WO2012068702A1 - Composés de benzo hétérocycliques insaturés à 5 éléments et procédés pour les préparer - Google Patents

Composés de benzo hétérocycliques insaturés à 5 éléments et procédés pour les préparer 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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group
benzothiophene
ethoxycarbonyl
substituted
acetyl
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PCT/CN2010/001881
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Chinese (zh)
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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/fr
Publication of WO2012068702A1 publication Critical patent/WO2012068702A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic 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
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic 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
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [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
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[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
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic 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
    • C07D495/04—Ortho-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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Abstract

L'invention concerne des composés de benzo hétérocycliques insaturés à 5 éléments, représentés par la formule (I) ainsi que leurs sels pharmaceutiquement acceptables, des procédés pour les préparer et leurs utilisations dans la préparation de médicaments pour traiter l'ostéoporose, chaque substituant de formule (I) ayant la définition mentionnée dans la description
PCT/CN2010/001881 2010-11-23 2010-11-23 Composés de benzo hétérocycliques insaturés à 5 éléments et procédés pour les préparer WO2012068702A1 (fr)

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WO2018067423A1 (fr) * 2016-10-04 2018-04-12 Merck Sharp & Dohme Corp. Composés de benzo [ b ] thiophène en tant qu'agonistes de piqûre
US10793557B2 (en) 2018-04-03 2020-10-06 Merck Sharp & Dohme Corp. Sting agonist compounds
US11285131B2 (en) 2017-08-04 2022-03-29 Merck Sharp & Dohme Corp. Benzo[b]thiophene STING agonists for cancer treatment
US11312772B2 (en) 2017-08-04 2022-04-26 Merck Sharp & Dohme Corp. Combinations of PD-1 antagonists and benzo [b] thiophene STING agonists for cancer treatment
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AU2017339418C1 (en) * 2016-10-04 2020-12-17 Merck Sharp & Dohme Llc Benzo[b]thiophene compounds as sting agonists
US10730849B2 (en) 2016-10-04 2020-08-04 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as STING agonists
CN110036001A (zh) * 2016-10-04 2019-07-19 默沙东公司 作为STING激动剂的苯并[b]噻吩化合物
US10414747B2 (en) 2016-10-04 2019-09-17 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as sting agonists
WO2018067423A1 (fr) * 2016-10-04 2018-04-12 Merck Sharp & Dohme Corp. Composés de benzo [ b ] thiophène en tant qu'agonistes de piqûre
US10703738B2 (en) 2016-10-04 2020-07-07 Merck Sharp & Dohme Corp. Benzo[b]thiophene compounds as STING agonists
KR20190056432A (ko) * 2016-10-04 2019-05-24 머크 샤프 앤드 돔 코포레이션 STING 효능제로서의 벤조[b]티오펜 화합물
TWI796306B (zh) * 2016-10-04 2023-03-21 美商默沙東有限責任公司 作為STING促效劑之苯并[b]噻吩化合物
AU2017339418B2 (en) * 2016-10-04 2020-04-16 Merck Sharp & Dohme Llc Benzo[b]thiophene compounds as sting agonists
EA037626B1 (ru) * 2016-10-04 2021-04-22 Мерк Шарп И Доум Корп. Соединения бензо[b]тиофена как агонисты sting
KR102312721B1 (ko) * 2016-10-04 2021-10-13 머크 샤프 앤드 돔 코포레이션 STING 효능제로서의 벤조[b]티오펜 화합물
CN110036001B (zh) * 2016-10-04 2022-03-22 默沙东公司 作为STING激动剂的苯并[b]噻吩化合物
US11285131B2 (en) 2017-08-04 2022-03-29 Merck Sharp & Dohme Corp. Benzo[b]thiophene STING agonists for cancer treatment
US11312772B2 (en) 2017-08-04 2022-04-26 Merck Sharp & Dohme Corp. Combinations of PD-1 antagonists and benzo [b] thiophene STING agonists for cancer treatment
US10793557B2 (en) 2018-04-03 2020-10-06 Merck Sharp & Dohme Corp. Sting agonist compounds
US11702430B2 (en) 2018-04-03 2023-07-18 Merck Sharp & Dohme Llc Aza-benzothiophene compounds as STING agonists

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