CN100372843C - 2,5-disubstituted-1,3-dioxygen cycle compound, their synthesis and application as PKC inhibiter - Google Patents
2,5-disubstituted-1,3-dioxygen cycle compound, their synthesis and application as PKC inhibiter Download PDFInfo
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- CN100372843C CN100372843C CNB2004100984308A CN200410098430A CN100372843C CN 100372843 C CN100372843 C CN 100372843C CN B2004100984308 A CNB2004100984308 A CN B2004100984308A CN 200410098430 A CN200410098430 A CN 200410098430A CN 100372843 C CN100372843 C CN 100372843C
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- MUVQIIBPDFTEKM-UHFFFAOYSA-N 2-aminobutane-1,3-diol Chemical compound CC(O)C(N)CO MUVQIIBPDFTEKM-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- HYANHJNUAZZLRC-UHFFFAOYSA-N 5-amino-4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(N)C=C(C(O)=O)C=C1C(O)=O HYANHJNUAZZLRC-UHFFFAOYSA-N 0.000 description 1
- 235000005288 Annona lutescens Nutrition 0.000 description 1
- 244000030795 Annona lutescens Species 0.000 description 1
- VSDHITKWYNSKSS-UHFFFAOYSA-N C1C(COCO1)NC(=O)C(F)(F)F Chemical compound C1C(COCO1)NC(=O)C(F)(F)F VSDHITKWYNSKSS-UHFFFAOYSA-N 0.000 description 1
- ZUHYKLSIVMRGOH-UHFFFAOYSA-N C1COC(OC1)(C(=O)CN)N Chemical compound C1COC(OC1)(C(=O)CN)N ZUHYKLSIVMRGOH-UHFFFAOYSA-N 0.000 description 1
- YMYDXGRSQWXXIK-UHFFFAOYSA-N CC1=C(C=C(C(=C1C(=O)O)C2=CC=C(C=C2)[N+](=O)[O-])C(=O)O)N Chemical compound CC1=C(C=C(C(=C1C(=O)O)C2=CC=C(C=C2)[N+](=O)[O-])C(=O)O)N YMYDXGRSQWXXIK-UHFFFAOYSA-N 0.000 description 1
- GCWHHHUJDGVIDM-UHFFFAOYSA-N CC1=CC=C(C=C1)C2=C(C(=C(C=C2C(=O)O)N)C)C(=O)O Chemical compound CC1=CC=C(C=C1)C2=C(C(=C(C=C2C(=O)O)N)C)C(=O)O GCWHHHUJDGVIDM-UHFFFAOYSA-N 0.000 description 1
- XDQHMPPYLUWMJG-INIZCTEOSA-N CCCC[C@@H](C(=O)NC1=C(C(=C(C(=C1)C(=O)O)C2=CC=C(C=C2)C)C(=O)O)C)N Chemical compound CCCC[C@@H](C(=O)NC1=C(C(=C(C(=C1)C(=O)O)C2=CC=C(C=C2)C)C(=O)O)C)N XDQHMPPYLUWMJG-INIZCTEOSA-N 0.000 description 1
- LAMRLMTXDPJBIK-HNNXBMFYSA-N CCCC[C@@H](C(=O)NC1=C(C(=C(C(=C1)C(=O)O)C2=CC=C(C=C2)[N+](=O)[O-])C(=O)O)C)N Chemical compound CCCC[C@@H](C(=O)NC1=C(C(=C(C(=C1)C(=O)O)C2=CC=C(C=C2)[N+](=O)[O-])C(=O)O)C)N LAMRLMTXDPJBIK-HNNXBMFYSA-N 0.000 description 1
- VJPSCDKZVFEQPD-HNNXBMFYSA-N CCCC[C@@H](C(=O)NC1=C(C(=C(C(=C1)C(=O)O)C2=CC=CC=C2)C(=O)O)C)N Chemical compound CCCC[C@@H](C(=O)NC1=C(C(=C(C(=C1)C(=O)O)C2=CC=CC=C2)C(=O)O)C)N VJPSCDKZVFEQPD-HNNXBMFYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
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- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- VEBVPUXQAPLADL-UHFFFAOYSA-N Ingenol Natural products C1=C(CO)C(O)C2(O)C(O)C(C)=CC32C(C)CC2C(C)(C)C2C1C3=O VEBVPUXQAPLADL-UHFFFAOYSA-N 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 230000001171 adenosinetriphosphoric effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 125000005340 bisphosphate group Chemical group 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 208000035475 disorder Diseases 0.000 description 1
- 238000003370 dye binding method Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-J ethylene glycol bis(2-aminoethyl)tetraacetate Chemical compound [O-]C(=O)CN(CC([O-])=O)CCOCCOCCN(CC([O-])=O)CC([O-])=O DEFVIWRASFVYLL-UHFFFAOYSA-J 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- VEBVPUXQAPLADL-POYOOMFHSA-N ingenol Chemical compound C1=C(CO)[C@@H](O)[C@]2(O)[C@@H](O)C(C)=C[C@]32[C@H](C)C[C@H]2C(C)(C)[C@H]2[C@H]1C3=O VEBVPUXQAPLADL-POYOOMFHSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
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- 150000002596 lactones Chemical group 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- NKAAEMMYHLFEFN-UHFFFAOYSA-M monosodium tartrate Chemical compound [Na+].OC(=O)C(O)C(O)C([O-])=O NKAAEMMYHLFEFN-UHFFFAOYSA-M 0.000 description 1
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- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
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- PEYTUVXFLCCGCC-YGHSORLUSA-N teleocidin b Chemical compound C1[C@@H](CO)NC(=O)[C@H](C(C)C)N(C)C2=CC([C@@](CC[C@]3(C)C=C)(C)C(C)C)=C3C3=C2C1=CN3 PEYTUVXFLCCGCC-YGHSORLUSA-N 0.000 description 1
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Images
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a 5-amido-1, 3-dioxycycle compound disclosed in a general formula I. The compound disclosed in the general formula I can be prepared by that acetal transfer reaction is generated on 2-amido-1, 3-propanediol or (2R, 3R)-2-amido-1, 3-butanediol as raw material and 1, 1, 3, 3-tetramethoxypropane under the catalysis of chlorotrimethylsilane to form a ring, or the acetalization reaction is generated on 2-amido-1, 3-propanediol, (2R, 3R)-2-amido-1, 3-butanediol or (2S)-2-amido-1, 3-butanediol as raw material and substituted benzaldehyde to form a ring, or the acylation reaction is generated on a 5-amido-1, 3-dioxycycle compound and glycine or L-alanine as raw materials under the condition with a condensing agent, such as DCC to generate a ring. The compound can serve as a PKC inhibitor and an anti-inflammatory agent.
Description
Technical field
It is novel 2 to the present invention relates to a class, and 5-two replaces-1, and the 3-dioxygen cycle compound relates to by aminodiol and 1,1,3, the acetal shift reaction of 3-tetramethoxy propane or prepare the method for this compound with the acetalation of substituted benzaldehyde, with and application.
Background technology
Protein kinase C (PKC) is a kinases family, is present among nearly all tissue.The activity of PKC relates to many important physical processes (for example function of Muscle contraction, neurotransmitter release, platelet activation, somatomedin and hormone or the like) and pathologic process, for example relevant myocardial ischemia and the multidrug resistance of cancer, inflammation, ischemical reperfusion injury, ischemia-reperfusion damage.(Basu?A，The?potential?of?protein?kinase?Cas?a?target?of?anticancer?treatment，Pharmac.Ther.1993，59，257-280；Weinstein?IB，Begemann?M，0.Disorders?in?cell?circuitry?associated?with?multistage?carcinogeneses：exploctable?targets?for?cancer?prevention?and?therapy，Clin?Cancer?Res，1997，3，2696-2702)。The contriver has conscientiously compared exogenous PKC agonist, Buddhist ripple ester, teleocidin, ingenol and endogenous PKC agonist diacylglycerol (Wender P.A., The chemistry-medicinecontinuum:Synthetic, computer, spectroscopic and biological studies on newchemotherapeutic leads, Pure.﹠amp; Apll.Chem, 1998,70 (3), constitutional features 539-546), and constitutional features (the Lee J of the competitive compound template of diacylglycerol of five-ring lactone structure, Conformationally constrained analogues of diacylglycerol, 10.Ultrapotent proteinkinase C ligands based on a chiral5-disubstituted tetrahydro-2-furanone template, J.Med.Chem, 1996,39,29-35; Lee J, Conformationally constrained analogues ofdiacylglycerol, 12.Ultrapotent protein kinase C ligands based on a chiral5-disubstituted tetrahydro-2-furanone template, J.Med.Chem., 1996,39,36-45) afterwards, recognize the potentiality of ring acetal as pkc inhibitor elder generation guide structure.
1989, the contriver has delivered the universal method with the synthetic ring of acetal shift reaction acetal, and disclosed special stability (the Peng SQ of this compounds, Winterfeldt E, Synthesis of malonaldehydemonoacetals, Liebigs Ann.Chem., 1989,1045-1047).2000, the contriver was by N-benzoyl-amido glycol and 1,1; 3, the acetal shift reaction of 3-tetramethoxy propane has been synthesized some ring acetal (Lanrong Bi, Ming Zhao; Chao Wang, Shiqi Peng, Stereoselective transacetalization of1; 1; 3,3-tetramethoxypropane and N-benzoylaminodiols, Eur.J.Org.Chem; 2000,2669-2676).The contriver had applied for 5-benzoyl-amido-1 in 2003; the 3-dioxygen cycle compound is as application (the 5-benzoyl-amido-1 of pkc inhibitor; 3-dioxygen cycle compound and preparation method thereof and the application in preparation inhibitors of protein kinase C medicine, application number: 03119229.7).For 5-benzoyl-amido-1, the 3-dioxygen cycle compound, the contriver has a mind to slough the 5-benzoyl so that improve PKC water-soluble, that have a mind to directly to measure them always always and suppresses active.
Summary of the invention
The object of the present invention is to provide the novel 5-amino-1 of a class, 3-dioxygen cycle compound, and the preparation method who changes compound, and use.
The objective of the invention is to be achieved through the following technical solutions.
The present invention proposes the 5-amino-1 that has shown in the general formula 1, the 3-dioxygen cycle compound,
General formula I
The present invention also provides the preparation method of the compound with above-mentioned general formula 1, this method comprises: with 2-amino-1, ammediol or (2R, 3R)-2-amino-1,3 butylene glycol is a raw material, under trimethylchlorosilane catalysis with 1,1,3,3-tetramethoxy propane generation acetal shift reaction Cheng Huan,, as shown in the formula described
As work as R
1=H, R
2=H, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; CH
2Symmetry connects the cyclic group of I-4; R
1=H, R
2=H, R
3=CH
2CH (OCH
3)
2Or R
4=CH
2CH (OCH
3)
2, during n=2;
Or with 2-amino-1, ammediol, (2R, 3R)-2-amino-1,3 butylene glycol or (2S)-2-amino-1,3 butylene glycol is a raw material, under acid catalysis with substituted benzaldehyde generation acetalation Cheng Huan, as shown in the formula described
R wherein
1=H, R
2=H, R
3=p-nitrophenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=m-nitro base, R
4=H, n=1; R
1=H, R
2=H, R
3=to chloro phenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=phenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=p-methylphenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=p-nitrophenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=m-nitro base, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=to chloro phenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=phenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=p-methylphenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=p-nitrophenyl, R
4=H, n=2; R
1=H, R
2=H, R
3=H, R
4=p-nitrophenyl, n=2; R
1=H, R
2=H, R
3=m-nitro base, R
4=H, n=2; R
1=H, R
2=H, R
3=H, R
4=m-nitro base, n=2; R
1=H, R
2=H, R
3=rubigan, R
4=H, n=2; R
1=H, R
2=H, R
3=H, R
4=rubigan, n=2; R
5Be included in R with one of phenyl
3In, be respectively the 3-nitro, H, 4-chlorine, 4-methyl and 4-nitro;
Wherein, the preparation of aminodiol can be described with following formula:
R wherein
1Be respectively CH
2OH, CH (CH
3) OH and CH
2COOH; R
2Be respectively CH
2OH, CH (CH
3) OH and CH
2COOCH
3R
3Be respectively CH
2OH, CH (CH
3) OH and CH
2CH
2OH;
Or with 5-amino-1,3-dioxygen cycle compound and glycine or L-L-Ala are raw material, and at condensing agent, as DCC, reacting under existing is prepared, as shown in the formula described:
Wherein the compound with general formula 1 statement as raw material is respectively: R
1=H, R
2=H, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; CH
2Symmetry connects the cyclic group of I-4; R
1=H, R
2=H, R
3=CH
2CH (OCH
3)
2Or R
4=CH
2CH (OCH
3)
2, n=2; R
1=H, R
2=H, R
3=p-nitrophenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=m-nitro base, R
4=H, n=1; R
1=H, R
2=H, R
3=to chloro phenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=phenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=p-methylphenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=p-nitrophenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=m-nitro base, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=to chloro phenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=phenyl, R
4=H, n=1; R
1=H, R
2=CH
3, R
3=p-methylphenyl, R
4=H, n=1; R
1=H, R
2=H, R
3=p-nitrophenyl, R
4=H, n=2; R
1=H, R
2=H, R
3=H, R
4=p-nitrophenyl, n=2; R
1=H, R
2=H, R
3=m-nitro base, R
4=H, n=2; R
1=H, R
2=H, R
3=H, R
4=m-nitro base, n=2; R
1=H, R
2=H, R
3=rubigan, R
4=H, n=2; Or R
1=H, R
2=H, R
3=H, R
4=rubigan, n=2;
Prepared compound is: R
1=Gly, R
2=H, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; R
1=L-Phe, R
2=H, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; R
1=Gly, R
2=CH
3, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; R
1=L-Phe, R
2=CH
3, R
3=CH
2CH (OCH
3)
2, R
4=H, n=1; R
1=L-Phe, R
2=H, R
3=CH
2CH (OCH
3)
2, R
4=H, n=2; R
1=L-Phe, R
2=H, R
3=H, R
4=CH
2CH (OCH
3)
2, n=2; R
1=Gly, R
2=H, R
3=p-nitrophenyl, R
4=H, n=1; R
1=Gly, R
2=H, R
3=m-nitro base, R
4H, n=1; R
1=Gly, R
2=H, R
3=rubigan, R
4=H, n=1; R
1=Gly, R
2=H, R
3=phenyl, R
4=H, n=1; R
1=Gly, R
2=H, R
3=p-methylphenyl, R
4=H, n=1; R
1=Gly, R
2=CH
3, R
3=p-nitrophenyl, R
4=H, n=1; R
1=Gly, R
2=CH
3, R
3=m-nitro base, R
4=H, n=1; R
1=Gly, R
2=CH
3, R
3=rubigan, R
4=H, n=1; R
1=Gly, R
2=CH
3, R
3=phenyl, R
4=H, n=1; R
1=Gly, R
2=CH
3, R
3=p-methylphenyl, R
4=H, n=1; R
1=Gly, R
2=H, R
3=p-nitrophenyl, R
4=H, n=2; R
1=Gly, R
2=H, R
3=H, R
4=p-nitrophenyl, n=2; R
1=Gly, R
2=H, R
3=m-nitro base, R
4=H, n=2; R
1=Gly, R
2=H, R
3=H, R
4=m-nitro base, n=2; R
1=Gly, R
2=CH
3, R
3=rubigan, R
4=H, n=2; Or R
1=Gly, R
2=CH
3, R
3=H, R
4=rubigan, n=2.
PKC (protein kinase C) extensively is distributed in numerous internal organs of Mammals and the cell, and is wherein the highest with brain content.Since the 1980's, the method for existing a large amount of extractions and purifying PKC.For example can extract and purifying PKC from animal visceras such as OX-heart, rat liver, ox brains.Maximum from the report of rat brain extraction and purifying PKC.When adopting three-step approach from extraction of fresh bovine brain and purifying PKC, enzymic activity still is that yield is all with suitable with purifying PKC from the rat brain extraction.Operation is simple, ox brain source is abundant.The present invention buys the fresh bovine brain from herding company, centrifugal through homogenate, Superfreezing, saltout, the DEAE column chromatography obtains partial purification PKC.Measured with the PKC that obtains of the present invention 1, the half-inhibition concentration (IC of 3-dioxygen cycle compound
50), specifically see embodiment.
It is of the present invention 1 that the present invention adopts the mice ear inflammatory model to estimate, the anti-inflammatory action of 3-dioxygen cycle compound.Be divided into the blank group at random with the male ICR mouse about body weight 18-22g, positive medication group and medication group, every group of 11 mouse, gastric infusion respectively, the left ear gabarit of single administration past small white mouse after 30 minutes is coated with dimethylbenzene (0.02ml), after 4 hours the dislocation of small white mouse cervical vertebra is put to death.Get circular auricle at two ears with the punch tool of diameter 9mm respectively, weigh, the weight difference of obtaining two circle auricles is as the swelling degree.Concrete outcome is seen embodiment.Test-results shows, and is of the present invention 1, and the 3-dioxygen cycle compound has tangible anti-inflammatory action.
In order to explain the present invention, provide a series of embodiment below.These examples are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Description of drawings
Fig. 1 is a reaction tubes typical curve among the embodiment 50.
Fig. 2 is a control tube typical curve among the embodiment 50.
Embodiment
The intermediate and the degree of purity of production that relate to confirm that with TLC EI-MS measures with the Trace MS System mass spectrograph of U.S. Thermo Finnigan company.Infrared spectra (IR) adopts the Avatar360 Fourier transformation infrared spectrometer of U.S. Nicolet company to measure.Nuclear magnetic resonance spectrum (NMR) adopts NEC AL-300FT NMRSystem to measure.The micro-fusing point instrument of the X75 that fusing point adopts Beijing instrument electric light instrument plant of section to produce is measured, and thermometer is not proofreaied and correct.Silica gel for chromatography is produced by Haiyang Chemical Plant, Qingdao.
The ox brain that determination of activity relates to is available from Beijing gold dimension herding company limited, and dialysis tubing and centrifugal ultrafiltration pipe are imported product.Phenylmethylsulfonyl fluoride, Trypsin inhibitor,Trasylol, dithiothreitol (DTT), two Oleic acid diglycerides, phosphatidylserine, mercaptoethanol, histone, adenosine-triphosphoric acid (ATP), the sweet bisphosphate of gland (ADP), the sweet phosphoric acid of gland (AMP), DEAE-Mierocrystalline cellulose, 1-(5-isoquinoline 99.9 sulfonyl)-2-methylpiperazine (H-7) are all available from Sigma company.Bovine serum albumin, Coomassie brilliant blue G250, ethyleneglycol-bis-N,N'-tetraacetic acid, N-tetraacethyl (EGTA), disodium ethylene diamine tetraacetate (EDTA), TBAH, ammonium sulfate, potassium primary phosphate, glycerine, Tris-HCl[three (methylol) aminomethane hydrochloride], calcium chloride, magnesium chloride, sodium hydroxide, hydrochloric acid, phosphoric acid and dehydrated alcohol etc. be homemade analytical pure.Freezing ultra-lowing centrifuge (Japanese HITACHI 20CRB2), Ultralow Temperature Freezer (U.S. NuAire-85 ℃ of Ultraloe Freezer), horizontal shaking table (German Heidolph Vibramax100), 721 type spectrophotometers, high performance liquid chromatograph (Waters).
Embodiment 22-amino-1, the preparation of ammediol
In the three-necked bottle of 250ml, add 200ml methyl alcohol, slowly drip 30ml (0.42mol) sulfur oxychloride under 0-5 ℃, last 20 minutes and dropwise, add 21g (0.2mol) L-Serine then, room temperature reaction 24 hours.The 36g L-serine methylester that obtains behind the pressure reducing and steaming solvent is white solid, dissolves in 560ml ethanol (95%) and makes methyl ester solution.
In the 2000ml three-necked bottle, add the mixed POTASSIUM BOROHYDRIDE aqueous solution that gets of 46g (0.85mol) POTASSIUM BOROHYDRIDE and 165ml water.Under the vigorous stirring, in the POTASSIUM BOROHYDRIDE aqueous solution, slowly drip L-serine methylester solution, constantly have hydrogen to emit in the reaction, dropwised in 5 hours in 0-5 ℃.Reaction mixture slowly rises to room temperature, reacts 12 hours, and TLC shows methyl esters disappearance (developping agent: C
2H
5OH: H
2O=7: 3, the triketohydrindene hydrate colour developing).Slowly drip the 60ml concentrated hydrochloric acid under the ice bath, last 1 hour, add 20% sodium hydroxide then and transfer about PH to 10.Reaction mixture filters, the an amount of absolute ethanol washing of the solid that obtains, filtrate decompression is concentrated into about 50ml, admix in the Anhydrous potassium carbonate, extracted 72 hours with the chloroform Soxhlet, the concentrating under reduced pressure chloroform is to doing, the red-brown oily matter that obtains is through molecular distillation, get 11.3g (62%) title compound, be faint yellow oily thing, solidify gradually after room temperature is placed.Mp.55-58 ℃ of .FAB-MS (m/e): 92[M+H]
+.IR (KBr): υ/cm
-1=3450 (OH), 3340 (NH).
1HNMR (DMSO-d
6): δ/ppm=2.635 (m, J=5.8Hz, 1H), 3.189 (q, J=5.5Hz, 2H), 3.283 (q, J=5.2Hz, 2H).
13CNMR (DMSO-d
6): δ/ppm=54.640,63.631. ultimate analysis (C
3H
10ClNO
2) calculated value C28.24, H7.90, N10.98; Measured value C28.48, H7.93, N10.79.
Embodiment 3. (2R, 3R)-preparation of 2-amino-1,3 butylene glycol
According to the operation of embodiment 2, replace the L-Serine with 30g (0.252mol) L-Threonine, the consumption of sulfur oxychloride becomes 37.5ml (0.525mol), and the consumption of POTASSIUM BOROHYDRIDE becomes 70g (1.3mol).Obtain 15.4g (58%) title compound, be faint yellow oily thing, solidify gradually after room temperature is placed.Mp50-52 ℃ of .FAB-MS (m/e): 106 [M+H]
+.IR (KBr): υ/cm
-1=3445 (OH), 3350 (NH), 1380 (CH
3).
1HNMR (DMSO-d
6): δ/ppm=1.019 (d, J=6.3Hz, 3H), 2.373 (m, J=3.3Hz, 1H), 3.195 (q, J=5.7Hz, 1H), 3.359 (q, J=5.7Hz, 1H), 3.472 (q, J=4.2Hz, 1H).
13CNMR (DMSO-d
6): δ/ppm20.239.000,58.324,63.607,66.780.[α]
D 20=-4.0 ° of (c=4.0, H
2O). ultimate analysis (C
4H
11NO
2) calculated value C45.69, H10.55, N13.33;
Embodiment 4. (2S)-2-amino-1, the preparation of 4-butyleneglycol
According to the operation of embodiment 2, replace the L-Serine with 12g (0.1mol) L-aspartic acid, the consumption of sulfur oxychloride becomes 15ml (0.42mol), and the consumption of POTASSIUM BOROHYDRIDE becomes 30g (0.55mol).Obtain 7.3g (38.5%) title compound, be faint yellow oily thing.FAB-MS (m/e): 106[M+H]
+.IR (KBr): υ/cm
-1=3425 (OH), 3350 (NH).
1HNMR (DMSO-d
6): δ/ppm=1.254 (m, J=4.3Hz, 1H), 1.488 (m, J=3.4Hz, 1H), 2.699 (m, J=2.4Hz, 1H), 3.118 (q, J=5.7Hz, 1H), 3.247 (q, J=5.1Hz, 1H), 3.487 (t, J=6.5Hz, 2H).
13CNMR (DMSO-d
6): δ/ppm=36.459,50.964,58.991,66.986.[α]
D 20=-13.5 ° of (c=4.0, H
2O). ultimate analysis (C
4H
11NO
2) calculated value C45.69, H10.55, N13.33;
Method 1: in the 10ml reaction flask, add 0.273g (3mmol) 2-amino-1, ammediol, 0.93g (6.6mmol) Trifluoroacetic Acid Ethyl Ester and 6ml anhydrous 1, the 4-dioxane, room temperature reaction 24 hours, TLC shows 2-amino-1, ammediol disappearance (developping agent: CHCl
3: MeOH=10: 1, soft board, vitriol oil colour developing).Reaction mixture is evaporated to dried; the trifluoroacetyl group amino-1 that obtains; ammediol with behind the 8ml acetic acid ethyl dissolution with 0.52g (3.17mmol) 1; 1; 3,3-tetramethoxy propane and 0.09ml concentrated hydrochloric acid mix, room temperature reaction 24 hours; TLC shows trifluoroacetyl group amino-1, ammediol disappearance (developping agent: CHCl
3: MeOH=20: 1, soft board, vitriol oil colour developing).Add 0.09ml ammoniacal liquor in the reaction mixture.Reaction mixture is evaporated to dried (the cis)-2-(2 that obtains, the 2-dimethoxy-ethyl)-5-trifluoroacetamido-1,3-dioxane and 0.6gNaOH, 15ml water and 15ml alcohol solution-forming, room temperature reaction 3 hours, TLC shows (cis)-2-(2, the 2-dimethoxy-ethyl)-and 5-trifluoroacetamido-1,3-dioxane disappearance (developping agent: CHCl
3: MeOH=10: 1, the triketohydrindene hydrate colour developing).Ice bath drips the 1ml concentrated hydrochloric acid down in reaction mixture, concentrating under reduced pressure is removed ethanol, water layer 45ml chloroform extraction three times, and the chloroform layer of merging anhydrous sodium sulfate drying filters, concentrating under reduced pressure, residue separates (eluent: CHCl through silica gel column chromatography
3: MeOH=15: 1) obtain 0.21g (37%) title compound, be faint yellow oily thing.
Method 2: in the 10ml reaction flask, add 0.273g (3mmol) 2-amino-1, ammediol 2ml anhydrous alcohol solution, transfer about PH to 4 with hydrochloric acid under the ice bath, be evaporated to driedly, residue adds 5ml dry DMF, 0.51g (3.11mmol) 1,1,3,3-tetramethoxy propane and 0.7g trimethylchlorosilane, room temperature reaction 24 hours, TLC shows 2-amino-1, ammediol disappearance (developping agent: CHCl
3: MeOH=10: 1, the triketohydrindene hydrate colour developing).Ice bath down in the reaction mixture logical ammonia to PH greater than 9, filter, an amount of DMF washs, and drains.The filtrate high vacuum is concentrated into dried, adds 2ml water in residue, and with 15ml chloroform extraction three times, combined chloroform layer, anhydrous sodium sulfate drying filters, and is evaporated to driedly, and residue separates (eluent: CHCl with silica gel column chromatography
3: MeOH=15: 1) obtain 0.367g (64%) title compound, be faint yellow oily thing.
FAB-MS (m/e): 192[M+H]
+.IR (KBr): υ/cm
-1=3337 (NH), 1380 and, 1364 (CH
3), 1180 and 1075 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.859 (s, 2H), 1.926 (t, J=5.7Hz, 2H), 2.665 (m, J=1.5Hz, 1H), 3.288 (s, 6H), 3.820 (q, J=4.3Hz, 2H), 3.899 (q, J=4.3Hz, 2H), 4.512 (t, J=6.0Hz, 1H), 4.598 (t, J=5.6Hz, 1H).
13CNMR (CDCl
3): δ/ppm=38.314,45.764,52.984,72.747,99.854,100.958. ultimate analysis (C
8H
17NO
4) calculated value C50.25, H8.96, N7.32;
The preparation of embodiment 6.N-trifluoroacetyl group glycine
In the 100ml reaction flask 3.0g (0.04mol) glycine is dissolved in the anhydrous THF of 75ml, 0 ℃ drips 15g (0.07mol) trifluoroacetic anhydride (TFAA) down, lasts 30 minutes, reaction mixture rises to room temperature gradually, react after 45 minutes, be evaporated to dried, residue and 60ml CHCl
3/ sherwood oil (1: 1) mixing solutions refluxed 10 minutes, and solid CHCl is filtered in cooling
3The washing of/sherwood oil (1: 1) mixing solutions obtains white solid 6.0g (66%) title compound, Mp117-118 ℃.
Embodiment 7. (cis)-2-(2, the 2-dimethoxy ethyl)-5-(Norleucyl amino)-1, the preparation of 3-dioxane
0.0536g in the 10ml reaction flask (0.28mmol) (cis)-2-(2; the 2-dimethoxy-ethyl)-and 5-amino-1,3-dioxane, 0.0481g (0.28mmol) N-TFA base glycine, 0.042g (0.31mmol) HOBt and the anhydrous THF of 3ml mix back 0 ℃ and add 0.058g (0.28mmol) DCC down.0 ℃ of reaction of reaction mixture elder generation 2 hours, room temperature reaction is 10 hours again, and TLC shows (cis)-2-(2, the 2-dimethoxy-ethyl)-5-amino-1,3-dioxane disappearance (developping agent: CHCl
3: MeOH=10: 1, soft board, vitriol oil colour developing).Reaction mixture concentrating under reduced pressure solvent is to doing, and residue adds the 8ml ethyl acetate, and stirring at room 30 minutes is filtered, and solid washs with ethyl acetate.Filtrate is used 5ml NaHCO
3(1%), 5ml water is respectively washed once; the ethyl acetate layer anhydrous sodium sulfate drying; filter, filtrate decompression is concentrated into dried, (the cis)-2-(2 that obtains; the 2-dimethoxy-ethyl)-5-trifluoroacetyl group glycyl amino-1; the 3-dioxane mixes with 0.05g NaOH, 10ml ethanol (80%), room temperature reaction 12 hours, and TLC shows (cis)-2-(2; the 2-dimethoxy-ethyl)-and 5-trifluoroacetyl group glycyl amino-1,3-dioxane disappearance (developping agent: CHCl
3: MeOH=10: 1, soft board, vitriol oil colour developing).Reaction mixture is evaporated to dried, and residue adds 2ml water, and with 20ml dichloromethane extraction twice, combined dichloromethane layer, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dried, residue purification by silica gel column chromatography (eluent: CHCl
3: MeOH=15: 1), obtain 0.0579g (83%) title compound, be faint yellow oily thing.EI-MS (m/e): 249[M+H]
+, 271[M+Na]
+.IR (KBr): υ/cm
-1=3315 and 3240 (NH), 1620 (C=O), 1379 and, 1360 (CH
3), 1160 and 1050 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.811 (s, 2H), 1.978 (t, J=5.7Hz, 2H), 3.339 (s, 6H), 3.418 (s, 2H), 3.959 (d, J=1.5Hz, 4H), 4.561 (t, J=5.9Hz, 1H), 4.705 (t, J=5.4Hz, 1H), 8.077 (s, 1H).
13CNMR (CDCl
3): δ/ppm=38.264,43.333,44.668,53.000,70.135,99.904,100.818,172.282. ultimate analysis (C
10H
20N
2O
5) calculated value C48.38, H8.12,11.28;
Embodiment 8. (cis)-2-(2, the 2-dimethoxy ethyl)-5-[(S)-alpha-amino group hydrocinnamoyl]-1, the preparation of 3-dioxane
0.0484g in the 10ml reaction flask (0.25mmol) (cis)-2-(2, the 2-dimethoxy-ethyl)-and 5-amino-1,3-dioxane, 0.098g (0.25mmol) N-Fmoc (Fluorenylmethoxycarbonyl)-L-phenylalanine, 0.038g (0.28mmol) HOBt (1-hydroxybenzotriazole) and the anhydrous THF of 3ml mix and add 0.052g (0.25mmol) DCC under back 0 ℃.0 ℃ of reaction of reaction mixture elder generation 2 hours, room temperature reaction is 10 hours again, and TLC shows (cis)-2-(2, the 2-dimethoxy-ethyl)-5-amino-1,3-dioxane disappearance (developping agent: CHCl
3: MeOH=15: 1, ultraviolet 254mm colour developing or triketohydrindene hydrate colour developing), reaction mixture concentrating under reduced pressure solvent is to doing, and residue adds the 8ml ethyl acetate, and stirring at room 30 minutes is filtered, and solid washs with ethyl acetate.Filtrate is used 5ml NaHCO
3(1%), 5ml water is respectively washed once, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into dried, (the cis)-2-(2 that obtains, the 2-dimethoxy-ethyl)-5-Fmoc-L-phenylalanyl amino-1, the 3-dioxane mixes with 0.05g NaOH, 10ml ethanol (80%), room temperature reaction 12 hours, and TLC shows (cis)-2-(2, the 2-dimethoxy-ethyl)-and 5-Fmoc-L-phenylalanyl amino-1,3-dioxane disappearance (developping agent: CHCl
3: MeOH=10: 1, soft board, vitriol oil colour developing).Reaction mixture is evaporated to dried, and residue adds 2ml water, and with 20ml dichloromethane extraction twice, combined dichloromethane layer, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dried, residue purification by silica gel column chromatography (eluent: CHCl
3: MeOH=20: 1), obtain 0.06g (70%) title compound, be faint yellow oily thing.EI-MS (m/e): 337[M-1]
+.IR (KBr): υ/cm
-1=3325 and 3230 (NH), 1620 (C=O), 1600,1570,1540,1446 (aromatic C=C), 1385 and, 1360 (CH
3), 1170 and 1055 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.518 (s, 2H), 1.949 (t, J=5.5Hz, 2H), 2.719 (q, J=7.7Hz, 1H), 3.278 (q, J=6.0Hz, 1H), 3.325 (s, 6H), 3.646 (q, J=4.3Hz, 1H), 3.911 (d, J=7.4Hz, 5H), 4.543 (t, J=5.8Hz, 1H), 4.677 (t, J=5.3Hz, 1H), 7.235 (d, J=8.0Hz, 2H), 7.265 (d, J=3.0Hz, 1H), 7.320 (t, J=7.5Hz, 2H), 8.060 (d, J=8.5Hz, 1H).
13CNMR (CDCl
3): δ/ppm=38.276,40.999,43.403,52.969,52.992,56.501,70.119,70.187,99.887,100.840,126.786,128.678,129.227,137.855,173.803.[α]
D 20=-48.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
17H
26N
2O
5) calculated value C60.34, H7.74, N8.28;
Embodiment 9 and 9 '. (2S, 4R, 5R)-2-(2, the 2-dimethoxy ethyl)-5-amino-4-methyl isophthalic acid, 3-dioxane and 2-[(2S, 4R, 5R)-and 5-amino-4-methyl isophthalic acid, 3-dioxane-2-yl] methylene radical-(2R, 4S, 5S)-5-amino-4-methyl isophthalic acid, the preparation of 3-dioxane
Method 1: according to the operation of embodiment 5 methods 1, with 0.315g (3mmol) (2R, 3R)-2-amino-1, the 3-butyleneglycol replaces 2-amino-1, and ammediol obtains 0.48g (78%) (2S, 4R, 5R)-and the amino 4-methyl isophthalic acid of 2-(2, the 2-dimethoxy-ethyl)-5-, 3-dioxane and 0.08g (11%) 2-[(2S, 4R, 5R)-and 5-amino-4-methyl isophthalic acid, 3-dioxane-2-yl] methylene radical-(2R, 4S, 5S)-5-amino-4-methyl isophthalic acid, the 3-dioxane is colorless oil, places after fixing for a long time.
Method 2: according to the operation of embodiment 5 methods 2, with 0.315g (3mmol) (2R, 3R)-2-amino-1, the 3-butyleneglycol replaces 2-amino-1, and ammediol obtains 0.48g (78%) (2S, 4R, 5R)-and the amino 4-methyl isophthalic acid of 2-(2, the 2-dimethoxy-ethyl)-5-, 3-dioxane and 0.06g (8%) 2-[(2S, 4R, 5R)-and 5-amino-4-methyl isophthalic acid, 3-dioxane-2-yl] methylene radical-(2R, 4S, 5S)-5-amino-4-methyl isophthalic acid, the 3-dioxane is colorless oil, places after fixing for a long time.
(2S, 4R, 5R)-and the amino 4-methyl isophthalic acid of 2-(2, the 2-dimethoxy-ethyl)-5-, 3-dioxane EI-MS:206[M+H]
+.IR (KBr): υ/cm
-1=3245 (NH), 1377 and, 1358 (CH
3), 1176 and1060 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.130 (d, J=6.0Hz, 3H), 1.624 (s, 2H), 1.872 (t, J=6.0Hz, 2H), 2.402 (t, J=1.8Hz, 1H), 3.250 (s, 3H), 3.258 (s, 3H), 3.793 (m, J=2.0Hz, 1H), 3.818 (d, J=2.0Hz, 2H), 4.493 (t, J=6.0Hz, 1H), 4.587 (t, J=5.5Hz, 1H).
13CNMR (CDCl
3) δ/ppm=17.467,38.078,48.787,52.595,52.815,73.323,74.993,99.442,100.848.[α]
D 20=-6.0 ° of (c=2.0, CHCl
3). ultimate analysis (C
9H
19NO
4) calculated value C52.67, H9.33, N6.82;
2-[(2S, 4R, 5R)-and 5-amino-4-methyl isophthalic acid, 3-dioxane-2-yl] methylene radical-(2R, 4S, 5S)-and 5-amino-4-methyl isophthalic acid, 3-dioxane EI-MS (m/e): 247[M+H]
+.IR (KBr): υ/cm
-1=3245 and 3230 (NH), 1379 and, 1365 (CH
3), 1185 and 1064 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.196 (d, J=6.5Hz, 6H), 1.729 (s, 4H), 1.956 (t, J=5.5Hz, 2H), 2.452 (d, J=1.5Hz, 2H), 3.857 (m, J=3.2Hz, 4H), 3.953 (d, J=1.5Hz, 1H), 3.975 (d, J=1.5HZ, 1H), 4.722 (t, J=5.5Hz, 2H).
13NMR (CDCl
3): δ/ppm=17.617,40.484,48.945,73.483,75.150,99.040.[α]
D 20=-43.0 ° (c=2.0, MeOH). ultimate analysis (C
11H
22N
2O
4) calculated value C53.64, H9.00, N11.37;
According to the operation of embodiment 7, by 0.052g (0.25mmol) (2S, 4R; 5R)-2-(2; the 2-dimethoxy ethyl)-and the amino 4-methyl isophthalic acid of 5-, 3-dioxane and 0.0435g (0.25mmol N-TFA base glycine) obtain 0.0568g (86%) title compound, are faint yellow oily thing.EI-MS (m/e): 263[M+H]
+, 285[M+Na]
+.IR (KBr): υ/cm
-1=3325 and 3240 (NH), 1627 (C=O), 1375 and, 1362 (CH
3), 1160 and1054 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.146 (d, J=6.3Hz, 3H), 1.980 (t, J=5.6Hz, 2H), 2.441 (s, 2H), 3.330 (s, 3H), 3.338 (s, 3H), 3.499 (s, 2H), 3.872 (s, 1H), 3.909 (s, 1H), 3.972 (t, J=5.6Hz, 2H), 4.576 (t, J=5.9Hz, 1H), 4.726 (t, J=5.3Hz, 1H), 7.825 (d, J=3.9Hz, 1H).
13CNMR (CDCl
3): δ/ppm=17.570,38.174,46.457,52.770,53.017,71.041,74.445,99.763,100.818.[α]
D 20=-6.0 ° of (c=2.0, CHCl
3). ultimate analysis (C
11H
22N
2O
5) calculated value C50.37, H8.45, N10.68;
Embodiment 11. (2S, 4R, 5R)-2-(2, the 2-dimethoxy ethyl)-5-[(S)-alpha-amino group phenylpropyl alcohol amido]-the 4-methyl isophthalic acid, the preparation of 3-dioxane
According to the operation of embodiment 8, by 0.052g (0.25mmol) (2S, 4R, 5R)-2-(2, the 2-dimethoxy ethyl)-and the amino 4-methyl isophthalic acid of 5-, 3-dioxane and 0.098g (0.25mmol) N-Fmoc-L-phenylalanine obtains 0.06g (67%) title compound, is faint yellow oily thing.EI-MS (m/e): 353[M+H]
+.IR (KBr): υ/cm
-1=3320and 3230 (NH), 1620 (C=O), 1598,1560,1535,1446 (aromatic C=C), 1380 and1360 (CH
3), 1169 and 1055 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.087 (d, J=6.0Hz, 3H), 1.707 (s, 2H), 1.953 (t, J=5.8Hz, 2H), 2.781 (q, J=7.5Hz, 1H), 3.272 (q, J=5.8Hz, 1H), 3.319 (s, 3H), 3.329 (s, 3H), 3.693 (q, J=4.3Hz, 1H), 3.847 (d, J=11.0Hz, 2H), 3.885 (t, J=3.5Hz, 1H), 3.939 (m, J=3.6Hz, 1H), 4.559 (t, J=5.8Hz, 1H), 4.704 (t, J=5.5Hz, 1H), 7.247 (d, J=7.5Hz, 2H), 7.265 (d, J=2.0Hz, 1H), 7.320 (t, J=7.5Hz, 2H), 7.893 (d, J=9.0Hz, 1H).
13CNMR (CDCl
3): δ/ppm=17.510,38.215,41.068,46.378,52.740,53.045,56.623,71.103,74.460,99.757,100.863,126.839,128.716,129.311,137.749,174.123.[α]
D 20=-68.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
18H
28N
2O
5) calculated value C61.34, H8.01, N7.95;
Embodiment 12. (5S)-2-(2, the 2-dimethoxy-ethyl)-5-amino-1, the preparation of 3-cyclic heptane dioxide
Method 1: according to the operation of embodiment 5 methods 1, with 0.315g (3mmol) (2S)-2-amino-1, the 4-butyleneglycol replaces 2-amino-1, ammediol obtains 0.16g (26%) title compound, is faint yellow oily thing.FAB-MS(m/e)：206[M+H]
+.
Method 2: according to the operation of embodiment 5 methods 2, with 0.315g (3mmol) (2S)-2-amino-1, the 4-butyleneglycol replaces 2-amino-1, ammediol obtains 0.256g (42%) title compound, is faint yellow oily thing.FAB-MS(m/e)：206[M+H]
+.
Embodiment 13 and 13 '. (2S, 5S)-2-(2, the 2-dimethoxy ethyl)-5-[(S)-alpha-amino group phenylpropyl alcohol amido]-1,3-cyclic heptane dioxide and (2R, 5S)-and 2-(2, the 2-dimethoxy ethyl)-5-[(S)-alpha-amino group phenylpropyl alcohol amido]-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 8, by 0.052g (0.25mmol) (5S)-2-(2, the 2-dimethoxy-ethyl)-5-amino-1,3-cyclic heptane dioxide and 0.098g (0.25mmol) N-Fmoc-L-phenylalanine obtains 0.041g (46%) (2S, 5S)-2-(2, the 2-dimethoxy ethyl)-5-[(S)-and alpha-amino group phenylpropyl alcohol amido]-1,3-cyclic heptane dioxide and 0.039 (44%g) (2R, 5S)-2-(2, the 2-dimethoxy ethyl)-5-[(S)-and alpha-amino group phenylpropyl alcohol amido]-1, the 3-cyclic heptane dioxide is faint yellow oily thing.
(2S, 5S)-2-(2, the 2-dimethoxy ethyl)-5-[(S)-alpha-amino group phenylpropyl alcohol amido]-1,3-cyclic heptane dioxide EI-MS (m/e): 353[M+H]
+.IR (KBr): υ/cm
-1=3320 and 3225 (NH), 1625 (C=O), 1600,1560,1535,1446 (aromatic C=C), 1385 and, 1358 (CH
3), 1168 and 1055 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.524 (s, 2H), 1.763 (m, J=4.0Hz, 2H), 1.894 (m, J=4.8Hz, 2H), 2.763 (q, J=7.7Hz, 1H), 3.207 (q, J=6.0Hz, 1H), 3.326 (s, 6H), 3.614 (m, J=4.4Hz, 2H), 3.702 (d, J=12.0Hz, 2H), 3.777 (q, J=5.0Hz, 1H), 4.196 (d, J=2.5Hz, 1H), 4.498 (t, J=6.0Hz, 1H), 4.765 (t, J=5.8Hz, 1H), 7.231 (d, J=7.5Hz, 2H), 7.312 (d, J=2.0Hz, 1H), 7.324 (t, J=7.5Hz, 2H), 7.674 (d, J=8.5Hz, 1H).
13NMR (CDCl
3): δ/ppm=35.034,37.299,40.984,47.507,52.855,52.954,56.288,60.895,69.731,100.314,101.496,126.809,128.624,129.334,137.672,173.345.[α]
D 20=-38.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
18H
28N
2O
5) calculated value C61.34, H8.01, N7.95; (2R, 5S)-2-(2, the 2-dimethoxy ethyl)-5-[(S)-alpha-amino group phenylpropyl alcohol amido]-1,3-cyclic heptane dioxide EI-MS (m/e) 353[M+H]
+.IR (KBr): υ/cm
-1=3306 and 3220 (NH), 1626 (C=O), 1600,1565,1540,1446 (aromatic C=C), 1380 and, 1360 (CH
3), 1180 and 1065 (C-O-C).
1HNMR (CDCl
3): δ/ppm=1.643 (s, 2H), 1.694 (m, J=4.0Hz, 2H), 1.856 (m, J=4.5Hz, 2H), 2.789 (q, J=7.3Hz, 1H), 3.188 (q, J=6.0Hz, 1H), 3.315 (s, 3H), 3.324 (s, 3H), 3.472 (m, J=4.4Hz, 2H), 3.643 (q, J=4.2Hz, 1H), 3.807 (m, J=3.9Hz, 1H), 3.904 (d, J=11.5Hz, 1H), 4.092 (q, J=3.8Hz, 1H), 4.495 (t, J=6.0Hz, 1H), 4.803 (t, J=5.8Hz, 1H), 7.226 (d, J=7.5Hz, 2H), 7.307 (d, J=2.0Hz, 1H), 7.331 (t, J=7.5Hz, 2H), 7.687 (d, J=8.0Hz, 1H).
13NMR (CDCl
3): δ/ppm=35.324,36.704,40.977,47.148,52.656,52.900,56.295,62.749,63.840,99.353,101.374,126.824,128.624,129.357,137.565,173.276.[α]
D 20=-30.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
18H
28N
2O
5) calculated value C61.34, H8.01, N7.95;
Embodiment 14. (cis)-2-substituted-phenyl-5-amino-1, method is led in the preparation of 3-dioxane
In the 50ml reaction flask, add 3.0mmol2-amino-1, ammediol, 3.01mmol tosic acid and 10ml dehydrated alcohol mix, concentrating under reduced pressure after the dissolving, residue mixes with 3.0mmol substituting group phenyl aldehyde and 40ml toluene, on reflux, install water trap additional, reaction refluxes and removed the water of generation in 6 hours, and TLC shows 2-amino-1, ammediol disappearance (developping agent: CHCl
3: MeOH=10: 1, ultraviolet 254nm colour developing or triketohydrindene hydrate colour developing).Reaction mixture is evaporated to dried, and stirring at room is 1 hour behind the residue usefulness 10ml acetic acid ethyl dissolution, filters, solid washs with ethyl acetate, the colorless solid that obtains dissolves with the 20ml methylene dichloride, and the solution that obtains mixes with 3.5mmol sodium bicarbonate and 20ml water, stirs 30 minutes.Place layering, water layer 20ml dichloromethane extraction twice, the combined dichloromethane layer, anhydrous sodium sulfate drying filters, washed with dichloromethane, filtrate decompression is concentrated into dried, and residue is through purification by silica gel column chromatography (eluent: CHCl
3: MeOH=15: 1), obtain title compound.
According to the operation of embodiment 14, by 273mg (3.0mmol) 2-amino-1, ammediol and 453mg (3.0mmol) paranitrobenzaldehyde obtains 625mg (93%) title compound, is faint yellow solid.Mp:112-113 ℃ of .FAB-MS (m/e): 225[M+H]
+.IR (KBr): υ/cm
-1=3370 (NH), 1605,1580,1540,1445 (aromatic C=C), 1190 and 1065 (C-O-C), 800 (1,4-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.733 (s, 2H), 2.839 (t, J=1.8Hz, 1H), 4.052 (q, J=4.3Hz, 2H), 4.179 (q, J=4.5Hz, 2H), 5.573 (s, 1H), 7.661 (q, J=3.7Hz, 2H), 8.216 (m, J=2.7Hz, 2H, aromatic H).
13CNMR (CDCl
3): δ/ppm=45.707,73.522,100.077,123.450,127.084,144.614,148.191. ultimate analysis (C
10H
12N
2O
4) calculated value C53.57, H5.39, N12.49;
Embodiment 16. (cis)-2-m-nitro base-5-amino-1, the preparation of 3-dioxane is according to the operation of embodiment 14, by 273mg (3.0mmol) 2-amino-1, ammediol and 453mg (3.0mmol) m-nitrobenzaldehyde obtains 604mg (90%) title compound, is faint yellow solid.Mp:50-52 ℃ of .FAB-MS (m/e): 225[M+H]
+.IR (KBr): υ/cm
-1=3360 (NH), 1608,1583,1541,1445 (aromaticC=C), 1190 and 1063 (C-O-C), 865,750,690 (1,3-disubstitude).
1HNMR (CDCl
3): δ/ppm=2.126 (s, 2H), 2.882 (s, 1H), 4.082 (d, J=11.4Hz, 2H), 4.181 (d, J=12.6Hz, 2H), 5.574 (s, 1H), 7.534 (t, J=8.0Hz, 1H), 7.816 (t, J=8.0Hz, 1H), 8.194 (q, J=3.2Hz, 1H), 8.367 (s, 1H).
13CNMR (CDCl
3) δ/ppm=45.649,73.209,99.969,121.406,123.780,129.260,132.169,140.048,146.117. ultimate analysis (C
10H
12N
2O
4) calculated value C53.57, H5.39, N12.49;
Embodiment 17. (cis)-2-rubigan-5-amino-1, the preparation of 3-dioxane
According to the operation of embodiment 14, by 273mg (3.0mmol) 2-amino-1, ammediol and 420mg (3.0mmol) 4-chloro-benzaldehyde obtains 613mg (96%) title compound, is colorless solid.Mp76-78 ℃ of .FAB-MS (m/e): 214[M+H]
+.IR (KBr): υ/cm
-1=3375 (NH), 1605,1583,1540,1444 (aromatic C=C), 1189 and 1065 (C-O-C), 815 (1,4-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.765 (s, 2H), 2.795 (s, 1H), 4.029 (m, J=6.4Hz, 2H), 4.122 (m, J=3.7Hz, 2H), 5.483 (d, J=7.2Hz, 1H), 7.240 (s, 1H), 7.335 (m, J=3.8Hz, 1H), 7.405 (m, J=3.1Hz, 2H).
13CNMR (CDCl
3): δ/ppm=45.756,73.407,100.991,127.389,128.453,134.749,136.719. ultimate analysis (C
10H
12ClNO
2) calculated value C56.21, H5.66, N6.56;
Embodiment 18. (cis)-2-phenyl-5-amino-1, the preparation of 3-dioxane
According to the operation of embodiment 14, by 273mg (3.0mmol) 2-amino-1, ammediol and 308mg (3.0mmol) phenyl aldehyde obtains 473mg (88%) title compound, is colorless solid.Mp:52-54 ℃ of .FAB-MS (m/e): 180[M+H]
+.IR (KBr): υ/cm
-1=3370 (NH), 1607,1580,1540,1440 (aromaticC=C), 1180 and 1062 (C-O-C), 740,695 (monosubstitude).
1HNMR (CDCl
3): δ/ppm=1.934 (s, 2H), 2.787 (s, 1H), 4.017 (d, J=10.5Hz, 2H), 4.141 (d, J=11.7Hz, 2H), 5.510 (d, J=7.5Hz, 1H), 7.363 (t, J=5.7Hz, 3H), 7.478 (q, J=3.1Hz, 2H).
13CNMR (CDCl
3) δ/ppm=45.772,73.300,101.791,125.865,128.271,128.964,138.136. ultimate analysis (C
10H
13NO
2) calculated value C67.02, H7.31, N7.82;
Embodiment 19. (cis)-2-p-methylphenyl-5-amino-1, the preparation of 3-dioxane is according to the operation of embodiment 14, by 273mg (3.0mmol) 2-amino-1, ammediol and 360mg (3.0mmol) p-tolyl aldehyde obtains 492mg (85%) title compound, is colorless solid.Mp:55-56 ℃ of .FAB-MS (m/e): 194[M+H]
+.IR (KBr): υ/cm
-1=3380 (NH), 1610,1580,1543,1445 (aromaticC=C), 1375 (CH
3), 1190 and 1060 (C-O-C), 800 (1,4-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.894 (s, 2H), 2.326 (s, 3H), 2.786 (s, 1H), 4.008 (d, J=4.3Hz, 2H), 4.134 (d, J=4.4Hz, 2H), 5.470 (s, 1H), 7.163 (d, J=7.8Hz, 2H), 7.363 (d, J=7.8Hz, 2H).
13CNMR (CDCl
3) δ/ppm=21.237,45.83,73.316,101.890,125.766,128.939,135.367,138.755. ultimate analysis (C
11H
15NO
2) calculated value C68.37, H7.82, N7.25;
Embodiment 20.2,8-two (p-nitrophenyl)-3, the preparation of 7-dioxy-1-aza-bicyclo [3.3.0] octane
Method 1: 0.273g in the 25ml reaction flask (3mmol) 2-amino-1, ammediol, 0.9g (6mmol) paranitrobenzaldehyde, 0.182g (3mmol) acetic acid and 20ml chloroform mix, on reflux, install water trap additional, reaction refluxes and was with water 10 hours, TLC shows 2-amino-1, ammediol disappearance (developping agent: CHCl
3: sherwood oil=1: 1, ultraviolet 254nm colour developing or triketohydrindene hydrate colour developing).The reaction mixture normal pressure spends the night at refrigerator cold-storage after boiling off 10ml left and right sides chloroform, separates out crystallization, filters, chloroform is washed once, dry, get white solid 1.05g, this solid is added in the 30ml water, stirring at room 1 hour, filter washing, vacuum drying, get 0.88g (82%) title compound, be colorless solid.
Method 2: 0.273g in the 25ml reaction flask (3mmol) 2-amino-1, ammediol, 0.9g (6mmol) paranitrobenzaldehyde and 20ml toluene mix, and install water trap on reflux additional, and reaction refluxes and was with water 12 hours, TLC shows 2-amino-1, ammediol disappearance (developping agent: CHCl
3: sherwood oil=1: 1, ultraviolet 254nm colour developing or triketohydrindene hydrate colour developing).The reaction mixture concentrating under reduced pressure boils off toluene, and residue adds 20ml water, stirring at room 24 hours, filter washing, 65 ℃ of vacuum dryings of the solid that obtains, purification by silica gel column chromatography (eluent: CHCl3: sherwood oil=1: 1), obtain 0.6g (56%) title compound, be white solid.Mp:176-178 ℃ of .FAB-MS (m/e): 357[M]
+.
1HNMR (CDCl
3): δ/ppm=3.882 (m, J=5.0Hz, 2H), 3.972 (m, J=4.2Hz, 1H), 4.051 (m, J=3.5Hz, 2H), 5.660 (s, 2H), 7.638 (q, J=12.6Hz, 4H), 8.157 (m, J=7.0Hz, 4H).
13CNMR (CDCl
3): δ/ppm=62.544,70.464,95.618,123.714,127.925,146.518,148.199. ultimate analysis (C
17H
15N
3O
6) calculated value C57.14, H4.23, N11.76;
Embodiment 21. (2S, 4R, 5R)-2-substituting group phenyl-5-amino-4-methyl isophthalic acid, the logical method of the preparation of 3-dioxane adds 3mmol (2R in the 50ml reaction flask, 3R)-2-amino-1,3-butyleneglycol, 3.01mmol tosic acid and 10ml dehydrated alcohol mix the back stirring and dissolving, the solution decompression that obtains concentrates and boils off ethanol, add 3mmol substituting group phenyl aldehyde and 40ml chloroform in the residue, install water trap on reflux additional, reaction refluxes and was with water 8 hours, and TLC shows (2R, 3R)-2-amino-1,3 butylene glycol disappearance (developping agent: CHCl
3: MeOH=10: 1, ultraviolet 254nm colour developing or triketohydrindene hydrate colour developing), reaction mixture is evaporated to dried, residue 10ml acetic acid ethyl dissolution, stirring at room 1 hour.Filter, the ethyl acetate washing, the white solid that obtains is put and is mixed with the dissolving of 20ml methylene dichloride and with the solution of 3.5mmol sodium bicarbonate and 20ml water after drying under reduced pressure spends the night in the moisture eliminator, stirs 30 minutes, places layering, twice of 20ml dichloromethane extraction of water layer, the dichloromethane layer anhydrous sodium sulfate drying that merges filters washed with dichloromethane, filtrate subtracts the Asia and is concentrated into driedly, and residue is through purification by silica gel column chromatography (eluent: CHCl
3: MeOH=15: 1), obtain title compound.
Embodiment 22. (2S, 4R, 5R)-and 2-p-nitrophenyl-5-amino-4-methyl isophthalic acid, the preparation of 3-dioxane
According to the operation of embodiment 21, obtain 628mg (88%) title compound by 450mg (3.0mmol) paranitrobenzaldehyde, be colorless solid.Mp80-82 ℃ of .EI-MS (m/e): 239[M+H]
+.IR (KBr): υ/cm
-1=3370 (NH), 1610,1579,1540,1440 (aromatic C=C), 1370 (CH
3), 1190 and1055 (C-O-C), 810 (1,4-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.289 (d, J=6.3Hz, 3H), 1.593 (s, 2H), 2.594 (s, 1H), 4.090 (d, J=5.7Hz, 1H), 4.109 (d, J=5.7Hz, 1H), 4.145 (m, J=6.2Hz, 1H), 5.589 (s, 1H), 7.659 (d, J=8.4Hz, 2H), 8.198 (d, J=9.0Hz, 2H).
13CNMR (CDCl
3) δ/ppm=17.668,48.830,74.165,76.184,99.945,123.425,127.142,144.697,148.101.[α]
D 20=-8.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14N
2O
4) calculated value C55.45, H5.92, N11.76; Measured value C55.36, H5.87, N11.67.
Embodiment 23. (2S, 4R, 5R)-and 2-m-nitro base-5-amino-4-methyl isophthalic acid, the preparation of 3-dioxane
According to the operation of embodiment 21, obtain 650mg (91%) title compound by 450mg (3.0mmol) m-nitrobenzaldehyde, be faint yellow solid .Mp50-52 ℃ .EI-MS (m/e): 239[M+H]
+.IR (KBr): υ/cm
-1=3360 (NH), 1610,1580,1540,1445 (aromatic C=C), 1360 (CH
3), 1190and1060 (C-O-C), 860,750,695 (1,3-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.298 (d, J=6.6Hz, 3H), 1.695 (s, 2H), 2.612 (s, 1H), 4.111 (m, J=2.7Hz, 2H), 4.181 (q, J=4.3Hz, 1H), 5.598 (s, 1H), 7.527 (t, J=8.0Hz, 1H), 7.820 (d, J=7.8Hz, 1H), 8.191 (d, J=8.4Hz, 1H), 8.361 (s, 1H).
13CNMR (CDCl
3) δ/ppm=17.685,48.830,74.082,76.135,99.887,121.480,123.722,129.252,132.277,140.180,148.117.[α]
D 20=-8.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14N
2O
4) calculated value C55.45, H5.92, N11.76; Measured value C55.56, H5.89, N11.69.
Embodiment 24. (2S, 4R, 5R)-and 2-rubigan-5-amino-4-methyl isophthalic acid, the preparation of 3-dioxane
According to the operation of embodiment 21, obtain 579mg (85%) title compound by 420mg (3.0mmol) 4-chloro-benzaldehyde, be colorless solid .Mp:45-46 ℃ .FAB-MS (m/e): 228.5[M+H]
+.IR (KBr): υ/cm
-1=3370 (NH), 1608,1580,1540,1445 (aromatic C=C), 1370 (CH
3), 1190and1065 (C-O-C), 825 (1,4-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.267 (d, J=6.6Hz, 3H), 1.668 (s, 2H), 2.575 (s, 1H), 4.052 (d, J=2.1Hz, 1H), 4.077 (d, J=5.7Hz, 1H), 4.119 (m, J=6.9Hz, 1H), 5.493 (s, 1H), 7.326 (t, J=4.1Hz, 2H), 7.407 (t, J=8.0Hz, 2H).
13CNMR (CDCl
3): δ/ppm=17.734,48.880,74.000,75.920,100.909 (OCHO), 127.488,128.436,134.683,136.768.[α]
D 20=-8.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14ClNO
2) calculated value C58.03, H6.20, N6.15;
Embodiment 25 (2S, 4R, 5R)-and 2-phenyl-5-amino-4-methyl isophthalic acid, the preparation of 3-dioxane
According to the operation of embodiment 21, obtain 464mg (85%) title compound by 308mg (3.0mmol) phenyl aldehyde, be weak yellow liquid .FAB-MS (m/e): 194[M+H]
+.IR (KBr): υ/cm
-1=3370 (NH), 1606,1580,1535,1440 (aromaticC=C), 1370 (CH3), 1180 and 1060 (C-O-C), 745,695 (monosubstitude).
1HNMR (CDCl
3): δ/ppm=1.237 (m, J=1.5Hz, 3H), 1.671 (s, 2H), 2.499 (s, 1H), 4.020 (d, J=4.5Hz, 2H), 4.081 (q, J=6.6Hz, 1H), 5.490 (s, 1H), 7.330 (m, J=3.9Hz, 3H), 7.472 (q, J=2.7Hz, 2H).
13CNMR (CDCl
3) δ/ppm=17.611,48.764,73.868,75.698,101.560,125.865,128.123,128.757,136.153.[α]
D 20=-8.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
15NO
2) calculated value C68.37, H7.82, N7.25;
Embodiment 26 (2S, 4R, 5R)-and 2-p-methylphenyl-5-amino-4-methyl isophthalic acid, the preparation of 3-dioxane
According to the operation of embodiment 21, obtain 466mg (75%) title compound by 360mg (3.0mmol) p-tolyl aldehyde, be colorless solid.Mp:63-64 ℃ of .FAB-MS (m/e): 207[M]
+.IR (KBr): υ/cm
-1=3380 (NH), 1610,1580,1535,1440 (aromaticC=C), 1375 (CH
3), 1190 and1065 (C-O-C), 800 (1,4-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.257 (d, J=6.6Hz, 3H), 1.649 (s, 2H), 2.318 (s, 3H), 2.538 (s, 1H), 4.040 (m, J=2.0Hz, 1H), 4.084 (m, J=2.2Hz, 1H), 4.119 (d, J=1.5Hz, 1H), 5.487 (s, 1H), 7.154 (d, J=8.1Hz, 2H), 7.362 (d, J=8.4Hz, 2H).
13CNMR (CDCl
3): δ/ppm=17.759,21.212,48.978,73.967,75.788,101.783,125.865,128.914,135.466,138.656.[α]
D 20=-8.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
12H
17NO
2) calculated value C69.54, H8.27, N6.76;
Embodiment 27 and 27 '. (2S, 5S)-2-substituting group phenyl-5-amino-1, the 3-cyclic heptane dioxide and (2R, 5S)-2-substituting group phenyl-5-amino-1, the preparation of 3-cyclic heptane dioxide
315mg in the 50ml reaction flask (3mmol) (2S)-2-amino-1, concentrating under reduced pressure boils off ethanol behind 4-butyleneglycol, 3.01mmol tosic acid and the 10ml dehydrated alcohol mixed dissolution, residue mixes with 3.0mmol substituting group phenyl aldehyde and 40ml chloroform, on reflux, install water trap additional, reaction refluxes and was with water 8 hours, TLC shows (2S)-2-amino-1,4-butyleneglycol disappearance (developping agent: CHCl
3: MeOH=10: 1, ultraviolet 254nm colour developing or triketohydrindene hydrate colour developing), reaction mixture is evaporated to dried, residue 10ml acetic acid ethyl dissolution, stirring at room 12 hours, filter, the ethyl acetate washing, the gained solid is put in the moisture eliminator and is dissolved with the 20ml methylene dichloride behind the drying under reduced pressure. and the solution that obtains mixes with 3.5mmol sodium bicarbonate and 20ml water, stirred 30 minutes, place layering, water layer 20ml dichloromethane extraction twice, the dichloromethane layer anhydrous sodium sulfate drying of merging, filter, washed with dichloromethane, filtrate decompression is concentrated into dried, and residue separates (eluent: CHCl through the silica gel thin-layer preparative chromatography
3: MeOH=15: 1), obtain respectively (2S, 5S) and (2R, 5S) isomer.
Embodiment 28 and 28 '. (2S, 5S)-2-p-nitrophenyl-5-amino-1, the 3-cyclic heptane dioxide and (2R, 5S)-2-p-nitrophenyl-5-amino-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 21, obtain 206mg (30%) (2S by 450mg (3.0mmol) paranitrobenzaldehyde, 5S)-2-p-nitrophenyl-5-amino-1,3-cyclic heptane dioxide and 144mg (21%) (2R, 5S)-2-p-nitrophenyl-5-amino-1, the 3-cyclic heptane dioxide is faint yellow solid.
(2S, 5S)-2-p-nitrophenyl-5-amino-1, Mp76-78 ℃ of .FAB-MS of 3-cyclic heptane dioxide (m/e): 239[M+H]
+.IR (KBr): υ/cm
-1=3380 (NH), 1610,1575,1540,1445 (aromatic C=C), 1190and1063 (C-O-C), 825 (1,4-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.685 (m, J=3.9Hz, 1H), 1.821 (s, 2H), 1.989 (m, J=4.5Hz, 1H), 3.153 (s, 1H), 3.610 (q, J=6.0Hz, 1H), 3.862 (m, J=4.3Hz, 3H), 5.793 (s, 1H), 7.665 (d, J=8.5Hz, 2H), 8.216 (d, J=9.0Hz, 2H).
13CNMR (CDCl
3) δ/ppm=38.688,49.879,61.269,69.684,99.276 (O
CHO), 123.383,127.465,146.407,147.886.[α]
D 20=+8.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14N
2O
4) calculated value C55.46, H5.92, N11.76; (2R, 5S)-2-p-nitrophenyl-5-amino-1, Mp:61-63 ℃ of .FAB-MS of 3-cyclic heptane dioxide (m/e) 239[M+H]
+.IR (KBr): υ/cm
-1=3378 (NH), 1610,1580,1540,1442 (aromatic C=C), 1193and1062 (C-O-C), 815 (1,4-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.401 (s, 2H), 1.621 (m, J=3.5Hz, 1H), 2.048 (m, J=2.4Hz, 1H), 3.160 (s, 1H), 3.702 (q, J=5.8Hz, 1H), 3.776 (m, J=3.4Hz, 2H), 3.912 (m, J=3.2Hz, 1H), 5.764 (s, 1H), 7.679 (d, J=8.0Hz, 2H), 8.221 (d, J=9.0Hz, 2H).
13CNMR (CDCl
3) δ/ppm=38.987,50.462,62.040,70.574,99.652,123.651,127.705,146.695,147.886.[α]
D 20=-16.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14N
2O
4) calculated value C55.46, H5.92, N11.76;
Embodiment 29 and 29 '. (2S, 5S)-2-m-nitro base-5-amino-1, the 3-cyclic heptane dioxide and (2R, 5S)-2-m-nitro base-5-amino-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 21, obtain 157mg (23%) (2S by 540mg (3.0mmol) m-nitrobenzaldehyde, 5S)-2-m-nitro base-5-amino-1,3-cyclic heptane dioxide and 104mg (15%) (2R, 5S)-2-m-nitro base-5-amino-1, the 3-cyclic heptane dioxide is faint yellow oily thing.
(2S, 5S)-2-m-nitro base-5-amino-1,3-cyclic heptane dioxide FAB-MS (m/e): 239[M+H]
+.IR (KBr): υ/cm
-1=3380 (NH), 1610,1570,1540,1441 (aromaticC=C), 1192 and1060 (C-O-C), 875,762,695 (1,3-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.253 (s, 1H), 1.674 (s, 2H), 1.976 (d, J=4.8Hz, 1H), 3.142 (s, 1H), 3.604 (q, J=6.2Hz, 2H), 3.855 (q, J=4.3Hz, 2H), 5.796 (s, 1H), 7.546 (t, J=8.0Hz, 1H), 7.822 (d, J=7.5Hz, 1H), 8.194 (d, J=7.8Hz .1H), 8.374 (s, 1H).
13CNMR (CDCl
3) δ/ppm=38.627,49.844,61.160,69.525,99.071,121.719,123.318,129.194,132.639,141.730,148.191.[α]
D 20=+12.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14N
2O
4) calculated value C55.46, H5.92, N11.76;
(2R, 5S)-2-m-nitro base-5-amino-1,3-cyclic heptane dioxide EI-MS (m/e): 239[M+H]
+.IR (KBr): υ/cm
-1=3378 (NH), 1610,1575,1540,1440 (aromatic C=C), 1185 and 1060 (C-O-C), 870,765,695 (1,3-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.456 (s, 2H), 1.609 (m, J=5.1Hz, 1H), 1.933 (d, J=5.1Hz, 1H), 3.096 (s, 1H), 3.757 (m, J=5.2Hz, 4H), 5.739 (d, J=6.0Hz, 1H), 7.505 (m, J=3.5Hz, 1H), 7.789 (q, J=4.3Hz, 1H), 8.145 (d, J=8.4Hz, 1H), 8.330 (d, J=1.8Hz, 1H).
13CNMR (CDCl
3) δ/ppm=38.096,50.287,62.631,69.870,98.593,120.800,123.142,129.863,132.953,141.985,147.638.[α]
D 20=-6.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14N
2O
4) calculated value C55.46, H5.92, N11.76;
Embodiment 30 and 30 '. (2S, 5S)-2-rubigan-5-amino-1, the 3-cyclic heptane dioxide and (2R, 5S)-2-rubigan-5-amino-1, the preparation of 3-cyclic heptane dioxide
According to the operation of embodiment 21, by 420mg (3.0mmol) 4-chloro-benzaldehyde obtain 198mg (29%) (2S, 5S)-2-rubigan-5-amino-1,3-cyclic heptane dioxide and 232mg (34%) (2R, 5S)-and 2-rubigan-5-amino-1, the 3-cyclic heptane dioxide is faint yellow solid.
(2S, 5S)-2-rubigan-5-amino-1, Mp48-49 ℃ of .EI-MS of 3-cyclic heptane dioxide (m/e): 227[M]
+.IR (KBr): υ/cm
-1=3370 (NH), 1610,1570,1540,1441 (aromaticC=C), 1185and1063 (C-O-C), 815 (1,4-disubstitude).
1HNMR (CDCl
3): δ/ppm=1.457 (s, 2H), 1.615 (m, J=3.3Hz, 1H), 1.964 (m, J=3.7Hz, 1H), 3.089 (s, 1H), 3.543 (q, J=6.0Hz, 1H), 3.818 (m, J=3.1Hz, 3H), 5.710 (s, 1H), 7.326 (m, J=2.6Hz, 2H), 7.415 (d, J=8.5Hz, 2H).
13CNMR (CDCl
3) δ/ppm=38.688,49.879,61.269,69.684,99.276,123.383,127.465,146.407,147.886 .[α]
D 20=+8.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14ClNO
2) calculated value C58.03, H6.20, N6.15;
(2R, 5S)-2-rubigan-5-amino-1, Mp56-57 ℃ of .EI-MS of 3-cyclic heptane dioxide (m/e): 227[M]
+.IR (KBr): υ/cm
-1=3375 (NH), 1610,1568,1545,1441 (aromaticC=C), 1180and1062 (C-O-C), 818 (1,4-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.469 (s, 2H), 1.602 (m, J=3.5Hz, 1H), 2.023 (m, J=2.4Hz, 1H), 3.134 (s, 1H), 3.724 (m, J=4.0Hz, 3H), 3.894 (m, J=3.2Hz, 1H), 5.695 (s, 1H), 7.334 (m, J=2.6Hz, 2H), 7.431 (d, J=8.0Hz, 2H).
13CNMR (CDCl
3) δ/ppm=38.779,50.268,61.376,69.966,99.856,127.762,128.312,134.117,138.084.[α]
D 20=-6.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
11H
14ClNO
2) calculated value C58.03, H6.20, N6.15;
Embodiment 31 (cis)-2-p-nitrophenyl-5-(Norleucyl amino)-1; the preparation of 3-dioxane is according to the operation of embodiment 7; by 55mg (0.25mmol) (cis)-2-p-nitrophenyl-5-amino-1; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 64mg (90%%) title compound, is faint yellow solid.Mp128-131 ℃ of .EI-MS (m/e): 282[M+H]
+.IR (KBr): υ/cm
-1=3370and3240 (NH), 1640 (C=O), 1605,1575,1540,1443 (aromatic C=C), 1190and1067 (C-O-C), 800 (1,4-disubstitude).
1HNMR (CDCl
3) 1.982 (s, 2H), 3.459 (s, 1H), 3.731 (d, J=5.1Hz, 1H), 3.847 (d, J=5.1Hz, 1H), 4.045 (d, J=9.9Hz, 2H), 4.168 (t, J=10.2Hz, 2H), 5.581 (d, J=27.0Hz, 1H), 7.635 (q, J=8.5Hz, 2H), 8.204 (m, J=5.6Hz, 2H).
13CNMR (CDCl
3) 43.226,44.660,70.786,100.011,123.475,127.068,144.194,148.241,172.446. ultimate analysis (C
12H
15N
3O
5) calculated value C51.24, H5.38, N14.94;
Embodiment 32 (cis)-2-m-nitro base-5-(Norleucyl amino)-1, the preparation of 3-dioxane
According to the operation of embodiment 7, by 55mg (0.25mmol) (cis)-2-m-nitro base-5-amino-1,3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 61mg (85%%) title compound, is faint yellow solid.Mp95-97 ℃ of .EI-MS (m/e): 282[M+H]
+.IR (KBr): υ/cm
-1=3370and 3251 (NH), 1640 (C=O), 1602,1575,1535,1440 (aromatic C=C), 1190and1065 (C-O-C), 860,765,690 (1,3-disubstitude).
1HNMR (CDCl
3) 2.418 (s, 2H), 3.476 (s, 1H), 4.059 (d, J=9.9Hz, 2H), 4.184 (t, J=12.6Hz, 4H), 5.635 (s, 1H), 7.563 (t, J=8.0Hz, 1H), 7.826 (d, J=7.8Hz, 1H), 8.226 (t, J=4.1Hz, 2H), 8.389 (s, 1H).
13CNMR (CDCl
3) 43.267,44.388,70.670,99.829,121.307,123.862,129.293,132.194,139.744,148.109,, 172.018 (CONH). ultimate analysis (C
12H
15N
3O
5) calculated value C51.24, H5.38, N14.94;
Embodiment 33 (cis)-2-rubigan-5-(Norleucyl amino)-1, the preparation of 3-dioxane
According to the operation of embodiment 7, by 35mg (0.25mmol) (cis)-2-rubigan-5-amino-1,3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 68mg (89%) title compound, is the off-white color solid.Mp99-102 ℃ of .EI-MS (m/e) 271[M+H]
+.IR (KBr): υ/cm
-1=3375and3240 (NH), 1638 (C=O), 1602,1570,1540,1440 (aromatic C=C), 1190and1065 (C-O-C), 815 (1,4-disubstitude).
1HNMR (CDCl
3) 1.623 (s, 2H), 3.416 (s, 2H), 3.898 (d, J=5.1Hz, 1H), 4.033 (d, J=10.5Hz, 2H), 4.153 (t, J=6.5Hz, 2H), 5.550 (s, 1H), 7.362 (m, J=2.1Hz, 2H), 7.427 (t, J=7.4Hz, 2H), 8.188 (s, 1H).
13CNMR (CDCl
3): 43.226,44.709,70.687,100.925,127.365,128.494,134.914,136.364,172.438. ultimate analysis (C
12H
15ClN
2O
3) calculated value C53.24,5.5810.35;
Embodiment 34 (cis)-2-phenyl-5-(Norleucyl amino)-1, the preparation of 3-dioxane
Operation according to embodiment 7; by 45mg (0.25mmol) (cis)-2-phenyl-5-amino-1; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 42mg (85%) title compound, is colorless solid .Mp96-98 ℃ .EI-MS (m/e) 237[M+1]
+.IR (KBr): υ/cm
-1=3373 and 3240 (NH), 1620 (C=O), 1601,1570,1540,1443 (aromatic C=C), 1190and1060 (C-O-C), 740and698 (monosubstitude).
1HNMR (CDCl
3) 1.596 (s, 2H), 3.411 (s, 2H), 3.644 (d, J=4.8Hz, 1H), 4.113 (d, J=1.5Hz, 2H), 4.165 (t, J=2.2Hz, 2H), 5.579 (s, 1H), 7.390 (m, J=2.5Hz, 3H), 7.494 (m, J=2.5Hz, 2H), 8.209 (s, 1H).
13CNMR (CDCl3) 43.316,44.742,70.712,101.774,125.881,128.345,129.137,137.848,172.446. ultimate analysis (C
12H
16N
2O
3) calculated value C61.00, H6.83, N11.86;
Embodiment 35 (cis)-2-p-methylphenyl-5-(Norleucyl amino)-1, the preparation of 3-dioxane
Operation according to embodiment 7; by 89mg (0.25mmol) (cis)-2-p-methylphenyl-5-amino-1; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 57mg (90%) title compound, is colorless solid .Mp105-108 ℃ .EI-MS (m/e) 250[M]
+.IR (KBr): υ/cm
-1=3370 and3230 (NH), 1639 (C=O), 1605,1570,1540,1442 (aromatic C=C), 1185 and 1065 (C-O-C), 805 (1,4-disubstitude).
1HNMR (CDCl
3) 1.614 (s, 2H), 2.354 (s, 3H), 3.407 (s, 1H), 3.738 (d, J=10.8Hz, 1H), 3.900 (s, 1H), 4.030 (t, J=6.0Hz, 2H), 4.141 (q, J=9.6Hz, 2H), 5.544 (s, 1H), 7.191 (d, J=7.8Hz, 2H), 7.382 (d, J=8.1Hz, 2H), 8.184 (s, H).
13CNMR (CDCl
3) 21.262,43.341,44.767,70.679,101.914,125.774,128.988,135.071,138.961,172.455. ultimate analysis (C
13H
18N
2O
3) calculated value C62.38, H7.25, N11.19;
Embodiment 36 (2S, 4R, 5R)-and 2-p-nitrophenyl-5-(Norleucyl amino)-4-methyl isophthalic acid, the preparation of 3-dioxane
Operation according to embodiment 7; by 59.5mg (0.25mmol) (2S; 4R; 5R)-2-p-nitrophenyl-5-amino-4-methyl isophthalic acid; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 57mg (95%) title compound, is faint yellow solid .Mp136-140 ℃ .EI-MS (m/e) 296[M+H]
+.IR (KBr): υ/cm
-1=3375 and 3240 (NH), 1640 (C=O), 1605,1572,1540,1443 (aromatic C=C), 1378 (CH
3), 1190and1065 (C-O-C), 806 (1,4-disubstitude).
1HNMR (CDCl
3): 1.223 (d, J=6.3Hz, 3H), 2.331 (s, 2H), 3.470 (s, 1H), 3.894 (d, J=4.5Hz, 2H), 4.024 (q, J=10.5Hz, 2H), 4.197 (m, J=3.9Hz, 1H), 6.117 (s, 1H), 7.646 (q, J=7.3Hz, 2H), 7.939 (d, J=9.0Hz, 1H), 8.205 (d, J=8.7Hz, 2H).
13CNMR (CDCl3) 17.611,44.363,46.267 (CONH
CH), 71.668,75.401,100.019,123.475,127.192,144.268,148.208,172.282.[α]
D 20=-34.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
13H
17N
3O
5) calculated value C52.88, H5.80, N14.23;
Embodiment 37 (2S, 4R, 5R)-and 2-m-nitro base-5-(Norleucyl amino)-4-methyl isophthalic acid, the preparation of 3-dioxane
Operation according to embodiment 7; by 59.5mg (0.25mmol) (2S; 4R; 5R)-2-m-nitro base-5-amino-4-methyl isophthalic acid; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 63mg (85%) title compound, is faint yellow solid .Mp78-81 ℃ .EI-MS (m/e) 296[M+H]
+.IR (KBr): υ/cm
-1=3375 and 3240 (NH), 1639 (C=O), 1602,1570,1535,1440 (aromatic C=C), 1375 (CH
3), 1190 and 1060 (C-O-C), 860,763,690 (1,3-disubstitude).
1HNMR (CDCl
3): 1.256 (d, J=6.3Hz, 3H), 2.330 (s, 2H), 3.494 (s, 2H), 3.941 (d, J=5.4Hz, 1H), 4.070 (m, J=11.3Hz, 2H), 4.224 (t, J=6.9Hz, 1H), 5.671 (s, 1H), 7.549 (m, J=5.2Hz, 1H), 7.842 (q, J=7.8Hz, 1H), 7.990 (d, J=9.6Hz, 1H), 8.220 (d, J=7.5Hz, 1H), 8.396 (s, 1H)
13CNMR (CDCl3) 17.611,44.643,46.201,71.659,75.393,99.854,121.389,123.845,129.293,132.260,139.851,148.150,172.858.[α]
D 20=-34.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
13H
17N
3O
5) calculated value C52.88, H5.80, N14.23;
Embodiment 38 (2S, 4R, 5R)-and 2-rubigan-5-(Norleucyl amino)-4-methyl isophthalic acid, the preparation of 3-dioxane
Operation according to embodiment 7; by 57mg (0.25mmol) (2S, 4R, 5R)-2-rubigan-5-amino-4-methyl isophthalic acid; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 58mg (82%) title compound, is faint yellow oily thing .EI-MS (m/e) 285[M+H]
+.IR (KBr): υ/cm
-1=3375 and3239 (NH), 1629 (C=O), 1602,1575,1540,1440 (aromatic C=C), 1375 (CH
3), 1190 and1060 (C-O-C), 810 (1,4-disubstitude).
1HNMR (CDCl
3): 1.144 (d, J=6.3Hz, 3H), 1.210 (s, 2H), 3.604 (s, 2H), 3.923 (d, J=11.9Hz, 1H), 4.022 (q, J=11.7Hz, 2H), 4.095 (q, J=11.1Hz, 1H), 5.502 (s, 1H), 7.389 (m, J=10.1Hz, 4H), 7.905 (d, J=9.3Hz, 1H).
13CNMR (CDCl3) 17.636,44.605,46.547,71.445,75.137,100.909,127.661,128.469,134.832,136.422,170.831.[α]
D 20=-36.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
13H
17ClN
2O
3) calculated value C54.84, H6.02, N9.84;
Embodiment 39 (2S, 4R, 5R)-and 2-phenyl-5-(Norleucyl amino)-4-methyl isophthalic acid, the preparation of 3-dioxane
Operation according to embodiment 7; by 49mg (0.25mmol) (2S, 4R, 5R)-2-phenyl-5-amino-4-methyl isophthalic acid; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 58mg (91%) title compound, is faint yellow oily thing .EI-MS (m/e) 251[M+H]
+.IR (KBr): υ/cm
-1=3370 and3237 (NH), 1620 (C=O), 1601,1565,1540,1445 (aromatic C=C), 1374 (CH
3), 1190 and1066 (C-O-C), 755 and 690 (monosubstitude).
1HNMR (CDCl
3) 1.221 (d, J=6.6Hz, 3H), 2.765 (s, 2H), 3.483 (s, 2H), 3.927 (q, J=11.6Hz, 1H), 4.097 (t, J=1.8Hz, 2H), 4.167 (m, J=4.7Hz, 1H), 5.573 (s, 1H), 7.386 (m, J=3.3Hz, 3H), 7.513 (q, J=3.2Hz, 2H), 7.945 (d, J=9.3Hz, 1H).
13CNMR (CDCl3) 17.685,44.207,46.481,71.503,75.088,101.725,126.038,128.321,129.062,137.914,172.282.[α]
D 20=-42.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
13H
18N
2O
3) calculated value C62.38, H7.25, N11.19;
Embodiment 40 (2S, 4R, 5R)-and 2-p-methylphenyl-5-(Norleucyl amino)-4-methyl isophthalic acid, the preparation of 3-dioxane
Operation according to embodiment 7; by 52mg (0.25mmol) (2S, 4R, 5R)-2-p-methylphenyl-5-amino-4-methyl isophthalic acid; 3-dioxane and 43mg (0.25mmol) N-TFA base glycine obtains 59mg (89%) title compound, is faint yellow oily thing.EI-MS (m/e): 265[M+H]
+.IR (KBr): υ/cm
-1=3370and 3240 (NH), 1639 (C=O), 1607,1570,1538,1442 (aromatic C=C), 1365 (CH
3), 1189and1065 (C-O-C), 815 (1,4-disubstitude).
1HNMR (CDCl
3) 1.212 (d, J=6.3Hz, 3H), 2.041 (s, 2H), (2.343 s, 3), 3.426 (s, 2H), 3.938 (d, J=1.5Hz, 1H), 3.970 (d, J=1.2Hz, 2H), 4.146 (m, J=4.0Hz, 1H), 5.552 (s, 1H), 7.183 (d, J=8.1Hz, 2H), 7.388 (q, J=8.1Hz, 2H), 7.959 (d, J=9.3Hz, 1H).
13CNMR (CDCl
3) 17.644,21.179,44.511,46.341,71.445,74.973,101.708,125.823,128.906,135.087,138.804,172.545.[α]
D 20=-34.0 ° of (C=1.0, CHCl
3). ultimate analysis (C
14H
20N
2O
3) calculated value C63.62, H7.63, N10.60;
Embodiment 41 (2S, 5S)-2-p-nitrophenyl-5-(Norleucyl amino)-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 7; by 59.5mg (0.25mmol) (2S; 5S)-2-p-nitrophenyl-5-amino-1; 3-cyclic heptane dioxide and 43mg (0.25mmol) N-TFA base glycine obtains 51mg (68%) title compound, is faint yellow solid .Mp135-138 ℃ .EI-MS (m/e) 295[M]
+.IR (KBr): υ/cm
-1=3370and 3240 (NH), 1635 (C=O), 1605,1572,1540,1443 (aromaticC=C), 1180 and1067 (C-O-C), 803 (1,4-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.557 (s, 2H), 1.883 (m, J=2.4Hz, 1H), 1.976 (m, J=4.7Hz, 1H), 3.403 (s, 2H), 3.610 (m, J=2.6Hz, 1H), 3.875 (m, J=5.1Hz, 2H), 3.991 (m, J=4.0Hz, 1H), 4.202 (q, J=4.0Hz, 1H), 5.819 (s, 1H), 7.681 (d, J=8.5Hz, 2H), 7.882 (d, J=7.5Hz, 1H), 8.227 (d, J=9.0Hz, 2H).
13CNMR (CDCl
3) δ/ppm=35.438,44.821,46.904,62.589,64.924,99.124,123.406,127.480,145.927,147.979,172.063.[α]
D 20=35.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
13H
17N
3O
5) calculated value C52.88, H5.80, N14.23;
Embodiment 42 (2R, 5S)-2-p-nitrophenyl-5-(Norleucyl amino)-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 7; by 59.5mg (0.25mmol) (2R; 5S)-2-p-nitrophenyl-5-amino-1,3-cyclic heptane dioxide and 43mg (0.25mmol) N-TFA base glycine obtains 59mg (79%) title compound, is faint yellow oily thing .EI-MS (m/e) 295[M]
+.IR (KBr): υ/cm
-1=3375 and3240 (NH), 1635 (C=O), 1605,1571,1540,1437 (aromatic C=C), 1190 and 1065 (C-O-C), 815 (1,4-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.552 (s, 2H), 1.848 (m, J=2.6Hz, 1H), 2.054 (m, J=3.2Hz, 1H), 3.354 (d, J=3.5Hz, 2H), 3.758 (m, J=4.4Hz, 2H), 3.924 (m, J=2.4Hz, 1H), 3.994 (m, J=4.7Hz, 1H), 4.307 (m, J=2.2Hz, 1H), 5.796 (s, 1H), 7.700 (d, J=9.0Hz, 2H), 7.805 (d, J=6.5Hz, 1H), 8.234 (d, J=9.0Hz, 2H).
13CNMR (CDCl
3) δ/ppm=35.217,44.699,47.240,60.972,68.562,99.650,123.437,127.427,146.064,147.979,172.017.[α]
D 20=-39.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
13H
17N
3O
5) calculated value C52.88, H5.80, N14.23;
Embodiment 43 (2S, 5S)-2-m-nitro base-5-(Norleucyl amino)-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 7; by 59.5mg (0.25mmol) (2S; 5S)-2-m-nitro base-5-amino-1,3-cyclic heptane dioxide and 43mg (0.25mmol) N-TFA base glycine obtains 59mg (79%) title compound, is faint yellow oily thing .EI-MS (m/e) 295[M]
+.IR (KBr): υ/cm
-1=3370 and3215 (NH), 1640 (C=O), 1602,1570,1535,1440 (aromatic C=C), 1190 and 1063 (C-O-C), 860,775,690 (1,3-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.888 (d, J=14.5Hz, 1H), 1.977 (m, J=5.0Hz, 1H), 2.140 (s, 2H), 3.450 (s, 2H), 3.619 (q, J=3.5Hz, 1H), 3.839 (q, J=1.5Hz, 1H), 3.897 (t, J=10.3Hz, 1H), 3.997 (m, J=3.9Hz, 1H), 4.203 (q, J=3.8Hz, 1H), 5.819 (s, 1H), 7.550 (t, J=8.3Hz, 1H), 7.829 (d, J=7.5Hz, 1H), 7.927 (d, J=8.5Hz, 1H), 8.192 (q, J=1.0Hz, 1H), 8.364 (s, 1H).
13CNMR (CDC1
3) δ/ppm=35.43,44.814,46.912,62.620,64.771,98.933,121.713,123.399,129.242,132.561,141.326,148.261,172.025.[α]
D 20=20.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
13H
17N
3O
5) calculated value C52.88, H5.80, N14.23;
Embodiment 44 (2R, 5S)-2-m-nitro base-5-(Norleucyl amino)-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 7; by 59.5mg (0.25mmol) (2R; 5S)-2-m-nitro base-5-amino-1,3-cyclic heptane dioxide and 43mg (0.25mmol) N-TFA base glycine obtains 63mg (85%) title compound, is faint yellow oily thing .EI-MS (m/e): 295[M]
+.IR (KBr): υ/cmu
-1=3370 and3195 (NH), 1630 (C=O), 1602,1575,1530,1438 (aromatic C=C), 1190 and 1065 (C-O-C), 860,765,698 (1,3-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.850 (t, J=6.8Hz, 1H), 2.042 (m, J=4.5Hz, 1H), 2.354 (s, 2H), 3.408 (d, J=4.0Hz, 2H), 3.759 (m, J=4.1Hz, 2H), 3.952 (m, J=5.9Hz, 2H), 4.301 (d, J=1.5Hz, 1H), 5.8785 (s, 1H), 7.556 (t, J=8.0Hz, 1H), 7.824 (d, J=7.5Hz, 1H), 7.905 (d, J=8.5Hz, 1H), 8.190 (q, J=1.5Hz, 1H), 8.409 (s, 1H).
13CNMR (CDCl
3) δ/ppm=35.079,44.371,47.408,60.918,68.379,99.436,121.560,123.406,129.281,132.675,141.388,148.238,171.529.[α]
D 20-24.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
13H
17N
3O
5) calculated value C52.88, H5.80, N14.23;
Embodiment 45 (2S, 5S)-2-rubigan-5-(Norleucyl amino)-1, the preparation of 3-cyclic heptane dioxide
Operation according to embodiment 7; by 57mg (0.25mmol) (2S; 5S)-2-rubigan-5-amino-1,3-cyclic heptane dioxide and 43mg (0.25mmol) N-TFA base glycine obtains 52mg (73%) title compound, is faint yellow solid .Mp120-124 ℃ .EI-MS (m/e) 284[M]
+.IR (KBr): υ/cm
-1=3378 and3240 (NH), 1620 (C=O), 1602,1578,1540,1430 (aromatic C=C), 1190 and 1063 (C-O-C), 815 (1,4-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.548 (s, 2H), 1.855 (d, J=14.5Hz, 1H), 1.951 (t, J=12.0Hz, 1H), 3.393 (s, 2H), 3.541 (t, J=5.8Hz, 1H), 3.843 (d, J=11.5Hz, 2H), 3.966 (d, J=12.0Hz, 1H), 4.202 (s, 1H), 5.744 (s, 1H), 7.338 (d, J=8.0Hz, 2H), 7.424 (d, J=8.0Hz, 2H), 7.850 (s, 1H).
13CNMR (CDCl
3) δ/ppm=35.537,44.860,46.942,62.383,64.420,99.597,127.801,128.357,134.285,137.604,172.017.[α]
D 20=36.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
13H
17ClN
2O
3) calculated value C54.84, H6.02, N9.84;
Embodiment 46 (2R, 5S)-2-rubigan-5-(Norleucyl amino)-1, the preparation of 3-cyclic heptane dioxide
According to the operation of embodiment 7, (2R, 5S)-2-rubigan-5-amino-1,3-cyclic heptane dioxide and 43mg (0.25mmol) N-TFA base glycine obtains 54mg (75%) title compound, is colorless solid by 57mg (0.25mmol).Mp107-109 ℃ of .EI-MS (m/e) 284[M]
+.IR (KBr): υ/cm
-1=3375 and3240 (NH), 1640 (C=O), 1602,1575,1540,1428 (aromatic C=C), 1190 and 1055 (C-O-C), 826 (1,4-disubstitude).
1HNMR (CDCl
3) δ/ppm=1.482 (s, 2H), 1.820 (q, J=4.7Hz, 1H), 2.026 (m, J=4.6Hz, 1H), 3.350 (d, J=2.5Hz, 2H), 3.718 (m, J=4.7Hz, 2H), 3.932 (m, J=6.7Hz, 2H), 4.299 (m, J=2.9Hz, 1H), 5.720 (s, 1H), 7.347 (d, J=8.0Hz, 2H), 7.450 (d, J=8.5Hz, 2H), 7.791 (d, J=6.0Hz, 1H).
13CNMR (CDCl
3) δ/ppm=35.209,44.692,47.232,60.445,68.204,100.054,127.686,128.304,134.163,137.726,171.956.[α]
D 20=-38.0 ° of (c=1.0, CHCl
3). ultimate analysis (C
13H
17ClN
2O
3) calculated value C54.84, H6.02, N9.84; .
Embodiment 47. is of the present invention 1, the anti-inflammatory activity of 3-dioxygen cycle target compound
With acetylsalicylic acid or of the present invention 1,3-dioxygen cycle target compound is pressed 30mg/kg dosage physiological saline wiring solution-forming, and the solution final concentration is 3mg/ml.Male ICR mouse about body weight 18-22g is divided into the blank group at random, positive controls and medication group, every group of 11 mouse, gastric infusion respectively, the left ear gabarit of single administration past small white mouse after 30 minutes is coated with dimethylbenzene (0.02ml), after 4 hours the dislocation of small white mouse cervical vertebra is put to death.Get circular auricle at two ears with the punch tool of diameter 9mm respectively, weigh, the weight difference of obtaining two circle auricles is as the swelling degree.The weight difference of two circle auricles is listed table 1 in, and data are learned processing by statistics, and P＜0.05 has been considered as significant difference.The data of dose-effect relationship are listed table 2 in, learn by statistics and handle, and P＜0.05 has been considered as significant difference.
Table 1 the present invention 1, the anti-inflammatory activity of 3-dioxygen cycle target compound
| Compound | Mean±SD(mg) | Compound | Mean±SD(mg) |
| Physiological saline | 3.23±0.74 | Embodiment 24 | 3.74±1.29 |
| Acetylsalicylic acid | 1.85±0.72 b) | |
2.54±1.00 |
| Embodiment 7 | 1.10±0.47 b，c) | Embodiment 31 | 2.14±0.83 a) |
| Embodiment 8 | 2.21±0.50 b) | Embodiment 32 | 1.11±0.42 b，c) |
| Embodiment 9 | 1.21±0.28 b，c) | Embodiment 33 | 1.17±0.40 b，c) |
| Embodiment 9 ' | 1.85±0.54 b) | Embodiment 34 | 1.59±0.56 b) |
| |
1.25±0.46 b) | Embodiment 35 | 1.74±0.79 b) |
| Embodiment 12 | 2.31±0.92 a) | Embodiment 36 | 1.86±1.01 b) |
| |
1.84±0.73 b) | Embodiment 37 | 1.86±0.88 a) |
| Embodiment 16 | 1.35±0.51 b) | Embodiment 38 | 1.81±0.92 b) |
| Embodiment 17 | 1.12±0.57 b，c) | Embodiment 40 | 2.22±0.74 a) |
| Embodiment 18 | 1.51±0.53 b) | Embodiment 41 | 1.56±0.54 b) |
| Embodiment 19 | 1.56±0.21 b) | Embodiment 45 | 1.88±0.86 b) |
| Embodiment 22 | 0.67±0.52 b，d) | Embodiment 46 | 2.36±0.66 a) |
| Embodiment 23 | 1.20±0.42 b，c) |
N=11, dosage are 30mg/kg, a) with contrast ratio P＜0.05, b) with contrast ratio P＜0.01, c) with aspirin than P＜0.05, d) with aspirin than P＜0.01.
The dose-effect relationship research of table 2 The compounds of this invention
| Compound | Mean±SDmg | ||
| Dosage=6mg/kg | Dosage=15mg/kg | Dosage=30mg/kg | |
| Embodiment 9 | 2.23±0.61 | 2.01±0.49 | 1.21±0.28 d) |
| Embodiment 17 | 2.97±1.31 | 1.56±0.27 b) | 1.12±0.57 |
| Embodiment 22 | 2.48±0.51 | 1.22±0.50 b) | 0.67±0.52 c) |
| Embodiment 23 | 3.45±1.01 | 1.96±0.88 b) | 1.20±0.42 c) |
| Embodiment 36 | 2.65±0.78 | 1.52±0.36 b) | 1.11±0.42 c) |
N=11, a) with low dosage than P＜0.05, b) with low dosage than P＜0.01, c) with middle dosage than P＜0.05, d) with middle dosage than P＜0.01.
The preparation of embodiment 49.PKC
Immerse 1 liter of ice-cold Buffer A (20mM Tris-HCl immediately getting about 500g fresh bovine brain below 4 ℃, pH7.5,3mM EDTA, the 50mM mercaptoethanol, 1mM PMSF, 10mg/L Trypsin inhibitor,Trasylol) in, the film on flush away surface and vascular tissue, be dipped into again among 2.5 liters of BufferA, and frozen centrifugation after the quick homogenate (9000 * g, 20min).Supernatant liquor slowly adds solid ammonium sulfate after glass fiber filters, make the concentration of ammonium sulfate reach 21% (weight/volume) after 1 hour, stirred 1 hour, frozen centrifugation (9000 * g, 20min).The supernatant liquor that obtains slowly adds solid ammonium sulfate again, makes ammonium sulfate concentrations reach 45% after 1 hour, stirred 1 hour, frozen centrifugation (9000 * g, 20min).Precipitation is dissolved among the 150ml Buffer B (20mM Tris-HCl, pH7.5,2mM EDTA, 50mM mercaptoethanol), and the dialysis tubing of packing into was then put among the Buffer B of 20 times of volumes dialysis 3 days, changed dialyzate every day.(barium chloride solution with 10% detects) frozen centrifugation behind the solution sulfate radical-free ion of dialysis tubing (30,000 * g, 30min).Get the 1ml supernatant liquor, survey protein content after diluting 50 times, contain protein 3.2g approximately, the residue supernatant liquor is added to by on the Buffer B equilibrated DEAE-Mierocrystalline cellulose chromatography post, with 2.5 liters of washings of Buffer B, flow velocity is 125ml/h, again with 4 liters of Buffer B gradient elutions that contain 0-0.3M sodium-chlor earlier, flow velocity is 60ml/h, collect effluent liquid, the about 50ml of every pipe measures the protein content and the PKC activity of each pipe, the effluent liquid of respectively managing that the enzymic activity peak occurs is merged, ultrafiltration and concentration adds 48ml glycerine, mixing to 112ml, inner protein 0.8g, it is frozen standby to put-85 ℃ of refrigerators.With the bovine serum albumin is standard protein, adopts the Xylene Brilliant Cyanine G dye binding method to measure protein content.Standard protein liquid concentration is 0.1mg/ml.Take by weighing the 0.05g Coomassie brilliant blue G250 during preparation Coomassie brilliant blue G250 (0.01%) dye liquor and be dissolved in the 25ml ethanol (95%), (85%, W/V), the adding distil water constant volume is to 500ml then to add 50ml phosphoric acid again.During the drawing standard curve each sample liquid is added in the test tube, mixing with the absorbance value at 721 spectrophotometric determination 595nm places, was an X-coordinate with the content of standard protein after 3 minutes, and absorbance is an ordinate zou, the drawing standard curve.
Embodiment 50. measures the PKC activity
The present invention selects for use reversed phase ion that the HPLC method is measured the PKC activity.PKC activates back catalysis histone (III-S) phosphorylation, consumes ATP, produces ADP or AMP, and the phosphorylation of every milligram of protein catalysis of per minute histone Histone (III-S) and the amount that consumes ATP are the ratio of PKC and live, and represent with nmol/min/mg.PKC is PS (phosphatidylserine), DG (two Oleic acid diglycerides) and Ca
2+The kinases that relies on activates physiology and the biochemical effect of back wide participation by the mediation of inositol lipid system of couriers.In partially purified PKC reaction system, some other enzyme of miscellaneous also can consume ATP, disturbs the determination of activity of PKC, sets up control tube (not add PS, DG and Ca
2+, just do not activate PKC) and can eliminate of the interference of other enzyme to the PKC determination of activity.
The chromatographic column that the present invention adopts is homemade Reversed-phase Rainbow C18 post Kromasil4.6 * 150mm, and the particle diameter of filler is 5 μ m.Detector is the PDA2996 of a Waters company diode-array detector, and the UV sensing range is 190-600nm.Pump is the 600E of a Waters company quaternary gradient pump.Flow velocity is 1ml/min, and temperature is 25 ℃, sample introduction 20 μ l.The detection wavelength is 259nm.Moving phase is that (20: 80v/v includes the 5mmol/L TBAH, pH7.0) to methyl alcohol/phosphate buffered saline buffer.
Buffer C be Tris-HCl (20mM, pH7.4).Reaction solution 1 contains Tris-HCl20mM, PS100 μ g/ml, DG10 μ g/ml, MgCl
210mM, CaCl
21mM, Histone (III-S) 1mg/ml, DTT1mM, pH7.4.Reaction solution 2 contains Tris-HCl20mM, MgCl
210mM, Histone (III-S) 1mg/ml, DTT1mM, EGTA0.1mg/ml, pH7.4.Reaction solution 3 contains ATP0.5mM.It is standby that all sample liquid prepare rearmounted refrigerator cold-storage.The protein content of enzyme liquid is 5mg/ml.
The ATP content that each test solution add-on of table 3 reaction tubes and HPLC record
| The |
1 | 2 | 3 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| Reaction solution 1 (μ l) | 200 | 200 | 200 | 200 | 200 | 200 | 200 | 200 | 200 | 200 |
| Reaction solution 3 (μ l) | 40 | 36 | 32 | 28 | 24 | 20 | 16 | 12 | 8 | 4 |
| Buffer C(μl) | 80 | 84 | 88 | 92 | 96 | 100 | 104 | 108 | 112 | 116 |
| ATP(nmol) | 20 | 18 | 16 | 14 | 12 | 10 | 8 | 6 | 4 | 2 |
The ATP content that each test solution add-on of table 4 control tube and HPLC record
| The |
1 | 2 | 3 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| Reaction solution 2 (μ l) | 200 | 200 | 200 | 200 | 200 | 200 | 200 | 200 | 200 | 200 |
| Reaction solution 3 (μ l) | 40 | 36 | 32 | 28 | 24 | 20 | 16 | 12 | 8 | 4 |
| Buffer C(μl) | 80 | 84 | 88 | 92 | 96 | 100 | 104 | 108 | 112 | 116 |
| ATP(nmol) | 20 | 18 | 16 | 14 | 12 | 10 | 8 | 6 | 4 | 2 |
By table 3 and table 4 each test solution is added to mixing in the 1.5ml plastic centrifuge tube, is put into rapidly in 30 ℃ of shaking baths and accurately places boiling water bath 1min termination reaction immediately behind the insulation 10min.Add 300 μ l chloroforms, vibration 1min, extracting lipid-soluble substance, the centrifugal 5min of 2000 * g, sucking-off supernatant liquor after the cooling.Add 300 μ l chloroforms, the centrifugal 5min of vibration 1min, 2000 * g, sucking-off supernatant liquor in the supernatant liquor again.Get 20 μ l supernatant liquor sample introductions, HPLC surveys the peak area at 259nm place, is X-coordinate with the content (nmol) of ATP, and peak area is an ordinate zou, and the drawing standard curve is asked regression equation and relation conefficient.The reaction tubes regression equation is y=50713.058x-30930.733, and the reaction tubes relation conefficient is r=0.9961, and the control tube regression equation is y=51649.32x+5017.933, and the control tube relation conefficient is r=0.9954.
Add 200 μ l reaction solution 1,40 μ l reaction solutions, 3,60 μ l Buffer C and 20 μ l enzyme liquid in the reaction tubes when measuring the PKC activity.Add 200 μ l reaction solution 2,40 μ l reaction solutions, 3,60 μ l Buffer C and 20 μ l enzyme liquid in the control tube.Behind the mixing, be put into rapidly and accurately be incubated 10min in 30 ℃ of shaking baths, place boiling water bath 1min termination reaction immediately.The cooling back adds 300 μ l chloroforms, vibration 1min, extracting lipid-soluble substance, the centrifugal 5min of 2000 * g, sucking-off supernatant liquor.Add 300 μ l chloroforms in the supernatant liquor again, vibration 1min, the centrifugal 5min of 2000 * g, sucking-off supernatant liquor.Get 20 μ l supernatant liquor sample introductions, HPLC detects the peak area at 259nm place, and the substitution regression equation can calculate the content of ATP in reaction tubes and the control tube, also just can calculate the amount of reaction tubes and control tube consumption ATP.The amount that reaction tubes consumes ATP deducts the amount that control tube consumes ATP, and then divided by the protein content in reaction times and the enzyme liquid, the ratio that is PKC is lived.Reaction tubes and control tube are respectively done 3 experiments.
Embodiment 51. is of the present invention 1, and the 3-dioxygen cycle compound suppresses the active half-inhibition concentration (IC of PKC
50)
It is of the present invention 1 to add 200 μ l reaction solutions, 1,40 μ l reaction solutions, 3,60 μ l in the reaction tubes, the solution of 3-dioxygen cycle compound and 20 μ l enzyme liquid.It is of the present invention 1 to add 200 μ l reaction solutions, 2,40 μ l reaction solutions, 3,60 μ l in the control tube, the solution of 3-dioxygen cycle compound and 20 μ l enzyme (PKC) liquid.Behind the mixing, be put into rapidly and accurately be incubated 10min in 30 ℃ of shaking baths, place boiling water bath 1min termination reaction immediately.The cooling back adds 300 μ l chloroforms, vibration 1min, extracting lipid-soluble substance, the centrifugal 5min of 2000 * g, sucking-off supernatant liquor.Add 300 μ l chloroforms in the supernatant liquor again, vibration 1min, the centrifugal 5min of 2000 * g, sucking-off supernatant liquor.Get 20 μ l supernatant liquor sample introductions, HPLC detects the peak area at 259nm place, and the substitution regression equation can calculate the content of ATP in reaction tubes and the control tube, also just can calculate the amount of reaction tubes and control tube consumption ATP.The amount that reaction tubes consumes ATP deducts the amount that control tube consumes ATP, and then divided by the protein content in reaction times and the enzyme liquid, the ratio that is PKC is lived.Reaction tubes and control tube are respectively done 3 experiments.Each compound is selected the concentration determination of 4-5 kind, the half-inhibition concentration (IC of mensuration
50) list table 5 in.
PKC half-inhibition concentration (the IC of table 5 compound of the present invention
50)
| Compound | IC 50(mM) | Compound | IC 50(mM) |
| Embodiment 9 | 3.18 | Embodiment 23 | 4.12 |
| Embodiment 9 ' | 2.87 | Embodiment 24 | 5.76 |
| Embodiment 12 | 0.92 | Embodiment 27 | 1.98 |
| |
3.36 | Embodiment 28 | 1.98 |
| Embodiment 16 | 1.47 | Embodiment 29 | 2.06 |
| Embodiment 17 | 1.58 | Embodiment 29 ' | 1.23 |
| Embodiment 18 | 3.90 | Embodiment 30 | 0.29 |
| Embodiment 19 | 3.82 | Embodiment 30 ' | 1.10 |
| Embodiment 22 | 2.77 |
Claims (6)
1. the described 5-amino-1 of general formula I, the 3-dioxygen cycle compound
Wherein, n=1, R
4Be H, R
1, R
2And R
3Can be following group: R
1=H, R
2=H, R
3=CH
2CH (OCH
3)
2R
1=Gly, R
2=H, R
3=CH
2CH (OCH
3)
2R
1=L-Phe, R
2=H, R
3=CH
2CH (OCH
3)
2R
1=H, R
2=CH
3, R
3=CH
2CH (OCH
3)
2R
1=Gly, R
2=CH
3, R
3=CH
2CH (OCH
3)
2R
1=L-Phe, R
2=CH
3, R
3=CH
2CH (OCH
3)
2R
1=H, R
2=H, R
3=p-nitrophenyl; R
1=H, R
2=H, R
3=m-nitro base; R
1=H, R
2=H, R
3=to chloro phenyl 1; R
1=H, R
2=H, R
3=phenyl; R
1=H, R
2=H, R
3=p-methylphenyl; R
1=H, R
2=CH
3, R
3=p-nitrophenyl; R
1=H, R
2=CH
3, R
3=m-nitro base; R
1=H, R
2=CH
3, R
3=to the chloro phenyl; R
1=H, R
2=CH
3, R
3=phenyl; R
1=H, R
2=CH
3, R
3=p-methylphenyl; R
1=Gly, R
2=H, R
3=p-nitrophenyl; R
1=Gly, R
2=H, R
3=m-nitro base; R
1=Gly, R
2=H, R
3=rubigan; R
1=Gly, R
2=H, R
3=phenyl; R
1=Gly, R
2=H, R
3=p-methylphenyl; R
1=Gly, R
2=CH
3, R
3=p-nitrophenyl 1; R
1=Gly, R
2=CH
3, R
3=m-nitro base; R
1=Gly, R
2=CH
3, R
3=rubigan; R
1=Gly, R
2=CH
3, R
3=phenyl; R
1=Gly, R
2=CH
3, R
3=p-methylphenyl.
2. the method for preparing compound of Formula I, general formula I represent to work as R
1=H, R
2=H, R
3=CH
2CH (OCH
3)
2Perhaps R
1=H, R
2=CH
3, R
3=CH
2CH (OCH
3)
2The time compound as claimed in claim 1, this method comprises with 2-amino-1, ammediol or (2R, 3R)-2-amino-1,3 butylene glycol is a raw material, under trimethylchlorosilane catalysis with 1,1,3,3-tetramethoxy propane generation acetal shift reaction Cheng Huan.
3. the method for preparing compound of Formula I, general formula I represent to work as R
1=H, R
2=H, R
3=p-nitrophenyl; R
1=H, R
2=H, R
3=m-nitro base; R
1=H, R
2=H, R
3=to the chloro phenyl; R
1=H, R
2=H, R
3=phenyl; R
1=H, R
2=H, R
3=p-methylphenyl; R
1=H, R
2=CH
3, R
3=p-nitrophenyl; R
1=H, R
2=CH
3, R
3=m-nitro base; R
1=H, R
2=CH
3, R
3=to the chloro phenyl; R
1=H, R
2=CH
3, R
3=phenyl; Perhaps R
1=H, R
2=CH
3, R
3Compound as claimed in claim 1 during=p-methylphenyl, this method comprise with 2-amino-1, ammediol or (2R, 3R)-2-amino-1,3 butylene glycol, under acid catalysis with substituted benzaldehyde generation acetalation Cheng Huan.
4. the method for preparing compound of Formula I, wherein the compound as raw material is to work as: R
1=H, R
2=H, R
3=CH
2CH (OCH
3)
2R
1=H, R
2=CH
3, R
3=CH
2CH (OCH
3)
2R
1=H, R
2=H, R
3=p-nitrophenyl; R
1=H, R
2=H, R
3=m-nitro base; R
1=H, R
2=H, R
3=to the chloro phenyl; R
1=H, R
2=H, R
3=phenyl; R
1=H, R
2=H, R
3=p-methylphenyl; R
1=H, R
2=CH
3, R
3=p-nitrophenyl; R
1=H, R
2=CH
3, R
3=m-nitro base; R
1=H, R
2=CH
3, R
3=to the chloro phenyl; R
1=H, R
2=CH
3, R
3=phenyl; Perhaps R
1=H, R
2=CH
3, R
3Compound of Formula I as claimed in claim 1 during=p-methylphenyl,
Compound as product is to work as: R
1=Gly, R
2=H, R
3=CH
2CH (OCH
3)
2R
1=L-Phe, R
2=H, R
3=CH
2CH (OCH
3)
2R
1=Gly, R
2=CH
3, R
3=CH
2CH (OCH
3)
2R
1=L-Phe, R
2=CH
3, R
3=CH
2CH (OCH
3)
2R
1=Gly, R
2=H, R
3=p-nitrophenyl; R
1=Gly, R
2=H, R
3=m-nitro base; R
1=Gly, R
2=H, R
3=rubigan; R
1=Gly, R
2=H, R
3=phenyl; R
1=Gly, R
2=H, R
3=p-methylphenyl; R
1=Gly, R
2=CH
3, R
3=p-nitrophenyl; R
1=Gly, R
2=CH
3, R
3=m-nitro base; R
1=Gly, R
2=CH
3, R
3=rubigan; R
1=Gly, R
2=CH
3, R
3=phenyl; Perhaps R
1=Gly, R
2=CH
3, R
3Compound of Formula I as claimed in claim during=p-methylphenyl,
This method comprises that with described compound and glycine or L-L-Ala as raw material be raw material, reacts in the presence of DCC, obtains described compound as product.
5. the described compound of the described general formula I of claim 1 is in the purposes of preparation in the inhibitors of protein kinase C.
6. the described compound of the described general formula I of claim 1 is in the purposes of preparation in the anti-inflammatory agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100984308A CN100372843C (en) | 2004-12-10 | 2004-12-10 | 2,5-disubstituted-1,3-dioxygen cycle compound, their synthesis and application as PKC inhibiter |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100984308A CN100372843C (en) | 2004-12-10 | 2004-12-10 | 2,5-disubstituted-1,3-dioxygen cycle compound, their synthesis and application as PKC inhibiter |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1785995A CN1785995A (en) | 2006-06-14 |
| CN100372843C true CN100372843C (en) | 2008-03-05 |
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| CN112480062B (en) * | 2020-12-14 | 2023-05-05 | 陕西中医药大学 | 5-lipoxygenase activating protein activity inhibitor and preparation method thereof |
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| CN1450064A (en) * | 2003-03-06 | 2003-10-22 | 北京北医迈劲医药生物科技有限公司 | 5-benzamido-1,3-dioxide cyclo group compound and preparation process thereof, and use in preparing protein kinase C inhibito medicine |
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| CN1450064A (en) * | 2003-03-06 | 2003-10-22 | 北京北医迈劲医药生物科技有限公司 | 5-benzamido-1,3-dioxide cyclo group compound and preparation process thereof, and use in preparing protein kinase C inhibito medicine |
Non-Patent Citations (2)
| Title |
|---|
| stereoselective transacetalization of1,1,3,3-tetramethoxypropane and N-benzoylaminodiols. lan rong bi ,ming zhao,chao wang ,shiqi peng.Eur.J.org,chem. 2000 * |
| synthesis of malonaldehyde monoacetals. peng SQ,Winterfeldt E.liebigs Ann.chem.. 1989 * |
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