHz, methanol-d
4): d 7.88-7.86 (m, 2H, Ph), 7.60-7.57 (m, 1H, Ph), 7.54-7.51 (m, 2H, Ph), 4.23 (t, 1H, J=6.0Hz, CHCO
2H), 2.66 (dd, 1H, J=6.0,15.5Hz, CHH (C=O) NH
2), 2.60 (dd, J=6.0,15.5Hz, CHH (C=O) NH
2);
13C NMR (125MHz, methanol-d
4): d 174.3,173.6, and 142.1,133.7,130.0,128.2,53.9,39.6; FAB-HRMS (M+H
+) value of calculation 273.0545, measured value 273.0540.
As shown in Figure 5, synthetic compound 27b.Prepare chemical compound 27b by the method identical, only be to use the 2-naphthalene sulfonyl chloride to replace the phenyl sulfonic acid chloride with Synthetic 2 7a.Thick yield: 16.06g (66%).
IR (KBr): n
Max3424,3289,2925,1851,1713,1673,1502,1399,1333,1258,1223,1191,1159,1127,1075,1023,964,866,822,794,714,669,638,548,477cm
-1 1H NMR (500MHz, DMSO-d
6): d8.40 (d, J=1.0Hz, 1H, naphthyl), 8.15 (d, J=9.0Hz, 1H, NHSO
2), 8.12 (d, J=8.0Hz, 1H, naphthyls), 8.07 (d, J=9.0Hz, 1H, naphthyls), 8.01 (d, J=8.0Hz, 1H, naphthyl), 7.81 (dd, J=1.5,8.8Hz, 1H, naphthyls), 7.68 (ddd, J=1.5,6.8,7.5Hz, 1H, naphthyl), 7.64 (ddd, J=1.5,6.8,7.5Hz, 1H
Naphthyl), 7.33 (bs, 1H, CONHH), 6.87 (bs, 1H, CONHH), 4.16 (bm, 1H, CHCH
2), 2.47 (dd, J=7.0,15.5Hz, 1H, CHCHH) 2.28 (dd, J=6.5,15.5Hz, 1H, CHCHH);
13C NMR (125MHz, DMSO-d
6): d 172.0,170.5, and 138.4,134.1,131.6,129.2,129.0,128.6,127.8,127.4,127.1,122.6,52.5,38.0; FAB-HRMS (M+H
+) value of calculation 323.0702, measured value 323.0708. synthetic compound 55 (b), wherein chemical compound 55-NH substituent group quilt-OH replaces.
Steps A: under 25 ℃, in 3-hydracrylic acid (0.073g, 0.16mmol, 1.0 equivalents) solution, add DMF (0.5ml, 0.32M), imidazoles (26.0mg, 0.38mmol, 2.4 equivalents) he TBDPSCl (0.046ml, 0.19mmol, 1.2 equivalents), allow to stir 2.5 hours.Then, utilize ether (10ml) dilute solution, reuse 5% hydrogen chloride saturated solution (2 * 10ml), water (2 * 10ml), saline (1 * 5ml) washing, at MgSO
4Last dry.By flash column chromatography purifying compounds (Silicon stone, 80% ether is in petroleum ether), apply it in the following step:
Step B: at room temperature, will in the phenylenediamine among the 5.5N HCl (10ml) (1.08g, 0.01mol) solution join the quilt that obtains by steps A protect intermediate (1.125g, 0.015mol) in.Reaction mixture refluxed 24 hours allows to be cooled to room temperature then.Vacuum evaporating solvent obtains precipitation, filters and utilize the ether washing, then,
Step C: remove the TBDPS group according to following method: THF (0.1M) solution of the intermediate (7.481mmol) that will be obtained by step B is cooled to 0 ℃, utilize azeotropic drying (benzene, 3 * 50ml) TBAF (22.44mmol) handle.Stir stirred reaction mixture 10 hours down at 0 ℃, utilize saturated hydration NH
4The Cl quenching.Separates two is utilized the mixture extraction water of ethyl acetate and ether.The organic facies of utilizing the salt water washing to merge, dry and concentrated.By silica gel chromatography, obtain pure compound 55 (b), wherein chemical compound 55-NH
2Substituent group quilt-OH replaces.Synthetic compound 55 (c), the wherein substituent group-NH of chemical compound 55
2Quilt-SH replaces.
At room temperature, to the phenylenediamine in 5.5N HCl (10ml) (1.08g, 0.01mol) add in the solution 3-mercaptopropionic acid (1.125g, 0.015mol).Reaction mixture refluxed 24 hours allows to be cooled to room temperature then.Vacuum evaporating solvent filters and utilizes ether washing, obtains pure compound 55 (c), wherein substituent group-the NH of chemical compound 55
2Quilt-SH replaces.
Synthetic compound 67 (b) and (c), wherein-NH-group quilt-S-or-the O-divalent group replaces (situation of NH-as shown in Figure 9).At room temperature, to 57 (0.10g, 0.20mmol; As above synthetic) DMF (8ml) solution in add 55 (b) or (c) (0.038g, 0.22mmol; As above synthetic) and triethylamine (0.06ml, 0.44mmol).After 25 ℃ are stirred 16 hours down, utilize EtOAc (10ml) and water (10ml) diluted reaction mixture.Layering utilizes ethyl acetate (2 * 10ml) aqueous layer extracted.Collect organic extract, utilize water (2 * 10ml) and saline (20ml) wash, at Na
2SO
4Last dry.Refilter and reduction vaporization after, by purification by flash chromatography residue (Silicon stone, ethyl acetate), obtain 67 (b) and (c).
Synthetic compound 20 (b) or (c), wherein-NH-group quilt-S-or-the O-divalent group replaces (situation of NH-as shown in Figure 9).At room temperature, to 67 (b) or (c) (0.068g, 0.11mmol; As above synthetic) CH
2Cl
2(2ml) add trifluoroacetic acid (2ml) in the solution.After 4 hours, vacuum evaporating solvent obtains grease, after RP-HPLC (C-18), obtains 20 (b) or (c).
As shown in Figure 5, synthetic compound 28a.(11.15g, water 280.0mmol) (50ml) solution is cooled to 0 ℃ to add NaOH in the round-bottomed flask that magnetic stirring bar is installed.Dripping bromine in 5 minutes (2.60ml, 50.0mmol), reactant mixture restir 5 minutes under this temperature.Under 0 ℃, once add protected amino acid 27a (10.44g, NaOH 38.0mmol) (3.10g, 70.0mmol, 30ml water) solution.Under this temperature, continue to stir 20 minutes, and removed cooling bath, be heated to 90 ℃ 30 minutes.After being cooled to 0 ℃, utilize the 1M concentrated hydrochloric acid that the pH value of reactant mixture is transferred to 7.Collect the colourless precipitation of gained by filtering.Utilize the water washing residue, dry down at about 50 ℃ and spend the night, obtain 28a, be colorless solid (6.95g, 75%).Crude product need not to be further purified use down.
IR (KBr): n
Max3509,3299,3058,2936,1636,1596,1522,1446,1413,1355,1340,1300,1246,1163,1094,1028,924cm
-1 1HNMR (500MHz, DMSO-d
6): d 7.84-7.82 (m, 2H, Ph), 7.66-7.63 (m, 1H, Ph), 7.60-7.56 (m, 2H, Ph), 7.58 (bm, 1H, NHSO
2Ph), 3.35 (bs, 2H, NH
2), 3.17 (dd, J=4.5,9.5Hz, 1H, CHCH
2), 3.01 (dd, J=2.5,12.0Hz, 1H, CHH), 2.80 (dd, J=9.5,12.0Hz, 1H, CHH);
13C NMR (125MHz, DMSO-d
6): d 169.4,139.1, and 132.7,129.2,126.8,52.7,41.7; FAB-HRMS (M+Na
+) value of calculation 245.0596, measured value 245.0599.
As shown in Figure 5, synthetic compound 28b.Prepare chemical compound 28b according to preparing the identical method of 28a, use 27b to substitute 27a.Just yield: 11.88g (81%) is light brown solid.
IR (KBr): n
Max3338,3241,3056,2831,2601,1651,1604,1513,1463,1404,1382,1335,1151,1076,1039,985,955,931,913,855,814,787,7 49,657,618,550,480Cm
-1 1H NMR (500MHz, DMSO-d
6): d 8.48 (br.s, 1H, naphthyl), 8.16-8.10 (2bd, 2H, naphthyl), 8.04 (d, J=8.5Hz, 1H,
Naphthyl), 7.85 (dd, J=2.0,8.5Hz, 1H, naphthyls), 7.70 (ddd, J=1.5,7.0,8.0Hz, 1H, naphthyls), 7.66 (ddd, J=1.0,7.0,8.0Hz, 1H, naphthyls), 7.45 (bm, 1H, NHSO
2), 3.54-3.19 (bm, 2H, NH
2), 3.23 (dd, overlapping, J=4.5,9.5Hz, 1H, CHCH
2), 3.04 (dd, J=4.5,12.00Hz, 1H, CHCHH), 2.83 (dd, J=9.5,12.00Hz, 1H, CHCHH);
13C NMR (125 MHz, DMSO-d
6): d 169.3,136.1, and 134.3,131.6,129.4,129.2,128.9,128.0,127.8,127.6,122.5,52.7,41.6; FAB-HRMS (M+H
+) value of calculation 295.0753, measured value 295.0761.
As shown in Figure 5, synthetic compound 29a.Be equipped be filled with in the sealing test tube of magnetic stirring bar 28a (4.88g, 20.0mmol) and 75ml anhydrous dimethyl oxygen base ethane.After adding the 3.0ml concentrated sulphuric acid, in argon gas atmosphere, reactant mixture is cooled to-78 ℃, the 40.0ml isobutene. is filled in the sealing test tube.After airtight, remove cooling bath, reactant mixture at room temperature stirred 48 hours.Reactant mixture is injected in the 100ml frozen water.Utilize ether (40ml) extraction water solution, utilize 6N NaOH aqueous solution with pH regulator to 12-13.(4 * 50ml) extraction unhindered aminas utilize NaHCO to utilize ethyl acetate
3Saturated aqueous solution (50ml), 5%KHSO
4Aqueous solution (50ml) and saline (50ml) sequentially wash the organic extract liquid that merges.Organic facies is at MgSO
4Last dry, the decompression sickness solvent removed in vacuo obtains 29a (10.9g, 55.5%), is pale solid.Crude product need not to be further purified use down.R
f=0.27 (silica gel, ethyl acetate);
IR (KBr) n
Max3372,3295,2981,2932,1726,1452,1337,1261,1161,1094,945,898,845,753cm
-1 1H NMR (500MHz, CDCl
3): d 7.86-7.84 (m, 2H, Ph), 7.58-7.54 (m, 1H, Ph), 7.51-7.48 (m, 1H, Ph), 3.76 (dd, J=4.0,5.5Hz, 1H, CHCH
2), 3.02 (dd, J=9.0,13.0Hz, 1H, CHH), 2.88 (dd, J=5.5,13.0Hz, 1H, CHH), 1.27 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 169.3,139.7, and 132.8,129.1,127.2,82.8,58.8,44.9,27.7; FAB-HRMS (M+H
+) value of calculation 301.1222, measured value 301.1211.
As shown in Figure 5, Synthetic 2 9b.Prepare chemical compound 29b according to preparing the identical method of 29a, use 28b to substitute 28a.Just yield: 4.56g (51%) is pale solid.R
f=0.25 (silica gel, ethyl acetate+2%v/v Et
3N);
IR (KBr): n
Max3360,3264,3057,2981,2935,2873,2747,1731,1588,1501,1455,1339,1254,1220,1157,1076,952,926,823,782,747,663,619,552,481cm
-1 1H NMR (500MHz, CDCl
3): d 8.40 (bs, 1H, naphthyl), 7.92 (bd, J=8.5Hz, 2H, naphthyls), 7.86 (d, J=8.0Hz, 1H, naphthyls), 7.82 (dd, J=1.5,8.5Hz, 1H,
Naphthyl), and 7.64-7.55 (2 * ddd, overlapping, J=1.0,7.0,8.5Hz, 2H, naphthyl), 3.84 (dd, J=4.2,5.8Hz, 1H, CHCH
2), 3.30-2.60 (bm, superimposed, 2H, NH
2), 3.03 (dd, J=4.2,13.4Hz, 1H, CHCHH), 2.88 (dd, J=5.8,13.4Hz, 1H, CHCHH), 1.08 (s, 9H, t-Bu);
13C NMR (125MHz, CDCl
3): d 169.2,136.3, and 134.9,132.0,129.5,129.2,128.9,128.6,127.8,127.5,122.4,82.9,58.6,44.6,27.5; FAB-HRMS (M+H
+) value of calculation 351.1379, measured value 351.1371.
As shown in Figure 6, synthetic compound 31.To acid 30 (5.0g, 27mmol; Aldrich) add in the toluene suspension trimethyl orthoacetate (17ml, 135mmol).With mixture heated to 80 ℃ 12 hours, removal of solvent under reduced pressure obtained 31, is colorless solid (5.26g, 98%).R
f=0.46 (silica gel, 25% ethyl acetate is in hexane);
IR (KBr): n
Max3061,2960,1714,1614,1542,1438,1351,1297,1262,1233,1130,871,755cm
-1 1H NMR (500MHz, CDCl
3): d 8.74 (dd, J=
4J (
1H-
1H)=2.0Hz,
4J (
1H-
19F)=and 7.0Hz, 1H, 2-Ar-H), 8.32 (ddd,
4J (
1H-
1H)=2.0Hz,
4J (
1H-
19F)=4.5Hz,
3J (
1H-
1H)=9.0,1H, 6-Ar-H), 7.39 (dd,
3J (
1H-
1H)=9.0Hz,
3J (
1H-
13F)=and 10.5Hz, 1H, 5-Ar-H);
13C NMR (125MHz, CDCl
3): d 164.1,159.1, and 156.9,136.5,127.8,118.8,118.7,52.9; FAB-HRMS (M+H
+) value of calculation 200.0281, measured value 200.0286.
As shown in Figure 6, synthetic compound 32.At room temperature, to 31 (4.0g, about 4g 4 molecular sieves of adding and 4.46g (0.22mmol) N in DMF 20mmol) (10ml) solution
3(CH
2)
2OTBS.After 10 minutes, add the THF solution of 2ml (2.0mmol) 1M TBAF.Mixture at room temperature stirred 4 hours, then by a bit of kieselguhr (celite
) filter.Filtrate collection utilizes water, saturated NaCO in ethyl acetate (100ml)
3Aqueous solution and saline sequentially wash.Organic extract liquid is at MgSO
4Last dry, filter and removal of solvent under reduced pressure, obtain yellow oil.Through flash column chromatography purification (silica gel, 40% ethyl acetate is in hexane), obtain 32, little yellow solid (3.85g, 73%).R
f=0.35 (silica gel, 40% ethyl acetate is in hexane);
IR (KBr): n
Max2950,2938,2114,1713,1620,1536,1438,1349,1303,1276,1247,1161,1136,918,760cm
-1 1H NMR (500MHz, CDCl
3): d 8.54 (d, J=2.0Hz, 1H, Ar), 8.22 (dd, J=2.0,9.0Hz, 1H, Ar), 7.13 (d, J=9.0Hz, 1H, Ar), 4.32 (t, J=5.0Hz, 2H, OCH
2), 3.94 (s, 3H, OCH
3), 3.71 (t, J=5.0Hz, 2H, CH
2N
3);
13C NMR (125MHz, CDCl
3): d 164.7,154.7, and 135.3,127.3,123.3,114.0,68.8,52.5,49.7; FAB-HRMS (M+Na
+) value of calculation 289.0549, measured value 289.0553.
As shown in Figure 6, synthetic compound 33.To 32 (3.85g, 14.0mmol) 1,4-diox: water (90ml: 30ml) add LiOHH in the solution
2O (1.2g, 28mmol).Reactant mixture at room temperature stirred 4 hours, added the saturated NH of 40ml then
4Cl solution.Organic solvent is removed in decompression, obtains yellow mud shape thing, and this mud shape thing is dissolved in the water, utilizes 1M KHSO
4Acidified aqueous solution.Utilize CH then
2Cl
2(3 * 70ml) extractions.The organic extract liquid that merges is at MgSO
4Last dry, to filter, removal of solvent under reduced pressure obtains 33, is yellow solid (3.50g, 99%).R
f=0.10 (silica gel, 60% ethyl acetate is in hexane);
IR (KBr): n
Max3087,2964,2877,2659,2539,2120,1699,1616,1534,1429,1359,1282,1163,1138,1079,1039,1002,929,847,763,687,642,546cm
-1 1H NMR (500MHz, methanol-d
4): d 8.40 (d, J=2.0Hz, 1H, Ar), 8.22 (dd, J=2.0,9.0Hz, 1H, Ar), 7.37 (d, J=9.0Hz, 1H, Ar), 4.37 (t, J=4.5Hz, 2H, OCH
2), 3.67 (t, J=5.0Hz, 2H, CH
2N
3);
13C NMR (125MHz, methanol-d
4): d 167.4,156.0, and 140.9,136.4,127.9,124.9,115.7,70.3,51.1; FAB-HRMS (M+Na
+) value of calculation 275.0392, measured value 275.0395.
As shown in Figure 6, synthetic compound 34.At room temperature, (0.33g is 1.10mmol) with acid 33 (0.286g, CH 1.10mmol) to amine 26
2Cl
2(30ml) add in the solution catalytic amount DMAP (0.03g, 0.22mol) and DDC (0.26g, 1.1mol).Reactant mixture stirred 4 hours under this temperature, the 1,3-Dicyclohexylurea of filtering-depositing, and filtrate is utilized water, saturated NaHCO
3Aqueous solution and saline sequentially wash.Organic solvent is removed in decompression, obtains grease, behind flash column chromatography purification (silica gel, 60% ethyl acetate is in hexane), obtains amide 34, is yellow solid (2.48g, 82%).R
f=0.28 (silica gel, 60% ethyl acetate is in hexane);
IR(KBr):n
max?3343,2977,2933,2112,1738,1710,1619,1531,1498,1366,1333,1280,1161,1084,1047cm
-1;
1H?NMR(500MHz,CDCl
3):d?8.23(d,J=2.0Hz,1H,Ar),7.98(dd,J=2.0,11.0Hz,1H,Ar),7.40(bt,1H,NHCO),7.39-7.31(m,5H,Ph),7.09(d,J=11.0Hz,1H,Ar),5.67(d,J=8.0Hz,1H,NHCO
2),5.21(s,2H,CH
2Ph),4.60-4.50(bm,1H,CHCH
2),4.30(t,J=6.0Hz,2H,OCH
2),3.95-3.85(bm,1H,CHCHH),3.78-3.70(bm,
Overlapping, 1H, CHCHH), 3.70 (t, J=6.0Hz, 2H, CH
2N
3), 1.43 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 170.0,164.9, and 153.8,139.8,135.0,133.0,128.7,128.6,126.9,124.6,114.3,81.0,68.8,67.9,49.8,33.8,28.2,25.5,24.8; FAB-HRMS (M+Cs
+) value of calculation 661.1023, measured value 661.1050.
As shown in Figure 6, synthetic compound 35ab.To azide 34 (50mg, THF 0.095mmol): H
2O (8ml THF: 0.04ml H
2O) add in the solution of mixture triphenylphosphine (50mg, 0.19mmol).Reactant mixture at room temperature stirred 14 hours, removal of solvent under reduced pressure.By flash column chromatography purification (silica gel, 20% methanol is in dichloromethane), obtain two main fractions (total recovery 80%).Fraction 1:17mg (faint yellow oily thing, 40%), fraction 2:17mg (faint yellow oily thing, 40%).In ninhydrin test, fraction 1 is positive, and fraction 2 is negative.Fraction 1 35a Rf=0.48 (silica gel, 20% methanol is in dichloromethane);
1H NMR (500MHz, CDCl
3): d 8.22 (m, 1H, Ar), 7.94 (d, J=9.0Hz, 1H, Ar), 7.43-7.30 (m, 6H), 7.07 (d, J=9.0Hz, 1H, Ar), 5.80 (d, J=6.0Hz, 1H, NHBoc), 5.19 (s, 2H, CH
2Ph), 4.54 (bm, 1H, CHNHBoc), 4.21 (bm, 2H, CH
2OAr), and 3.87-3.76 (m, 2H), 3.19 (s, 2H, CH
2NH
2), 2.75 (bs, 2H, NH
2), 1.41 (s, 9H,
tBu); FAB-HRMS (M+H
+) value of calculation 503.2142, measured value 503.2162. fraction 2 35b Rf=0.86 (silica gel, 20% methanol is in dichloromethane);
1HNMR (500MHz, CDCl
3): d=8.46 (m, 1H, Ar), 8.42 (t, J=6.5Hz, 1H, NHAr), 7.79 (dd, J=2.5,11.0Hz, 1H, Ar), 7.38-7.28 (m, 5H, Ar), 7.21 (m, 1H, NHCO), 6.80 (d, J=11.0Hz, 1H, Ar), 5.85 (d, J=9.0Hz, 1H, NHBoc), 5.19 (s, 2H, CH
2Ph), 4.53 (m, 1H, CHNHBoc), 3.92 (t, J=6.5Hz, 2H, CH
2OH), 3.88-3.73 (m, 2H, CH
2NH (CO)), 3.52-3.38 (m, 2H, CH
2NHAr), 1.41 (s, 9H,
tBu); FAB-HRMS (M+Cs
+) value of calculation 635.118, measured value 635.110.
As shown in Figure 6, synthetic compound 10.At room temperature, to 35a (0.023g, THF 0.046mmol): H
2O (6ml: 2ml) add LiOHH in the solution of mixture
2O (4ml, 0.092mmol).Stirred the mixture 4 hours, and utilized the acetic acid acidify then.Removal of solvent under reduced pressure, residue need not to be further purified in next step uses.In the 2ml of thick acid anhydrous DMF solution, add N, the N-diisopropylethylamine (9ml, 0.05mmol) and 1H-pyrazoles carboxyl amidine HCl (8mg, 0.05mmol).After 16 hours, removal of solvent under reduced pressure, residue obtains 10 (3.25mg, 13%) by RP-HPLC (C-18) purification, is light yellow solid.R
t=20.5 minutes;
1H NMR (500MHz, D
2O): d 8.33 (d, 1H, J=2.0Hz, Ar), 7.98 (dd, 1H, J=2.0,9.0Hz, Ar), 7.30 (d, J=9.0Hz, 1H, Ar), 4.42 (m, 1H, CHNHBoc), 4.34 (t, J=4.0Hz, 2H, CH
2NH (CO)), 3.82 (m, 2H, NH
2(C=NH) NHCH
2, 3.63 (t, 2H, J=4.0Hz, 2H, CH
2O); FAB-HRMS (M+Cs
+)Value of calculation 587.0866, measured value 587.0895.
As shown in Figure 6, synthetic compound 37.At room temperature, to 34 (0.10g, CH 0.019mmol)
2Cl
2(4ml) add trifluoroacetic acid (4ml) in the solution.Stirred the mixture 2 hours.Solvent removed in vacuo obtains light yellow oil, and (Silicon stone, 5% methanol is in dichloromethane) obtains 37 after purification by flash chromatography, is grease (0.07g, 84%).R
f=0.19 (Silicon stone, 5% methanol is in dichloromethane);
1H NMR (500MHz, CDCl
3): d 8.21 (d, J=2.0Hz, 1H, 2-Ar-H), 7.95 (dd, J=2.0,11.0Hz, 1H, 6-Ar-H), 7.39-7.29 (m, 5H, Ar), 7.21 (bm, 1H), 7.05 (d, J=9.0Hz, 1H), 5.16 (s, 2H, CH
2Ph), 4.27 (t, J=5.0Hz, 2H, CH
2OAr), 3.67 (t, J=5.0Hz, 2H, CH
2N
3), 3.95-3.78 (bm, 1H, CHNH
2), 3.65-3.52 (bm, 1H, CHCHH), 4.32-4.31 (bm, 1H, CHCHH);
13C (125MHz, CDCl
3): d 164.9,153.7, and 139.2,135.1,133.1,128.6,128.5,128.4,127.0,124.6,114.2,68.7,67.4,49.7,33.8,25.5; FAB-HRMS (M+Cs
+) value of calculation 561.0499, measured value 561.0507.
As shown in Figure 6, synthetic compound 38a.At room temperature, to 37 (0.13g, CH 0.30mmol)
2Cl
2Add N (10ml), the N-diisopropylethylamine (0.07ml, 0.39mmol) and benzene sulfonyl chloride (0.034ml, 0.33mmol).After 4 hours, utilize CH
2Cl
2(10ml) and water (10ml) diluted reaction mixture.Layering utilizes saturated sodium bicarbonate solution and salt water washing organic layer and dry (MgSO
4).Solvent removed in vacuo obtains grease, obtains 38a behind preparation of lamina chromatogram purification (Silicon stone, 60% ether is in hexane), is grease (0.13g, 78%).R
f=0.43 (Silicon stone, 60% ether is in hexane);
1H NMR (500MHz, CDCl
3): d 8.26 (d, J=2.0Hz, 1H, 2-Ar-H), 7.98 (dd, J=2.0,9.0Hz, 1H, 6-Ar-H), 7.81 (d, J=8.0Hz, 2H, Ar), 7.53 (t, J=8.0Hz, 1H, the p-phenyl), 7.42 (t, J=8.0Hz, 2H, the m-phenyl), and 7.31-7.30 (m, 3H, Ar), 7.22-7.21 (m, 2H, Ar), 7.08 (d, J=9.0Hz, 1H, 5-Ar-H), 7.03 (t, J=5.5Hz, 1H), 5.03 (d, J=12.0Hz, 1H, PhCHH), 4.99 (d, J=12.0Hz, 1H, PhCHH), 4.29 (t, J=4.5Hz, 2H, CH
2O), 4.16 (dd, J=4.0,7.5Hz, 1H, CHCHH), 3.92-3.87 (m, 1H, CHCH
2), 3.72-3.67 (m, overlapping, 3H, CHCHH, CH
2N
3);
13C NMR (125MHz, CDCl
3): d 169.2,165.2, and 153.7,139.3,138.7,134.3,133.1,132.9,129.1,128.4,128.3,126.9,126.5,124.9,114.1,68.7,68.1,55.4,49.7,42.4; FAB-HRMS (M+Cs
+) value of calculation 701.0431, measured value 701.0442.
As shown in Figure 6, synthetic compound 38b.Prepare chemical compound 38b according to preparing the identical method of 38a, use the 1-naphthalene sulfonyl chloride to substitute benzene sulfonyl chloride.Yield: 0.031g (57%) is grease.R
f=0.18 (5% methanol is in dichloromethane);
IR (thin film): n
Max3277,2930,2112,1740,1652,1618,1523,1496,1348,1280,1162,1125,984,910,772cm
-1.
1H NMR (500MHz, CDCl
3): d 8.60 (d, J=11.0Hz, 1H, naphthyl), 8.21 (dd, J=2.0,9.3Hz, 1H, naphthyl), 8.03 (d, J=2.9Hz, 1H, 2-Ar-H), 8.01 (d, J=10.4Hz, 1H, naphthyl), 7.87 (d, J=9.3Hz, 1H, naphthyls), 7.81 (dd, J=2.9,11.0Hz, 1H, 6-Ar-H), 7.62 (ddd, J=1.7,8.7,8.7Hz, 1H, naphthyl), 7.54 (ddd, J=1.3,8.8,8.8Hz, 1H, naphthyl), 7.47 (dd, J=9.4,10.1Hz, 1H, naphthyl, 7.28-7.22 (m, 3H, Ph), 7.12-7.07 (m, 2H, Ph), 6.98 (d, J=11.0Hz, 1H, 5-Ar-H), 6.69 (dd, J=7.5Hz, 1H, NHCO), 6.22 (d, J=9.5Hz, 1H, NHSO
2), 4.89 (d, J=15.0Hz, 1H, CHHPh), 4.83 (d, J=15Hz, 1H, CHHPh), 4.25 (t, J=6.0Hz, 2H, OCH
2), 4.13 (ddd, J=5.4,9.4,9.5Hz, 1H, CHCH
2), 3.74 (ddd, J=5.4,7.4,17.5Hz, 1H, CHCHH), 3.69 (t, J=6.1Hz, 2H, CH
2N
3), 3.67 (ddd, overlapping, J=7.5,9.0,17.5Hz, 1H, CHCHH);
13C NMR (125MHz, CDCl
3): d 169.3,165.1, and 153.7,139.1,134.8,134.4,134.0,13 3.5,132.9,129.9,129.0,128.6,128.5,128.3,127.7,126.3,124.8,124.1,114.0,68.7,67.9,55.7,49.8,42.2; FAB-HRMS (M+Cs
+)Value of calculation 751.0587, measured value 751.0599.
As shown in Figure 6, synthetic compound 39a and 41a.Prepare chemical compound 39a and 41a according to preparing the identical method of 35ab, use chemical compound 38b to substitute 38a.Yield: F1=0.029g, F2=0.028g; Total recovery: 80%.In ninhydrin test, F2 is positive, and F1 is not.R
f(F1) 41a=0.39 (Silicon stone, 10% methanol in dichloromethane).
1H NMR (500MHz, CDCl
3): d 8.35 (bs, 1H, 2-Ar-H), 8.31 (bs, 1H, CH
2NHAr), 7.76-7.60 (m, overlapping, 3H, Ar), 7.50 (bs, 1H), 7.38 (t, J=9.0Hz, 1H, Ar), 7.28 (t, J=9.0Hz, 2H, Ar), 7.26-7.13 (m, 5H, Ar), 6.86 (d, J=11.0Hz, 1H, Ar), 6.64 (d, J=11.0Hz, 1H, NHSO
2), 4.92 (d, J=15.0Hz, 1H, PhCHH), 4.86 (d, J=15.0Hz, 1H, PhCHH), 4.26-4.23 (m, 1H, CHCH
2), 3.80-3.67 (m, overlapping, 4H, HOCH
2, CHCH
2), 3.34-3.31 (bm, CH
2NHAr), 2.92 (bs, CH
2OH); R
f(F2) 39a=0.16 (Silicon stone, 20% methanol is in dichloromethane);
1H NMR (500MHz, CDCl
3): d 8.24 (bs, 1H, Ar), 7.94 (d, J=9.0Hz, 1H, Ar), 7.80 (d, J=8.0Hz, 2H), 7.49 (t, J=8.0Hz, 1H, Ph), 7.40 (t, J=8.0Hz, 2H, ph), 7.30-7.28 (m, 3H, Ar), 7.19-7.18 (m, overlapping, 3H, Ar, NH (CO)), 7.02 (d, J=9.0Hz, 1H, Ar), 5.01 (d, J=12.5Hz, 1H, PhCHH), 4.97 (d, J=12.5Hz, 1H, PhCHH), 4.18-4.15 (m, overlapping, 3H, CHCH
2, OCH
2), 3.86-3.84 (m, 1H, CHCHH), 3.70-3.68 (m, 1H, CHCHH), 3.15-3.13 (bm, 2H, OCH
2NH
2), 2.82 (bm, 2H, NH
2);
13C NMR (125MHz, CDCl
3): d 169.5,165.4, and 154.4,139.9,138.8,134.4,133.0,132.8,129.0,138.5,128.4,127.0,126.3,125.0,114.1,71.4,68.0,55.4,42.3,40.7; FAB-HRMS (M+Cs
+) value of calculation 675.0526, measured value 675.0546.
As shown in Figure 6, synthetic compound 11.Prepare chemical compound 11 according to preparing chemical compound 10 identical methods, use 40a to substitute 36b.Yield: 3.31g (13%).
1H?NMR(500MHz,
Methanol-d
4): d 8.26 (d, J=2.0Hz, 1H, Ar), 8.04 (dd, J=2.0,8.5Hz, 1H, Ar), 7.82-7.80 (m, 2H, Ph), 7.47-7.36 (m, 4H, 5-ArH, Ph), 4.35 (t, J=5.0Hz, 2H, OCH
2), 4.19 (dd, J=4.0,14.0Hz, 1H, CHCH
2), 3.75 (dd, J=4.0,14.0Hz, 1H, CHCHH), 3.68 (t, J=5.0Hz, 2H, CH
2NH (C=N)), 3.47 (dd, J=11.0,14.0Hz, 1H, CHCHH).
As shown in Figure 6, preparation chemical compound 12.At room temperature, to benzyl ester 41a (0.10g, THF 0.22mmol): H
2O (3ml: 1ml) add LiOHH in the solution
2O (18.5mg, 0.44mmol).After stirring 4 hours, utilize the acetic acid acidified reaction mixture, solvent removed in vacuo obtains thick sour 42a.In the DMF of sour 42a (5ml) solution, add N, and the N-diisopropylethylamine (38ml, 0.22mmol).After 50 ℃ were stirred 16 hours down, solvent removed in vacuo obtained grease, obtains 12 (5.4mg, 5%) afterwards at RP-HPLC (C-18), is light yellow solid.R
t=14.9 minutes;
1H NMR (600MHz, CDCl
3): d 8.26 (d, J=2.0Hz, 1H, Ar), 7.67-7.65 (m, 2H, ph), 7.64 (dd, J=2.0,9.0Hz, Ar), 7.24-7.18 (m, 3H, Ph), 7.06 (d, J=9.0Hz, Ar), 4.49 (t, J=4.0Hz, 2H, CH
2OH), 4.15 (dd, J=6.0,10.0Hz, 1H, CHCH
2), 3.86 (t, J=4.0Hz, 2H, CH
2N (C=NH) NH
2), 3.70 (dd, J=6.0,14.0Hz, 1H, CHCHH), 3.35 (dd, J=10.0,14.0Hz, 1H, CHCHH);
13C NMR (150MHz, CDCl
3): d 167.6,164.9,147.2,141.7,132.4,130.5,129.6,127.7,126.8,125.6,125.5,122.2,112.5,70.4,42.6,28.7,23.2. EFI mass spectrum (M+H
+) value of calculation 495, measured value 495.
As shown in Figure 6, synthetic compound 39b.To azide 38b (0.031g, THF 0.05mmol): H
2O (8ml: 0.04ml) add in the solution triphenylphosphine (0.026g, 0.1mmol).After at room temperature stirring 12 hours, solvent removed in vacuo obtains white solid.Behind preparation of lamina chromatogram purification (Silicon stone, 20% methanol is in dichloromethane) solid, obtain 39b, be grease (0.013g, 44%).R
f=0.1 (silica gel, 10% methanol is in dichloromethane);
IR (thin film): n
Max3361,3282,3070,2922,2851,1742,1650,1620,1527,1456,1349,1322,1280,1162,1126,989,910 cm
-1 1H NMR (500MHz, CDCl
3): d=8.63 (d, J=10.8Hz, 1H, naphthyl), 8.17 (dd, J=1.0,9.1Hz, 1H, naphthyl), 8.02 (d, J=2.5Hz, 1H, Ar), 7.92 (d, J=10.3Hz, 1H, naphthyls), 7.77 (d, J=10.3Hz, 1H, naphthyl), 7.72 (dd, J=2.6,11.0Hz, 1H, Ar), 7.58 (dd, J=8.3,8.3Hz, 1H, naphthyl), 7.49 (dd, J=7.3,7.3Hz, 1H, naphthyl), 7.41 (dd, J=7.5,7.5Hz, 1H, naphthyl), 7.23-7.16 (m, 3H, Ph), 7.09-7.04 (m, 2H, Ph), 6.84 (d, J=11.1Hz, 1H, Ar), 4.83 (d, J=15.2Hz, 1H, CHHPh), 4.76 (d, J=15.2Hz, 1H, CHHPh), 4.23 (dd, J=5.8,9.1Hz, 1H, CHCH
2), 4.10-4.04 (bm, 2H, OCH
2), 3.95-3.61 (bm, 5H, CH
2NH
2, CHCHH), and 3.18-3.05 (bm, 1H, CHCHH);
13C NMR (125MHz, CDCl
3): d 169.6,165.3, and 154.2,146.9,134.6,134.5,134.0,13 3.9,133.2,129.8,129.0,128.6,128.5,128.4,128.2,127.8,127.0,125.9,124.9,124.2,124.1,114.3,67.6,55.9,42.0,40.5,29.6; FAB-HRMS (M+Cs
+)Value of calculation 725.0682, measured value 725.0695.
As shown in Figure 6, synthetic compound 13.Prepare chemical compound 13 according to preparing chemical compound 10 identical methods, use 40b to substitute 36b.Yield: 1.8mg (15%) is light yellow solid.
R
t=21.2 minutes;
1H NMR (500MHz, methanol-d
4): d 8.63 (d, J=9.0Hz, 1H, naphthyl), 8.17 (dd, J=1.5,7.5Hz, 1H, naphthyl), 7.94 (d, J=8.5Hz, 1H, naphthyls), 7.88 (d, J=2.5Hz, 1H, Ar), 7.76-7.70 (m, overlapping, 2H, 6-Ar-H, naphthyl-), 7.57 (ddd, J=1.0,6.5,9.3Hz, 1H, naphthyl), 7.47 (dd, J=7.5,8.0Hz, 1H, naphthyl), 7.42 (ddd, J=1.0,7.0,7.5Hz, 1H, naphthyls), 7.25 (d, J=9.0Hz, 1H, Ar), 4.36 (t, J=5.0Hz, 1H, CH
2O), 4.18 (dd, J=4.5,9.5Hz, 1H, CHCHH), 3.72 (t, J=5.0Hz, 2H, CH
2NH), 3.65 (dd, J=4.5,13.5Hz, 1H, CHCHH), 3.41 (dd, J=9.5,13.5Hz, 1H, CHCHH); EFI mass spectrum value of calculation (M+H
+) 545, measured value 545.
As shown in Figure 7, preparation chemical compound 51.At room temperature, to ethylaminoethanol (43) (1.0ml, 16.0mmol) DMF (30ml) solution in add 1,3-two-(tert-butoxycarbonyl)-2-methyl-2-sulfo-pseudo-urea (48) (4.81g, 16.0mmol), triethylamine (4.63ml, 32.0mmol) and mercuric chloride (II) (4.48g, 16.0mmol).After 4 hours, utilize the ethyl acetate diluted reaction mixture, by a bit of kieselguhr (celite
) filter.Utilize water (2 * 20ml), saline (20ml) wash filtrate sequentially, at MgSO
4Last dry.After filtering and pressurizeing evaporating solvent, crude compound obtains 51 by the flash column chromatography purification, is colorless solid (4.95g, 98%).R
f=0.43 (silica gel, 50% ethyl acetate is in hexane); IR (KBr): n
Max3329,3142,2977,2934,2870,1724,1644,1443,1412,1360,1299,1103,1052,1027,864,809,778cm
-1 1H NMR (500MHz, CDCl
3): d 11.48 (bs, 1H, NHCO
2), 8.66 (m, 1H, CH
2NH), 4.54 (bs, 1H, OH), 3.74 (t, J=4.5Hz, 2H, CH
2OH), 3.54 (dt, J=5.5,5.5Hz, 2H, CH
2NH), 1.47 (s, 9H,
tBu), 1.45 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 162.8,157.4, and 153.1,83.5,79.2,63.1,44.4,28.2,28.0; FAB-HRMS (M+H
+) value of calculation 304.1872, measured value 304.1878.
As shown in Figure 7, synthetic compound 52.At room temperature, to piperazine (44) (3.45ml adds 1 in DMF 12.0mmol) (10ml) solution, 3-two-(tert-butoxycarbonyl)-2-methyl-2-sulfo-pseudo-urea (48) (0.87g, 3.00mmol).After 14 hours, utilize ethyl acetate and water diluted reaction mixture.Layering, utilize water (2 * 20ml), saline (20ml) sequentially washs organic layer, at Na
2SO
4Last dry.Removal of solvent under reduced pressure obtains 52, is colorless solid (0.93g, 95%).R
f=0.34 (silica gel, 10% methanol is in dichloromethane);
IR (KBr): n
Max3294,2980,2931,2856,1749,1664,1605,1527,1448,1367,1305,1230,1149,1116,1019,893,842,730,682cm
-1.
1H NMR (500MHz, methanol-d
4): d 3.48 (t, J=5.0Hz, 4H, (CH
2)
2N (C=N), 2.83 (t, J=5.0Hz, 4H, (CH
2)
2NH), 1.46 (s, 9H,
tBu);
13C NMR (125MHz, methanol-d
4): d154.4,81.4,48.2,46.0,28.6; FAB-HRMS (M+Na
+)Value of calculation 341.1226, measured value 341.1235.
As shown in Figure 7, preparation chemical compound 53.At room temperature, to aminohexane mercaptan (45) (114mg adds N in DMF 1.00mmol) (5ml) solution, N '-two-tert-butoxycarbonyl thiourea (49) (276mg, 1.00mmol) and triethylamine (2.79ml, 2.00mmol).After 14 hours, utilize 5ml water diluted reaction mixture, utilize ethyl acetate (3 * 10ml) extractions.The extract that utilizes the salt water washing to merge is at MgSO
4Last dry.After filtration and the solvent evaporated under reduced pressure, crude compound obtains 53 by flash column chromatography purification (silica gel, 25% ether is in hexane), is the colorless solid (191mg, 59.8%) to air-sensitive.R
f=0.16 (Silicon stone, 25% ether is in hexane); IR (KBr): n
Max3327,3132,2978,2931,1726,1643,1565,1431,1363,1329,1280,1227,1133,1088,1058,855,809,760,606cm
-1 1H NMR (500MHz, CDCl
3): d 11.45 (bs, 1H, (C=N) NH (C=O)), 8.61 (bt, J=5.9Hz, 1H, CH
2NH), 3.74 (bdt, J=6.0,6.5Hz, 2H, CH
2NH), 2.85 (t, J=6.5Hz, 2H, CH
2SH), 1.47 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 163.4,156.1, and 153.1,83.2,79.3,39.2,37.0,28.3,28.1; FAB-HRMS calculates and only surveys the S-S dimer!
As shown in Figure 7, synthetic compound 54.At room temperature, to ethylenediamine (54) (3.45ml, 51.6mmol) DMF (50ml) solution in add 1,3-two-(tert-butoxycarbonyl)-2-methyl-2-sulfo-pseudo-urea (48) (3.00g, 10.33mmol), triethylamine (2.88g, 20.7mmol) and mercuric chloride (II) (2.81g, 10.3mmol).After 4 hours, utilize 20ml ethyl acetate diluting reaction chemical compound, by a bit of kieselguhr (celite
) filter.Utilize water (2 * 50ml), saline (50ml) wash filtrate sequentially, at MgSO
4Last dry.The flash column chromatography purification (silica gel, 20%MeOH, in ethyl acetate ,+2%v/v Et
3N), obtain 54, be colorless solid (1.60g, 51.2%).R
f=0.30 (silica gel, 20% MeOH, in ethyl acetate ,+2%v/v Et
3N);
IR (KBr): n
Max3446,3389,3259,2978,2819,1728,1706,1656,1626,1521,1485,1365,1253,1171,1093,1049,888,802,738,699,562 cm
-1 1H NMR (500MHz, CDCl
3): d 11.38 (bs, 1H, (C=N) NH (C=O)), 8.61 (bt, 1H, CH
2NH (C=N)), 3.45 (bdt, J=5.5,5.5Hz, 2H, CH
2NH), 2.85 (t, J=5.5Hz, 2H, CH
2NH
2), 1.46 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 163.4,156.4, and 153.1,83.1,79.2,41.8,40.9,28.2; FAB-HRMS (M+H
+) value of calculation 303.2032, measured value 303.2037.
As shown in Figure 7, synthetic compound 55.At room temperature, to phenylenediamine (1.08g, add in 5.5N HCl (10ml) solution 0.01mol) the b-alanine (1.125g, 0.015mol).Reaction mixture refluxed 24 hours allows to be cooled to room temperature then.Solvent removed in vacuo obtains precipitation, filters this precipitation and utilizes ether (1.70g, 73%) washing.R
f=0.12 (20% methanol is in dichloromethane);
1H NMR (500MHz, D
2O): d7.73-7.72 (m, 2H, Ar), 7.55-7.53 (m, 2H, Ar), 3.61-3.55 (m, 4H, CH
2CH
2);
13C NMR (125MHZ, D
2O): d FAB-HRMS (M+H
+) value of calculation 162.1031, measured value 162.1029.
As shown in Figure 7, synthetic compound 56.At room temperature, (1.0ml adds 2-(3 in DMF 0.015mol) (10ml) solution to ethylenediamine (46), 5-dimethyl pyrazole base)-4, and 5-dehydrogenation imidazoles hydrobromate (50) (3.67g, 0.015mol) and N, the N-diisopropylamine (2.61ml, 0.015mol).Stir after 11 hours, in compound of reaction, add ether (12ml), generate white precipitate.Filter this precipitation and utilize the ether washing, obtain 56 (1.59g, 51%).
IR (KBr): n
Max3164,1681,1599,1484,1287,1211,1137,1069,952cm
-1 1H NMR (500MHz, D
2O): d 3.54 (bs, 4H, NHCH
2CH
2NH), 3.17 (t, J=6.0Hz, CH
2NH), 2.65 (t, J=6.0Hz, CH
2NH
2);
13C NMR (125MHz, D
2O): d 160.9,45.3, and 43.6,40.3; FAB-HRMS (M+H
+) value of calculation 129.1140, measured value 129.1134.
As shown in Figure 8, synthetic compound 58.Under 0 ℃, to 3-nitro-4-fluobenzoic acid (30) (1.59g, 8.57mmol; Aldrich) add in benzene (40ml) solution DMF (0.03ml, 0.40mmol) and oxalyl chloride (3.73ml, 20.2mmol).After 6 hours, solvent removed in vacuo.(1.73g 8.57mmol) is dissolved in CH with the yellow thickness grease of gained
2Cl
2(20ml).Solution is cooled to 0 ℃, and the adding triethylamine (1.28ml, 9.20mmol).The amino alanine 29a of tert-butyl ester 2-(2.32g, CH 7.70mmol) are protected in adding
2Cl
2(40ml) solution.After 4 hours, utilize water diluting reaction chemical compound.After the layering, utilize dichloromethane (2 * 50ml) aqueous phase extracted.Utilize saturated NaHCO
3The organic extract liquid that-solution washing merges is at MgSO
4Last dry.After filtration and the solvent evaporated under reduced pressure, this crude compound obtains 58 by flash column chromatography purification (silica gel, 45% ethyl acetate is in hexane), is yellow foam (3.90g, 98%).R
f=0.19 (silica gel, 40% ethyl acetate is in hexane);
IR (KBr): n
Max3286,2980,2936,1730,1653,1619,1537,1493,1448,1349,1314,1159,1131,1092cm
-1 1H NMR (500MHz, CDCl
3): d 8.56 (dd,
4J (
1H-
1H)=2.5Hz,
4J (
1H-
19F)=and 7.5Hz, 1H, 2-Ar-H), 8.12 (ddd,
4J (
1H-
1H)=2.5Hz,
4J (
1H-
19F)=4.0Hz,
3J (
1H-
1H)=and 9.0Hz, 1H, 6-Ar-H), and 7.84 (d, J=7.5Hz, 2H, o-phenyl), 7.58 (d, J=7.5 Hz, 1H, p-phenyl), 7.50 (t, J=7.5Hz, 2H, m-Ar), 7.34 (dd,
3J (
1H-
1H)=9.0Hz,
3J (
1H-
19F)=10.0Hz, Ar-H), 7.13 (t, J=5.5Hz, 1H, (C=O) NH), 5.89 (d, J=8.0Hz, 1H, CHNHSO
2Ph), 3.97-3.92 (m, 2H, CHH, CHCH
2), 3.60-3.54 (m, 1H, CHH), 1.29 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.1,164.5, and 158.1,156.0,138.6,134.2,134.1,133.2,130.9,129.2,127.2,125.6,118.9,118.7,84.2,55.8,42.5,27.6; FAB-HRMS (M+Cs
+) value of calculation 600.0217, measured value 600.0195.
As shown in Figure 8, synthetic compound 59.Prepare chemical compound 59 according to preparing chemical compound 58 identical methods, only be to use the 2-naphthalene sulfonyl chloride to substitute benzene sulfonyl chloride.Yield: 985mg (96%) is pale solid.R
f=0.24 (silica gel, 50% ethyl acetate is in hexane); IR (KBr): n
Max3395,3297,3083,2981,2937,1734,1671,1620,1534,1494,1460,1345,1264,1156,1128,1079,977,918,833,750,661,617,549,479 cm
-1 1H NMR (500MHz, CDCl
3): d 8.46 (dd,
4J (
1H-
1H)=2.5Hz,
4J (
1H-
19F)=and 7.0Hz, 1H, 2-Ar-H), 8.38 (d, J=2.0Hz, 1H, naphthyls), 8.02 (ddd,
4J (
1H-
1H)=2.5Hz,
4J (
1H-
19F)=4.0Hz,
3J (
1H-
1H)=and 8.8Hz, 1H, 6-Ar-H), 7.90 (bd, overlapping, J=8.5Hz, 1H, naphthyl), 7.88 (bd, overlapping, J=8.5Hz, 1H, naphthyl), 7.83 (bd, J=8.0Hz, 1H, naphthyl), 7.79 (dd, J=2.0,8.0Hz, 1H, naphthyl), 7.62 (ddd, J=1.0,7.5,8.5Hz, 1H, naphthyls), (7.58 ddd, J=1.0,7.5,8.5Hz, 1H, naphthyl), 7.27 (br.dd, J=6.0,8.5Hz, 1H, CONH), 7.18 (bdd
3J (
1H-
1H)=9.0Hz,
3J (
1H-
19F)=and 10.0Hz, 1H, 5-Ar-H), 6.15 (d, J=8.0Hz, 1H, NHSO
2), 4.06 (ddd, J=4.0,5.5,8.0Hz, 1H, CHCH
2), 3.93 (ddd, J=4.0,6.0,11.0Hz, 1H, CHCHH), 3.57 (ddd, J=5.5Hz, 8.5Hz, 1H, CHCHH), 1.17 (s, 9 H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.3,164.3, and 158.0,155.8,135.5,134.7,134.1,134.0,131.8,130.5,129.5,129.1,128.6,127.7,125.4,122.0,118.6,118.4,83.9,55.9,42.3,27.4; FAB-HRMS (M+Cs
+) value of calculation 650.0373, measured value 650.0358.
As shown in Figure 8, synthetic compound 60.Under 0 ℃, in the round-bottomed flask that magnetic stirring bar is installed, put into NaH (60% suspension is in mineral oil) (0.16g, 3.96mmol) and THF (10ml).In stirred suspension, add 51 (0.55g, THF 1.80mmol) (5ml) solution.Under this temperature, continue to stir again 30 minutes, grey suspension standby.Be equipped with filling aromatics fluoride 58 in the round-bottomed flask of magnetic stirring bar (0.1g, 0.30mmol) and DMF (10ml).Cooling solution to 0 ℃, the 5.5ml suspension that will before prepare by syringe adds.At 0 ℃ after following 8 hours, by adding entry (10ml) reaction is stopped, utilizing the ethyl acetate dilution.Water phase separated is also utilized ethyl acetate (3 * 25ml) extractions.Utilize water (2 * 10ml) and saline (10ml) sequentially wash the organic extract liquid that merges, at MgSO
4Last dry.After filtration and the solvent evaporated under reduced pressure, residue obtains 60 by flash column chromatography purification (Silicon stone, 60% ethyl acetate is in hexane), is light yellow foam (0.15g, 66%).R
f=0.1 8 (Silicon stone, 50% ethyl acetate is in hexane);
IR (KBr): n
Max3331,2978,2951,1733,1645,1619,1532,1367,1319,1277,1144,1051,1025cm
-1 1H NMR (500MHz, CDCl
3): d 11.43 (bs, 1H, (C=N) NH (C=O)), 8.76 (bt, J=5.5Hz, 1 H, CH
2NH (C=N)), 8.32 (d, J=2.5Hz, 1H, Ar), 8.00 (dd, J=2.5,9.0Hz, 1H, Ar), 7.85-7.84 (m, 2H, Ph), 7.58 (t, J=8.0Hz, 1H, Ph), 7.49 (t, J=8.0Hz, 2H, Ph), 7.20 (d, J=9.0Hz, 1H, Ar), 6.95 (t, J=8.0Hz, 1H, NHCO), 5.84 (d, J=7.5Hz, 1H, HNSO
2), 4.28 (t, J=5.5Hz, 2H, CH
2O), and 3.96-3.87 (m, overlapping, 4H, CHCH
2, CH
2NH (C=N)), 3.60-3.54 (m, 1H, CHCH
2), 1.50 (s, 9H,
tBu), 1.48 (s, 9H,
tBu), 1.28 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.2,165.0, and 163.3,156.5,154.5,154.1,150.9,139.4,138.8,133.1,132.7,129.2,127.2,126.5,125.0,114.5,84.0,83.4,68.1,55.9,42.4,39.4,28.3,28.0,27.6; FAB-HRMS (M+Cs
+) value of calculation 883.1949, measured value 883.1970.
As shown in Figure 8, synthetic compound 11.To 60 (30.0mg, CH 0.04mmol)
2Cl
2(2ml) drip trifluoroacetic acid (2ml) in the solution.Reactant mixture stirred 2 hours down at 25 ℃.Removal of solvent under reduced pressure, residue obtains 11 by RP-HPLC (C-18) purification, is light yellow solid (22.0mg, 92%).R
t=12.2 minutes;
IR (KBr): n
Max3418,1679,1529,1433,1354,1319,1278,1198,1161,1092,1046,932,837,802,756,688cm
-1 1H NMR (500MHz, methanol-d
4): d 8.26 (d, J=2.0Hz, 1H, Ar), 8.04 (dd, J=2.0,8.5Hz, 1H, Ar), 7.82-7.80 (m, 2H, Ph), 7.47-7.36 (m, 4H, Ar), 4.35 (t, J=5.0Hz, 2H, OCH
2), 4.19 (dd, J=4.0,14.0Hz, 1H, CHCH
2), 3.75 (dd, J=4.0,14.0Hz, 1H, CHCHH), 3.68 (t, J=5.0Hz, 2H, CH
2NH (C=N)), 3.47 (dd, J=11.0,14.0Hz, 1H, CHCHH);
13C NMR (125MHz, methanol-d
4): d 167.7,155.0, and 142.2,140.7,134.5,133.6,130.0,128.2,125.9,115.7,69.8,43.3,41.8,25.2; FAB-HRMS (M+H
+) value of calculation 495.1298, measured value 495.1311.
As shown in Figure 8, synthetic compound 61.To 58 (100mg, add 53 in DMF 0.20mmol) (10ml) solution (68mg, 0.22mmol).After at room temperature stirring 4 hours, utilize water (10ml) diluted reaction mixture, utilize ethyl acetate (3 * 10ml) aqueous phase extracted.Utilize water (2 * 10ml) and saline (20ml) sequentially wash the organic extract liquid that merges, at Na
2SO
4Last dry.Filter and reduction vaporization, residue obtains 61 by flash column chromatography (silica gel, 50% ethyl acetate is in hexane) purification, is light yellow foam (110mg, 73%).R
f=0.48 (silica gel, 60% ethyl acetate is in hexane); IR (film): n
Max3318,2925,1723,1623,1517,1412,1324,1158cm
-1 1H NMR (500MHz, CDCl
3): d 11.47 (bs, 1H, (C=N) NH (C=O)), 8.59 (d, J=2.5Hz, 1H, Ar), 8.56 (t, J=10.0Hz, 1H, NH), 8.43 (t, J=10.0Hz, 1H, NH), 7.93 (dd, J=2.5Hz, 10.0Hz, 1H, Ar), 7.84 (d, J=9.0Hz, 2H, Ph), 7.53 (t, J=10.0Hz, 1H, Ph), 7.46 (t, J=10.0Hz, 2H, Ph), 7.21 (d, J=10.0Hz, 1H, Ar), 6.81 (t, J=10.0Hz, 1H, CONH), 5.87 (d, J=10.0Hz, 1H, NHSO
2), 3.98-3.93 (m, 1H, CHCH
2), 3.87-3.82 (m, 1H, CHCHH), 3.72-3.55 (m, 5H, CHCHH, NHCH
2, CH
3NH (C=N)), 1.52 (s, 9H,
tBu), 1.47 (s, 9H,
tBu), 1.27 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.4,165.7, and 163.3,156.6,153.2,146.9,139.1,134.7,133.0,131.4,129.1,127.2,126.2,121.0,114.4,83.7,83.5,79.5,56.2,42.4,42.2,39.0,28.3,28.0,27.6; FAB-HRMS (M+Cs
+) value of calculation 882.2109, measured value 882.2129.
As shown in Figure 8, synthetic compound 14.Prepare chemical compound 14 according to preparing chemical compound 11 identical methods, only be to use 61 to substitute 60.Yield: 33.2g (92%) is yellow solid.R
t=15.9 minutes;
IR (KBr): n
Max3364,3245,2998,2584,1669,1624,1555,1520,1433,1313,1198,1161,923,756,722cm
-1 1H NMR (500MHz, methanol-d
4): d 8.61 (d, J=2.5Hz, 1H, Ar), 7.92 (dd, J=2.5,9.0Hz, 1H, Ar), 7.81 (d, J=7.0Hz, 2H, Ph), 7.47-7.40 (m, 3H, Ph), 7.11 (d, J=9.0Hz, 1H, Ar), 4.19 (dd, J=5.0,9.0Hz, 1H, CHCH
2), 3.72 (dd, J=5.0,13.5Hz, 1H, CHCHH), 3.67 (t, J=6.0Hz, 2H, NHCH
2), 3.52 (t, J=6.0Hz, 2H, NHCH
2), 3.46 (dd, J=9.0,13.5Hz, 1H, CHCHH);
13C NMR (125MHz, methanol-d
4): d 168.3,159.0, and 148.0,142.1,135.8,133.6,132.9,130.0,127.8,125.0,122.3,114.8 43.2,42.5,41.1,31.1; FAB-HRMS (M+H
+) value of calculation 494.1458, measured value 494.1444.
As shown in Figure 8, synthetic compound 62.Under 0 ℃, to 54 (1.60mg, add in THF 5.0mmol) (50ml) solution NaH (60% suspension is in mineral oil) (200mg, 5.00mmol).After 15 minutes, with gained mercaptides solution for standby.By syringe, to 58 (100mg, add in DMF 0.20mmol) (10ml) solution mercaptides solution (5.0ml, 0.5mmol).After at room temperature 12 hours, reaction is stopped, utilizing the ethyl acetate dilution by adding entry (10ml).Utilize ethyl acetate (3 * 25ml) aqueous phase extracted after the phase-splitting.Utilize water (2 * 10ml) and saline (10ml) sequentially wash the organic extract liquid that merges, at MgSO
4Last dry.Behind filtration and the reduction vaporization, residue obtains 62 by flash column chromatography purification (silica gel, 40% ethyl acetate is in hexane), is light yellow foam (35mg, 23%).R
f=0.32 (silica gel, 40% ethyl acetate is in hexane);
R
f=0.32 (silica gel, 40% ethyl acetate in hexanes);
1H NMR (500MHz, CDCl
3): d 11.45 (bs, 1H, (C=N) NH (C=O)), 8.65 (bt, overlapping, J=4.5Hz, 1H, CH
2NH (C=N)), 8.63 (d, overlapping, J=2.0Hz, 1H, Ar), 8.22 (d, J=8.5Hz, 1H, Ar), 8.15 (dd, J=2.0,8.5Hz, 2H, Ar), 7.84 (d, J=8.0Hz, 2H, Ph), 7.56 (t, J=7.5Hz, 1H, Ph), 7.48 (bdd, J=7.0,8.0Hz, 2H, Ph), 6.98 (t, J=5.5Hz, 1H, CONH), 5.72 (d, J=7.0Hz, 1H, NHSO
2), 3.99-3.93 (bm, 1H, CHCH
2), 3.88 (ddd, J=4.5,5.5,13.5Hz, 1H, CHCHH), 3.70-3.58 (m, 3H, CHCHH, CH
2NH (C=N)), 3.26 (t, J=8.0Hz, 2H, SCH
2), 1.57 (s, 9H,
tBu), 1.50 (s, 9H,
tBu), 1.30 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.2,165.1, and 163.4,156.3,153.1,145.3,141.0,138.9,133.1,132.3,130.3,129.2,127.7,127.2,124.7,84.0,83.5,79.6,55.9,42.4,39.2,30.1,28.4,28.0,27.6; FAB-HRMS (M+Cs
+) value of calculation 899.1720, measured value 899.1753.
As shown in Figure 8, synthetic compound 15.Prepare chemical compound 15 according to preparing chemical compound 11 identical methods, only be to use 62 to substitute 60.Yield: 23.0g (92%) is yellow solid.R
t=16.0 minutes;
1H NMR (500MHz, methanol-d
4): d 8.58 (d, J=2.0Hz, 1H, Ar), 8.06 (dd, J=2.0,8.5Hz, 1H, Ar), 7.82 (d, J=7.0Hz, 2H, Ph), 7.71 (d, J=8.5Hz, 1H, Ph), 7.48-7.41 (m, 3H, Ar), 4.23 (dd, J=5.0,9.0Hz, 1H, CHCH
2), 3.80-3.76 (m, 1H, CHCHH), 3.56 (t, J=6.5Hz, 2H, CH
2NH (C=N)), and 3.50-3.43 (m, 1H, CHCHH), 3.34 (t, J=6.5Hz, 2H, SCH
2);
13CNMR (125MHz, methanol-d
4): d 167.6,155.2, and 142.1,140.7,133.5,133.3,132.5,128.3,128.0,126.0,43.4,40.7,32.3; FAB-HRMS (M+H
+) value of calculation 511.1070, measured value 511.1058.
As shown in Figure 8, synthetic compound 65.To 58 (100mg, add 52 in DMF 0.20mmol) (10ml) solution (68mg, 0.22mmol).After 6 hours, utilize water (25ml) and ethyl acetate diluted reaction mixture.Utilize ethyl acetate (3 * 30ml) aqueous phase extracted after the phase-splitting.Utilize water (2 * 20ml) and saline (20ml) sequentially wash the organic extract liquid that merges, at Na
2SO
4Last dry.Behind filtration and the reduction vaporization, residue is by flash column chromatography purification (silica gel, 40 ﹠amp; 50% ethyl acetate is in hexane), obtain 65, be light yellow foam (120mg, 83%).R
f=0.30 (silica gel, 40% ethyl acetate is in hexane);
IR (film): n
Max3266,2977,1743,1621,1520,1451,1367,1304,1158,1130,1094,1014cm
-1 1H NMR (500MHz, CDCl
3): d 10.22 (bs, 1H, (C=N) HN (C=O)), 8.29 (d, J=2.5Hz, 1H, Ar), 7.92 (dd, J=2.5,9.0Hz, 1H, Ar), 7.85-7.84 (m, 2H, Ph), 7.83-7.82 (m, 1H), 7.56 (t, J=7.0Hz, 1H, Ph), 7.48 (t, J=7.0Hz, 2H, Ar-H), 7.08 (d, J=9.0Hz, 1H, Ar-H), 6.93 (t, J=6.0Hz, 1H, CO (NH)), 5.85 (d, J=8.0Hz, 1H, NHSO2), 3.96-3.87 (m, 2H, CHCH
2, CHCHH), 3.80-3.70 (bm, 4H, NH (CH
2)
2), 3.59-3.54 (m, 1H, CHCHH), 3.23-3.21 (m, 4H, N (CH
2)
2), 1.48 (s, 18H,
tBu), 1.26 (s, 9H,
tBu);
13C NMR (500MHz, CDCl
3): d 168.3,165.3, and 155.2,147.5 140.9,138.8,133.1,132.0,129.2,127.2,126.3,126.0,119.9,84.0,56.0,50.3,42.2,28.1,27.6; FAB-HRMS (M+Cs
+) value of calculation 908.2265, measured value 908.223 3.
As shown in Figure 8, synthetic compound 16.Prepare chemical compound 16 according to preparing chemical compound 11 identical methods, only be to use 66 to substitute 65.Yield: 15.0g (93%) is yellow solid.R
t=15.3 minutes;
IR (KBr): n
Max3367,3239,2925,2857,1662,1613,1523,1449,1388,1320,1199,1173,113 5,1093,992,837,802,721cm
-1 1H NMR (500MHz, methanol-d
4): d 8.22 (d, J=2.0Hz, 1H, Ar), 7.95 (dd, J=2.0,8.5Hz, 1H, Ar), 7.79 (m, 2H, Ph), 7.47-7.38 (m, 3H, Ph), 7.32 (d, J=8.5Hz, 1H, Ar), 4.21 (dd, J=5.0,9.0Hz, 1H, CHCH
2), 3.74 (dd, J=5.0,10.0Hz, 1H, CHCHH), 3.67-3.65 (m, 4H, N (CH
2)
2), 3.49-3.44 (m, 1H, CHCHH), 3.31-3.29 (m, 4H, N (CH
2)
2);
13C NMR (125MHz,
Methanol-d
4): d 172.6,167.9, and 158.4,148.3,142.8,142.2,129.9,56.6,50.9,46.3,43.3; FAB-HRMS (M+H
+) value of calculation 520.1614, measured value 520.1630.
As shown in Figure 8, synthetic compound 63.Under 0 ℃, to 51 (130mg, add in THF 0.43mmol) (5.0ml) solution NaH (60% suspension is in mineral oil) (70mg, 1.74mmol).Under this temperature, continue to stir again 15 minutes, grey suspension standby.(200mg adds alkanol (2.5ml) in DMF 0.39mmol) (20ml) solution to 59.After stirring 1 hour under 0 ℃, add remaining 2.5ml alkanol.At 0 ℃ after following 3 hours, by adding the saturated NH of 10ml
4Cl solution stops reaction, utilizes the ethyl acetate dilution.Utilize ethyl acetate (3 * 25ml) aqueous phase extracted after the phase-splitting.Utilize water (2 * 10ml) and saline (10ml) sequentially wash the organic extract liquid that merges, at MgSO
4Last dry.Behind filtration and the reduction vaporization, residue obtains 63 by flash column chromatography purification (silica gel, 50% ethyl acetate is in hexane), is yellow solid (211mg, 69%).R
f=0.16 (silica gel, 50% ethyl acetate is in hexane);
IR (KBr): n
Max3330,2979,2934,1728,1620,1570,1531,1416,1329,1281,1156,1079,1023,970,916,816,753,660,618,552,477cm
-1 1H NMR (500MHz, CDCl
3): d 11.45 (bs, 1H, (C=N) NH (C=O)), 8.78 (bt, 1H, CH
2NH (C=N)), 8.37 (s, 1H, Ar), and 8.26 (d, J=2.0Hz, 1H, naphthyls), 7.92-7.87 (2 * d, J=8.0Hz, 2H, naphthyl), 7.90 (d, J=8.5Hz, 1H, Ar), 7.83 (d, J=8.5Hz, 1H,
Naphthyl), 7.79 (dd, J=2.0,8.5Hz, 1H, naphthyls), 7.64-7.55 (2 * br.dd, 2H, naphthyl), 7.07 (d, J=8.5Hz, 1H, Ar), 6.90 (dd, J=5.5,5.5Hz, 1H, CH
2NH (C=O)), 5.95 (d, J=7.5Hz, 1H, NHSO
2), 4.22 (t, J=5.3Hz, 2H, OCH
2), 4.02 (ddd, J=4.0,7.5,8.5Hz, 1H, CHCH
2), 3.93-3.83 (m, overlapping, 3H, CHCHH, CH
2NH (C=N)), 3.55 (ddd, J=5.5,8.5,13.5Hz, 1H, CHCHH), 1.50 (s, 9H,
tBu), 1.47 (s, 9H,
tBu), 1.17 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.3,164.9, and 156.4,154.0,152.9,139.3,135.6,134.9,132.6,132.0,129.6,129.2,129.1,128.7,127.8,127.7,127.6,126.3,125.0,122.1,114.4,84.0,83.5,68.0,56.1,42.3,39.5,28.3,28.0,27.5; FAB-HRMS (M+Cs
+) value of calculation 933.2105, measured value 933.2116.
As shown in Figure 8, synthetic compound 17.Prepare chemical compound 17 according to preparing chemical compound 11 identical methods, only be to use 63 to substitute 60.Yield: 32.7g (99%), for canescence to light brown solid.R
t=14.5 minutes;
IR (KBr): n
Max=3421,2999,2898,1657,1635,1528,1383,1351,1322,1276,1198,1157,1132,1080,1046,979,823,754,660,550cm
-1 1H NMR (500MHz, methanol-d
4): d 8.15 (s, 1H, naphthyl), 7.93 (d, J=2.0Hz, 1H, Ar), 7.72 (d, J=8.0Hz, 1H, naphthyl), and 7.69-7.58 (m, 4H, naphthyl, Ar), (7.42-7.35 2 * ddd, superimposed, 2H, naphthyl), 6.92 (d, J=9.0Hz, 1H, Ar), 4.21 (dd, J=4.5,9.8Hz, 1H, CHCH
2), 4.13 (t, J=5.0Hz, 2H, OCH
2), 3.61 (dd, J=4.5,13.5Hz, 1H, CHCHH), 3.57 (t, J=4.5Hz, 2H, CH
2NH (C=N)), 3.28 (dd, J=9.8Hz, 13.5Hz, 1H, CHCHH);
13CNMR (125MHz, methanol-d
4): d 172.8,167.1, and 159.3,154.9,140.1,139.5,13 5.9,134.1,133.4,130.3,130.2,129.5,128.8,128.7,128.4,127.3,125.7,123.5,115.3,69.7,56.8,43.1,41.8; FAB-HRMS (M+H
+) value of calculation 545.1455, measured value 545.1471.
As shown in Figure 8, synthetic compound 64.At room temperature, to 59 (50mg, add 53 in 1-Methyl-2-Pyrrolidone 0.10mmol) (1ml) solution (58mg, 0.19mmol).After 4 hours, utilize water (10ml) diluted reaction mixture, utilize ethyl acetate (3 * 10ml) aqueous phase extracted.Utilize water (2 * 5ml) and saline (5ml) sequentially wash the organic extract liquid that merges, at MgSO
4Last dry.Behind filtration and the reduction vaporization, residue obtains 64 by flash column chromatography purification (silica gel, 50% ethyl acetate is in hexane), is yellow solid (76mg, 99%).R
f=0.22 (silica gel, 50% ethyl acetate is in hexane);
IR (KBr): n
Max3300,3065,2975,2931,1734,1660,1620,1535,1497,1347,1261,1159,1129,1079,972,917,817,751,661,551,477cm
-1 1H NMR (500MHz, CDCl
3): d 11.49 (bs, 1H, (C=N) NH (C=O)), 8.58 (bt, 1H, CH
2NH (C=N)), 8.47 (d, J=2.0Hz, 1H, Ar), 8.41 (dd, J=5.5Hz, 1H, NHCH
2), 8.37 (d, J=2.0Hz, 1H, naphthyls), and 7.90-7.84 (m, overlapping, 3H, naphthyl), 7.86 (dd, J=2.0,9.0Hz, 1H, Ar), (7.79 dd, J=2.0,8.5Hz, 1H, naphthyl), 7.59 (ddd, J=1.5Hz, 7.0,7.0Hz, 1H, naphthyl), 7.54 (ddd, J=1.5Hz, 7.0,7.0Hz, 1H, naphthyl), 7.12 (d, J=9.0Hz, 1H, Ar), 6.69 (t, J=5.5Hz, 1H, CH
2NH (C=O)), 5.89 (d, J=8.0Hz, 1H, NHSO
2), 4.03 (ddd, J=4.0,8.0,8.5Hz, 1H, CHCH
2), 3.85 (ddd, J=4.0,6.0,14.0Hz, 1H, CHCHH), 3.70 (bdt, J=5.5,5.5Hz, 2H, NHCH
2), 3.61-3.50 (m, 3H, CHCHH, CH
2NH (C=N)), 1.52 (s, 9H,
tBu), 1.47 (s, 9H,
tBu), 1.18 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.5,165.6, and 156.6,153.2,146.9,136.0,134.8,134.6,132.0,131.3,129.6,129.2,128.9,128.6,127.8,127.6,126.0,122.2,120.8,114.3,83.8,83.6,56.4,42.4,42.2,39.1,28.3,28.0,27.6; FAB-HRMS (M+Cs
+) value of calculation 932.2265, measured value 932.2285.
As shown in Figure 8, synthetic compound 18.Prepare chemical compound 18 according to preparing chemical compound 11 identical methods, only be to use 64 to substitute 60.Yield: 81.7g (90%) is the orange colour solid.R
t=12.4 minutes;
IR (KBr): n
Max3364,1676,1624,1556,1520,1426,1315,1241,1200,1158,1133,1076,1025,999,824,757,719,660,549,479cm
-1 1H NMR (500MHz, methanol-d
4): d 8.17 (bs, 1H, naphthyl), 8.14 (d, J=2.0Hz, 1H, Ar), 7.72 (d, J=8.0Hz, 1H, naphthyl), 7.68-7.65 (m, 2H, naphthyl), 7.57 (bd, overlapping, J=9.5Hz, 1H, naphthyl), 7.55 (dd, overlapping, J=2.0,9.0Hz, 1H, Ar), 7.41 (ddd, J=1.5,7.0,8.0Hz, 1H, naphthyls), 7.36 (ddd, J=1.5,7.0,8.0Hz, 1H, naphthyl), 6.74 (d, J=9.0Hz, 1H, Ar), 4.25 (dd, J=4.5,10.0Hz, 1H, CHCH
2), 3.62 (dd, J=4.5,14.0Hz, 1H, CHCHH), 3.52 (t, J=6.0Hz, 2H, NHCH
2), 3.41 (t, J=6.0Hz, 2H, NHCH
2), 3.30 (dd, J=10.0,14.0Hz, 1H, CHCHH);
13C NMR (125MHz, methanol-d
4): d 173.0,167.8, and 147.8,139.5,135.9,135.3,133.4,130.3,130.2,129.3,128.7,128.6,128.3,127.2,123.5,121.5,114.5,57.0,42.9,42.5,41.5; FAB-HRMS (M+Na
+) value of calculation 566.1434, measured value 566.1453.
As shown in Figure 8, synthetic compound 66.At room temperature, to 59 (150mg, add 52 in DMF 0.29mmol) (5ml) solution (190mg, 0.58mmol).After 20 hours, utilize water (25ml) and ethyl acetate diluted reaction mixture.After the phase-splitting, utilize ethyl acetate (3 * 30ml) extractions.Utilize water (2 * 20ml) and saline (20ml) sequentially wash the organic extract liquid that merges, at MgSO
4Last dry.Behind filtration and the reduction vaporization, residue obtains 66 by flash column chromatography purification (silica gel, 40% ethyl acetate is in hexane), is yellow solid (240mg, 99%).R
f=0.33 (silica gel, 50% ethyl acetate is in hexane);
IR (KBr): n
Max3397,2979,2933,1741,1610,1524,1454,1367,1303,1239,1157,1015,975,834,752,661,615,552,477cm
-1 1H NMR (500MHz, CDCl
3): d 11.49 (bs, 1H, (C=N) NH (C=O), 8.38 (bs, 1H, naphthyls), 8.24 (d, J=2.0Hz, 1H, Ar), 7.90 (bd, J=7.5Hz, 1H, naphthyl), 7.87 (brd, J=9.0Hz, 1H, naphthyl), 7.83 (dd, superimposed, J=2.0,8.5Hz, 1H, Ar), 7.82 (d, superimposed, J=8.0Hz, 1H, naphthyl), 7.79 (dd, J=2.0,8.5Hz, 1H, naphthyl), and 7.64-7.55 (2 * bddd, overlapping, 2H, naphthyl), 7.13 (bm, 1H, NH (C=O)), 6.98 (d, J=9.0Hz, 1H, Ar), 4.01 (ddd, J=3.5,8.0,9.0Hz, 1H, CHCH
2), 3.88 (ddd, J=4.0,6.0,13.5Hz, 1H, CHCHH), 3.73 (bm, 4H, NCH
2), 3.55 (ddd, J=5.5,8.5,13.5Hz, 1H CHCHH), 3.18 (bm, 4H, NCH
2), 1.48 (s, 18H,
tBu), 1.15 (s, 9H,
tBu);
13C NMR (125MHz, CDCl
3): d 168.6,165.1, and 155.2,147.3,140.9,135.6,134.9,132.0,129.6,129.2,129.0,128.7,127.8,127.7,126.2,126.0,122.1,119.8,119.7,83.9,56.1,50.3,42.2,28.2,28.0,27.3; FAB-HRMS (M+Cs
+) value of calculation 958.2422, measured value 958.2458.
As shown in Figure 8, synthetic compound 19.Prepare chemical compound 19 according to preparing chemical compound 11 identical methods, only be to use 66 to substitute 60.Yield: 31.9g (93%) is light yellow solid.R
t=11.1 minutes;
IR (KBr): n
Max3401,3297,3251,2996,2928,1659,1613,1523,1451,1385,1323,1199,1157,1138,1078,992,808,753,720,660,549cm
-1 1H NMR (500MHz, methanol-d
4): d 8.19 (bs, 1H, naphthyl), 7.93 (d, J=2.0Hz, 1H, Ar), 7.76 (bd, J=9.0Hz, 1H, naphthyls), 7.71-7.61 (m, overlapping, 3H, naphthyl, Ar), 7.55 (dd, J=2.0Hz, 8.8Hz, 1H, naphthyl), and 7.44-7.36 (2 * ddd, overlapping, 2H, naphthyl), 6.91 (d, J=8.5Hz, 1H, Ar), 4.21 (dd, J=4.5,9.5Hz, 1H, CHCH
2), 3.61 (dd, J=4.5,13.5Hz, 1H, CHCHH), 3.55 (m, 4H, NCH
2), 3.29 (dd, J=9.5,13.5Hz, 1H, CHCHH), 3.15-3.09 (m, 4H, NCH
2);
13C NMR (125MHz, methanol-d
4): d167.6,158.5,148.2,142.1,139.4,136.0,133.5,133.3,130.4,130.3,129.7,128.9,128.5,127.3,126.7,123.6,121.2,50.9,49.6,48.6,46.4; FAB-HRMS (M+Cs
+) value of calculation 702.0747, measured value 702.0784.
As shown in Figure 9, synthetic compound 67.At room temperature, to 57 (0.10g, add 55 in DMF 0.20mmol) (8ml) solution (0.038g, 0.22mmol) and triethylamine (0.06ml, 0.44mmol).After stirring 16 hours under 25 ℃, utilize EtOAc (10ml) and water (10ml) diluted reaction mixture.Layering utilizes ethyl acetate (2 * 10ml) aqueous layer extracted.Collect organic extract liquid, utilize water (2 * 10ml) and saline (20ml) wash, at Na
2SO
4Last dry.Behind filtration and the reduction vaporization, residue obtains 67 by flash column chromatography purification (silica gel, ethyl acetate), is light yellow solid (110mg, 92%).R
f=0.43 (silica gel, ethyl acetate);
1H NMR (500MHz, methanol-d
4): d 8.57 (d, J=2.0Hz, 1H, Ar), 7.96 (bm, 1H, Ar), 7.83 (dd, J=2.0,9.0Hz, 1H, Ar), and 7.80-7.78 (m, 2H, Ar), 7.48-7.39 (m, 4H, Ar), 7.18 (dd, J=4.0,6.0Hz, 2H), 7.06 (d, J=9.0Hz, 1H, Ar), 4.12 (dd, J=6.0,8.0Hz, 1H, CH
2CH), 3.89 (t, J=7.0Hz, 2H, CH
2Ar), 3.65 (dd, J=5.0,14.0Hz, 1H, CHHCH), 3.46 (dd, J=8.0,14.0Hz, 1H, CHHCH), 3.26 (t, J=7.0Hz, 2H, CH
2NH), 1.22 (s, 9H,
tBu);
13C NMR (125MHz, methanol-d
4): d 170.4,168.1, and 164.8,153.6,147.9,142.2,135.6,133.6,132.6,132.4,130.1,128.1,127.7,123.5,121.8,114.9,83.3,57.3,43.2,42.3,27.9; EFI mass spectrum (M+H
+) value of calculation 609, measured value 609.
As shown in Figure 9, synthetic compound 20.At room temperature, to 57 (0.068g, CH 0.11mmol)
2Cl
2(2ml) add trifluoroacetic acid (2ml) in the solution.After 4 hours, solvent removed in vacuo obtains grease, at RP-HPLC (C-18) afterwards, obtains 20, is yellow solid (0.056g, 97%).
1H NMR (500MHz, methanol-d
4): d 8.65 (d, J=1.0Hz, 1H, Ar), 7.93 (dd, J=1.0,9.0Hz, 1H, Ar), 7.81 (d, J=8.0Hz, 2H, Ph), 7.74 (dd, J=3.0,6.0Hz, 2H, Ar), 7.58 (dd, J=3.0,6.0Hz, Ar), 7.48 (t, J=7.0Hz, 1H, Ph), 7.43 (t, J=8.0Hz, 2H, Ph), 7.16 (d, J=9.0Hz, 1H, Ar), 4.20 (dd, J=5.0,9.0Hz, 1H, CHCHH), 4.04 (t, J=6.5Hz, 2H, CH
2Ar), 3.74 (dd, J=5.0,14.0Hz, 1H, CHCHH), 3.54 (t, J=6.5Hz, 2H, CH
2NH), 3.45 (dd, J=9.0,14.0Hz, 1H, CHCHH);
13C NMR (125MHz, methanol-d
4): d 172.6,168.1, and 152.6,147.3,142.0,135.7,133.5,133.1,132.4,132.3,130.0,127.9,127.8,127.4,122.5,114.8,114.6,56.8,43.2,41.2,27.2; FAB-HRMS (M+Cs
+) value of calculation 685.0482, measured value 685.0461.
As shown in Figure 9, synthetic compound 68.At room temperature, to 57 (0.06g, add 56 in DMF 0.13mmol) (10ml) solution (0.03g, 0.14mmol) and triethylamine (0.04ml, 0.29mmol).After 12 hours, solvent removed in vacuo obtains 68, is thick yellow oil (0.09g, 110%).R
f=0.23 (40% methanol is in dichloromethane);
1HNMR (500MHz, methanol-d
4): d 8.63 (d, J=2.0Hz, 1H, Ar), 7.93 (dd, J=2.0,9.0Hz, 1H, Ar), 7.82 (d, J=6.5Hz, 2H, Ph), 7.48-7.42 (m, 3H, Ph), 7.09 (d, J=9.0Hz, 1H, Ar), 4.08-4.06 (m, 1H, CHCHH), 3.68-3.62 (m, overlapping, 5H, NHCH
2CH
2NH, CHCHH), 3.50-3.44 (m, 1H, CHCHH), 3.30 (t, J=3.5Hz, 2H, CH
2NHAr), 1.24 (s, 9H,
tBu); The EFI mass spectrum
Value of calculation (M+H
+) 573, measured value 573.
As shown in Figure 9, synthetic compound 21.At room temperature, to 68 (0.09g, CH 0.14mmol)
2Cl
2(5ml) add trifluoroacetic acid (5ml) in the solution.After 4 hours, solvent removed in vacuo obtains grease, at RP-HPLC (C-18) afterwards, obtains 21, is yellow solid (0.07g, 83%).R
t=14.0 minutes;
1H NMR (500MHz, methanol-d
4): d 8.64 (bs, 1H, Ar), 7.94 (d, J=9.0Hz, 1H, Ar), 7.82 (d, J=7.0Hz, 2H, Ph), 7.48 (t, J=7.0Hz, 1H, Ph), 7.43 (t, J=7.0Hz, 1H, Ph), 7.12 (d, J=9.0Hz, 1H, Ar), 4.20 (dd, J=5.0,9.0Hz, 1H, CHCH
2), 3.73 (dd, J=5.0,14.0Hz, 1H, CHCHH), 3.70-3.66 (m, overlapping, 7H, NCH
2CH
2N, CH
2N (C=N)), 3.52 (t, J=6.0Hz, 2H, CH
2NHAr), 3.45 (dd, J=9.0,14.0Hz, 1H, CHCHH);
13C NMR (125MHz, methanol-d
4): d 172.7,168.3, and 161.6,148.0,142.1,135.8,133.5,132.9,130.0,128.0,127.7,122.3,114.9,56.7,44.1,43.2,42.9,42.7; FAB-HRMS (M+H
+) value of calculation 520.1614, measured value 520.1630.
As shown in figure 10, synthetic compound 69.At room temperature, (0.10g is blown into NH in dry DMF 0.20mmol) (10ml) solution to fluoride 57
3 (g) Steam 1 hour.After 4 hours, utilize ethyl acetate and water diluted reaction mixture.Layering and utilize water (2 * 10ml), saline (20ml) washing organic layer, dry (Na
2SO
4).Solvent removed in vacuo obtains 61, is light yellow oil (0.09g, 93%).R
f=0.25 (silica gel, 50% ethyl acetate is in hexane);
IR (thin film): n
Max3359,1729,1631,1516,1308,1258,1158,1093cm
-1 1H NMR (500MHz, methanol-d
4): d 8.54 (d, J=2.0Hz, 1H, Ar), 7.83-7.81 (m, 2H, Ar), 7.74 (dd, J=2.0,9.0Hz, 1H, Ar), 7.52-7.43 (m, 3H, Ar), 6.97 (d, J=9.0Hz, 1H, Ar), 4.12 (dd, J=6.0,8.0Hz, 1H, CH), 3.64 (dd, J=6.0,13.5Hz, 1H, CHH), 3.47 (dd, J=8.0,13.5Hz, 1H, CHH), 1.25 (s, 9H
tBu);
13C NMR (125MHz, methanol-d
4): d170.5,168.3,149.4,142.2,134.8,133.6,131.7,130.1,128.1,127.1,122.2,119.9,83.4,57.3,43.2,27.9; FAB-HRMS value of calculation (M+Cs
+) 597.0420, measured value 597.0439.
As shown in figure 10, synthetic compound 70.At room temperature, in argon gas atmosphere, (0.23g adds 10%Pd/C (0.10g) in methanol 0.50mmol) (15ml) solution to amine 69.Flask is equipped with then and contains H
2 (g)Balloon.After 8 hours, by a bit of kieselguhr (celite
) filter reaction mixture, solvent removed in vacuo obtains 70, is light brown grease (0.19g, 90%).R
f=0.11 (silica gel, 80% ethyl acetate is in hexane);
IR (thin film): n
Max3360,2979,1729,1625,1582,1542,1508,1447,1369,1310,1248,1160,1093,758,721,688,590cm
1 1H NMR (500MHz, methanol-d
4): d 7.82-7.80 (m, 2H, Ar), 7.53-7.49 (m, 1H, Ar), 7.46-7.43 (m, 2H, Ar), 7.11 (d, J=2.0Hz, 1H, Ar), 7.05 (d, J=2.0Hz, 1H, Ar), 6.64 (d, J=8.5Hz, 1H, Ar), 4.08 (dd, J=7.5,14.5Hz, 1H, CH), 3.61 (dd, J=6.0,13.5Hz, 1H, CHH), 3.47 (dd, J=8.0,13.5Hz, 1H, CHH), 1.22 (s, 9H
tBu);
13C NMR (125MHz, methanol-d
4): d 170.8,170.6, and 142.1,141.2,134.8,133.7,130.1,128.1,124.5,120.6,116.5,115.5,83.3,57.5,43.1,28.0; FAB-HRMS value of calculation (M+Na
+) 435.1702, measured value 434.1727.
As shown in figure 10, synthetic compound 71.To diamidogen 70 (0.092g, add in ethanol 0.20mmol) (20ml) solution triethylamine (0.032ml, 0.22mmol) and the isothiocyanic acid phenylester (0.028ml, 0.22mmol).After 14 hours, solvent removed in vacuo obtains being the brown residue, by preparation of lamina chromatograph (silica gel, 5% methanol is in dichloromethane) purification, obtains 71, is brown solid (0.082g, 69%).R
f=0.16 (silica gel, 5% methanol is in dichloromethane);
IR (thin film): n
Max3316,3061,2978,1729,1624,1504,1448,1368,1309,1252,1159,1092,837,733 cm
-1 1H NMR (500MHz, CDCl
3): d 8.15 (bs, 1H, NH), 7.81 (d, J=7.5Hz, 2H, Ar), 7.56-7.03 (m, 14H), 6.78 (bs, 1H, NHC=O), 6.58 (d, J=8.0Hz, 1H, HNSO
2Ph), 4.51 (bs, 1H), 4.05 (bs, 1H), 3.67 (bs, 1H), 1.20 (s, 9H,
tBu);
1H NMR (500MHz, CDCl
3): d 180.3,168.6, and 167.4,147.0,143.3,139.6,137.6,132.7,129.0,128.4,127.1,126.6,125.4,123.5,116.1,83.2,60.3,56.5,42.0,27.5; FAB-HRMS value of calculation (M+Cs
+) 702.0821, measured value 702.0797.
As shown in figure 10, synthetic compound 72.At room temperature, to thiourea 71 (0.077g, add in DMF 0.14mmol) (10ml) solution triethylamine (0.02ml, 0.14mmol) and mercuric chloride (II) (0.04g, 0.14mmol).After 4 hours, by a bit of kieselguhr (celite
) filter and be immersed in the ethyl acetate.Solvent removed in vacuo obtains 72 brown residues (0.05g, 81%), carries it into next step.R
f=0.32 (silica gel, 5% methanol is in dichloromethane);
1H NMR (500MHz, CDCl
3): d 7.98 (m, 2H, Ar), 7.53-6.90 (m, 15H, Ar), 4.16 (m, 1H, CH), 3.83 (bs, 1H, CHH), 3.62 (bs, 1H, CHH), 1.25 (bs, 9H,
tBu); FAB-HRMS value of calculation (M+Cs
+) 668.0944, measured value 668.0923.
As shown in figure 10, synthetic compound 22.Prepare chemical compound 22 according to preparing chemical compound 10 identical methods, only be to use 72 to substitute 36b.Yield: 0.04g (88%).R
t=14.8 minutes;
1H NMR (500MHz, methanol-d
4): d 7.85-7.82 (m, 3H, Ar), 7.75 (dd, J=1.5,8.5Hz, 1H, Ar), 7.56-7.41 (m, 9H, Ar), 4.22 (dd, J=5.0,9.0Hz, 1H, CH), 3.78 (dd, J=5.0,13.5Hz, CHH), 3.48 (dd, J=9.0,13.5Hz, CHH);
13C NMR (150MHz, methanol-d
4): d171.9,169.2,150.7,141.6,136.2,133.1,131.2,130.9,130.6,129.5,128.3,127.5,124.6,124.1,111.9,111.8,56.1,42.8; FAB-HRMS value of calculation (M+H
+) 480.1342, measured value 480.1352.
Claims (19)
2, RGD analogies according to claim 1, wherein aryl is selected from phenyl, 1-naphthyl and 2-naphthyl.
3, according to the RGD analogies of claim 2, R wherein
2For-SO
2-aryl.
5, RGD analogies according to claim 1, wherein these analogies are represented by following structural:
9, RGD analogies according to claim 1, wherein these analogies are represented by following structural:
12, RGD analogies according to claim 1, wherein these analogies are represented by following structural:
13, RGD analogies according to claim 1, wherein these analogies are represented by following structural:
15, RGD analogies according to claim 1, wherein these analogies are represented by following structural:
16, preparation is by the method for the RGD analogies of following general formula,
R wherein
1Be selected from one of following groups:
And X be selected from sulfur ,-divalent group of NH-and oxygen; R
2Be selected from-CO
2-the tert-butyl group ,-the CO-aryl and-SO
2-aryl,
This method comprises the following steps:
Step 1: the nitro aryl precursor of being represented by following structural that contains the fluorin radical that links to each other with nitro aryl rings covalency is provided:
R wherein
3Be acid protecting group; Then,
Step 2: replace by nucleophilic aromatic, utilize to contain the nucleopilic reagent replacement fluorin radical that is protected guanidine radicals group, generate and protected the RGD analogies; At last,
Step 3: utilize acid will be protected RGD analogies deprotection.
18, RGD analogies according to claim 17, wherein aryl is selected from phenyl, 1-naphthyl and 2-naphthyl.
19, to α
Iibβ
3The cell attachment and the α that regulate
vβ
3The method that the difference of the cell attachment of regulating suppresses, the method comprising the steps of:
Express alpha
Iibβ
3Cell select the solution of RGD analogies to contact with containing, described analogies are selected from claim 5,7,9,11,14 or 15 chemical compound, the concentration of RGD analogies is enough to suppress α in the wherein said solution
Iibβ
3The cell attachment of regulating,
Wherein repressed α
Iibβ
3The cell attachment of regulating is at least approximately greater than α
vβ
3100 times of the cell attachment of regulating.
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US09/110,885 | 1998-07-06 |
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JP (1) | JP2002519377A (en) |
KR (1) | KR20010079497A (en) |
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CA (1) | CA2336774A1 (en) |
HU (1) | HUP0104509A3 (en) |
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Cited By (3)
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CN102653559B (en) * | 2003-12-03 | 2014-09-10 | 斯克利普斯研究院 | Integrin alphaiibbeta3 specific antibodies and peptides |
CN108430488A (en) * | 2015-11-26 | 2018-08-21 | 大和药品株式会社 | Angiogenesis inhibitors |
CN109535035A (en) * | 2019-01-08 | 2019-03-29 | 吉尔生化(上海)有限公司 | A kind of preparation method of the N- benzyloxycarbonyl group -3- amino-alanine tert-butyl ester |
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GB9805655D0 (en) | 1998-03-16 | 1998-05-13 | Celltech Therapeutics Ltd | Chemical compounds |
GB9814414D0 (en) | 1998-07-03 | 1998-09-02 | Celltech Therapeutics Ltd | Chemical compounds |
GB9826174D0 (en) | 1998-11-30 | 1999-01-20 | Celltech Therapeutics Ltd | Chemical compounds |
ATE375330T1 (en) | 2000-04-17 | 2007-10-15 | Ucb Pharma Sa | ENAMINE DERIVATIVES AS CELL ADHESION MOLECULES |
US6486174B2 (en) | 2000-08-07 | 2002-11-26 | 3-Dimensional Pharmaceuticals, Inc. | Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists |
AU2003212558A1 (en) | 2002-03-20 | 2003-09-29 | Koninklijke Philips Electronics N.V. | Active matrix electroluminescent display devices, and their manufacture |
CN113773260B (en) * | 2021-08-26 | 2023-09-22 | 华南师范大学 | Covalent-like organic material and preparation method and application thereof |
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JPH08502484A (en) * | 1992-10-14 | 1996-03-19 | メルク エンド カンパニー インコーポレーテッド | Fibrinogen receptor antagonist |
WO1994012181A1 (en) * | 1992-12-01 | 1994-06-09 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
CA2190870A1 (en) * | 1994-05-27 | 1995-12-07 | George D. Hartman | Compounds for inhibiting osteoclast-mediated bone resorption |
JP2000508319A (en) * | 1996-04-10 | 2000-07-04 | メルク エンド カンパニー インコーポレーテッド | αvβ3 antagonist |
-
1999
- 1999-07-06 HU HU0104509A patent/HUP0104509A3/en unknown
- 1999-07-06 EP EP99932289A patent/EP1094812A4/en not_active Withdrawn
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- 1999-07-06 KR KR1020017000144A patent/KR20010079497A/en not_active Application Discontinuation
- 1999-07-06 CN CN99808280A patent/CN1308534A/en active Pending
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CN102653559B (en) * | 2003-12-03 | 2014-09-10 | 斯克利普斯研究院 | Integrin alphaiibbeta3 specific antibodies and peptides |
CN108430488A (en) * | 2015-11-26 | 2018-08-21 | 大和药品株式会社 | Angiogenesis inhibitors |
CN109535035A (en) * | 2019-01-08 | 2019-03-29 | 吉尔生化(上海)有限公司 | A kind of preparation method of the N- benzyloxycarbonyl group -3- amino-alanine tert-butyl ester |
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NO20010085L (en) | 2001-03-05 |
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ZA200007405B (en) | 2001-09-21 |
BR9911885A (en) | 2001-03-27 |
AU4862599A (en) | 2000-01-24 |
HUP0104509A3 (en) | 2002-05-28 |
JP2002519377A (en) | 2002-07-02 |
EP1094812A1 (en) | 2001-05-02 |
SK242001A3 (en) | 2001-10-08 |
KR20010079497A (en) | 2001-08-22 |
WO2000001383A1 (en) | 2000-01-13 |
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HUP0104509A2 (en) | 2002-04-29 |
CA2336774A1 (en) | 2000-01-13 |
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