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WO2012068702A1 - 苯并五元不饱和杂环类化合物及其制备方法 - Google Patents

苯并五元不饱和杂环类化合物及其制备方法 Download PDF

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WO2012068702A1
WO2012068702A1 PCT/CN2010/001881 CN2010001881W WO2012068702A1 WO 2012068702 A1 WO2012068702 A1 WO 2012068702A1 CN 2010001881 W CN2010001881 W CN 2010001881W WO 2012068702 A1 WO2012068702 A1 WO 2012068702A1
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benzothiophene
ethoxycarbonyl
substituted
acetyl
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PCT/CN2010/001881
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English (en)
French (fr)
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李卓荣
郭会芳
司书毅
李雪
薛司徒
刘宗英
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中国医学科学院医药生物技术研究所
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Priority to PCT/CN2010/001881 priority Critical patent/WO2012068702A1/zh
Publication of WO2012068702A1 publication Critical patent/WO2012068702A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12Radicals substituted by oxygen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80Radicals substituted by oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56Radicals substituted by oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems

Definitions

  • the present invention relates to a benzo five-membered unsaturated heterocyclic compound, and discloses a process for preparing the benzo five-membered unsaturated heterocyclic compound, and to the benzo five-membered unsaturated heterocyclic compound. Use in anti-osteoporosis and pharmaceutical compositions containing such compounds as active ingredients. Background technique
  • Osteoporosis is a common global disease that occurs mostly in the middle-aged and elderly population, especially in menopausal women.
  • the main clinical feature is the reduction of systemic bone mass in the microstructural destruction of bone tissue.
  • the risk of fractures in people with osteoporosis is significantly increased, especially in the wrist, spine and hip joints. It is estimated that 30-50% of women and 15-30% of men with osteoporosis will experience fractures during their lifetime. Patients with fractures have longer hospital stays than those with diabetes, breast cancer, or myocardial infarction. There are approximately 75 million osteoporotic patients in the United States, Europe, and Japan.
  • osteoblasts Ostoblast
  • osteoclasts Ostoclast
  • Bone Morphogenetic Protein-2 (BMP-2:) plays an important role in bone formation and bone repair.
  • Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2, INFUSE® Bone Graft) was approved by the US FDA for autologous bone transplantation and localization in 2007 for its promotion of bone deposition and repair of long bones.
  • Alveolar ridge augmentation was approved by the US FDA for the treatment of tibiofibular fractures in 2004 and was approved by the FDA for spinal fusion in 2002.
  • BMP-2 is a member of the BMPs family of osteoinductive growth factors stored in bone and belongs to the transforming growth factor (TGF2P) superfamily.
  • BMP-2 first synthesizes a large precursor molecule, a dormant protein that, upon activation, is hydrolyzed by a protease to form a carboxy-terminal monomer containing 100-140 amino acids. The two monomers are linked by a chain disulfide bond to form a mature and active dimer with a relative molecular mass of 18,000.
  • the BMP-2 receptor belongs to the transforming growth factor beta receptor superfamily and has a serine/threonine protein kinase structure with a signaling mechanism similar to that of the TGF-beta receptor.
  • Type II receptors recruit and phosphorylate Smadl, Smad5 and Smad8 proteins in the cytoplasm and assist the Smadl-Az-HsN3 triplet complex. Into the nucleus, this plays a decisive role in the directed differentiation of osteoblasts; type II receptors do not play a key role in the directed differentiation of osteoblasts, but type II receptors bind to BMP-2 and activate I. Type receptors and greatly enhance the affinity of BMP-2 for receptors.
  • the binding of the BMP-2 protein to the type II receptor of BMP-2 activates the protein kinase activity of the receptor, catalyzing the intracellular GS region of the type I receptor (characteristically conserved SGSGSG sequence)
  • the second amino acid residue, glutamine, is converted to aspartic acid, and the type I receptor is activated to bind to Smadl or Smad5 and phosphorylate the serine at the carboxy terminus of Smadl or Smad5, thereby activating the Smadl or Smad5 protein.
  • Smads protein is a key transcriptional coping regulator that transduces the BMP-2 signaling pathway from the cell surface to the nucleus.
  • the activated Smadl or Smad5 protein is transferred from the cell paddle to the nucleus and acts directly and indirectly on downstream target genes, such as the ALP gene, which ultimately promotes bone formation.
  • BMP-2 promotes bone formation in two ways: First, it promotes osteoblast differentiation. BMP-2 in the bone matrix can recruit bone marrow stem cells and induce bone marrow stem cells to differentiate into osteoblasts and chondrocytes, and then form new bone by calcium salt deposition. BMP-2 also induces osteoblast differentiation and remodeling of young bone in mesenchymal cells. BMP-2 also promotes osteoblast differentiation and inhibits apoptosis during bone regeneration and repair. The second is to promote the expression of other osteogenic factors. BMP-2 can increase the expression of osteoblast marker genes OPN, CbfaK Col I alphaK BSP, ALP, fabp4 (fatty acid coupled protein 4), etc. The corresponding proteins of these genes play a key role in osteoblast differentiation.
  • OPN osteoblast marker genes
  • CbfaK Col I alphaK BSP ALP
  • fabp4 fatty acid coupled protein 4
  • osteoporosis citrus gene one or more genes
  • BMP-2 bone morphogenetic protein-2
  • the 3'-UTR (3'-untranslated regions of the BMP-2 protein gene bmp-2 in mammals and fish are highly conserved, indicating that the 3,-UTR of bmp-2 is evolutionarily Subject to (selective pressure.
  • This conserved region has been shown to be an important regulator of bmp-2 gene transcription, and regulation of the 3'-UTR of bmp-2 can affect the expression of the gene bmp-2, which in turn affects the BMP-2 protein. And expression of other osteoporosis-related factors.
  • Zhang Yueqin et al. established an anti-osteoporosis drug screening model that promotes BMP-2 up-regulation with the bmp-2 promoter as a drug target (see Chinese Patent Application: 03104750.5) And use this model to screen for microbial sources and chemically synthesized compounds. Through extensive screening work, it was found that a class of compounds with a five-membered unsaturated heterocyclic structure has a significant up-regulation of BMP-2 activity and was verified in ovarian ablation model rats. It does have the effect of improving the symptoms of osteoporosis (see Chinese patent ZL 200610008114.6).
  • the present invention further designs, synthesizes and screens a series of benzo five-membered unsaturated heterocyclic compounds (Formula I) which can be represented by the following general formula, especially the 2-acyl benzo-5-membered compounds thereof.
  • Unsaturated heterocyclic compounds through structural structural modification and structure-activity relationship studies, can provide a new lead structure for osteoporosis treatment, and start from the active compounds that can up-regulate BMP-2 protein, and further develop a new type of bone-promoting Anti-osteoporosis drugs.
  • the present invention provides a series of benzo five-membered unsaturated heterocyclic compounds having the structure of the general formula (I) or a pharmaceutically acceptable salt thereof, which has an up-regulating BMP-2 expression activity and can be used for the treatment of osteoporosis .
  • the present invention also provides a method for synthesizing the benzo five-membered unsaturated heterocyclic compound.
  • the present invention also provides the use of the benzo five-membered unsaturated heterocyclic compound in the treatment of osteoporosis and related patients due to osteoporosis.
  • the present invention also provides a pharmaceutical composition for treating osteoporosis, which comprises the above benzopenta-unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention mainly designs a compound of the formula I which synthesizes a benzothiophene, a benzofuran or a hydrazine having a 2-position carboxylic acid ester substituted at a different position on the benzene ring (4-, 5-, 6-, 7-).
  • a compound having a phenylpropenyl group is introduced at the 2-position, and a compound having a methyl sulfone or methyl sulfoxide is introduced at the 2-position.
  • the phenyl ring is bonded with a thiol group, a halogen, a methoxy group, an amino group, an acyl group, a carboxyl group or the like with different substituents, and a different conjugated extension of the 2-position acetyl group to up-regulate the BMP-2 activity of the compound. influences.
  • the designed target compound structure is shown in Table 1, and the benzene ring in Formula I may have a ruthenium Substituents such as thiol, halo, halo fluorenyl; thiophene, furan ring or pyrrole moiety
  • 1 is a fluorenyl group, an alkoxy group, a carboxyl group, a sulfone methyl group, a sulfoxide methyl group, a substituted aryl propylene structure, or the like.
  • the present invention provides a benzo five-membered unsaturated heterocyclic compound having the structure of the formula I or a pharmaceutically acceptable substance,
  • X represents 0, S or NR 7 , wherein R 7 represents H, a hydrocarbyl group, a halogenated hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group or a hydrocarbyloxy group;
  • Y represents CO or CR OH
  • R represents the following groups: H, OH, a hydrocarbon group having 1 to 18 carbons, a carboxyl group, an acyl group, an alkoxy group, a sulfonic acid group;
  • R 2 represents the following groups: H, a hydrocarbon group having 1 to 18 carbons, a halogen, an acyl group, a carboxyl group, an amino group or a substituted amino group, a sulfonic acid group, a nitrile group or an acyl alkoxy group;
  • R4 represents the following groups: H, a hydrocarbyl group, a decyloxy group, a halogen or a haloalkyl group, a carboxyl group, an amino group or a substituted amino group, an amide group, an acyl group, an ester group or a sulfonic acid group;
  • R 6 represents the following group: H, a hydrocarbyl group, a decyloxy group, a halogen or a halogenated fluorenyl group, a carboxyl group, an amino group or a substituted amino group, an acyl group, an amide group, an ester group or a sulfonic acid group, etc.;
  • R4 and ⁇ are bonded together by carbon, oxygen or nitrogen to form a 5-7 membered ring structure or a 5-7 membered ring structure having a substituent R 1Q wherein R 1Q represents H, a hydrocarbon group, a halogenated hydrocarbon group, a carbonyl hydrocarbon group, a hydroxyl group. Hydrocarbyl, aminohydrocarbyl or hydrocarbyloxy.
  • Hydrocarbyl may mean a straight or branched alkyl or cycloalkyl group having from 1 to 18 carbon atoms, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl , sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. or their corresponding cyclodecyl groups.
  • Alkoxy may be an alkoxy group having 1 to 18 carbon atoms, for example, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, sec. Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like.
  • Acyl may be a hydrocarbon substituted acyl or aryl acyl group having 1 to 18 carbons, such as formyl, acetyl, isopropyl acyl, n-propyl acyl, allyl acyl, cyclopropyl acyl, n-butyl Acyl, isobutyl acyl, sec-butyl acyl, tert-butyl acyl, n-pentyl acyl, isopentyl acyl, n-hexyl acyl, isohexyl acyl, phenyl acyl, tolyl acyl and the like.
  • ester group may be a hydrocarbon-substituted ester group (hydrocarbyl oxy group) or an aryl ester group having 1 to 18 carbons, such as formyloxy group, acetoxy group, isopropyl acyloxy group, n-propyl acyl group.
  • Acylamino may be a hydrocarbon-substituted amide or arylamino group having 1 to 18 carbons, such as methylamido, ethylamido, isopropylamido, n-propylamido, allylacyl Amino, cyclopropylamido, n-butylamido, isobutylamido, sec-butylamido, tert-butylamido, n-pentylamino, isopentylamino, n-hexylamino, dissident Amino group, Phenylamino, tolylamino and the like.
  • the benzo five-membered unsaturated heterocyclic compound provided by the present invention or a pharmaceutically acceptable salt thereof when it has a substituent group, it generally means a C1-C6 lower fluorenyl group, a lower decyloxy group, a halogen group, an amino group, etc., especially
  • the substituent of the substituted amino group may be a C2-C6 fluorenyl group.
  • the hydrocarbon group in the halogenated hydrocarbon group, the carbonyl hydrocarbon group, the hydroxyalkyl group or the amino hydrocarbon group is a C1-C6 hydrocarbon group.
  • the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof according to the present invention, the corresponding benzothiophene/furan, anthraquinone compound, in particular, has an effect of significantly upregulating the expression activity of bone morphogenetic protein BMP-2, in vivo
  • the results of the anti-osteoporosis study showed that the compounds of the present invention have an effect of improving the symptoms of osteoporosis in SAMP6 mice.
  • the benzo five-membered unsaturated heterocyclic compound comprises 2-substituted phenylacryloyl-benzothiophene, 2-substituted phenylacryloyl-benzofuran, or a benzene ring partially passed, and formaldehyde is condensed to form an adjacent two A compound obtained after the structure of a phenyl ether.
  • the benzo five-membered unsaturated heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof preferably comprises a benzothiophene or benzofuran compound in which the substituent at the 2-position is a 2-hydrocarbyloxyformyl group or a 2-hydrocarbylacyl group.
  • the benzo five-membered unsaturated heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof preferably comprises a 2-position substituent of 2-(2,-methylsulfone or methylsulfoxideacetyl) or 2-(2, a benzothiophene, benzofuran or anthracene compound in which -methylsulfoxide or methyl sulfoxide is substituted with - ⁇ -hydroxy)ethyl.
  • benzo five-membered unsaturated heterocyclic compound of the present invention may be selected from the following specific compounds:
  • the present invention also provides a method for synthesizing a compound of the formula (I).
  • the synthesis method comprises the following steps: using a substituted nitrobenzaldehyde (hydrazine) as a starting material, and using a mercaptoethanol to carry out an aromatic nucleophilic substitution reaction under the catalysis of an alkaline reagent, the N0 2 of the raw material is taken by an ethylthio group.
  • intermediate (III) is produced; a halogenated reagent 0 (Z represents a leaving group), which is reacted with an intermediate ( ⁇ ) under the catalysis of an alkaline reagent to obtain a derivative of a 2-substituted acylbenzothiophene (IV) );
  • the synthesis method is as follows: using substituted o-nitrobenzaldehyde ( ⁇ ) as a starting material, and catalyzing with an alkaline reagent, with a thiol reagent Directly reacting to obtain a derivative of 2-substituted acylbenzothiophene (W);
  • the intermediate (W) is hydrolyzed under basic conditions to obtain a carboxylic acid derivative (V) wherein R 3 ', R , R 5 ', R 6 ' correspond to the groups after hydrolysis of R 3 , R 4 , R 5 , R 6 , respectively
  • the intermediate (IV) is aldehyde-condensed with the R 9 -substituted phenyl formaldehyde intermediate (VII) to obtain a compound of the R 9 substituted phenyl acryloyl group (covered)
  • the synthesis method is as follows: using substituted o-hydroxybenzaldehyde ( ⁇ ) as a starting material, in alkaline reagents
  • the intermediate ( ⁇ ) is further reacted with a sulfinylmethyl derivative under strong base and heating to obtain a 2-(2,-substituted methyl sulfoxide) acylbenzofuran derivative (XIV), (XIV) continues Oxidation and reduction give the compound 2-(2,-substituted sulfone)acetobenzofuran derivative (XV) and 2-(2,-substituted sulfone or methyl sulfoxide-hydrazine-hydroxy)ethylbenzofuran, respectively.
  • Derivative (XVI) is reacted with a sulfinylmethyl derivative under strong base and heating to obtain a 2-(2,-substituted methyl sulfoxide) acylbenzofuran derivative (XIV), (XIV) continues Oxidation and reduction give the compound 2-(2,-substituted sulfone)acetobenzofuran derivative (XV) and 2-(2,-substitute
  • Route 4 The synthesis method comprises the following steps: using substituted NR 7 -2-acetyl oxime (XVII ) as a starting material, and performing aldol condensation with the substituted phenylformaldehyde intermediate (W) under the catalysis of an alkaline reagent to obtain 2 positions.
  • the present invention finds a compound of the formula (I), 2-nonyloxycarbonyl-benzothiophene/furan derivative
  • the representative compounds (8b, 3c, S25, G39) of the above various compounds all have the effect of improving osteoporosis symptoms in SAMP6 mice, and the present invention provides them in the treatment of osteoporosis.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising said compound, which may contain a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
  • the compounds of formula I of the invention and pharmaceutical compositions are useful in the preparation of anti-osteoporosis drugs.
  • the pharmaceutical composition provided by the present invention may be in various administration forms prepared according to a conventional production method in the pharmaceutical field, for example, by mixing the active ingredient with one or more carriers, and then preparing the desired dosage form.
  • the pharmaceutical composition of the present invention preferably contains the active ingredient in a weight ratio of from 0.1% to 99.5%, and most preferably contains from 0.5% to 99.5% by weight of the active ingredient.
  • the above formulations can be prepared by conventional pharmaceutical methods.
  • useful pharmaceutical adjuvants include excipients (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium metasilicate Aluminum; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc., binders (eg gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegration Agents (such as cellulose derivatives such as sodium carboxymethylcellulose, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, cety
  • the compound of the present invention can be synthesized stably and reproducibly.
  • the plasmid PYJ was transiently transfected into MC3T3E1 cells by: 100 ⁇ ! 7 wells of appropriate concentration of MC3T3E1 cells in 96 wells. Incubate in a sterile plastic culture plate for 8 h, dilute the appropriate amount of PYJ plasmid DNA in a sterile centrifuge tube with 25 ⁇ ! 7 well serum-free, double-anti-DMEM medium, and use 25 ⁇ ! 7 well serum-free in another sterile centrifuge tube. Dilute the DMEM medium with 0.5 ⁇ ! 7-well LF2000 Reagent.
  • the detection conditions are: no excitation light wavelength, emission light wavelength is empty, Positioning delay is 1.0, Number of intervals is 1, Interval time is 1.0s, setting the instrument reading before shaking mode, shaking diameter is 1 Millimeter, using the set of positive controls, blank controls, and related data and calculation formulas, calculate the up-regulation rate of the sample. The results are shown in Table 1.
  • Up-regulation rate (sample luminescence number - DMSO luminescence number) / DMSO luminescence number ⁇ 100%
  • the activity of the synthesized compound was evaluated by the above-described ⁇ -2 screening model. 0.1% DMSO was used as the negative control, 0.4 M Lovastatin was used as the positive control, and the test drug concentration was 4 ⁇ .
  • the activity measurement results are shown in Table 1.
  • Table 1 shows the structures of preferred compounds of the invention, but does not limit the invention in any way.
  • the positive control drugs were lovastatin (Lovastatin, Lov, purchased from Zhejiang Ruibang Pharmaceutical Co., Ltd.) and strontium mnelate (Sr, purchased from Beijing Huafeng Lianbo Technology Co., Ltd.); 0.5% MC (methylcellulose aqueous solution).
  • BMP-2 antibody purchased from American Abeam (item number abl4933), secondary antibody purchased from American Zymed (product number PV6001).
  • BAP mouse bone alkaline phosphatase
  • DPD deoxypyridinoline
  • the osteocalcin test kit is a product of Beijing Zhongtong Lanbo Clinical Laboratory.
  • the urinary creatinine (Cr) kit is manufactured by Baiding Bioengineering (Beijing) Co., Ltd.
  • mice After purchasing SAMP6 mice, they were placed in the laboratory animal room barrier system, and the common word feed was used for one week. Female rats are each caged, and males are each caged. At room temperature 18-23 °C, the water is sufficient, the water bottle and litter are changed twice a week, and the weight is averaged every 10 days. The bone density of the mice was measured, and the SAMP6 male and female mice were randomly divided according to the bone density value. The mice were divided into 7 groups, 2 female rats and 3 male rats in each group. Female 1 cage 2, male 1 cage 1 .
  • the lanthanum strontium was dissolved in physiological saline, and the remaining drugs were all suspended in 0.5% MC.
  • Preparation method of 0.5% MC (methylcellulose) solution Add 5 g of MC to 1000 ml of distilled water and mix well.
  • the dose of the experimental drug was set as follows: lovastatin and lanthanum strontium were administered at doses of 10 mg/kg-d and 625 mg/kg'd, respectively, and the remaining doses were 30 mg/kg. d, the blank group was given a 0.5% MC solution.
  • the mode of administration is all intragastric. It was administered at 9 am every day, once a day, continuously, and administered for 3 months for 13 weeks.
  • the experimental results are as follows:
  • BMP-2 expression level in mice At the end of the administration, the left femur of the mice was frozen and sectioned, and then BMP-2 immunohistochemical staining was performed to determine the cytoplasmic staining level of BMP-2 positive cells. The specific values and statistical results are shown in Table 2.
  • the results of immunohistochemical staining of mouse femur BMP-2 showed that the expression of BMP-2 in femur tissues of all the mice was significantly improved compared with the control group (MC) of the rapidly aging mouse model.
  • the expression of BMP-2 in the Lov, G39, 3c and 8b groups was significantly improved, and no significant difference was found in the Sr and S25 groups.
  • the expression levels of BMP-2 in the femur of mice in the G39 and 8b groups were comparable to those in the Lov group.
  • the expression level of femur BMP-2 in the 3c-administered group was higher than that in the Lov and Sr control groups.
  • Bone mineral density in mice was measured using a digital cone beam flash bone densitometer OSTEOCORE 3 manufactured by MEDILINK, France.
  • the bone densitometer is a dual energy X-ray absorptiometry
  • ROIs BMD (g/cm 2 )
  • the bone mineral density measurement after 13 weeks of continuous administration showed that compared with the model control group, the bone density of the mice in the Lov, Sr, S25, 3c and 8b administration groups increased, and the increase in the 3c and 8b groups was more pronounced.
  • the bone mineral density of the 8b group was the most obvious.
  • the spinal bone density of the mice in the Low Sr, 3c and 8b groups was significantly increased.
  • the bone density of the spine in the Lov group was the most obvious; S25, 3c and 8b were administered.
  • the bone density of the left hind leg of the mice in the group was significantly increased, and the changes of the control drugs Lov and Sr were not obvious.
  • the trend of bone mineral density in mice can also be seen from Table 3.
  • the spinal bone density of the mice in each test group increased during the administration period, and the increase trend of the drug-administered group was stronger than that of the model control group.
  • the bone density of the left hind leg of the group showed a decreasing trend, and the decrease trend of the drug-administered group was slower than that of the model control.
  • the curve of bone mineral density in the whole body of mice was complicated during the administration. After 1 month of administration, the bone mineral density of the mice decreased, and then gradually increased. The peak of bone mineral density in SAMP6 mice occurs around 4 months, and then the bone density decreases gradually. After administration for a period of time, the bone density of the whole body has been improved relative to the initial administration.
  • the G39 group was more special. After 2 months of administration, the G89 group had the most obvious increase in bone mineral density, spinal bone density, and left hind leg bone density. However, the bone density was not more than 3 months after administration. Increase Image, the reason for further
  • Morphometry of mouse bone tissue After the end of the administration, the right femur of the mouse was taken into a non-decalcified bone slice to determine the histomorphometric data of the bone tissue. Morphometry of non-decalcified bone sections was performed using a Leica-Qwin image analyzer system.
  • Trabecular volume percentage (TBV%): The percentage of trabecular bone volume to the total volume of the bone marrow cavity measured, is the main indicator of bone mass level; trabecular bone absorption surface percentage (TRS%): irregular, rugged The percentage of the trabecular surface that accounts for the surface of the trabecular bone, which determines the activity of osteoclasts; the percentage of trabecular bone formation surface (TFS%): the percentage of the osteoid surface covered by osteoblasts to the trabecular surface. It can determine the activity of osteoblasts; the average width of the inner surface of the cortex (OSW): the average width of the osteoids covered by osteoblasts on the inner surface of the cortex.
  • OSW average width of the osteoids covered by osteoblasts on the inner surface of the cortex.
  • TBV% ⁇ The percentage of trabecular bone volume (TBV% ⁇ determined), the femoral TBV% of each group was significantly higher than that of the model control group, and the TBV% of the Lov control group and the G39, S25, and 8b drug groups increased significantly. Ding 8 ⁇ % is the main indicator to measure the bone level, indicating that the bone mass of the mice in each drug-administered group is higher than that in the model control group (MC group).
  • TFS% trabecular bone formation surface percentage
  • TRS% The percentage of trabecular bone absorption surface (TRS%) was determined.
  • TRS% of the Sr control group was comparable to that of the model group, and the TRS% of all other groups were lower than the model control group.
  • TRS% refers to the percentage of irregular, uneven trabecular surface that occupies the surface of the trabecular bone, which determines the activity of osteoclasts. From the results, except for Sr, other drugs have a tendency to reduce the activity of mouse osteoclasts, but there is no statistically significant difference.
  • OSW intraosseous bone-like bone
  • the band of blue river-like sputum in the photo of the non-decalcified bone section of the mouse is the trabecular bone.
  • the photo is taken in part, which does not represent the whole bone, but the model control group (MC group) can be seen.
  • MC group model control group
  • mice Changes in body weight of the mice: During the administration, the body weight of the mice was weighed on the 0th, 5th, 12th, 21st, 37th, 51st, 66th, and 80th day of administration, and the weights of the 8th time were all non-fasting body weight. Detailed data and trends are shown in Table 5. The body weight of each group of mice increased slowly, suggesting that each group of mice had no serious toxicity. Table 5 Changes in body weight of mice during administration (non-fasting weight) Group j 0d 5d 12d 21d 37d 51d 66d 80d
  • reaction solution was poured into ice-water, the solid was collected by filtration, the solid was dissolved in chloroform, dried over anhydrous Na 2 S0 4, filtered, and spin dry the solvent by silica gel column chromatography to give a yellow solid 5.80 g (94%).
  • Example 5 2-(2,-Methylsulfoxide)acetyl-5,6-methylenedioxy-benzothiophene (8c) was synthesized as a yellow material from compound 8b. Solid powder (90%).
  • Example 12 2-ethoxycarbonyl-5-methoxy-benzofuran (l ib) Using 3-methoxy-6-hydroxybenzaldehyde and ethyl bromoacetate as starting materials, the white solid 2-ethoxycarbonyl-5-methoxy-benzofuran was obtained by the method of Example 7. ).
  • Example 19 2-Acetyl-5-methoxycarbonyl-benzothiophene (lc) Under ice-cooling, 3-aldehyde--4-nitro-benzoic acid methyl ester (1.95 g, 9.3 mmol), anhydrous K 2 C0 3 (1.55 g, 11.2 mmol) and ethanethiol were added to 60 ml of DMF. 0.70 mg, 11.3 mmol). After stirring for 10 min, it was stirred at room temperature for 1 h. The K 2 C0 3 was filtered off, the DMF was evaporated to dryness, and the crude product was dissolved in chloroform. The chloroform phase was washed with water and dried over anhydrous sodium sulfate. After the solvent was evaporated to dryness, silica gel column chromatography was afforded white crystals of 3- aldehyde 4-ethylthio-benzoic acid methyl ester (lb) 1.81 g (86.5%).
  • Example 22 2-acetyl-6-methoxycarbonyl-benzothiophene (2c) using 3-aldehyde-4-nitro-benzoic acid methyl ester and ethyl mercaptan as raw materials, The reaction of the method of Example 19 gave a yellow solid, 2-ethylthio-3- aldehyde-benzoic acid methyl ester (2-b) (101.2%).
  • the compound 2c was used as a starting material to give a brown solid product, 2-acetyl-6-carboxy-benzothiophene (59%).
  • the compound 4b was used as a starting material to give a pale-yellow solid of 2-(2'-methylsulfinyl)acetyl-4-chloro-benzothiophene (4c) (59%).
  • the compound 10b was used as a starting material to give a yellow solid, 2-(2'-methylsulfoxide) acetyl-4-methoxy-benzofuran (10c) (76%).
  • the compound 13b was used as a starting material to give a yellow solid, 2-(2'-methylsulfoxide)acetyl-7-methoxy-benzofuran (13c) (66%).
  • the compound 8c was used as a starting material to give a white solid 2-(1 '-hydroxy-2,-methylsulfoxide)ethyl-5,6-methylenedioxy-benzothiophene as a white solid. 8e) (96%).
  • the compound 2c was used as a starting material to give a white solid (2-(1'-hydroxy)ethyl-6-methoxycarbonyl-benzothiophene (2f) (92%).
  • Example 38 (E 2-[3,-(2",3",4,,-Trimethoxyphenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dE) Using compound 2c and 2,3,4-trimethoxybenzaldehyde as starting materials, the reaction of Example 31 gave a yellow-green oil (E 2-[3,-(2",3",4,,- Trimethoxybenzene)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dE) (32%).
  • Example 40 E 2-[3,-(2,--Chlorophenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene (ldBl) was synthesized from compound lc and o-chlorobenzaldehyde. The reaction of the method of Example 31 gave a yellow solid of 2-[3,-(2"-chlorophenyl)acryloyl]-5-ethoxycarbonyl-benzothiophene (ldBl) (62%).
  • Example 42 (E 2-[3,-(2,--chlorophenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2dB) using compound 2c and o-chlorobenzaldehyde as raw materials, according to The reaction of Example 31 was carried out to give a brown-yellow solid (3 ⁇ 4-2-[3,-(2"-chlorophenyl)acryloyl]-6-ethoxycarbonyl-benzothiophene (2%) (20%).
  • Example 46 2-(anthracene-hydroxy-2,-methylsulfoxide)ethyl-5-methoxy-benzofuran (l ie) Using compound 11c as a starting material, the reaction was obtained in the same manner as in Example 10 Yellow solid 2-(anthracene-hydroxy-2,-methylsulfoxide)ethyl-5-methoxy-benzofuran (l ie) (89%).
  • Example 47 (E 2-[3,-(4,,-methoxyphenyl)acryloyl]-5,6-dimethoxy-indole (G33-1) Using 2-acetyl-5,6-dimethoxyanthracene and p-methoxybenzaldehyde as starting materials, the reaction of Example 31 was carried out to obtain a solid (T 2-[3'-(4"-methoxybenzene). )acryloyl]-5,6-dimethoxy-oxime (74.5%) 0
  • Example 31 Using 1-methyl-2-acetyl-5,6-dimethoxyanthracene and p-methoxybenzaldehyde as starting materials, the reaction of Example 31 gave a solid methyl-2-[3'-(4 "-Methoxybenzene)acryloyl]-5,6-dimethoxy-oxime (77.1%).
  • Example 31 Using 1-chloroethyl-2-acetyl-5,6-dimethoxyanthracene and p-methoxybenzaldehyde as starting materials, the reaction of Example 31 gave the solid chloroethyl-2-[3,- (4"-Methoxybenzene)acryloyl]-5,6-dimethoxy-anthracene (70.2%).
  • Example 31 Using 1-(2,-hydroxyethyl)-2-acetyl-5-acetoxyindole and p-fluorobenzaldehyde as starting materials, the reaction of Example 31 gave a solid (2,-hydroxyethyl)-2. -[3,-(4"-Fluorophenyl)acryloyl]- 5-acetoxy-oxime (70.5%).
  • Example 31 Using 1-( 2,-aminoethyl)-2-acetyl-5-acetoxy anthracene and p-fluorobenzaldehyde as starting materials, the reaction of Example 31 gave the solid-1-(2,-aminoethyl) -2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-oxime (58.0%).
  • Example 31 Using 1-(2,-methoxyethyl)-2-acetyl-5-acetoxyindole and p-fluorobenzaldehyde as starting materials, the reaction of Example 31 gave a solid £ 1-(2,-A Oxyethyl)-2-[3,-(4"-fluorophenyl)acryloyl]-5-acetoxy-oxime (70.5%).
  • Example 1 Using 6-methyl 2-nitrobenzaldehyde and ethyl decylacetate as starting materials, the procedure of Example 1 was carried out to obtain solid particles 2-ethoxycarbonyl-4-methyl-benzothiophene (69.3%). .
  • Example 55 2-Heptanoyl-5,6-dimethyl-benzothiophene (17) as 4, 5-dimethyl-2-nitro -benzaldehyde, ethanethiol and 1-chlorooctyl-2-one as starting materials, reacted according to the method of Example 19 to give solid 2-heptanoyl-5,6-dimethyl-benzothiophene (17) (50 %).
  • Example 61 2-(4,-chlorohexylsulfenyl)acetyl-5,6-dimethoxy -Benzothiophene (21c) Using compound 21b as a starting material, the compound was reacted according to the method of Example 2 to give solid 2-(4,-chlorohexylsulfoxide)acetyl-5,6-dimethoxy-benzothiophene (21c) ) ( 85%)
  • Example 63 2-(6,-Hydroxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene (22b) as compound 2-nitro-4,5-dimethoxybenzaldehyde and Thioglycolic acid-6 '-hydroxyhexyl ester is the original The reaction was carried out in the same manner as in Example 15 to give solid 2-(6,-hydroxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene (22b) (50%).
  • Example 64 2-(6,-Methoxyhexyl)oxycarbonyl-5,6-dimethoxy-benzothiophene (23b) as compound 2-nitro-4,5-dimethoxybenzene Formaldehyde and thioglycolic acid-6'-methoxyhexyl ester were used as raw materials, and reacted according to the method of Example 15 to obtain a solid 2-(6'-methoxyhexyl)oxycarbonyl-5,6-dimethoxy-benzene. And thiophene (23b) (63%).
  • Example 65 2-(6,-methoxypentylsulfenyl)acetyl-5,6-dimethoxy-benzothiophene (23c)
  • Compound 23b was used as a starting material and was reacted according to the procedure of Example 2 to give solid 2-(6'-methoxypentylsulfenyl)acetyl-5,6-dimethoxy-benzothiophene (23c) (86%)
  • Example 67 2-Ethoxycarbonyl-5,6-(2,-chloroethyl)methylenedioxy-benzothiophene (25b) with 3,4-(2,-chloroethyl)-
  • the bis-oxo-6-nitrobenzaldehyde and ethyl decylacetate were used as starting materials, and the solid 2-ethoxycarbonyl-5,6-(2,-chloroethyl)methylenedioxy was synthesized according to the method of Example 1.
  • Example 68 2-ethoxycarbonyl-5,6-(1,-hydroxyethyl)methylenedioxy-benzothiophene (26b) with 3,4-(indolyl-hydroxyethyl)methylene Dioxy-6-nitrobenzaldehyde and ethyl decylacetate were used as starting materials, and solid 2-ethoxycarbonyl-5,6-(indolyl-hydroxyethyl)methylenedioxy-benzene was synthesized according to the method of Example 1. Thiophene (26b) (68.0%)
  • Example 69 2-Ethoxycarbonyl-5,6-(anthracene-aminoethyl)methylenedioxy-benzothiophene (27b) with 3,4-(-aminoethyl)methylenedioxy Using -6-nitrobenzaldehyde and ethyl decylacetate as starting materials, a solid 2-ethoxycarbonyl-5,6-(indolyl-aminoethyl)methylenedioxy-benzothiophene was synthesized according to the method of Example 1. (26b) (68.0%).
  • Example 70 2- ethoxycarbonyl -5,6- ( ⁇ - methoxyethyl) methylenedioxy - benzothiophene (28b) with 3, 4- (1 - methoxyethyl Methylene dioxy-6 nitrobenzaldehyde and ethyl thioglycolate As a raw material, a solid 2-ethoxycarbonyl-5,6-(-methoxyethyl)methylenedioxy-benzothiophene (26b) (68.0%) was obtained.

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Description

苯并五元不饱和杂环类化合物及其制备方法 技术领域
本发明涉及一类苯并五元不饱和杂环化合物, 并公开了所述苯并五元 不饱和杂环类化合物的制备方法, 本发明还涉及所述苯并五元不饱和杂环 类化合物在抗骨质疏松中的应用以及含有该类化合物作为活性组分的药物 组合物。 背景技术
骨质疏松症是一种全球性常见疾病, 多发于中老年人群, 尤其是绝经 期女性, 临床主要特征是骨组织微结构破坏的全身性骨量减少。 患骨质疏 松人群的骨折风险明显增加, 尤其是腕关节、 脊柱和髋关节的伤害。 据估 计, 患骨质疏松人群中, 30_50%的女性和 15-30%的男性在他们一生中会 遭遇骨折。 骨折患者住院时间超过糖尿病、 乳腺癌或心肌梗塞患者的住院 时间。 在美国、 欧洲和日本, 总共约有七千五百万骨质疏松患者。 国际骨 质疏松基金会和中国健康促进基金会在 2008年共同发布的《骨质疏松症防 治中国白皮书》 中介绍我国至少有 6944万人患有骨质疏松症, 2.1亿人属 于低骨量,存在骨质疏松症的风险。我国 50岁以上的人群中骨质疏松症总 患病率为 15.7%, 而且随着人口寿命的延长, 这一比例还在逐步增加。 该 《白 ^皮书》指出, 在我国 70-80%的中老年骨折是因骨质疏松引起的, 其中 每年新发椎体骨折约有 181万人,髋部骨折病例为 23万。 中国老年人口在 以每年 5.2%的速度增加, 这也意味着潜在骨质疏松症患者的增加。 目前保 守地估计每年仅用于治疗中老年患者大腿骨折的费用已经高达 104亿人民 币, 这个数据到 2020年将超过 217亿。
― 在骨的形成过程中, 成骨细胞 (Osteoblast)和破骨细胞 (Osteoclast)相互 协调, 使骨质的形成与溶解处于一种动态平衡, 维持骨质的不断更新。 当 此协调失衡, 骨吸收超过骨形成时, 即导致骨质疏松。
成年骨具有很明显的骨重建过程, 1965年首次发现这个骨自身修复的 功能, 并发现骨形态发生蛋白 (Bone Morphogenetic Protein, BMP )是这个过 程中的活性分子。 之后, 又发现了 BMP蛋白家族。 现代越来越多的证据 表明骨形态发生蛋白 -2 (Bone Morphogenetic Protein-2, BMP-2:)在骨形成和 骨修复过程中起重要作用。 重组人 BMP-2蛋白(Recombinant Human Bone Morphogenetic Protein-2, rhBMP-2, INFUSE® Bone Graft) 因其促进骨沉积 以及对长骨的修复作用, 在 2007年被美国 FDA批准用于自体骨移植以及 局部牙槽嵴增高术, 在 2004年被美国 FDA批准用于胫骨骨折的治疗, 在 2002年被 FDA批准用于脊柱融合术。 在德国, 治疗胫骨骨折时, 注射一 针重组人 BMP-2蛋白的费用大约是 2970欧元, 且使用该药不能从健康保 险公司获得偿付。 因此, 使用重组人 BMP-2蛋白将给患者带来沉重的经济 负担。
BMP-2是储存在骨内的骨诱导生长因子 BMPs家族成员之一,属于转 化生长因子 β (transforming growth factorp, TGF2P)超家族成员。 BMP-2先 合成一个大前体分子, 为一种休眠蛋白, 一旦激活即被蛋白酶水解形成一 个含 100-140个氨基酸的羧基端单体。 两个单体以链间二硫键连接而成一 个成熟有活性的二聚体, 相对分子质量达到 18000。 BMP-2受体属于转化 生长因子 β受体超家族成员, 具有丝氨酸 /苏氨酸蛋白激酶结构, 其信号传 递机制与 TGF-β受体类似。与 ΒΜΡ-2信号传递有关的 ΒΜΡ-2受体分为 I 型 和 II型, I型受体募集并磷酸化细胞质内的 Smadl、 Smad5和 Smad8蛋白, 并协助 Smadl-Az-HsN3 三联体复合物进入核内, 这对成骨细胞的定向分 化起决定性作用; II型受体虽在成骨细胞的定向分化过程中未起关键作用, 但 II型受体与 BMP-2结合后, 可激活 I型受体, 并大大增强 BMP-2 对受 体的亲和力。 BMP-2蛋白与 BMP-2的 II型受体结合后受体的蛋白激酶活 性被激活, 催化 I型受体细胞内 GS区 (具特征性保守的 SGSGSG序列)的 倒数第 2个氨基酸残基谷氨酰胺转换成天门冬氨酸, I型受体被活化后与 Smadl 或 Smad5结合并磷酸化 Smadl 或 Smad5羧基端的丝氨酸,从而激 活 Smadl或 Smad5 蛋白。 Smads蛋白作为 TGF2P相关转导途径的主要组 成部分,是转导 BMP-2信号途径从细胞表面至胞核的关键转录辅助调节因 子。 被激活的 Smadl 或 Smad5 蛋白由细胞桨转入细胞核后, 以直接和间 接方式作用于下游靶基因, 如 ALP 基因, 最终促进骨形成。
研究显示, BMP-2从两方面促进骨形成: 一是促进成骨细胞分化。 骨 基质中的 BMP-2 可募集骨髓干细胞并诱导骨髓干细胞分化为成骨细胞及 软骨细胞, 再通过钙盐沉积形成新骨。 BMP-2还诱导间叶细胞中成骨细胞 的分化及幼骨的重塑。 BMP-2在骨的再生和修复过程中也促进成骨细胞的 分化并抑制其凋亡。 二是促进其他成骨因子的表达。 BMP-2能够增加成骨 细胞标志基因 OPN、 CbfaK Col I alphaK BSP、 ALP、 fabp4 (脂肪酸偶联 蛋白 4)等的表达, 这些基因的相应蛋白在成骨细胞分化中起非常关键的作 用。
有研究表明骨质疏松症柑关基因 (一个或多个基因) 位于染色体 20 短臂上的一个区域内, 而骨形态发生蛋白 -2 (BMP-2) 蛋白基因是其中的 一个相关基因。 哺乳动物和鱼类的 BMP-2 蛋白基因 bmp-2 的 3'-UTR (3 '-untranslated regions, 基因 3'端未翻译区)高度保守, 这说明 bmp-2 的 3,-UTR在进化上经受 (选择压。这段保守区域被证实是 bmp-2基因转录后 重要的调节因子,对 bmp-2的 3'-UTR的调节可影响基因 bmp-2的的表达, 进而影响 BMP-2蛋白及其他骨质疏松相关因子的表达。
为了获得新型促进骨形成的药物, 本研究所张月琴等建立了以 bmp-2 启动子为药物作用靶点的促 BMP-2上调的抗骨质疏松药物筛选模型(参见 中国专利申请: 03104750.5 ) , 并应用该模型对微生物来源及化学合成的 化合物进行筛选。 通过大量的筛选工作, 发现一类具有五元不饱和杂环结 构的化合物具有明显上调 BMP-2的活性,并在卵巢摘除模型大鼠体内验证 其确有改善骨质疏松症状的效果 (参见中国专利 ZL 200610008114.6) 。 本发明在上述研究的基础上, 进一步设计、 合成和筛选一系列可以用 以下通式表示的苯并五元不饱和杂环类化合物 (式 I ) , 尤其是其中的 2- 酰基苯并五元不饱和杂环化合物, 经过系统结构改造与构效关系研究, 可 以为骨质疏松治疗提供新的先导结构,并从可以上调 BMP-2蛋白的活性化 合物入手, 进一步开发出了新型促骨形成的抗骨质疏松药物。
Figure imgf000006_0001
式 ( I ) 发明内容
本发明提供了具有通式( I )结构的苯并五元不饱和杂环类化合物系列 或其药用盐, 该类化合物具有上调骨形成蛋白 BMP-2 表达活性, 可用于 治疗骨质疏松症。
本发明还提供了所述苯并五元不饱和杂环类化合物的合成方法。
本发明还提供了所述苯并五元不饱和杂环类化合物在治疗骨质疏松症 以及由于骨质疏松所导致的相关病患方面的应用。
本发明还提供了可治疗骨质疏松症的药物组合物,该药物组合物以上述 苯并五元不饱和杂环类化合物或其药用盐为活性组分。
本发明主要设计合成以苯环上不同位置 (4-, 5-, 6-, 7- )被取代的 2位羧 酸酯的苯并噻吩、 苯并呋喃或吲哚为母核的式 I化合物、 在 2-位引入带有 苯丙烯基的化合物、 以及在 2-位引入带有甲砜或甲基亚砜的化合物。 讨论 苯环上连有垸基、 卤素、 甲氧基、 氨基、 酰基、 羧基等带有不同取代基, 以及 2-位乙酰基在空间上的不同的共轭延伸对化合物上调 BMP-2活性的 影响。 所设计的目标化合物结构如表 1所示, 式 I中的苯环上可以带有垸 基、 垸氧基、 卤素、 卤代垸基等取代基; 噻吩、 呋喃环或吡咯结构部分的
1^为垸基、 烷氧基、 羧基、 砜甲基、 亚砜甲基、 取代芳丙烯基结构等。
本发明提供了具有如通式 I所示结构的苯并五元不饱和杂环化合物或 药用 ,
Figure imgf000007_0001
式中,
X代表 0、 S或 NR7, 其中 R7代表 H、 烃基、 卤代烃基、 羰基烃基、 羟基烃基、 氨基烃基或烃氧基;
Y代表 CO 或 CR OH; R 代表以下基团: H、 OH、 含有 1-18个碳的 烃基、 羧基、 酰基、 烷氧基、 磺酸基;
^代表以下基团: H、 OH、 含有 1-18个碳的烃基、 羧基、 酰基、 烷 氧基、磺酸基、 CH2S(0)nR8、 R9取代苯丙烯基; 其中 R8代表 H、 含有 1-18 个碳的烃基、 卤代烃基、 羟基烃基或烃氧基, n=l-2; R9代表 H、 烃基、 烷 氧基、 卤素、 羧基、 氨基或取代的氨基; 且^可以与 相同, 也可以与 不同;
R2代表以下基团: H、 含有 1-18个碳的烃基、 卤素、 酰基、 羧基、 氨 基或取代的氨基、 磺酸基、 腈基或酰基烃氧基等;
代表以下基团: H、 烃基、 烷氧基、 卤素或卤代垸基、 羧基、 氨基 或取代的氨基、 酰基、 酰胺基、 酯基或磺酸基等;
R4代表以下基团: H、 烃基、 垸氧基、 卤素或卤代烷基、 羧基, 氨基 或取代的氨基、 酰胺基、 酰基、 酯基或磺酸基等;
代表以下基团: H、 烃基、 垸氧基、 卤素或卤代垸基、 羧基、 氨基 或取代的氨基、 酰基、 酰胺基、 酯基或磺酸基等;
R6代表以下基团: H、 烃基、 垸氧基、 卤素或卤代垸基、 羧基、 氨基 或取代的氨基、 酰基、 酰胺基、 酯基或磺酸基等; 或者,
R4与 ^通过碳、 氧或氮连接在一起形成 5-7元环结构或带有取代基 R1Q的 5-7元环结构, 其中 R1Q代表 H、 烃基、 卤代烃基、 羰基烃基、 羟基 烃基、 氨基烃基或烃氧基。
以上定义中所述的:
"烃基"可以是指碳原子数在 1-18的直链或支链的烷基或环烷基, 例 如, 甲基、 乙基、 异丙基、 正丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 正戊基、 异戊基、 正己基、 异己基等或其相应的环垸基。
"垸氧基"可以是碳原子数在 1-18的烷氧基, 例如, 甲氧基、 乙氧基、 异丙氧基、 正丙氧基、 正丁氧基、 异丁氧基、 仲丁氧基、 叔丁氧基、 正戊 氧基、 异戊氧基、 正己氧基、 异己氧基等。
"酰基 "可以是具有 1-18个碳的烃取代酰基或芳基酰基,例如甲酰基、 乙酰基、 异丙基酰基、 正丙基酰基、 烯丙基酰基、 环丙基酰基、 正丁基酰 基、 异丁基酰基、 仲丁基酰基、 叔丁基酰基、 正戊基酰基、 异戊基酰基、 正己基酰基、 异己基酰基、 苯基酰基、 甲苯基酰基等。
"酯基"可以是具有 1-18个碳的烃取代酯基(烃基酰氧基)或芳基酯 基, 例如甲酰氧基、 乙酰氧基、 异丙基酰氧基、 正丙基酰氧基、 烯丙基酰 氧基、 环丙基酰氧基、 正丁基酰氧基、 异丁基酰氧基、 仲丁基酰氧基、 叔 丁基酰氧基、 正戊基酰氧基、 异戊基酰氧基、 正己基酰氧基、 异己基酰氧 基、 苯基酰氧基、 甲苯基酰氧基等。
"酰氨基" 可以是具有 1-18个碳的烃取代酰氨基或芳基酰氨基, 例 如甲基酰氨基、 乙基酰氨基、 异丙基酰氨基、 正丙基酰氨基、 烯丙基酰氨 基、 环丙基酰氨基、 正丁基酰氨基、 异丁基酰氨基、 仲丁基酰氨基、 叔丁 基酰氨基、 正戊基酰氨基、 异戊基酰氨基、 正己基酰氨基、 异己基酰氨基、 苯基酰氨基、 甲苯基酰氨基等。
本发明提供的苯并五元不饱和杂环化合物或其药用盐中, 当有取代基 团时, 通常是指 C1-C6的低级垸基、 低级垸氧基、 卤素、 氨基等, 尤其是, 取代的氨基的取代基可以是 C2-C6的垸基。
本发明的苯并五元不饱和杂环化合物或其药用盐结构式的取代基中, 所述卤代烃基、羰基烃基、羟基烃基、氨基烃基中的烃基为 C1-C6的烃基。
根据本发明提供的苯并五元不饱和杂环化合物或其药用盐, 其相应的 苯并噻吩 /呋喃、 吲哚类化合物, 尤其具有显著上调骨形成蛋白 BMP-2表 达活性的效果, 体内抗骨质疏松作用研究结果显示, 本发明的化合物有改 善 SAMP6小鼠骨质疏松症状的效果。
优选地,所述苯并五元不饱和杂环化合物包括 2-取代苯丙烯酰-苯并噻 吩、 2-取代苯丙烯酰 -苯并呋喃、 或苯环部分通过 、 以甲醛缩合而形 成邻二苯醚结构后得到的化合物。
本发明所述苯并五元不饱和杂环化合物或其药用盐结构优选包括, 2 位的取代基为 2-烃氧基甲酰基或 2-烃基酰基的苯并噻吩或苯并呋喃化合 物。
本发明所述苯并五元不饱和杂环化合物或其药用盐结构优选包括, 2 位的取代基为 2-(2,-甲砜或甲基亚砜乙酰基)或 2-(2,-甲砜或甲基亚砜取代 -Γ-羟基)乙基的苯并噻吩、 苯并呋喃或吲哚化合物。
作为非限定性示例, 本发明所述的苯并五元不饱和杂环化合物可以选 自下列具体化合物:
2-乙氧甲酰-苯并噻吩
2-(2,-甲基亚砜基) -乙酰苯并噻吩
2-(2,-甲砜基)乙酰-苯并噻吩
2-乙氧甲酰 -5,6-亚甲基二氧-苯并噻吩
2- (2,-甲基亚砜基)乙酰 -5,6-亚甲基二氧-苯并噻吩 2-(2,-甲砜基)乙酰 -5,6-亚甲基二氧-苯并噻吩
2-乙氧甲酰-苯并呋喃
2-(2,-甲基亚砜基) -乙酰苯并呋喃
2-乙氧甲酰 -4-氯-苯并噻吩
2-(1,-羟基 -2,-甲基亚砜基) -乙基-苯并噻吩
2-乙氧甲酰- 4-甲氧基-苯并呋喃
2-乙氧甲酰- 5-甲氧基-苯并呋喃
2-乙氧甲酰 -6-甲氧基-苯并呋喃
2-乙氧甲酰 -7-甲氧基 -苯并呋喃
2-乙氧甲酰 -5,6-二甲氧基-苯并噻吩
2-乙氧甲酰- 7-氟-苯并呋喃
2-乙氧甲酰 -5,7-二氯-苯并呋喃
2-乙氧甲酰 -5-甲氧甲酰-苯并噻吩
2-乙酰 -5-甲氧甲酰-苯并噻吩 '
2-乙氧甲酰 -6-甲氧甲酰-苯并噻吩
2-乙酰 -5-羧基-苯并噻吩
2-乙酰 -6-甲氧甲酰-苯并噻吩
2-乙酰- 6-羧基-苯并噻吩
2-(2,-甲基亚砜基)乙酰 -4-氯-苯并噻吩
2- (2,-甲基亚砜基)乙酰 -4-甲氧基-苯并呋喃
2- (2,-甲基亚砜基)乙酰 -5-甲氧基-苯并呋喃
2-(2,-甲基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩
2-(2,-甲基亚砜基)乙酰 -6-甲氧基-苯并呋喃
2- (2,-甲基亚砜基)乙酰 -7-甲氧基-苯并呋喃
2-乙氧甲酰 -6-二乙氨基-苯并呋喃
-2-[3,-(4"-甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻吩 ( )-2-[3'-(4"-甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻吩 2-(Γ -羟基 -2,-甲基亚砜基)乙基 -5,6-亚甲基二氧-苯并噻吩
2-(1 '-羟基)乙基 -5-甲氧甲酰-苯并噻吩
2-(Γ-羟基)乙基 -6-甲氧甲酰-苯并噻吩
f¾)-2-肉桂酰 -6-乙氧甲酰-苯并噻吩
(E 2-[3,-(2",3",4,,-三甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻吩
(¾-2-[3,-(2",3",4"-三甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻吩 f¾j-2-肉 桂酰 -5-乙氧甲酰-苯并噻吩
(¾-2-[3,-(2"-氯苯基)丙烯酰 ]-5-乙氧甲酰 -苯并噻吩^ -2-[3,-(2"-氯苯 基)丙烯酰 ]-5-甲氧甲酰-苯并噻吩
fE 2-[3,-(2,,-氯苯基)丙烯酰 ]-6-乙氧甲酰-苯并噻吩
(¾)-2-[3,-(3",4"-二甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻吩
(¾-2-[3 '-(3",4"-二甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻吩
2-(2'—甲砜基)乙酰 -5-甲氧基-苯并呋喃
2-(1,-羟基 -2,-甲基亚砜)乙基 -5-甲氧基-苯并呋喃
fE 2-[3,-(4,,-甲氧基苯)丙烯酰 ]-5,6-二甲氧基 -Π引哚
小甲基 -2- [3,-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基 -Π引哚
-1-氯乙基 -2-[3,-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基』引哚
-1-乙酰基 -2-[3,-(4"_氟苯)丙烯酰 ]-5,6-二甲氧基 -吲哚
f¾M-(2,-羟乙基 )-2-[3,-(4"-氟苯)丙烯酰 ]-5-乙酰氧基 -吲哚
(£ 1-(2,-氨基乙基)-2-[3,-(4"-氟苯)丙烯酰]-5-乙酰氧基-吲哚
(Ε 1-(2,-甲氧基乙基) -2-[3,-(4,,-氟苯)丙烯酰 ]-5-乙酰氧基』引哚 2-乙氧甲酰 -4-甲基-苯并噻吩
2-庚酰 -5,6-二甲基-苯并噻吩
2-戊氧甲酰 -5,6-二氨基苯并噻吩
2-酮酸-苯并噻吩 2-(Γ,2'-二羰基)戊基苯并噻吩
2- (丁基亚砜基)乙酰 -5,6-二氨基-苯并噻吩
2-(4'-氯庚氧甲酰) -5,6-二甲氧基-苯并噻吩
2-(4,-氯己基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩
2-(6'-羟基己基:)氧甲酰 -5,6-二甲氧基-苯并噻吩
2-(6,-羟基戊亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩
2^(6'-甲氧基己基)氧甲酰 -5,6-二甲氧基-苯并噻吩
2-(6,-甲氧基戊基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩
2-乙氧甲酰 -5,6-乙基亚甲基二氧-苯并噻吩
2-乙氧甲酰 -5,6-(2,-氯乙基)亚甲基二氧-苯并噻吩
2-乙氧甲酰 -5,6-(1,-羟乙基)亚甲基二氧-苯并噻吩
2-乙氧甲酰 -5,6-(1,-氨乙基)亚甲基二氧-苯并噻吩
2-乙氧甲酰- 5,6-(1,-甲氧基乙基)亚甲基二氧-苯并噻吩
2-乙酰苯并噻吩
(Ε 2-(3'-(4"_甲氧基苯)丙烯酰) -苯并噻吩
2-乙酰-苯并呋喃 '
本发明还提供了式 ( I ) 相关化合物的合成方法。
Α、 当式 (I) 中的 X为 S, Y代表 CO 或 CR OH, 为 CH2S(0)nR8 或 取代苯丙烯基结构时,采用路线 1或路线 2所示方法首先得到中间体 ( IV ) , 其中, R2, R3, , R5, R6, R8, R9, n, '的定义同权利要求 1, R„代表 H、 OH、 含有 1-18个碳的烃基、 羧基、 酰基、 烷氧基或磺酸基; 路线 1 :
Figure imgf000012_0001
合成方法为: 以取代的 硝基苯甲醛 (Π) 为起始原料, 在碱性试剂 催化下, 使用巯基乙醇进行芳香的亲核取代反应, 原料的 N02被乙硫基取
.R
代, 生成中间体 (III) ; 在碱性试剂催化下, 卤代试剂 0 (Z代表 离去基团),与中间体(ΙΠ)反应,得到 2-取代酰基苯并噻吩的衍生物(IV);
路线 2:
Figure imgf000013_0001
II IV
合成方法为: 以取代的邻硝基苯甲醛 (Π) 为起始原料, 在碱性试剂 催化下, 与巯基试剂
Figure imgf000013_0002
直接进行反应得 2-取代酰基苯并噻吩的衍 生物 (W) ; ,
进一步, 所述中间体 (W) 可分别进行如下反应得到相应的通式 I化 合物:
a. 当 R3, , R5, R6中的一个或多个为酯基时, 中间体 (W) 在碱 性条件下水解得到羧酸衍生物 (V) , 其中 R3', R , R5', R6'分别相应于 R3, R4, R5, R6水解后的基团
Figure imgf000013_0003
; 或
b. 中间体 (IV) 经还原得到相应的羟基衍生物 (VI)
Figure imgf000014_0001
IV VI ; 或
c. 当 R„为甲基时, 中间体 (IV) 与 R9取代的苯基甲醛中间体 (VII) 进行羟醛缩合, 得到 2位为 R9取代苯丙烯酰的化合物 (覆)
Figure imgf000014_0002
d. 当 „为垸氧基时, 中间体 (IV) 可进行如下反应得到相应的通式 I化合物:
Figure imgf000014_0003
XI
中间体 (IV) 在强碱与加热下, 与亚磺酰甲基衍生物反应得到化合物 2-(2,-取代甲基亚砜)酰基苯并噻吩衍生物 (K) , 继续进行氧化和还原分 别得到化合物 2-(2,-取代甲砜乙酰基)苯并噻吩衍生物 ( X ) 和 2-(2,-取代 甲砜或甲基亚砜 -Γ-羟基)乙基苯并噻吩衍生物 (XI) ;
B、 当式( I )中的 X为 0, Y代表 CO 或 CR OH, R!为 CH2S(0)nR8 时, 其合成采用路线 3所示方法得到中间体 (ΧΙΠ) , 其中, R2, R3, , R5, Re, R8, n, R 的定义同权利要求 1, R12代表以下基团: H、 OH、 含 有 1-18个碳的烃基、 羧基、 酰基、 垸氧基、 磺酸基 路线 3 :
Figure imgf000015_0001
合成方法为: 以取代的邻羟基苯甲醛 (ΧΠ)为起始原料, 在碱性试剂催
R2
13
化下, 与卤代试剂 0 (Z代表离去基团) 进行反应, 生成 2-羰基类 ( XIII ) 化合物;
其中, 当 R12为垸氧基时, 中间体 (ΧΠΙ ) 可进行如下反应得到相应 的通式 I化合物:
Figure imgf000015_0002
XVI
中间体 (ΧΠΙ)再在强碱与加热下,与亚磺酰甲基衍生物反应得到 2-(2,- 取代甲基亚砜)酰基苯并呋喃衍生物 (XIV), (XIV)继续进行氧化和还原分别 得到化合物 2-(2,-取代砜基)乙酰苯并呋喃衍生物 (XV)和 2-(2,-取代甲砜或甲 基亚砜 -Γ-羟基)乙基苯并呋喃衍生物 (XVI);
C、 当式 ( I ) 中 X为 NR7, Y代表 CO, 为 R9取代苯丙烯基结构 时, 其合成采用路线 4所示方法, 其中, R2, R3, R4 , R5, R6, R7, R9的 定义同权利要求 1 ;
路线 4:
Figure imgf000016_0001
合成方法为: 以取代的 N-R7-2-乙酰吲哚 (XVII ) 为起始原料, 在碱性 试剂催化下, 与取代的苯基甲醛中间体 (W )进行羟醛縮合, 得到 2位为 R9取代的苯丙烯酰目标物 (XVIII ) 。
本发明发现了通式( I ) 中化合物, 2-垸氧甲酰-苯并噻吩 /呋喃衍生物
(化合物 3b, 5b, 6b, 7b, 9b, 10b, l ib, 12b, 13b, 16b, 18b, 21b, 22b, 23b 等) 、 2-乙酰 /羟乙基苯并噻吩 /呋喃衍生物 (化合物 G39, lc, le, 2c, 2e, If, 2f等) 、 2-取代苯丙烯酰-苯并噻吩 /呋喃衍生物 (化合物 S25 , IdA, ldBl, ldC, 2dA, 2dB, 2dC, 2dD, G33-1 , G33-2, G33-3 , G33-4, G33-5 , G33-6, G33-7等) 、 2- ( 2-亚砜基 /砜基) -乙酰苯并噻吩 / 呋喃衍生物(化合物 3c, 3d, 4c, 7c, 9c, 10c, l id, l ie, 12c, 13c, 18c, 22c, 23c等) 、 苯基部分 R4、 R5为甲醛缩邻二苯醚结构衍生物 (化合物 8b, 8c, 8e, 24b, 25b, 26b, 27b, 28b 等) 等具有显著上调骨形成蛋白 BMP-2 表达活性。体内抗骨质疏松作用研究结果, 前述各类化合物中的代 表化合物 (8b, 3c, S25 , G39) 均有改善 SAMP6小鼠骨质疏松症状的效 果, 本发明提供了它们在治疗骨质疏松方面的应用。
本发明还提供了含有所说化合物的药物组合物, 可以含有治疗有效量 的上述化合物或其药用盐为活性成分, 以及含有一种或多种药学上可接受 的载体。
本发明的式 I化合物和药物组合物可用于制备抗骨质疏松药物。
本发明提供的药物组合物可以是按照药学领域的常规生产方法制备的 各种给药剂型, 例如使活性成分与一种或多种载体混合, 然后将其制成所 需的剂型。 例如可将化合物本身或其与可药用赋形剂、 稀释剂等的混合物 以片剂、 胶囊、 颗粒剂、 散剂或糖浆剂的形式口服给药或以注射剂的形式 非口服给药。本发明的药物组合物优选含有重量比为 0.1%-99.5%的活性成 分, 最优选含有重量比为 0.5%-99.5%的活性成分。 上述制剂可通过常规制 药方法制备。 可用的药用辅剂的例子包括赋形剂 (例如糖类衍生物如乳糖、 蔗糖、 葡萄糖、 甘露糖醇和山梨糖醇; 淀粉衍生物如玉米淀粉、 土豆淀粉、 糊精和羧甲基淀粉; 纤维素衍生物如结晶纤维素、 羟丙基纤维素、 羧甲基 纤维素、 羧甲基纤维素钙、 羧甲基纤维素钠; 阿拉伯胶; 右旋糖酐; 硅酸 盐衍生物如偏硅酸镁铝;磷酸盐衍生物如磷酸钙;碳酸盐衍生物如碳酸钙; 硫酸盐衍生物如硫酸钙等)、 粘合剂 (例如明胶、 聚乙烯吡咯垸酮和聚乙二 醇)、 崩解剂 (例如纤维素衍生物如羧甲基纤维素钠、 聚乙烯吡咯烷酮)、 润 滑剂 (例如滑石、 硬脂酸钙、 硬脂酸镁、 鲸蜡、 硼酸、 苯甲酸钠、 亮氨酸)、 稳定剂 (对羟基苯甲酸甲酯、 对羟基苯甲酸丙酯等)、 矫味剂 (例如常用的甜 味剂、酸味剂和香料等)、稀释剂和注射液用溶剂 (例如水、 乙醇和甘油等)。
药效实验
按照以上所说路线和方法, 能够稳定、 可重复性地合成得到本发明化 合物。
实验一 体外 BMP-2上调活性筛选
用已构建好的上调 BMP-2 筛选模型 (具体参见中国专利申请: 03104750.5的记载内容) , 质粒 PYJ瞬时转染 MC3T3E1细胞, 具体过程 为: 将 100 μ!7孔适量浓度的 MC3T3E1细胞在 96孔无菌塑料培养板内培 养 8h, 用 25 μ!7孔无血清无双抗 DMEM培养基稀释适量 PYJ质粒 DNA 于无菌离心管中,在另一个无菌离心管中用 25 μ!7孔无血清无双抗 DMEM 培养基稀释 0.5 μ!7孔 LF2000 Reagent, 在 5 min之内, 将上述两管合并混 匀, 室温下再孵育 20 min, 将混合后的转染悬液加到上述 96孔板内, 每 孔 50 μί, 充分混匀后将 96孔板置于 37°C二氧化碳培养箱内, 培养一定时 间然后加入适量浓度的药物作用细胞后再进行荧光检测; 具体检测过程如 下: 弃去 96孔板中的培养基, 用 200 μΙ7孔 的 PBS (ρΗ 7.0) 轻轻漂洗细 胞后, 完全弃去 PBS, 加入 25 μΙ7孔的 l xPLB, 室温下振摇 15 min, 使细 胞完全裂解, 将裂解液完全吸出到荧光分析用 96 孔白板相应孔内, 加入 70 μΙ7孔的分析试剂 LAR II于分析用白板内后, 立即(5 min内)将分析用 白板置于 Galaxy分光光度计内; 检测条件为: 无激发光波长, 发射光波长 为 empty, Positioning delay为 1.0, Number of intervals为 1, Interval time 为 1.0s, 设置仪器读数前要为振摇模式, 振摇直径为 1毫米, 利用设置的 阳性对照、 空白对照以及相关的数据和计算公式, 计算样品的上调率。 结 果见表 1。
上调率 = (样品发光数 - DMSO发光数) / DMSO发光数 χ100% 本发明采用上述 ΒΜΡ-2筛选模型对所合成的化合物的活性进行评价。 选用 0.1%DMSO为阴性对照, 0.4 M Lovastatin为阳性对照, 试验药物浓 度为 4 μ Μ, 活性测定结果如表 1所示。 表 1给出了本发明的优选化合物 的结构, 但不以任何方式限制本发明。 表 1 本发明化合物的结构及体外上调 ΒΜΡ-2的活性
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多次活性测定试验结果证明, 本发明化合物对骨形态形成蛋白一 2均 有上调作用。 其中, 表 1中化合物 2dB,7b, 5b, lc, 6b, le, 2c, 2e, 2f, 2dA,8b, 10b, lib, 12b, G33-1, G33-2, G33-4, G33-5, G33-6, G33-7,24b 的活性强于对照药, 化合物 6b, le, 2e, 2c, 12b等的上调率在 100%左右, 化合物 ldBl, 4c, 10c, 8e, 3c, 23c的活性与对照药相当。 实验例二 体内活性实验
在体外活性筛选结果的基础上, 选择本课题组合成的化合物 G39、 S25、 3c和 8b 进行了体内活性评价。选择 SAMP6 (Senescence-accellerated mouse, strain P6, 购于北京大学医学部实验动物中心) 快速老化小鼠做为 体内活性筛选模型, 19周大 SAMP6小鼠, SPF级。 共 35只, 14只雌性 小鼠, 21雄性小鼠。 雌性小鼠体重 25-35g, 雄性小鼠体重 30-38g。 ; 阳性 对照药为洛伐他汀 (Lovastatin, Lov, 购自浙江瑞帮药业有限公司)和雷尼酸 锶 (Strontium mnelate, Sr, 购自北京华奉联博科技有限公司); 空白对照组 为 0.5%MC (甲基纤维素水溶液) 。
试剂: 免疫组化所用一抗 BMP-2抗体购自美国 Abeam (货号 abl4933), 二抗购自美国 Zymed (货号 PV6001).小鼠骨碱性磷酸酶 (BAP) 试剂盒和 小鼠 (尿液)脱氧吡啶啉 (DPD) 试剂盒为美国 ADL公司产品。 骨钙素试 剂盒为北京中同蓝博临床检验所产品。 尿肌酐 (Cr)试剂盒为柏定生物工程 (北京)有限公司生产。
购买 SAMP6小鼠后, 置于本所实验动物房屏障系统, 普通词料喂养, 适应一周。 雌鼠每笼两只, 雄鼠每笼一只。 室温 18-23 °C, 食水充足, 水 瓶和垫料每周更换两次, 平均每 10天称一次体重。测量小鼠骨密度, 按照 骨密度值对 SAMP6雌雄小鼠分别进行随机分组, 小鼠分为 7组, 每组 2 只雌鼠, 3只雄鼠。 雌鼠 1笼 2只, 雄鼠 1笼 1只。
雷尼酸锶用生理盐水溶解, 其余药物均用 0.5% MC做成悬浮液。
0.5%MC (甲基纤维素) 溶液的配制方法: 将 5g MC加入 1000ml 蒸馏水 中, 搅拌均匀。
实验药物的给药剂量设定为:洛伐他汀和雷尼酸锶给药剂量分别为 10 mg/kg-d和 625 mg/kg'd, 其余化合物的给药剂量均为 30 mg/kg'd, 空白组 给予 0.5%MC溶液。 给药方式均为灌胃。 每天上午 9点给药, 每天一次, 连续给药, 给药 3个月, 共 13周。 实验结果如下:
小鼠体内 BMP-2表达水平: 给药结束取小鼠左侧股骨做冰冻切片, 然 后进行 BMP-2免疫组化染色,测定了 BMP-2阳性反应细胞胞浆着色水平。 具体数值和统计结果见表 2。 表 2 各给药组 SAMP6小鼠体内 BMP-2阳性细胞面积百分比 (mean±SD) compound Lova Sr MC G39b S25 3ca 8ba area% 2.23±0.52 2.19±0.71 1.25±0.21 2.19±0.31 2.47±0.79 2.48±0.76 2.27±0.51 a与空白对照 MC组相比, p<0.05 (n=5); b与空白对照 MC组相比, p<0.005 (n=5)。 小鼠股骨 BMP-2免疫组化染色测定结果,与快速老化小鼠模型对照组 (MC)相比, 所有给药组小鼠股骨组织中的 BMP-2表达均有明显提高。 其 中, Lov、 G39、 3c和 8b组的 BMP-2表达具有显著性提高, Sr和 S25组 未见显著性差异。 试验药物 G39和 8b组小鼠股骨 BMP-2表达水平与 Lov 组相当, 3c给药组小鼠股骨 BMP-2表达水平高于 Lov和 Sr对照组。
小鼠骨密度:使用法国 MEDILINK公司生产的数字锥束闪光骨密度仪 OSTEOCORE 3测量小鼠骨密度, 该骨密度仪属于双能 X光骨密度仪
(dual-energy X-ray absorptiometry, DXA)。 数据分析采用仪器自带的小动物 分析软件 (V6.14), 在软件环境下, 手动填充小鼠骨骼, 软件计算填充区域 的骨密度。 分析骨密度选择了 3个感兴趣区域 (ROIs: regions of interest): 1. total: 全身; 2. spine: 脊柱; 3. left hind leg: 左侧后腿。 骨密度采集时间 点分别为给药的第 0周 (小鼠 19周龄), 第 4周 (小鼠 23周龄), 第 8周 (小 鼠 27周龄), 第 12周 (小鼠 31周龄)。 各个时间点的骨密度数据见表 3。
表 3 各时间点 3个 ROIs的 BMD数据 (mean±SD) group age/weeks 19 23 27 31
ROIs BMD(g/cm2)
Lov 0.067±0.002 0.069±0.003 0.069±0.003 0.070±0.003
Sr 0.068±0.003 0.065±0.003 0.069±0.002 0.070±0.007
MC 0.067±0.003 0.065±0.004 0.067±0.004 0.067±0.002
G39 total 0.066±0.005 0.066±0.004 0.074±Ό.009 0.068±0.002
S25 0.065±0.002 0.064±0.004 0.068±0.004 0.070±0.006
3c 0.067±0.004 0.067±0.006 0.069±0.005 0.072±0.005
8b 0.067±0.002 0.066±0.004 0.068±0.007 0.072±0.003a
Lov 0.057±0.005 0.073±0.009 0.091±0.007 0.095±0.007a Sr 0.060±0.009 0.066±0.010 0.089±0.015 0.090±0.019
MC 0.056±0.007 0.071±0.005 0.082±0.014 0.087±0.007
G39 spine 0.053±0.007 0.067±0.013 0.094±0.020 0.086±0.004
S25 0.052±0.007 0.064±0.010 0.083±0.008 0.089±0.013
3c 0.060±0.008 0.072±0.015 0.088士 0.011 0.090±0.013
8b 0.055±0.008 0.069±0.013 0.081±0.006 0.091±0.008
Lov 0.061±0.006 0.055±0.003 0.053±0.003 0.046±0.003
Sr 0.065±0.005 0.051±0.01 1 0.049±0.003 0.047±0.006
MC left 0.059±0.004 0.050±0.003 0.047士0.002 0.046±0.002
G39 hind leg 0.064±0.003 0.056±0.002 0.059±0.002 0.050士 0.001
S25 0.061±0.007 0.051±0.003 0.048±0.003 0.050±0.007
3c 0.064±0.004 0.051±0.006 0.043±0.002 0.050士 0.004
8b 0.064±0.003 0.050±0.003 0.049±0.003 0.053±0.008 a与空白对照 MC组相比, p<0.05 (n=5);
连续给药 13周后骨密度测定结果显示, 与模型对照组相比: Lov、 Sr、 S25、 3c和 8b给药组小鼠的全身骨密度均有增加, 其中, 3c和 8b组增加 更加明显, 8b组小鼠的全身骨密度增高最明显; Low Sr、 3c和 8b给药组 小鼠的脊柱骨密度增加比较明显, Lov组小鼠脊柱骨密度增高最明显; S25、 3c和 8b给药组小鼠的左侧后腿骨密度均有明显增加, 对照药 Lov和 Sr组 变化不明显。
从表 3还可以看出小鼠骨密度的变化趋势, 给药期间各试验组小鼠的 脊柱骨密度均呈增加趋势, 给药组的增加趋势较模型对照组更强; 给药期 间各试验组小鼠的左侧后腿骨密度均呈减低趋势, 给药组的减低趋势较模 型对照有所减缓。 给药期间小鼠全身骨密度变化曲线比较复杂, 在给药 1 个月后, 小鼠全身骨密度呈下降趋势, 然后呈逐渐增加趋势。 SAMP6小鼠 骨密度的峰值出现在 4个月龄左右, 之后骨密度会逐渐降低。 而给药一段 时间之后, 相对给药初期, 全身骨密度己见改善。 G39组情况比较特殊, 给药 2个月后 G39组小鼠的全身骨密度、脊柱骨密度和左侧后腿骨密度增 加最明显, 但, 在给药满 3个月时的骨密度不但没再增加反而出现减少现 象, 其原因有待进一步研究。
小鼠骨组织形态计量学: 给药结束后, 取小鼠右侧股骨做成不脱钙骨 切片, 以测定骨组织形态计量学数据。 采用 Leica-Qwin图像分析仪系统, 对不脱钙骨切片进行形态计量。骨小梁体积百分比 (TBV%): 骨小梁体积占 被测骨髓腔总体积的百分比, 是衡量骨量水平的主要标志; 骨小梁吸收表 面百分比 (TRS%):不规则、凹凸不平的骨小梁表面占骨小梁表面的百分比, 它可判断破骨细胞的活性; 骨小梁形成表面百分比(TFS% ) : 有成骨细胞 被覆的类骨质表面占骨小梁表面的百分比, 它可判断成骨细胞的活性; 皮 质内表面类骨质平均宽度 (OSW) : 皮质内表面有成骨细胞被覆的类骨质 的平均宽度。 各给药组详细数据见表 4。
表 4 各给药组 SAMP6小鼠骨组织形态计量学数据 (mean±SD)
Group TBV% TFS% TRS% OSW )
Lov 7.44±2.05a 6.22±0.97a 6.64±1.64 6.59士 0.29a
Sr 6.72±5.47 5.25士 2.03 7.56±1.86 5.63±0.66
MC 3.88±0.58 4.46±0.47 7.47±1.12 5.93±0.42
G39 4.95士 0.80a 5.89±0.61b 7.09±1.31 5.55±0.82
S25 8.94士 3.68a 6.54±0.81b 6.29土 1.48 5.50±0.82
3c 5.95士 1.93 5.13士 0.82 6.45士0.60 5.85士 0.64
8b 7.10±2.15a 5·55±0.93 6.45士 0.82 5.76±0.58
a与空白对照 MC组相比, p<0.05 (n=5); b与空白对照 MC组相比, p<0.005 (n=5)。 骨小梁体积百分比 (TBV%^定结果,各给药组小鼠股骨 TBV%均较模 型对照组明显提高,其中, Lov对照组和 G39、 S25、 8b药物组小鼠的 TBV% 提高明显。 丁8¥%是衡量骨量水平的主要标志, 说明各给药组小鼠的骨量 均较模型对照组 (MC组)有所升高。
骨小梁形成表面百分比 (TFS%)测定结果, 各给药组小鼠股骨 TFS°/0¾ 较模型对照组明显提高, 其中, Lov对照组、 G39、 S25组小鼠的 TFS°/^ 平较模型对照组有显著提高。 TFS%是有成骨细胞被覆的类骨质表面占骨小 梁表面的百分比, 它可判断成骨细胞的活性。 结果证实 Lov组、 G39组和 S25组明显改善了小鼠的成骨细胞活性。
骨小梁吸收表面百分比 (TRS%)测定结果, Sr对照组小鼠的 TRS%与模 型组相当,其它所有给药组小鼠的 TRS%均低于模型对照组。 TRS%是指不 规则、 凹凸不平的骨小梁表面占骨小梁表面的百分比, 它可判断破骨细胞 的活性。 从结果上看, 除 Sr外, 其他药物均有降低小鼠破骨细胞活性的趋 势, 但从统计学上均未见显著性差异。
皮质内表面类骨质平均宽度 (OSW)测定结果, Lov药物对照组小鼠的 OSW与模型对照组相比有明显提高, 其它各给药组小鼠的 OSW与模型组 相比没有明显差异。 OSW是皮质骨中成骨细胞活跃程度的重要标志, 因此 除 Lov之外, 其他化合物在增加皮质骨成骨细胞活性上没有作用。
小鼠不脱钙骨切片照片中蓝色河流状蜿蜒的条带即是骨小梁, 照片取的是 部分区域, 不能代表整个骨头的情况, 但可以看出模型对照组 (MC组)的骨小梁 比各给药组要少。
骨组织形态计量学的测定结果表明 Lov、 G39、 S25和 8b可以改善小 鼠骨量水平; Lov、 G39和 S25改善了小鼠成骨细胞的活性, 但对皮质骨 成骨细胞活性没有作用; 各给药组对小鼠的破骨细胞活性作用不明显。
小鼠体重变化: 给药期间, 在给药的第 0, 5, 12, 21, 37, 51 , 66, 80天 称取小鼠的体重, 这 8次体重均为非空腹体重。 详细数据和走势见表 5。 各组小鼠的体重均缓慢增加, 提示各组小鼠均没有严重毒性。 表 5 给药期间小鼠体重变化 (非空腹体重) 组另 j 0d 5d 12d 21 d 37d 51 d 66d 80d
Lov 35.40±1.95 35.83±1.56 36.40±1.90 36.16±2.00 37.94±1.55 39.17±1.12 38.55±1.45 38.92±1.53 Sr 33.24±4.84 34.39±5.18 35.84±4.40 34.43±5.16 35.33±4.34 37.39±5.15 37.70±3.96 36.47±5.88 MC 31.17±3.26 32.01±2.24 33.38±1.42 33.35±2.07 34.58±1.92 35.64±2.46 36.03±1.89 36.04±2.59 G39 32.62±4.47 32.51±4.55 34.54±4.01 33.33±4.52 34.52±4.75 35.91±5.70 36.06±5.63 36.04±5.92 S25 31.81±2.77 32.31±3.56 33.60±2.72 32.56±2.89 33.61i4.10 36.82±3.31 35.95±4.01 36.59±2.05 3c 33.91±4.04 34.09±4.92 35.15±4.78 35.02±5.04 36.16±4.89 37.48±4.69 37.46±4.99 37.57±4.89 8b 34.47±2.54 35.04±2.67 36.74±4.96 36.31±4.87 37.88±6.17 40.25±5.43 40.46±5.96 39.98±3.96 具体实施方式
以下实施例可以使本专业技术人员更全面的理解本发明, 但不以任何 方式限制本发明。 本发明中所有化合物的结构均经1 H NMR所确定。 实施例 1 : 2-乙氧甲酰-苯并噻吩 (3b)
在以冰浴降温至 0°C下的、 含有邻硝基苯甲醛 (4.5 g, 30 mmol) 和无 水 K2CO3(5.0 g, 36.2 mmol)的 DMF(60 ml)中, 缓慢滴加巯基乙酸乙酯 (3.29 ml, 30 mmol) 0 滴加完毕, 0°C搅拌 30 min, 然后在 60°C油浴中反应 12 h。 把反应液倒入冰水中, 过滤收集固体, 氯仿溶解固体, 无水 Na2S04干燥, 过滤, 旋干溶剂后以硅胶柱层析分离后得到黄色固体 5.80 g(94%)。
iHNMR ( CDC13) δ: 1.42(t, J = 7.0 Hz, 3H), 4.42(q, J = 7.0 Hz, 2H), 7.39-7.47(m, 2H), 7.86-7.89(m, 2H), 8.06 (s, 1H). MS (EI+) m/z: 206[M]+. HRMS (EI+ ): found 206.0397[M]+, (Calcd for C„H10O2S: 206.0397 )。 实施例 2: 2-(2,-甲基亚砜基) -乙酰苯并噻吩 (3c)
氮气保护下, 把 60%氢化钠 (280 mg)放入三颈瓶, 石油醚洗三次洗去 包埋氢化钠的油脂。 加上盛有 DMSO(8 ml)的恒压滴液漏斗, 减压抽干剩 余的少量石油醚。把 DMSO加入氢化钠中, 迅速在恒压滴液漏斗中加入溶 有 2-乙氧甲酰-苯并噻吩 (3b) ( 200 mg, 0.97 mmol) 的 THF(8 ml)。 迅速抽 尽空气, 放入氮气, 反复三次。 将上述反应体系加热到 70-75°C, 溶液放 出大量氢气。 放完气泡, 冷至室温后加上冰浴降温, 缓慢滴加滴液漏斗中 的 THF溶液。 加毕, 室温搅拌 30 min。 将反应液倾入 3倍体积 (60 ml) 冰水中。 用 2N盐酸调 PH至 3〜4。 用氯仿 (80 mlx2)抽提反应液, 合并液用 蒸馏水 (160 mlx3)洗。 氯仿用无水 Na2S04干燥。 滤除 Na2S04, 蒸干氯仿相 得黄色固体 202 mg(87%)。 ]HNMR (CDCI3) δ: 2.79(s, 3H), AB system(4.33, 4.41, J= 13.2 Hz, 2H), 7.43(t, J=7Hz, IH), 7.51(t, J= 7.0 Ηζ,ΙΗ), 7.88(d, J= 7.0 Hz, IH), 7.94(d, J = 7.0 Hz, IH), 8.09(s, IH). MS (EI+) m/z: 238 [M]+. HRMS (EI+ ): found 238.0102 [M]+, (Calcd for CUHK SZ: 238.0122 )。 实施例 3: 2-(2,-甲砜基)乙酰-苯并噻吩 (3d)
2-(2,-甲基亚砜基)乙酰-苯并噻吩 (3c) (50 mg, 0.21 mmol) 溶解于冰醋 酸中 (2ml) , 冰浴冷却下缓慢加入 30%H2O2 (1 ml) 。 加毕, 室温搅拌 反应 5-6h。 加入二氯甲烷 (3 ml χ2)萃取出产物, 旋干溶剂后硅胶柱层析分 离后得到白色固体 2-(2,-甲砜基)乙酰-苯并噻吩 24mg (45%) 。
1HNMR(CDC13)5: 3.17(s, 3H), 4.60(s,2H), 7.45(t, J= 7.0 Hz, 1H), 7.53(t,
J= 7.0 Hz, IH), 7.89(d, J= 8.0 Hz, 1H), 7.96(d, J 8.0 Hz, IH), 8.11(s, IH). HRMS (EI+): found 254.0074 [M]+, (Calcd for C„H10O3S2: 254.0071)。
实施例 4: 2-乙氧甲酰 -5,6-亚甲基二氧-苯并噻吩 (8b)
以 3,4-亚甲基二氧 -6硝基苯甲醛和巯基乙酸乙酯为原料, 按照实施例 1 的方法合成得到橙黄色固体 2-乙氧甲酰 -5,6-亚甲基二氧-苯并噻吩 (68.5%) 0
]HNMR (CDCI3) δ: 1.39(t, J = 7.2 Hz, 3H), 4.37(q, J = 7.2 Hz, 2H), 6.04(s, 1H), 7.19(s, IH), 7.20(s, IH), 7.89(s, IH). MS (EI+) m/z: 250 [M]+. HRMS (EI+): found 250.0305 [M]+, (Calcd for C12H10O4S: 282.0002 )。
实施例 5: 2-(2,-甲基亚砜基)乙酰 -5,6-亚甲基二氧-苯并噻吩 (8c) 以化合物 8b为原料, 按照实施例 2的方法合成得到淡黄色固体粉末 (90%)。
" lWM (CDCI3) δ: 2.77(s, 3H), AB system(4.26, 4.33, J= 13.2 Hz, 2H), 6.08(s, IH), 7.22(s, 1H), 7.24(s, 1H), 7.91(s, 1H)。 HRMS (EI+ ): found 282.0002 [M]+, (Calcd for C12H1()04S2: 282.0021 )。 实施例 6: 2-(2,-甲砜基)乙酰 -5,6-亚甲基二氧-苯并噻吩 (8d) 以化合物 8c为原料, 按照实施例 3 的方法合成得到淡黄色固体粉末 (80.0%)
^MR ( CDC13 ) 5:3.15(s, 3H), 4.53(s, 2H), 6.09(s, 2H), 7.22(s, 1H), 7.24(s, 1H), 7.94(s, 1H)。 MS (EI+) m/z : 298 [M]+. HRMS (EI+ ): found 297.9967 [M]+, (Calcd for C12H10O5S2: 297.9970 )。 实施例 7: 2-乙氧甲酰-苯并呋喃 (9b)
向反应瓶中依次加入 DMF(5ml), 溴代乙酸乙酯(118 mg, 0.71 mmol), 水杨醛(146.6 mg, 1.2 mmol), 无水碳酸钾(166 mg, 1.2 mmol )。 100°C油浴 反应 4 h, 恢复至室温后, 先蒸除 DMF。 再用氯仿溶解, 水洗氯仿相。 分 层时, 氯仿相出现很多不溶物。 抽滤滤除不溶物, 用氯仿洗滤饼多次。 旋 干溶剂后硅胶柱层析分离后得到 57 mg淡黄色油状物 (55.9%)。
iHNMR CDCH 1.35(t, J= 7.2 Hz, 3H), 4.37(q, J= 7.2 Hz, 2H), 7.22(t; J = 7.6 Hz, 1H), 7.36(t, J = 7.6 Ηζ,ΙΗ), 7.45(s, 1H), 7.51(d, J = 8.0 Hz, 1H), 7.60(d, J = 8.0 Hz, 1H)。 MS (ESI+) m/z: 191.4 [M+H]+.HRMS (EI+ ): found 297.9967 [M]+, (Calcd for CuH10O3: 190.0630 )。 实施例 8: 2-(2,-甲基亚砜基)乙酰苯并呋喃 (9c)
以 9b为原料, 按照实施例 2的方法合成得到黄色固体 2-(2,-甲基亚砜 基)乙酰-苯并呋喃 (29.6%)。
!HNMR ( CDCI3 ) δ: 2.85(s, 3H), AB system(4.30, 4.39, J= 13.2 Hz, 2H), 7.35(t, J= 7.2 Hz, 1H), 7.54(t, J= 7.2 Hz, 1H), 7.61(d, J= 8.0 Ηζ,ΙΗ), 7.68(s, 1H), 7.75(d, J = 8.0 Hz, 1H)。 MS (EI+) m/z: 222 [M]+. HRMS (EI+ ): found 222.0350 [M]+, (Calcd for C„H10O3S: 222.0351 )。 实施例 9: 2-乙氧甲酰 -4-氯-苯并噻吩 (4b)
氢氧化钠 (100 mg, 2.5 mmol)溶于水 (0.2 ml)中,冰浴下缓慢加入巯基乙 酸乙酯 (0.28 ml, 2.5 mmol),室温搅拌 0.5 h。加入 2-氯 -6-氟-苯甲醛 (200 mg, 1.26 mmol)和二氧六环 (2 ml), 70°C油浴反应 7 h。 过滤, 氯仿洗滤饼。 全 自动快速制备色谱仪层析分离后得到淡黄油状产物, 冷却后为黄色固体。
JHNMR ( CDC13 ) δ: 1.43(t, J = 7.0 Hz, 3H), 4.43(q, J = 7.0 Hz, 2H), 7.35-7.41(m, 2H), 7.73-7.75(m, 1H)。 MS (EI) : 240. 'CNMR ( CDC13 ) δ: 14.30(C-2"), 61.83(C-1 "), 121.25(C-3), 124.81(C-7), 127.46(C-6), 128.35(C-5), 130.46(C-4), 134.76(C-4a), 137.27(C-2), 143.10(C-7a), 162.39(C-1 ').MS (EI+) m/z : 240 岡+, 242 [M+2] +· HRMS (EI+ ): found 240.0014 [M]+, (Calcd for C„H902SC1: 240.0012)。 实施例 10: 2-(Γ-羟基 -2,-甲基亚砜基) -乙基-苯并噻吩 (3e)
2-(2,-甲基亚砜基) -乙酰苯并噻吩(3c)(100 mg, 0.42 mmol)加入到
THF(2 ml)和蒸熘水 (2 ml)的混合液中, 搅拌溶解。 冰浴下分批加入硼氢化 钠 (20 mg, 0.53 mmol), 室温搅拌反应 0.5 h。 过滤, 滤液用氯仿提取。 旋干 溶剂后硅胶柱层析分离后得到淡黄色固体 2-(1,-羟基 -2,-甲基亚砜基) -乙基- 苯并噻吩 46 mg(54.2%)o
!HNMR ( CDCI3 ) δ: 2.74(s, 3H), 3.06-3.32(m,2H), 5.73-5.77(m, 1H),
7.29(s, 1H), 7.32-7.36(m, 2H), 7.73-7.83(m, 2H)。 MS (ESI+) m/z: 263.0 [M+Na] +.HRMS (ESI+ ): found 263.01885 [M+Na]+, (Calcd for CuH1202S2Na: 263.01764)。 实施例 11 : 2-乙氧甲酰 -4-甲氧基-苯并呋喃 (10b)
以 2-甲氧基 -6-羟基苯甲醛和溴代乙酸乙酯为原料,按照实施例 7的方 法合成得到淡黄固体 2-乙氧甲酰 -4-甲氧基-苯并呋喃 (100%)。
!HNMR (CDC13)6: 1.42 (t, J = 7.2 Hz, 3H), 3.95(s, 3H), 4.43(q, 7.2 Hz, 2H), 6.68 (d, J = 8.0 Hz, lH),7.19(d, J = 8.0 Hz, 1H), 7.36(t, J = 7.2 Hz, 1H), 7.62(s, 1H). MS (EI+) m/z: 220[M] +. HRMS (EI+ ): found 220.0732 [M]+, (Calcd for C12H1204: 220.0736)。 实施例 12: 2-乙氧甲酰 -5-甲氧基-苯并呋喃 (l ib) 以 3-甲氧基 -6-羟基苯甲醛和溴代乙酸乙酯为原料, 按照实施例 7的方 法合成得到白色固体 2-乙氧甲酰 -5-甲氧基-苯并呋喃 (82%)。
1HNMR (CDC13)5: 1.43 (t, J = 12 Hz, 3H), 3.85(s, 3H), 4.44(q, J = 7.2 Hz, 2H), 7.05 (d, J = 2.4 Hz, IH), 7.06(dxd, J = 8.2 Hz, 2.4Hz, IH), 7.46-7.49(m, 2H). MS (EI+) m/z: 220[M] +. HRMS (EI+ ): found 220.0733 [M] +, (Calcd for C12H1204: 220.0736)。 实施例 13 : 2-乙氧甲酰 -6-甲氧基-苯并呋喃 (12b)
以 4-甲氧基 -2-羟基苯甲醛和溴代乙酸乙酯为原料, 按照实施例 7的方 法合成得到白色固体 2-乙氧甲酰 -6-甲氧基-苯并呋喃 (68%)。
!HNMR (CDC13)5: 1.42 (t, J = 7.2 Hz, 3H), 3.87(s, 3H), 4.42(q, J = 7.2
Hz, 2H), 6.94 (dxd, J = 8.8 Hz, 2.0 Hz, lH),7.07(d, J = 2.0 Hz, 1H), 7.47(s, IH), 7.53(d, J = 8.8 Hz, 1H).MS (EI+) m/z: 220[M] +. HRMS (EI+ ): found 220.0739 [M]+, (Calcd for C12H1204: 220.0736)。
实施例 14: 2-乙氧甲酰 -7-甲氧基-苯并呋喃 (13b)
以 3-甲氧基 -2-羟基苯甲醛和溴代乙酸乙酯为原料,按照实施例 7的方 法合成得到白色固体 2-乙氧甲酰 -7-甲氧基 -苯并呋喃 (58%)。
JHNMR (CDC13)5: 1.42 (t, J = 7.2 Hz, 3H), 4.02 (s, 3H), 4.44(q, J = 7.2 Hz, 2H), 6.92 (d, J = 7.6 Hz, lH),7.21(d, J= 7.6 Hz, IH), 7.22(dxd, J= 7.6 Hz; 3.2 Hz, IH), 7.52(s, IH). MS (EI+) m/z: 220 [M] +.HRMS (EI+ ): found 220.0733 [M]+,(Calcd for C12H1204: 220.0736)。
实施例 15 : 2-乙氧甲酰 -5,6-二甲氧基-苯并噻吩 (7b)
在 25ml DMF中加入 2-硝基 -4,5-二甲氧基苯甲醛(2.0 g, 9.5 mmol)和 催化量的 NaOH, 冰浴降温至 0°C下, 缓慢滴加巯基乙酸乙酯 (1.25 ml, 11.4 mmol)0 滴加完毕, 0°C搅拌反应 30 min, 然后 100°C油浴反应 2 h。 把反应 液倒入冰水中, 过滤收集固体, 氯仿溶解固体, 无水 Na2S04干燥过夜。 旋 干溶剂后硅胶柱层析分离后得到白色固体 2-乙氧甲酰 -5,6-二甲氧基 -苯并 噻吩 1.58 g (62.6 %)。
1HNMR (CDC13)5: 1.405 (t, J = 7.2 Hz, 3H), 3.95(s, 3H), 3.98(s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 7.24(s, 1H), 7.25(s, 1H), 7.93(s, 1H). MS (EI+) m/z: 266 [M] +. HRMS (EI+ ): found 266.0613 [M]+, (Calcd for C13H1404S: 266.0631 )。
实施例 16: 2-乙氧甲酰 -7-氟-苯并呋喃 (14b)
以 3-氟 _2-羟基苯甲醛和溴代乙酸乙酯为原料, 按照实施例 7的方法反 应得到黄色油状 2-乙氧甲酰 -7-氟-苯并呋喃 (47%)。
'HNMR (CDC13)6: 1.43 (t, J =7.2 Hz, 3H), 4.45(q, J = 7.2 Hz, 2H),7.14-7.25(m, 2H), 7.43(d, J = 8.0 Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H). MS (EI+) m/z: 208 [M] +· HRMS (EI+ ): found 208.0531 [M]+, (Calcd for CuH C^F: 208.0536 ) o
实施例 17: 2-乙氧甲酰 -5,7-二氯-苯并呋喃 (15b)
以 3,5-二氯 -2-羟基苯甲醛和溴代乙酸乙酯为原料, 按照实施例 7的方 法反应得到白色固体 2-乙氧甲酰 -5,7-二氯-苯并呋喃 (65%)。
!HNMR (CDCl3)5: 1.44(t, J = 7.2 Hz, 3H), 4.46(q, J = 7.2 Hz, 2H ), 7.46(d, J = 1.6 Hz, 1H), 7.48(s, 1H), 7.57(d, J = 1.6 Hz, 1H). MS (EI+) m/z: 258[M]+, 260 [M+2] +, 262 [M+4] +. HRMS (EI+ ): found 257.9840 [M]+, (Calcd for CnH803Cl2: 257.9850 ) c
实施例 18: 2-乙氧甲酰 -5-甲氧甲酰-苯并噻吩 (5b)
以 2-硝基 -5-甲氧甲酰苯甲醛和巯基乙酸乙酯为原料,按照实施例 1的 方法反应得到白色固体 2-乙氧甲酰 -5-甲氧甲酰-苯并噻吩 (5b)(97%)。
!HNMR (CDCl3)6: 1.43(t, J= 7.2 Hz, 3H), 3.97(s, 3H), 4.43(q, J= 7.2 Hz, 2H), 7.91(d, J = 8.4 Hz, 1H), 8.10(d, J = 8.4 Hz, 1H), 8.12(s, 1H), 8.58(s, 1H ). HRMS (EI+ ): found 264.0452 [M]+, (Calcd for C13H1204S: 264.0456 )。
实施例 19: 2-乙酰 -5-甲氧甲酰-苯并噻吩 (lc) 冰浴下, 向 60ml DMF中依次加入 3-醛基 -4-硝基 -苯甲酸甲酯 (1.95 g, 9.3 mmol), 无水 K2C03(1.55 g, 11.2 mmol )和乙硫醇 (0.70 mg, 11.3 mmol)。 搅拌 lO min后, 室温搅拌 l h。 滤去 K2C03, 蒸干 DMF, 氯仿溶解粗品, 水洗氯仿相, 氯仿相用无水硫酸钠干燥。 旋干溶剂后硅胶柱层析分离后得 到白色固体 3-醛基 4-乙硫基 -苯甲酸甲酯 (l-b)1.81 g (86.5%)。
!HNM (CDC13)5:1.44 (t, J = 7.6 Hz, 3H), 3.05 (q, J = 7.6 Hz, 2H), 3.94(s, 3H), 7.42 (d, J= 8.4 Hz, 1H), 8.12 (dd, J= 8.6 Hz, 1.6 Ηζ,ΙΗ), 8.44 (d, ·/= 1.6 Hz, 1H), 10.25 (s, 1H)。
向 20ml DMF中依次加入 3-醛基 4-乙硫基 -苯甲酸甲酯 (l-b)(1.0 g, 4.5 mmol), 氧化钙(125 mg, 2.2 mmol), 氯代丙酮(825 mg, 8.9 mmol)。 90°C油 浴反应 10 h。 过滤, 滤液蒸干。 氯仿溶解粗品, 水洗氯仿相, 氯仿相用无 水硫酸钠干燥。旋干溶剂后硅胶柱层析分离后得到淡黄固体 2-乙酰 -5-甲氧 甲酰-苯并噻吩 0.929 g(88.9%)0
!ΗΝΜΚ (CDC13)5: 2.69(s, 3H), 3.98(s, 3H), 7.93(d, J = 8.4 Hz, 1H), 8.00(s, 1H), 8.1 l(d, J = 8.4 Hz, 1H), 8.61(s, 1H). HRMS (EI+ ): found 234.0339 [M]+, (Calcd for C12H10O3S: 234.0351 )。 实施例 20: 2-乙氧甲酰 -6-甲氧甲酰-苯并噻吩 (6b)
以 2-硝基 -4-甲氧甲酰苯甲醛和巯基乙酸乙酯为原料,按照实施例 1的 方法反应得到白色固体 2-乙氧甲酰 -6-甲氧甲酰-苯并噻吩 (6b)(97%)。
iHNMR (CDCl3)5:1.43(t, J= 7.2 Hz, 3H), 3.97(s, 3H), 4.43(q, J= 7.2 Hz,
2H), 7.91(d, J = 8.4 Hz, 1H), 8.04(d, J = 8.4 Hz, 1H), 8.07(s, 1H ), 8.58(s, 1H).
HRMS (EI+ ): found 264.0449 [M]+, (Calcd for C13H1204S: 264.0456 )。 实施例 21 : 2-乙酰 -5-羧基-苯并噻吩 (le)
将 2-乙酰基 -5-甲氧甲酰-苯并噻吩 ( lc) (133 mg, 0.57 mmol )加入 5 ml 二氧六环中, 搅拌溶解。 把溶有NaOH(34 mg, 0.85 mmol)的2 ml水加入二 氧六环中, 室温搅拌 2 h。蒸干反应液, 用水溶解粗品, 5%盐酸调 PH至 2, 析出固体。 过滤, 滤饼用水洗, 烘干得 36 mg棕色固体产物 2-乙酰 -5-羧基 -苯并噻吩 (29%)。
1HNMR (CDC13) 6:2.66(s, 3H), 8.01(dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.15(d, J = 8.4 Hz, IH), 8.48(s, 1H), 8.61(s, IH), 13.1(s, IH). MS (ESF) m/z: 219[M-H]'. HRMS (ESI" ): found 219.01148 [M- H] -, (Calcd for CnH703S: 219.01159)。 实施例 22: 2-乙酰 -6-甲氧甲酰-苯并噻吩 (2c) 以 3-醛基 -4-硝基-苯甲酸甲酯和乙硫醇为原料, 按照实施例 19的方法 反应得到黄色固体 2-乙硫基 -3-醛基 -苯甲酸甲酯 (2-b)(101.2%)。
1HNMR (CDC13)5:1.39 (t, J = 7.6 Hz, 3H), 3.06 (q, J = 7.6 Hz, 2H),
3.96(s, IH), 7.90(s, IH), 7.90(s, IH), 8.08(s, IH), 10.44(s, IH).
以化合物 2-b和氯代丙酮为原料,按照实施例 19的方法反应得到黄色 固体 (73%)。 ]HNMR (CDC13)5: 2.69(s, 3H), 3.97(s, 3H),7.94 (d, J= 8.4 Hz, IH), 7.96 (s, 1H), 8.05 (d, J = 8.4 Hz, IH), 8.59 (s, IH). HRMS (EI+ ): found 234.0343 [M]+, (Calcd for C12H10O3S: 234.0351 )。 实施例 23 : 2-乙酰 -6-羧基-苯并噻吩 (2e)
以化合物 2c为原料, 按照实施例 21的方法反应得到棕色固体产物 2- 乙酰 -6-羧基-苯并噻吩 (59%)。
1HNMR (CDCI3) δ:2.67 (s, 3H), 7.97 (dd, J= 8.4 Hz, 1.2Hz, IH), 8.10 (d, J = 8.4 Hz, IH), 8.40 (s, IH), 8.65 (s, IH), 13.2 (s, IH). HRMS (ESF ): found 219.01326 [M-H]-, (Calcd for CnH703S: 219.01159 )。 实施例 24: 2-(2,-甲基亚砜基)乙酰 -4-氯-苯并噻吩 (4c)
以化合物 4b为原料, 按照实施例 2的方法反应得到淡黄色固体 2-(2'- 甲基亚砜基)乙酰 -4-氯-苯并噻吩 (4c) ( 59%) 。
]HNMR (CDCI3) δ:2.83 (s, 3H), AB system(4.38, 4.45, J = 13. Hz, 2H),
7.46 (d, J = 4.5 Hz, 2H), 7.79 (t, J = 4.5 Hz, 1H), 8.24 (s, IH). HRMS (EI+ ): found 271.9733 [M]+, (Calcd for C11H9O2S2CI: 271.9733 )。 实施例 25 : 2_(2'-甲基亚砜基)乙酰 -4-甲氧基-苯并呋喃 (10c)
以化合物 10b为原料, 按照实施例 2的方法反应得到黄色固体 2-(2'- 甲基亚砜基)乙酰 -4-甲氧基-苯并呋喃 (10c) ( 76%) 。
JHNMR (CDCI3) δ: 2.80 (s, 3H), 3.98 (s, 3H), AB system(4.26, 4.39, J =
13.5 Hz, 2H), 6.71 (d, J= 8.0 Hz, 1H),7.19 (d, J= 8.0 Hz, IH), 7.47 (t, J= 8.0 Hz, IH ), 7.79 (s, IH). HRMS (EI+ ): found 252.0437 [M]+, (Calcd for C12H1204S: 252.0456 实施例 26: 2-(2,-甲基亚砜基)乙酰 -5-甲氧基-苯并呋喃 (11c)
以化合物 l ib为原料, 按照实施例 2的方法反应得到黄色固体 2-(2'- 甲基亚砜基)乙酰 -5-甲氧基-苯并呋喃 (11c) ( 83%) 。
!HNMR (CDCI3) δ: 2.79 (s, 3H), 3.86(s, 3H), AB system(4.27, 4.37, J = 13.2 Hz, 2H), 7.10 (d, J = 2.0 Hz, lH),7.15(dxd, J = 8.8 Hz, 2.0 Hz, IH), 7.48 (d, J = 8.8 Hz, IH ), 7.60(s, IH). HRMS (EI+ ): found 252.0439 [M]+, (Calcd for Ci2H1204S: 252.0456 )0 实施例 27: 2-(2,-甲基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩 (7c) 以化合物 7b为原料, 按照实施例 2的方法反应得到黄色固体 2-(2'-甲 基亚砜基)乙酰- 5,6-二甲氧基-苯并噻吩 (7c) ( 96%) 。
iHNMR (CDCI3) δ: 2.78 (s, 3H), 3.96(s, 3H),3.99(s, 3H), AB system(4.28; 4.35, J = 13.6 Hz, 2H), 7.25 (s, IH), 7.28 (s, IH ), 7.96(s, IH). HRMS (EI+ ): found 298.0306 [M]+, (Calcd for C13H1404S2: 298.0334 )。 实施例 28: 2-(2,-甲基亚砜基)乙酰 -6-甲氧基-苯并呋喃 (12c)
以化合物 12b原料, 按照实施例 2的方法反应得到黄色固体 2- (2'-甲 基亚砜基)乙酰 -6-甲氧基-苯并呋喃 (12c) ( 51%) 。
1HNMR (CDCI3) δ: 2.79 (s, 3H), 3.89(s, 3H), AB system(4.23, 4.33, J =
13.2 Hz, 2H), 6.97(dxd, J = 8.8 Hz, 2.0 Hz, IH), 7.04 (s, IH), 7.60 (d, J = 8.8 Hz, IH ), 7.62 (s, IH). HRMS (EI+ ): found 252.0443 [M]+, (Calcd for
Figure imgf000042_0001
实施例 29: 2-(2,-甲基亚砜基)乙酰 -7-甲氧基-苯并呋喃 (13c)
以化合物 13b为原料, 按照实施例 2的方法反应得到黄色固体 2-(2'- 甲基亚砜基)乙酰 -7-甲氧基-苯并呋喃 (13c) ( 66% ) 。
lHNMR (d6-DMSO) δ: 2.73 (s, 3Η), 3.97 (s, 3H), AB system (4.46, 4.57, J = 14.0 Hz, 2H), 7.17(d, J= 7.6 Hz, IH), 7.30 (t, J = 7.6 Hz, IH), 7.41 (d, J = 7.6 Hz, IH ), 8.08 (s, IH). HRMS (EI+ ): found 252.0459 [M]+, (Calcd for C12H1204S: 252.0456 )。 实施例 30: 2-乙氧甲酰 -6-二乙氨基-苯并呋喃 (16b)
以 4-二乙氨基水杨醛为原料, 按照实施例 7的方法反应得到黄色油状 2-乙氧甲酰 -6-二乙氨基-苯并呋喃 (16b) (36%)。
JHNMR (CDC13) δ: 1.20 (t, J = 6.8 Hz, 6H), 1.41. (t, J = 7.2 Hz, 3H), 3.41 (q, J = 6.8 Hz, 4H), 4.41 (q, J = 7.2 Hz, 2H), 6.73 (d, J = 8.8 Hz, IH), 6.76 (s, IH), 7.40 (s, 1H), 7.43 (d, J = 8.8 Hz, IH). MS (EI+) m/z: 261 [M]+. HRMS (EI+ ): found 261.1365[M]+, (Calcd for C15H19N03: 261.1365 )。 实施例 31 : -2-[3,-(4"-甲氧基苯)丙烯酰] -6-乙氧甲酰-苯并噻吩 (2dC)
向 10ml无水乙醇中依此加入 2-乙酰基 -6-甲氧甲酰-苯并噻吩 (2c) ( 100 mg, 0.43 mmol ),催化量的乙醇钠,对甲氧基苯甲醛(87.2 mg, 0.64 mmol )。 室温搅拌 1.5 h, 蒸干乙醇, 氯仿溶解粗品, 过滤。 水洗氯仿相, 无水硫酸 钠干燥氯仿相。 旋干溶剂后硅胶柱层析分离后得到黄绿色固体 78 mg ( 52%) 。
1HNMR (CDCI3) δ: 1.45(t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 15.2 Hz, IH), 7.65 (d, J = 8.4 Hz, 2H), 7.90 (d, J= 15.2 Hz, 1H), 7.96(d, J = 8.4 Hz, 1H), 8.07 (d, J= 8.4 Hz; 1H), 8.11 (s, IH), 8.62 (s, IH). HRMS (EI+ ): found 366.0920 [M]+, (Calcd for C21H1804S: 366.0926)。 实施例 32 : (£)-2-[3,- (4"-甲氧基苯)丙烯酰] -5-乙氧甲酰-苯并噻吩 (ldC)
以化合物 lc和对甲氧基苯甲醛为原料, 按照实施例 31的方法反应得 到黄绿色固体 )-2-[3,-(4"-甲氧基苯)丙烯酰] -5-乙氧甲酰-苯并噻吩 (ldC) ( 34%) 。
!HNMR (CDC13) δ: 1.45(t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 15.2 Hz, IH), 7.65 (ά, J = 8.4 Hz, 2H), 7.89 (d, J = 15.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, IH), 8.15 (s, IH), 8.64 (s, IH). HRMS (EI+ ): found 366.0916[M]+, (Calcd for C21H1804S: 366.0926)。 实施例 —33 : 2-(Γ-羟基 -2,-甲基亚砜基)乙基 -5,6-亚甲基二氧-苯并噻吩
(8e)
以化合物 8c为原料, 按照实施例 10的方法反应得到白色固体 2-(1 '- 羟基 -2,-甲基亚砜基)乙基 -5,6-亚甲基二氧-苯并噻吩 (8e) ( 96%) 。
!HNMR (CDCI3) δ: 2.74 (s, 3H), 2.03-3.30(m, 2H), 5.68 (dxd, J = 9.2 Hz, 2.8Hz ), 6.01 (s, 1H), 7.12 (s, 1H), 7.13 (s, 1H), 7.20 (s, IH). MS (ESI+) m/z: 307[M+Na]+. HRMS (ESI+ ): found 307.00916[M+Na]+, (Calcd for C12H1204S2Na: 307.00747)。 实施例 34: 2-(Γ-羟基)乙基 -5-甲氧甲酰-苯并噻吩 (If)
以化合物 lc为原料,按照实施例 10的方法反应得到淡粉色固体 2-(1 '- 羟基)乙基 -5-甲氧甲酰-苯并噻吩 (If) ( 92%) 。
iHNMR (CDCI3) δ: 1.67 (d, J = 6.4 Hz), 2.18 (s,lH), 3.95 (s, 3H), 5.22 (q; J = 6.4 Hz,2H), 7.25 (s, IH), 7.84 (d, J = 8.4 Hz, IH), 7.95 (d, J= 8.4 Hz, 1H), 7.95(d, J = 8.4 Hz, 1H), 8.41 (s, IH). MS (EI+) m/z: 236 [M]+. HRMS (EI+ ): found 236.0498 [M]+, (Calcd for C12H1203S: 236.0507)。 实施例 35 : 2-(Γ-羟基)乙基 -6-甲氧甲酰-苯并噻吩 (2f)
以化合物 2c为原料, 按照实施例 10的方法反应得到白色固体 2-(1 '- 羟基)乙基 -6-甲氧甲酰-苯并噻吩 (2f) ( 92%) 。
]HNMR (CDC13) δ: 1.67 (d, J= 6.4 Hz), 1.80 (s,lH), 3.95 (s, 3H), 5.23 (q; J = 6.4 Hz, 2H), 7.24 (s, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.99 (d, J= 8.4 Hz, 1H);
7.95(d, J = 8.4 Hz, IH), 8.53 (s, IH). MS (EI+) m/z: 236 [M]+. HRMS (EI+ ): found 236.0507 [M]+, (Calcd for C12H1203S: 236.0507)。
实施例 36: -2-肉桂酰 -6-乙氧甲酰-苯并噻吩 (2dA)
以化合物 2c和苯甲醛为原料, 按照实施例 31的方法反应得到淡黄色 固体 2-肉桂酰 -6-乙氧甲酰-苯并噻吩 (2dA) ( 17% ) 。
λΉΝΜΚ (CDCI3) δ: 1.45(t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.45-7.47 (m, 3H), 7.54 (d, J = 15;6 Hz, IH), 7.69-7.71 (m, 2H), 7.93 (ά, J = 15.6 Hz, IH), 7.97 (d, J = 8.4 Hz, IH), 8.08 (d, J = 8.4 Hz, IH), 8.14 (s, IH), 8.63 (s, IH). MS (EI+) m/z: 336 [M]+. HRMS (EI+ ): found 336.0793[M]+, (Calcd for C20H16O3S: 336.0820)。
实施例 37: -2-[3,-(2",3",4"-三甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻 吩 (IdE)
以化合物 lc和 2,3,4-三甲氧基苯甲醛为原料, 按照实施例 31 的方法 反应得到黄色固体 (¾)-2-[3,-(2",3",4"-三甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯 并噻吩(IdE) ( 30%)
!HNMR (CDCI3) δ: 1.44(t, J = 7.2 Hz, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 3.99(s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.75 (d, J = 8.8 Hz, IH), 7.42 (d, J = 8.8 Hz, IH), 7.59 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.4 Hz, IH), 8.08(d, J = 15.6 Hz, IH), 8.11-8.14 (m, 2H), 8.64(s, IH). HRMS (EI+ ): found 426.1147[M]+, (Calcd for C23H2206S: 426.1137)。 实施例 38: (E 2-[3,-(2",3",4,,-三甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻 吩 (2dE) 以化合物 2c和 2,3,4-三甲氧基苯甲醛为原料, , 按照实施例 31 的方 法反应得到黄绿色油状物 (E 2-[3,-(2",3",4,,-三甲氧基苯)丙烯酰 ]-6-乙氧甲 酰-苯并噻吩 (2dE) ( 32%) 。
!HNMR (CDC13) δ: 1.44(t, J = 7.2 Hz, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 3.99(s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.75 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 15.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.09(d, J = 15.6 Hz, 1H), 8.09 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.63 (s, 1H). HRMS (EI+ ): found 426.1125 [M]+, (Calcd for C23H2206S: 426.1137)。 实施例 39: -2-肉桂酰 -5-乙氧甲酰-苯并噻吩 (IdA)
以化合物 lc和苯甲醛为原料, , 按照实施例 31的方法反应得到黄色 固体 fE 2-肉桂酰 -5-乙氧甲酰-苯并噻吩 (IdA) ( 62%) 。
!HNMR (CDCI3) δ: 1.44(t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.54 (s, 3H), 7.59 (d, J = 15.2 Hz, 1H), 7.68-7.69 (m, 2H), 7.91 (d, J= 15.2 Hz, 1H): 7.94 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 8.64 (s, 1H). MS (ΕΓ) m/z: 336[M]+. HRMS (EI+ ): found 336.0796[M]+, (Calcd for C20H16O3S: 336.0820)。 实施例 40: E 2-[3,-(2,,-氯苯基)丙烯酰 ]-5-乙氧甲酰-苯并噻吩 (ldBl) 以化合物 lc和邻氯苯甲醛为原料, 按照实施例 31的方法反应得到黄 色固体 -2-[3,-(2"-氯苯基)丙烯酰 ]-5-乙氧甲酰-苯并噻吩 (ldBl) ( 62%)。
^MR (CDCI3) δ: 1.44 (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H),
7.35-7.37 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 15.6 Hz, 1H),7.79 (dxd, J = 8.0 Hz, 2.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.30 (d, J = 15.6 Hz, 1H), 8.65 (s, 1H). MS (EI+) m/z: 370 [M]+, 372 [M+2]+. HRMS (EI+ ): found 370.0418 [M]+, (Calcd for C2oH1503SCl: 370.0430)。 实施例 41 : -2-[3'-(2"-氯苯基)丙烯酰 ]-5-甲氧甲酰-苯并噻吩 (ldB2) 以化合物 lc和邻氯苯甲醛为原料, 按照实施例 31的方法反应得到棕 黄固体 -2-[3'-(2"-氯苯基)丙烯酰 ]-5-甲氧甲酰-苯并噻吩 (ldB2) (25%):
1HNMR (CDCI3) δ: 3.97 (s, 3H), 7.34-7.39 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 15.6 Hz, 1H), 7.79 (dxd, J = 8.0 Hz, 2.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 8.30 (d, J = 15.6 Hz, 1H), 8.64 (s, 1H). MS (EI+) m/z: 356[M]+, 358[M+2]+. HRMS (EI+ ): found 356.0254 [M]+, (Calcd for C19H1303SC1: 356.0274)。 实施例 42: (E 2-[3,-(2,,-氯苯基)丙烯酰 ]-6-乙氧甲酰-苯并噻吩 (2dB) 以化合物 2c和邻氯苯甲醛为原料, 按照实施例 31的方法进行反应得 到棕黄色固体 (¾-2-[3,-(2"-氯苯基)丙烯酰 ]- 6-乙氧甲酰-苯并噻吩 (2dB) ( 20%) 。
1HNMR (CDCI3) δ: 1.44 (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.35-7.37 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 15.6 Hz, 1H),7.79 (dxd, J = 8.0 Hz, 2.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 8.30 (d, J = 15.6 Hz, 1H), 8.63 (s, 1H). MS (EI+) m/z: 370 [M]+. HRMS (EI+ ): found 370.0420[M]+, (Calcd for C20H15O3SCl: 370.0430)。 实施例 43 : ¾)-2-[3,-(3",4"-二甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻吩 (2dD)
以化合物 2c和 3,4-二甲氧基苯甲醛为原料, 按照实施例 31的方法反 应得到褐色油状物 (E 2-[3,-(3",4,,-二甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻 吩 (2dD) ( 10%) 。
!HNMR (CDCI3) δ: 1.45(t, J = 7.2 Hz, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 4.44 (q, J= 7.2 Hz, 2H), 6.93 (d, J= 8.4 Hz, 1H), 7.20 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 15.6 Hz, 1H), 7.88 (d, J = 15.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.63 (s, 1H). MS (EI+) m/z: 396[M]+. HRMS (EI+ ): found 396.1015[M]+, (Calcd for C22H20O5S: 396.1031)。 实施例 44: (E 2-[3,-(3", 4"-二甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻吩 (ldD)
以化合物 lc和 3,4-二甲氧基苯甲醛为原料, 按照实施例 31的方法反 应得到黄色油状物 f¾-2-[3'-(3", 4"-二甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并 噻吩(ldD) ( 10% ) 。
!HNMR (CDC13) δ: 1.44(t, J 7.2 Hz, 3H), 3.94 (s, 3H), 3.98 (s, 3H),
4.45(q, J = 7.2 Hz, 2H), 6.93 (d, J 8.4 Hz, 1H), 7.20 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 15.2 Hz, 1H), 7.88 (d, J = 15.2 Hz, 1H), 7.95 (ά, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.17 (s, 1H), 8.65 (s, 1H). MS (EI+) m/z: 396[M]+. HRMS (EI+ ): found 396.1032[M]+, (Calcd for C22H20O5S: 396.1031)。
实施例 45 : 2-(2,-甲砜基)乙酰 -5-甲氧基-苯并呋喃 (l id)
以化合物 11c为原料,按照实施例 3的方法合成得到淡黄色固体 2-(2'- 甲砜基)乙酰- 5-甲氧基-苯并呋喃 (57.0%)。
1HNMR ( CDCI3 ) 5:3.16(s, 3H), 3.86(s, 3H), 4.58(s, 2H), 7.10 (d, J= 2.4 Hz, 1H), 7.17 (dxd, J = 9.0 Hz, 2.4 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.65 (s,
1H)。 MS (EI+) m/z: 268[M]+. HRMS (EI+ ): found 268.0416[M]+, (Calcd for
C12H10O5S: 268.0405)。
实施例 46: 2-(Γ-羟基 -2,-甲基亚砜)乙基 -5-甲氧基-苯并呋喃 (l ie) 以化合物 11c为原料, 按照实施例 10的方法反应得到淡黄固体 2-(Γ- 羟基- 2,-甲基亚砜)乙基 -5-甲氧基-苯并呋喃 (l ie) ( 89%) 。
]HNMR ( CDCI3 ) δ:2.75 (s, 3H), 3.12-3.37 (m, 2H), 3.84 (s, 3H), 5.50-5.56 (m 1H), 6.71 (d, J= 5.2 Hz, 1H), 6.88 (dxd, J = 8.8 Hz, 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H)。 MS (ESI+) m/z: 277.3 [M+Na]+. HRMS (ESI+ ): found 277.05280[M+Na]+, (Calcd for C12H14O4SNa:277.05105)。 实施例 47: (E 2-[3,-(4,,-甲氧基苯)丙烯酰 ]-5,6-二甲氧基 -吲哚 (G33-1) 以 2-乙酰 -5, 6-二甲氧基吲哚和对甲氧基苯甲醛为原料, 以实施例 31 的方法反应得到固体 (T 2-[3'-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基 -吲哚 (74.5%) 0
JH NMR (CDC13) δ: 3.73 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 6.67 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.95 (s, 1H), 7.09 (s, 2H), 7.38 (s, 1H), 7.54 (d, J = 15.2 Hz, 1H), 7.68 (s, 2H), 11.63 (br, 1H). MS(EI+) m/z: 337[M]+. 实施例 48: 甲基 -2-[3,-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基 -吲哚
(G33-2)
以 1-甲基 -2-乙酰 -5, 6-二甲氧基吲哚和对甲氧基苯甲醛为原料,以实施 例 31 的方法反应得到固体 甲基 -2-[3 '-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲 氧基 -吲哚 (77.1%)。
lR NMR (CDCI3) δ: 3.60 (s, 3H), 3.73 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 6.67 (d, J = 15.2 Hz, 1H), 6.57 (s, 2H), 7.09 (s, 2H), 7.41 (s, 1H), 7.54 (d, J = 15.2 Hz, 1H), 7.68 (s, 2H). MS(EI+) m/z: 351 [M]+. 实施例 49: (Ελΐ-氯乙基 -2-[3,-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基-吲 哚 (G33-3)
以 1-氯乙基 -2-乙酰- 5, 6-二甲氧基吲哚和对甲氧基苯甲醛为原料,以实 施例 31 的方法反应得到固体 氯乙基 -2-[3,-(4"-甲氧基苯)丙烯酰 ]-5,6- 二甲氧基 -Π引哚 (70.2%)。
^ NMR (CDCI3) δ: 2.14 ( m,3H), 3.70 (s, 3H), 3.82 (s, 3H), 3.92 (s, 3H),
5.80 (m, 1H),6.66 (d, J = 15.2 Hz, 1H), 6.59 (s, 2H), 7.1 l(s, 2H), 7.38 (s, 1H), 7.53 (d, J= 15.2 Hz, 1H), 7.71 (s, 2H). MS(EI+) m/z: 399[M]+. 实施例 50: -1-乙酰基 -2-[3,-(4"-氟苯)丙烯酰 ]-5,6-二甲氧基 -吲哚 (G33-4)
以 1, 2-二乙酰 -5, 6-二甲氧基吲哚和对氟苯甲醛为原料, 以实施例 31 的方法反应得到固体 -1-乙酰基 -2-[3,-(4"-氟苯)丙烯酰 ]-5,6-二甲氧基-吲 哚 (72.6%)。 !H NMR (CDCI3) δ: 2.19 ( m,3H), 3.73 (s, 3H), 3.94 (s, 3H), 6.68 (d, J = 15.2 Hz, 1H), 6.81 (s, 2H), 7.1 l(s, 2H), 7.43 (s, 1H), 7.53 (d, J= 15.2 Hz, 1H), 7.69 (s, 2H). MS(EI+) m/z: 367 [M]+. 实施例 51 : (E)-\- ( 2,-羟乙基) -2-[3,-(4"-氟苯基)丙烯酰 ]-5-乙酰氧基 -吲哚 (G33-5)
以 1- ( 2,-羟乙基) -2-乙酰 -5-乙酰氧基吲哚和对氟苯甲醛为原料, 以 实施例 31 的方法反应得到固体 ( 2,-羟乙基) -2-[3,-(4"-氟苯基)丙烯 酰]- 5-乙酰氧基 -吲哚 (70.5%)。
!H NMR (CDCI3) δ: 2.33 ( s,3H), 4.08 (m, 4H),4.30 ( s,lH) , 6.70 (d, J = 15.2 Hz, 1H), 7.02(m, 2H),7.35(m, 4H), 7.42 (s, 1H), 7.53 (d, J= 15.2 Hz, 1H); 7.80 (m, 1H). MS(EI+) m/z: 367 [M]+. 实施例 52: (E)-\- ( 2,-氨基乙基) -2-[3,-(4"-氟苯基)丙烯酰 ]-5-乙酰氧 基 -吲哚 (G33-6)
以 1- ( 2,-氨基乙基) -2-乙酰 -5-乙酰氧基吲哚和对氟苯甲醛为原料, 以实施例 31 的方法反应得到固体 -1- ( 2,-氨基乙基) -2-[3,-(4"-氟苯基) 丙烯酰 ]-5-乙酰氧基 -吲哚 (58.0%)。
lU NMR (CDCI3) δ: 2.33 ( s,3H), 3.12 (m, 2H), 4.11 (m, 2H), 5.80(s,2H), 6.68 (d, J = 15.2 Hz, 1H), 6.98 (m, 2H), 7.02(m, 2H),7.36(m, 4H), 7.42 (s, 1H) 7.53 (d, J = 15.2 Hz, 1H), 7.84 (m, 1H). MS(EI+) m/z: 366 [M]+. 实施例 53 : E)-\- ( 2,-甲氧基乙基) -2-[3,-(4"-氟苯基)丙烯酰 ]_5-乙酰 氧基 -Π引哚 (G33-7)
以 1- ( 2,-甲氧基乙基) -2-乙酰 -5-乙酰氧基吲哚和对氟苯甲醛为原料, 以实施例 31的方法反应得到固体 £ 1- ( 2,-甲氧基乙基) -2-[3,-(4"-氟苯基) 丙烯酰 ]-5-乙酰氧基 -吲哚 (70.5%)。
!H NMR (CDCI3) δ: 2.32 ( s,3H), 3.24 ( s,3H), 3.85 (m, 2H), 4.08 (m, 2H),
6.68 (d, J= 15.2 Hz, 1H), 7.02 (m, 2H), 7.36(m, 4H), 7.41 (s, 1H), 7.53 (d, J = 15.2 Hz, IH), 7.82 (m, IH). MS(EI+) m/z: 381 [M]+. 实施例 54: 2-乙氧甲酰 -4-甲基-苯并噻吩 (lg)
以 6-甲基 2-硝基苯甲醛和巯基乙酸乙酯为原料, 按照实施例 1的方法 进行操作, 得固体颗粒 2-乙氧甲酰 -4-甲基-苯并噻吩 (69.3%)。
1HNMR (CDC13)5: 1.45 (t, J = 7.2 Hz, 3H), 2.35(s, 3H), 4.46(q, J = 7.2
Hz, 2H), 7.38(m, 2H), 7.74(m, 1H), 7.98(s, 1H)。 MS(EI+) m/z: 220 [M]+. 实施例 55 : 2-庚酰 -5, 6-二甲基-苯并噻吩 (17) 以 4, 5-二甲基 -2-硝基-苯甲醛、 乙硫醇和 1-氯代辛垸 -2-酮为原料, 按 照实施例 19的方法反应得到固体 2-庚酰 -5, 6-二甲基-苯并噻吩 (17)(50%)。
1HNMR (CDC13)S: 0.96 (t, J = 7.2 Ηζ,, 3H), 1.30 (m, 6H), 1.48 (m, 2H),
2.35 (s, 6H), 2.89 (m, 2H), 7.54 (s,2H), 7.86 (s, IH). MS(EI+) m/z: 274 [M]+. 实施例 56: 2-戊氧甲酰 -5, 6-二氨基苯并噻吩 (18b)
以 5,6-二氨基 -6硝基苯甲醛和巯基乙酸戊酯为原料, 按照实施例 1的 方法合成得到固体 2-戊氧甲酰 -5, 6-二氨基苯并噻吩 (61%)。 1H MR (CDC13)6: 0.90(t, ·/ = 7.2 Hz,, 3H), 1.30 (m, 4H), 1.75 (m, 2H),
4.35 (m, 2H),5.80(s, 4H), 6.73(s, 1H), 6.80(s, 1H),8.22 (s,lH). MS (EI+) m/z: 278[M]+. 实施例 57: 2-酮酸-苯并噻吩 (19)
以 2-硝基苯甲醛和巯基 2-羰丙酸为原料, 按照实施例 1的方法合成得 到固体 2-酮酸-苯并噻吩 (51.5%)。
^MR ( CDC13 ) iHNMR (CDC13)5: 7.32(t, J = 7.0 Hz, IH), 7.49(t, J = 7.0 Ηζ,ΙΗ), 7.76(d, J = 7.0 Hz, 1H), 7.79(d, «/ = 7.0 Hz, 1H), 7.94(s, 1H), 12.6 (s, IH). MS(EI+) m/z: 206 [M]+. 实施例 58: 2- ( Γ , V -二羰基) 戊基苯并噻吩 (20)
以 2-硝基苯甲醛和 1-巯己基 -2,3-二酮为原料, 按照实施例 1的方法合 成得到固体 2- ( Γ , 2, -二羰基) 戊基苯并噻吩 (40.2%)。
!ΗΝΜΚ( CDC13 ) !HNMR (CDC13)5: 0.96(t, J 7.2 Hz,, 3 H), 1.65 (m, 2H), 2.40 (m, 2H), 7.33(t, J = 7.0 Hz, IH), 7.46(t, J = 8.0 Hz,lH), 7.70(d, J = 7.0 Hz, IH), 7.82(d, J= 8.0 Hz, 1H), 8.05(s, IH). MS(EI+) m/z: 232 [M]+. 实施例 59: 2- (丁基亚砜基)乙酰 -5,6-二氨基 -苯并噻吩 (18c)
以化合物 18b ( 2-戊氧甲酰 -5, 6-二氨基苯并噻吩) 为原料, 按照实施 例 2 的方法反应得到固体 2- (丁基亚砜基)乙酰 -5,6-二氨基-苯并噻吩 (18c) ( 80%) 。
JHNMR ( CDC13 ) δ: 0.90(t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.78 (m, 2H), AB system(4.28, 4.36, J = 13.2 Hz, 2H), 5.80(s, 4H), 6.72(s, 1H), 6.78(s, 1H),7.88 (s,lH). MS (EI+) m/z: 306[M]+. 实施例 60: 2-(4' -氯庚氧甲酰 )-5,6-二甲氧基-苯并噻吩 (21b)
以化合物 2-硝基 -4,5-二甲氧基苯甲醛和巯基乙酸 -4' -氯庚酯为原料, 按照实施例 15的方法反应得到固体 2-(4 ' -氯庚氧甲酰) -5,6-二甲氧基 -苯并 噻吩 (21b) ( 55%) 。
iHNMR (CDC13)6: 0.96(t, J = 7.2 Hz, 3H), 1.33 (m, 2H), 1.60 (m,
6H),3.46(m, 1H), 3.73(s, 3H),3.96(s, 3H), 4.28 (m, 2H), 7.18(s, IH), 7.25(s,
IH), 8.30(s, IH). MS (EI+) m/z: 370 [M] +. 实施例 61 : 2-(4,-氯己基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩 (21c) 以化合物 21b为原料, 按照实施例 2的方法反应得到固体 2-(4,-氯己 基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩 (21c) ( 85%)
iHNMR (CDC13)5: 0.96(t, J = 7.2 Hz, 3H), 1.33 (m, 4H), 1.56 (m, 4H),3.46(m, IH), 3.73(s, 3H),3.95(s, 3H), AB system(4.30, 4.39, J = 13.2 Hz, 2H), 7.19(s, 1H), 7.26(s, 1H), 8.25(s, IH). MS (EI+) m/z: 398 [M] +.
实施例 63 : 2-(6, -羟基己基)氧甲酰 -5,6-二甲氧基-苯并噻吩 (22b) 以化合物 2-硝基 -4,5-二甲氧基苯甲醛和巯基乙酸 -6 ' -羟基己酯为原 料, 按照实施例 15的方法反应得到固体 2-(6, -羟基己基)氧甲酰 -5,6-二甲 氧基-苯并噻吩 (22b) ( 50%) 。
!HNMR (CDC13)5: 1.28(m, 4H), 1.48(m, 2H), 1.76(m, 2H), 3.52 (m, 2H), 3.73(s, 3H), 3.95(s, 3H), 4.26 (m, 2H), 5.02(s, IH), 7.21(s, IH), 7.30(s, 1H), 8.09(s, IH). MS (EI+) m/z: 338 [M] +· 实施例 63 : 2-(6, -羟基戊基亚砜基)乙酰- 5,6-二甲氧基-苯并噻吩 (22c) 以化合物 22b为原料, 按照实施例 2的方法反应得到固体 2-(6' -羟基 戊基亚砜基)乙酰 ,6-二甲氧基-苯并噻吩 (22c) ( 81%)
'HNMR (CDC13)5: 1.29(m, 4H), 1.50(m, 2H), 1.76(m, 2H), 3.53 (m, 2H), 3.73(s, 3H), 3.96(s, 3H), AB system(4.30, 4.39, J = 13.2 Hz, 2H), 5.16(s, 1H),
7.29(s, IH), 7.32(s, IH), 8.16(s, IH). MS (EI+) m/z: 366 [M] +.
实施例 64: 2-(6, -甲氧基己基)氧甲酰 -5,6-二甲氧基-苯并噻吩 (23b) 以化合物 2-硝基 -4,5-二甲氧基苯甲醛和巯基乙酸 -6' -甲氧基己基酯为 原料, 按照实施例 15的方法反应得到固体 2-(6' -甲氧基己基)氧甲酰 -5,6- 二甲氧基-苯并噻吩 (23b) ( 63%) 。
l NMR (CDC13)S: 1.29(m, 4H), 1.46(m, 2H), 1.75(m, 2H), 3.24(s, 3H),
3.37 (m, 2H), 3.72(s, 3H), 3.93(s, 3H), 4.25 (m, 2H), 7.19(s, IH), 7.28 (s, IH), 8.19(s, IH). MS (EI+) m/z: 352 [M] +. 实施例 65: 2-(6,-甲氧基戊基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩 (23c) 以化合物 23b为原料, 按照实施例 2的方法反应得到固体 2-(6' -甲氧 基戊基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩 (23c) ( 86%)
!HNMR (CDC13)S: 1.31(m, 4H), 1.48(m, 2H), 1.76(m, 2H), 3.24(s, 3H),
3.38 (m, 2H), 3.73(s, 3H), 3.92(s, 3H), AB system(4.30, 4.39, J = 13.2 Hz, 2H) 7.18(s, IH), 7.26(s, 1H), 7.91(s, IH). MS (EI+) m/z: 380 [M] +.
实施例 66: 2 -乙氧甲酰 -5,6-乙基亚甲基二氧-苯并噻吩 (24b)
以 3,4-乙基亚甲基二氧 -6硝基苯甲醛和巯基乙酸乙酯为原料, 按照实 施例 1 的方法合成得到固体 2-乙氧甲酰 -5,6-乙基亚甲基二氧-苯并噻吩 (68.5%)
lHNMR ( CDCI3 ) δ: 0.96 ( m, 3H), 1.42(t, J= 7.2 Hz, 3H), 2.13(m,2H), 4.37(q, J 7.2 Hz, 2H), 6.04(m, 1H), 7.21(s, 1H), 7.26(s, IH), 7.91(s, IH). MS (EI+) m/z: 278 [M]+.
实施例 67: 2-乙氧甲酰 -5,6-(2, -氯乙基)亚甲基二氧-苯并噻吩 (25b) 以 3,4- ( 2, -氯乙基) 亚甲基二氧 -6硝基苯甲醛和巯基乙酸乙酯为原 料, 按照实施例 1 的方法合成得到固体 2-乙氧甲酰 -5,6-(2, -氯乙基)亚甲 基二氧-苯并噻吩 (25b)(62.0%)。
!HNM ( CDCI3 ) δ: 1.43(t, J = 7.2 Hz, 3H), 1.59(d, J = 5.0 Hz, 3H), 4.38(q, J = 7.2 Hz, 2H), 4.63(m, IH), 6.23(m, 1H), 7.18(s, 1H), 7.23(s, IH), 7.96(s, IH). MS (ΕΓ) m/z: 312 [M]+.
实施例 68 : 2-乙氧甲酰-5,6-(1, -羟乙基)亚甲基二氧-苯并噻吩 (26b) 以 3,4- ( Γ -羟乙基) 亚甲基二氧 -6硝基苯甲醛和巯基乙酸乙酯为原 料, 按照实施例 1 的方法合成得到固体 2-乙氧甲酰 -5,6- (Γ -羟乙基)亚甲 基二氧-苯并噻吩 (26b) (68.0%)
XWMR ( CDCI3 ) δ: 1.42(t, J= 7.2 Hz, 3H), 2.28(m,2H), 3.53 ( m, 2H) , 4.38(q, J = 7.2 Hz, 2H), 5.16(s,lH), 5.96(m, IH), 7.18(s, IH), 7.25(s, 1H), 7.98(s, IH). MS (EI+) m/z: 294 [M]+.
实施例 69: 2-乙氧甲酰 -5,6-(Γ -氨乙基)亚甲基二氧-苯并噻吩 (27b) 以 3,4- ( -氨乙基) 亚甲基二氧 -6硝基苯甲醛和巯基乙酸乙酯为原 料, 按照实施例 1 的方法合成得到固体 2-乙氧甲酰 -5,6- (Γ -氨乙基)亚甲 基二氧-苯并噻吩 (26b) (68.0%)。
!HNMR ( CDCI3) δ: 1.42(t, J = 7.2 Hz, 3H), 2.35(m,2H), 2.65 ( m, 2H) , 4.12(s,lH), 4.38(q, J = 7.2 Hz, 2H), 5.98(m, IH), 7.16(s, 1H), 7.27(s, IH), 8.02(s, IH). MS (EI+) m/z: 293 [M]+.
实施例 70: 2-乙氧甲酰 -5,6-(Γ -甲氧基乙基)亚甲基二氧-苯并噻吩 (28b) 以 3,4- ( 1, -甲氧基乙基) 亚甲基二氧 -6硝基苯甲醛和巯基乙酸乙酯 为原料, 按照实施例 1的方法合成得到固体 2-乙氧甲酰- 5,6-( -甲氧基乙 基)亚甲基二氧-苯并噻吩 (26b) (68.0%)。
^MR CDCl^S: 1.42(t, J= 7.2 Hz, 3H), 2.26(m,2H), 3.24( s, 3H), 3.37 ( m, 2H) , 4.38(q, J = 7.2 Hz, 2H), 5.98(m, 1H), 7.18(s, 1H), 7.25(s, 1H), 8.03(s, 1H). MS (EI+) m/z: 308[M]+.

Claims

权利要求
1、 具有如通式 I所示结构的苯并五元不饱和杂环化合物或其药用盐,
Figure imgf000055_0001
式中,
X代表 0、 S或 NR7, 其中 R7代表 H、 烃基、 卤代烃基、 羰基烃基、 羟基烃基、 氨基烃基或烃氧基;
Y代表 CO 或 CRi'OH; Ι 代表以下基团: H、 OH、 含有 1-18个碳的 '烃基、 羧基、 酰基、 垸氧基、 磺酸基;
' ^代表以下基团: H、 OH、 含有 1-18个碳的烃基、 羧基、 酰基、 垸 氧基、磺酸基、 CH2S(0)nR8或 R9取代苯丙烯基;其中 R8代表 H、含有 1-18 个碳的烃基、 卤代烃基、 羟基烃基或烃氧基, n=l-2; R9代表 H、 烃基、 烷 氧基、 卤素、 羧基、 氨基或取代的氨基; 且 ^可以与 相同, 也可以与 Ι 不同;
R2代表以下基团: H、 含有 1-18个碳的烃基、 卤素、 酰基、 羧基、 氨 基或取代的氨基、 磺酸基、 腈基或酰基烃氧基等;
代表以下基团: H、 烃基、 垸氧基、 卤素、 羧基、 氨基或取代的氨 基、 酰基、 酯基或磺酸基等;
代表以下基团: H、 烃基、 垸氧基、 卤素、 羧基, 氨基或取代的氨 基、 酰基、 酯基或磺酸基等;
1 5代表以下基团: H、 烃基、 烷氧基、 卤素、 羧基、 氨基或取代的氨 基、 酰基、 酯基或磺酸基等;
代表以下基团: H、 烃基、 烷氧基、 卤素、 羧基、 氨基或取代的氨 基、 酰基、 酯基或磺酸基等; 或者,
R4与 R5通过碳、 氧或氮连接在一起形成 5-7元环结构或带有取代基 R1()的 5-7元环结构, 其中 R1()代表 H、 烃基、 卤代烃基、 羰基烃基、 羟基 烃基、 氨基烃基或烃氧基。 .
2、如权利要求 1所述的苯并五元不饱和杂环化合物或其药用盐,其中, 所述苯并五元不饱和杂环化合物包括 2-取代苯丙烯酰 -苯并噻吩、 2-取代苯 丙烯酰 -苯并呋喃、 2-取代苯丙烯酰-吲哚或苯环部分通过 、 R5以甲醛缩 合而形成邻二苯醚结构后得到的化合物。
3、如权利要求 1所述的苯并五元不饱和杂环化合物或其药用盐,其中, 所述苯并五元不饱和杂环化合物或其药用盐结构包括, 2位的取代基为 2- 烃氧基酰基或 2-烃基酰基的苯并噻吩、 苯并呋喃或吲哚化合物。
4、如权利要求 1所述的苯并五元不饱和杂环化合物或其药用盐,其中, 所述苯并五元不饱和杂环化合物或其药用盐结构包括, 2 位的取代基为 2-(2,-甲砜或甲基亚砜乙酰基)或 2_(2,-甲砜或甲基亚砜取代 -Γ-羟基) 乙基 的苯并噻吩、 苯并呋喃或吲哚化合物。
5、如权利要求 1所述的苯并五元不饱和杂环化合物或其药用盐,其包 括:
2-乙氧甲酰-苯并噻吩
2-(2,-甲基亚砜基) -乙酰苯并噻吩
2-(2,-甲砜基)乙酰-苯并噻吩
2-乙氧甲酰 -5,6-亚甲基二氧-苯并噻吩
2-(2,-甲基亚砜基)乙酰 -5,6-亚甲基二氧-苯并噻吩
2-(2,-甲砜基)乙酰 -5,6-亚甲基二氧 _苯并噻吩
2-乙氧甲酰-苯并呋喃
2-(2,-甲基亚砜基)-乙酰苯并呋喃
2-乙氧甲酰 -4-氯-苯并噻吩 2-(Γ-羟基 -2'-甲基亚砜基) -乙基-苯并噻吩
2-乙氧甲酰 -4-甲氧基-苯并呋喃
2-乙氧甲酰 -5-甲氧基-苯并呋喃
2-乙氧甲酰 -6-甲氧基-苯并呋喃
2-乙氧甲酰 -7-甲氧基-苯并呋喃
2-乙氧甲酰 -5,6-二甲氧基-苯并噻吩
2-乙氧甲酰- 7-氟-苯并呋喃
2-乙氧甲酰 -5,7-二氯-苯并呋喃
2-乙氧甲酰 -5-甲氧甲酰-苯并噻吩
2-乙酰 -5-甲氧甲酰-苯并噻吩
2-乙氧甲酰- 6-甲氧甲酰-苯并噻吩
2-乙酰 -5-羧基-苯并噻吩
2-乙酰 -6-甲氧甲酰-苯并噻吩
2-乙酰 -6-羧基-苯并噻吩
2-(2,-甲基亚砜基)乙酰 -4-氯-苯并噻吩
2-(2,-甲基亚砜基)乙酰 -4-甲氧基-苯并呋喃
2-(2,-甲基亚砜基)乙酰 -5-甲氧基-苯并呋喃
2-(2,-甲基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩
2_(2,-甲基亚砜基)乙酰 -6-甲氧基-苯并呋喃
2-(2,-甲基亚砜基)乙酰 -7-甲氧基-苯并呋喃
2-乙氧甲酰 -6-二乙氨基-苯并呋喃
(£ 2-[3,-(4"-甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻吩
CE)-2-[3,-(4,,-甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻吩
2-(1,-羟基 -2,-甲基亚砜基)乙基 -5,6-亚甲基二氧-苯并噻吩
2-(Γ-羟基)乙基 -5-甲氧甲酰-苯并噻吩
2-(1,-羟基)乙基 -6-甲氧甲酰-苯并噻吩 2-肉桂酰 -6-乙氧甲酰-苯并噻吩
(¾)-2-[3,-(2",3",4"-三甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻吩
(¾-2-[3,- (2,,,3",4"-三甲氧基苯)丙烯酰 ]-6-乙氧甲酰 -苯并噻吩 -2-肉 桂酰 -5-乙氧甲酰-苯并噻吩
(E 2-[3,-(2,,-氯苯基)丙烯酰 ]-5-乙氧甲酰 -苯并噻吩^ -2-[3,-(2"-氯苯 基)丙烯酰 ]-5-甲氧甲酰-苯并噻吩
(E 2- [3,-(2,,-氯苯基)丙烯酰 ]-6-乙氧甲酰-苯并噻吩
(¾-2-[3,-(3",4"-二甲氧基苯)丙烯酰 ]-6-乙氧甲酰-苯并噻吩
(¾>-2-[3,-(3",4"-二甲氧基苯)丙烯酰 ]-5-乙氧甲酰-苯并噻吩
2-(2'-甲砜基)乙酰 -5-甲氧基-苯并呋喃
2-(1,-羟基 -2,-甲基亚砜)乙基 -5-甲氧基-苯并呋喃
-2-[3 '-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基 -吲哚
小甲基 _2_[3,_(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基 -H引哚
小氯乙基 -2-[3,-(4"-甲氧基苯)丙烯酰 ]-5,6-二甲氧基-吲哚
(¾>小乙酰基 -2-[3,-(4"-氟苯)丙烯酰 ]-5,6-二甲氧基 -吲哚
(¾小(2,-羟乙基 )-2-[3,-(4,,-氟苯)丙烯酰 ]-5-乙酰氧基』引哚
(Ε 1-(2,-氨基乙基) -2-[3,-(4"-氟苯)丙烯酰 ]-5-乙酰氧基 -吲哚
(Ε 1-(2,-甲氧基乙基) -2-[3,-(4"-氟苯)丙烯酰 ]- 5-乙酰氧基 -吲哚
2-乙氧甲酰 -4-甲基-苯并噻吩
2-庚酰 -5,6-二甲基-苯并噻吩
2-戊氧甲酰 -5,6-二氨基苯并噻吩
2-酮酸-苯并噻吩 .
2-(Γ, 2'-二羰基)戊基苯并噻吩
2- (丁基亚砜基)乙酰 -5,6-二氨基-苯并噻吩
2-(4'-氯庚氧甲酰) -5,6-二甲氧基-苯并噻吩
2-(4,-氯己基亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩 2-(6,-羟基己基)氧甲酰 -5,6-二甲氧基-苯并噻吩
2-(6,-羟基戊亚砜基)乙酰 -5,6-二甲氧基-苯并噻吩
2-(6,-甲氧基己基)氧甲酰 -5,6-二甲氧基-苯并噻吩
2-(6,-甲氧基戊基亚砜基:)乙酰- 5,6-二甲氧基-苯并噻吩
2-乙氧甲酰 -5,6-乙基亚甲基二氧-苯并噻吩
2-乙氧甲酰 -5,6-(2,-氯乙基)亚甲基二氧-苯并噻吩
2-乙氧甲酰 -5,6-(1,-羟乙基)亚甲基二氧-苯并噻吩
2-乙氧甲酰 -5,6-(1,-氨乙基)亚甲基二氧-苯并噻吩
2-乙氧甲酰 -5,6-(1,-甲氧基乙基)亚甲基二氧-苯并噻吩
2-乙酰苯并噻吩
^-2-(3,-(4"-甲氧基苯)丙烯酰) -苯并噻吩
2-乙酰-苯并呋喃
6、制备权利要求 1中具有通式( I )所示结构的苯并五元不饱和杂环 化合物或其药用盐的方法, 其特征在于:
A、 当式 (I) 中的 X为 S, Y代表 CO 或 CR OH, 为 CH2S(0)nR8 或 R9取代苯丙烯基结构时,采用路线 1或路线 2所示方法首先得到中间体 ( IV ) , 其中, R2, R3, , R5, R6, R8, R9, n, Ι 的定义同权利要求 1, Ru代表 Η、 ΟΗ、 含有 1-18个碳的烃基、 羧基、 酰基、 烷氧基或磺酸基; 路线 1 :
Figure imgf000059_0001
合成方法为: 以取代的邻硝基苯甲醛 (Π ) 为起始原料, 在碱性试剂 催化下, 使用巯基乙醇进行芳香的亲核取代反应, 原料的 Ν02被乙硫基取 R,
.R 11
代, 生成中间体 (III) ; 在碱性试剂催化下, 卤代试剂 0 (Z代表 离去基团),与中间体(III)反应,得到 2-取代酰基苯并噻吩的衍生物(W);
路线 2:
Figure imgf000060_0001
II IV
合成方法为: 以取代的邻硝基苯甲醛 (II) 为起始原料, 在碱性试剂 催化下, 与巯基试剂
Figure imgf000060_0002
直接进行反应得 2-取代酰基苯并噻吩的衍 生物 (W) ;
进一步, 所述中间体 (W) 可分别进行如下反应得到相应的通式 I化 合物:
a. 当 R3, , 5, R6中的一个或多个为酯基时, 中间体 (W) 在碱 性条件下水解得到羧酸衍生物 (V) , 其中 R3', R , R5', R6'分别相应于 R3, R4, R5, R6水解后的基团
Figure imgf000060_0003
b. 中间体 (W) 经还原得到相应的羟基衍生物 (YD
Figure imgf000060_0004
; 或 c. 当 R„为甲基时, 中间体 (IV ) 与 R9取代的苯基甲醛中间体 (VII) 进行羟醛缩合, 得到 2位为 R9取代苯丙烯酰的化合物 ( )
Figure imgf000061_0001
d. 当 Ru为烷氧基时, 中间体 (IV) 可进行如下反应得到相应的通式 I化合物:
Figure imgf000061_0002
XI
中间体 (W ) 在强碱与加热下, 与亚磺酰甲基衍生物反应得到化合物 2-(2,-取代甲基亚砜)酰基苯并噻吩衍生物 (IX) , 继续进行氧化和还原分 别得到化合物 2-(2,-取代甲砜乙酰基)苯并噻吩衍生物 (X ) 和 2-(2,-取代 甲砜或甲基亚砜 -Γ-羟基) 乙基苯并噻吩衍生物 (XI) ;
B、 当式( I )中的 X为 0, Y代表 CO 或 CR OH, RJ为 CH2S(0)nR8 时, 其合成采用路线 3所示方法得到中间体(XIII) , 其中, R2, R3, R4, R5, R6, R8, n, R '的定义同权利要求 1, R12代表以下基团: H、 OH、 含 有 1-18个碳的烃基、 羧基、 酰基、 垸氧基、 磺酸基
路线 3:
Figure imgf000062_0001
合成方法为: 以取代的邻羟基苯甲醛 GOO为起始原料, 在碱性试剂催
R2 化下, 与卤代试剂 0 (Z代表离去基团) 进行反应, 生成 2-羰基类 ( XIII ) 化合物;
其中, 当 R12为烷氧基时, 中间体 (XIII ) 可进行如下反应得到相应 的通式 I化合物:
Figure imgf000062_0002
XVI
中间体 (ΧΙΠ)再在强碱与加热下,与亚磺酰甲基衍生物反应得到 2-(2'- 取代甲基亚砜)酰基苯并呋喃衍生物 (XIV), (XIV)继续进行氧化和还原分别 得到化合物 2-(2,-取代砜基)乙酰苯并呋喃衍生物 (XV)和 2-(2,-取代甲砜或甲 基亚砜 - -羟基)乙基苯并呋喃衍生物 (XVI);
C、 当式 ( I ) 中 X为 NR7, Y代表 CO, 为 R9取代苯丙烯基结构 时, 其合成采用路线 4所示方法, 其中, R2, R3, R4 , R5, R6, R7, R9的 定义同权利要求 1 ;
路线 4:
Figure imgf000063_0001
合成方法为: 以取代的 N-R7-2-乙酰吲哚 (XVII ) 为起始原料, 在碱性 试剂催化下, 与取代的苯基甲醛中间体 (VII ) 进行羟醛缩合, 得到 2位为 R9取代的苯丙烯酰目标物 (XVIII ) 。
7、权利要求 1中具有通式 I所示结构的苯并五元不饱和杂环化合物或 其药用盐在制备治疗骨质疏松病症的药物中的应用。
8、 一种用于抗骨质疏松的药物组合物, 其特征在于, 该药物组合物中 含有治疗有效量的权利要求 1 所述苯并五元不饱和杂环化合物或其药用 盐, 并含有一种或多种药学上可接受的药物辅剂。
9、 如权利要求 8所述的药物组合物, 其中, 所述苯并五元不饱和杂环 化合物或其药用盐作为活性成分, 在该药物组合物中的重量含量为 0.1%-99.5%。
10、 如权利要求 8所述的药物组合物, 其中, 该药物组合物中含有重 量比为 0.5%-99.5%的活性成分。
11、 如权利要求 8所述组合物在制备抗骨质疏松药物中的应用。
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