CN101906093B - Benzo five-membered unsaturated heterocycle compound and preparation method thereof - Google Patents

Benzo five-membered unsaturated heterocycle compound and preparation method thereof Download PDF

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CN101906093B
CN101906093B CN 200910246709 CN200910246709A CN101906093B CN 101906093 B CN101906093 B CN 101906093B CN 200910246709 CN200910246709 CN 200910246709 CN 200910246709 A CN200910246709 A CN 200910246709A CN 101906093 B CN101906093 B CN 101906093B
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thionaphthene
acyloxy
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ethoxycarbonyl
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CN101906093A (en
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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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Institute of Medicinal Biotechnology of CAMS
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Abstract

The invention provides a benzo five-membered unsaturated heterocycle compound and a preparation method thereof. The compound has the structure shown in the general formula (I). A test shows that the compound has the activity for up regulating the bone morphogenetic protein BMP-2 expression and the function of resisting osteoporosis. The invention also provides a medicine composition containing the compound as the active ingredient. An in-vitro activity test shows that the compound represents obvious up-regulating function for the bone morphogenetic protein BMP-2 expression; and an SAMP6 rapid ageing mice in-vivo activity test result shows that the compound has the function of improving the osteoporosis of ageing model mice. The invention provides a basis for further research and development of the osteoporosis-resisting medicine of the compound.

Description

Benzo five-membered unsaturated heterocycle compound and preparation method thereof
Technical field
The present invention relates to a class benzo five-membered unsaturated heterocycle compound, and the preparation method of described benzo five-membered unsaturated heterocycle compound is disclosed, the invention still further relates to described benzo five-membered unsaturated heterocycle compound in osteoporosis application and contain this compounds as the pharmaceutical composition of active ingredient.
Background technology
Osteoporosis is a kind of global common disease, is mainly in mid-aged population, especially climacteric the women, clinical principal character is that the general bone amount that the osseous tissue microstructure is destroyed reduces.The risk of bone fracture of suffering from the osteoporosis crowd obviously increases the especially injury of wrist joint, backbone and hip joint.According to estimates, suffer among the osteoporosis crowd, the women of 30-50% and the male sex of 15-30% can meet with fracture in life at them.The fracture patient hospital stays surpasses diabetes, mammary cancer or myocardial infarction patient's hospital stays.In the U.S., Europe and Japanese, 75,000,000 sufferers of osteoporosis face are arranged approximately altogether.International osteoporosis foundation and China's Healthy promotion foundation are introduced China and are had at least 6,944 ten thousand people to suffer from osteoporosis in " osteoporosis is prevented and treated Chinese white paper " of common issue in 2008,2.1 in low bone amount, there is the risk of osteoporosis in hundred million Genus Homos.The osteoporosis total prevalence rate is 15.7% among the crowd of China more than 50 years old, and along with the population life-time dilatation, this ratio is also progressively increasing.Should " white paper " point out that cause that because of osteoporosis wherein annual New Development vertebral fracture has 1,810,000 people approximately in person in middle and old age's fracture of China 70-80%, the Hip Fracture case is 230,000.China's elderly population increase in the speed with annual 5.2%, and this also means the increase of potential patients with osteoporosis.Conservatively estimate the annual expense that only is used for the treatment of the middle-older patient fracture of thigh at present up to 10,400,000,000 Renminbi, these data will be above 21,700,000,000 to the year two thousand twenty.
In the forming process of bone, scleroblast (Osteoblast) and osteoclast (Osteoclast) are coordinated mutually, make the formation of sclerotin and dissolving be in a kind of running balance, keep the continual renovation of sclerotin.Unbalance when this coordination, when bone resorption surpasses bone forming, namely cause osteoporosis.
Adult bone has bone process of reconstruction clearly, and nineteen sixty-five is found the function that this bone self is repaired first, and finds that (Bone Morphogenetic Protein BMP) is bioactive molecule in this process to Delicious peptide.Afterwards, found bmp protein family again.Modern more and more evidences shows bone morphogenesis protein-2, and (Bone Morphogenetic Protein-2 BMP-2) plays an important role in bone forming and bone repair process.Recombinant human B MP-2 albumen (Recombinant Human BoneMorphogenetic Protein-2, rhBMP-2,
Figure G2009102467099D00021
Bone Graft) promotes bone apposition because of it and to the repair of long bone, be used for autologous bone transplanting and local alveolar ridge augmentation in 2007 by drugs approved by FDA, be used for the treatment of fracture of tibia in 2004 by drugs approved by FDA, be used for spinal fusion in 2002 by the FDA approval.In Germany, during the treatment fracture of tibia, the expense of injecting a pin recombinant human B MP-2 albumen approximately is 2970 Euros, and uses this medicine not obtain reimbursemen from health insurance companies.Therefore, use recombinant human B MP-2 albumen to bring heavy economical load to the patient.
BMP-2 is stored in one of bone inductive factor BMPs family member in the bone, belongs to transforming growth factor-beta (transforming growth factor β, TGF2 β) superfamily member.The earlier synthetic larger precursor molecule of BMP-2 is a kind of dormancy albumen, is contained 100-140 amino acid whose carboxyl terminal monomer in case activate namely by one of protease hydrolysis formation.Two monomers are with the interchain disulfide bond activated dimer of maturation that is formed by connecting, and relative molecular mass reaches 18000.The BMP-2 acceptor belongs to the transforming growth factor superfamily member, has the serine/threonine protein kitase structure, and its signal pass through mechanism and TGF-beta receptor are similar.The BMP-2 acceptor relevant with the transmission of BMP-2 signal is divided into I type and II type, the I receptor is raised and the intracytoplasmic Smad1 of phosphorylation, Smad5 and Smad8 albumen, and assist Smad1-Az-HsN3 triplet mixture to enter in the nuclear, this plays a decisive role to osteoblastic directed differentiation; Though the II receptor does not play a crucial role in osteoblastic directed differentiation process, the II receptor can activate the I receptor after BMP-2 is combined, and strengthens the avidity of the acceptor of BMP-2 greatly.The protein kinase activity of acceptor was activated after BMP-2 albumen was combined with the II of BMP-2 receptor, the second-to-last amino-acid residue glutamine in GS district in the catalysis I receptor cell (the SGSGSG sequence that the tool characteristic is conservative) converts aspartic acid to, the I receptor is activated the back and be combined the Serine of pSmad1 also or Smad5 carboxyl terminal with Smad1 or Smad5, thus activation Smad1 or Smad5 albumen.Smads albumen is that the key of transduction BMP-2 signal pathway from cell surface to karyon transcribed the auxiliary adjustment factor as the chief component of the relevant transduction pathway of TGF2 β.After the Smad1 that is activated or Smad5 albumen change nucleus over to by cytoplasm, act on the downstream target gene with direct and indirect mode, as the ALP gene, finally promote bone forming.
Studies show that BMP-2 promotes bone forming from two aspects: the one, promote osteoblast differentiation.BMP-2 in the ground substance of bone can raise bone marrow stem cell and induce bone marrow stem cell to be divided into scleroblast and chondrocyte, forms new bone by calcium deposition again.BMP-2 also induces reinventing of osteoblastic differentiation and young bone in the mesenchymal cell.BMP-2 also promotes osteoblastic differentiation and suppresses its apoptosis in the regeneration of bone and repair process.The 2nd, promote the expression of other osteogenic factors.BMP-2 can increase the expression of scleroblast marker gene OPN, Cbfa1, Col I alpha1, BSP, ALP, fabp4 (lipid acid coupling protein 4) etc., and the corresponding protein of these genes plays a part very crucial in osteoblast differentiation.
There are some researches show that osteoporosis genes involved (one or more gene) is positioned at a zone on karyomit(e) 20 galianconism, and bone morphogenesis protein-2 (BMP-2) protein gene is one of them genes involved.3 '-UTR of the BMP-2 protein gene bmp-2 of Mammals and fish (3 '-untranslated regions, gene 3 ' is held untranslated district) high conservative, 3 '-UTR of this explanation bmp-2 has stood to select to press in evolution.This section conservative region is proved to be important regulatory factor after the bmp-2 genetic transcription, to the adjusting of 3 ' of bmp-2-UTR can influence gene bmp-2 expression, and then influence the expression of BMP-2 albumen and other osteoporosis correlation factors.
In order to obtain the osteoplastic medicine of novel promotion, it is that the osteosporosis resistant medicament screening model that raises of the short BMP-2 of drug target is (referring to Chinese patent application: 03104750.5), and use this model the compound of microbe-derived and chemosynthesis is screened that the Zhang Yueqin of this institute etc. has set up with the bmp-2 promotor.By a large amount of screening operations, find that the compound that a class has a five-membered unsaturated heterocycle structure has the activity of obvious rise BMP-2, and in ovariectomy rat model body checking its truly have the effect (referring to Chinese patent ZL 200610008114.6) of improving the osteoporosis symptom.
The present invention is on the basis of above-mentioned research; further design, synthetic and screen a series of benzo five-membered unsaturated heterocycle compounds (formula I) that can represent with following general formula; especially wherein 2-acyl group benzo five-membered unsaturated heterocycle compound; through system architecture transformation and structure activity study; can provide new first guide structure for osteoporosis therapy; and start with from the active compound that can raise BMP-2 albumen, further developed novel short osteoplastic osteosporosis resistant medicament.
Figure G2009102467099D00041
Formula (I)
Summary of the invention
The invention provides benzo five-membered unsaturated heterocycle compound series or its pharmaceutical salts of (I) structure that has general formula, this compounds has the bone morphogenetic protein of rise BMP-2 expression activity, can be used for treating osteoporosis.
The present invention also provides the synthetic method of described benzo five-membered unsaturated heterocycle compound.
The present invention also provides described benzo five-membered unsaturated heterocycle compound in treatment osteoporosis and because the application aspect the relevant sufferer that osteoporosis causes.
The present invention also provides the pharmaceutical composition that can treat osteoporosis, and this pharmaceutical composition is active ingredient with above-mentioned benzo five-membered unsaturated heterocycle compound or its pharmaceutical salts.
The present invention mainly designs synthetic with different positions (4-on the phenyl ring, 5-, 6-, 7-) thionaphthene of substituted 2 carboxylicesterss, cumarone or indoles are the formula I compound of parent nucleus, introduce in the 2-position compound that has cinnamyl group and the compound that has first sulfone or methyl sulfoxide in the introducing of 2-position.Be connected with alkyl, halogen, methoxyl group, amino, acyl group, carboxyl etc. on the discussion phenyl ring and have different substituents, and ethanoyl different conjugation spatially in 2-position is extended the influence of compound being raised the BMP-2 activity.Designed target compound structure is as shown in table 1, can have substituting groups such as alkyl, alkoxyl group, halogen, haloalkyl on the phenyl ring among the formula I; The R of thiophene, furan nucleus or pyrrole structure part 1Be alkyl, alkoxyl group, carboxyl, sulfone methyl, sulfoxide methyl, the fragrant propenyl structure of replacement etc.
The invention provides the benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof with structure shown in general formula I,
Figure G2009102467099D00051
In the formula,
X represents O, S or NR 7, R wherein 7Represent H, alkyl, halo alkyl, carbonyl alkyl, hydroxy alkylene, hydrocarbyl amino or-oxyl;
Y represents CO or CR 1' OH; R 1' representative following group: H, OH, the alkyl that contains 1-18 carbon, carboxyl, acyl group, alkoxyl group, sulfonic group;
R 1Represent following group: H, OH, the alkyl that contains 1-18 carbon, carboxyl, acyl group, alkoxyl group, sulfonic group, CH 2S (O) nR 8, R 9The substituted benzene propenyl; R wherein 8Represent H, contain alkyl, halo alkyl, hydroxy alkylene or the-oxyl of 1-18 carbon, n=1-2; R 9The amino that represents H, alkyl, alkoxyl group, halogen, carboxyl, amino or replace; And R 1Can with R 1' identical, also can with R 1' difference;
R 2Amino, sulfonic group, itrile group or the acyl group-oxyl etc. that represent following group: H, the alkyl that contains 1-18 carbon, halogen, acyl group, carboxyl, amino or replace;
R 3Amino, acyl group, amide group, ester group or the sulfonic group etc. that represent following group: H, alkyl, alkoxyl group, halogen or haloalkyl, carboxyl, amino or replace;
R 4Represent following group: H, alkyl, alkoxyl group, halogen or haloalkyl, carboxyl, amino or amino, amide group, acyl group, ester group or the sulfonic group etc. that replace;
R 5Amino, acyl group, amide group, ester group or the sulfonic group etc. that represent following group: H, alkyl, alkoxyl group, halogen or haloalkyl, carboxyl, amino or replace;
R 6Amino, acyl group, amide group, ester group or the sulfonic group etc. that represent following group: H, alkyl, alkoxyl group, halogen or haloalkyl, carboxyl, amino or replace; Perhaps,
R 4With R 5Be joined together to form the 5-7 ring structure or have substituent R by carbon, oxygen or nitrogen 10The 5-7 ring structure, R wherein 10Represent H, alkyl, halo alkyl, carbonyl alkyl, hydroxy alkylene, hydrocarbyl amino or-oxyl.
Described in more than defining:
" alkyl " can refer to that carbonatoms is at the alkyl or cycloalkyl of the straight or branched of 1-18, for example, methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl etc. or its corresponding cycloalkyl.
" alkoxyl group " can be that carbonatoms is at the alkoxyl group of 1-18, for example, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy etc.
" acyl group " can be hydrocarbon substituted acyl or the aryl-acyl with 1-18 carbon, for example formyl radical, ethanoyl, sec.-propyl acyl group, n-propyl acyl group, allyl group acyl group, cyclopropyl acyl group, normal-butyl acyl group, isobutyl-acyl group, sec-butyl acyl group, tertiary butyl acyl group, n-pentyl acyl group, isopentyl acyl group, n-hexyl acyl group, isohexyl acyl group, phenyl acyl group, tolyl acyl group etc.
" ester group " can be hydrocarbon ester appended (alkyl acyloxy) or the aryl ester group with 1-18 carbon, for example methanoyl, acetoxyl group, sec.-propyl acyloxy, n-propyl acyloxy, allyl group acyloxy, cyclopropyl acyloxy, normal-butyl acyloxy, isobutyl-acyloxy, sec-butyl acyloxy, tertiary butyl acyloxy, n-pentyl acyloxy, isopentyl acyloxy, n-hexyl acyloxy, isohexyl acyloxy, phenyl acyloxy, tolyl acyloxy etc.
" amido " can be that the hydrocarbon with 1-18 carbon replaces amido or aryl amido, for example methyl amido, ethyl amido, sec.-propyl amido, n-propyl amido, allyl group amido, cyclopropyl amido, normal-butyl amido, isobutyl-amido, sec-butyl amido, tertiary butyl amido, n-pentyl amido, isopentyl amido, n-hexyl amido, isohexyl amido, phenyl amido, tolyl amido etc.
In the benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof provided by the invention, when substituted radical, typically refer to low alkyl group, lower alkoxy, halogen, amino of C1-C6 etc., especially, the substituting group of the amino of replacement can be the alkyl of C2-C6.
In the substituting group of benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof structural formula of the present invention, the alkyl in described halo alkyl, carbonyl alkyl, hydroxy alkylene, the hydrocarbyl amino is the alkyl of C1-C6.
According to benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof provided by the invention, its corresponding thionaphthene/furans, Benzazole compounds, especially the effect that has remarkable rise bone morphogenetic protein BMP-2 expression activity, the function of resisting osteoporosis result of study shows in the body, and compound of the present invention has the effect of improving SAMP6 mouse osteoporosis symptom.
Preferably, described benzo five-membered unsaturated heterocycle compound comprises that 2-substituted benzene acryloyl-thionaphthene, 2-substituted benzene acryloyl-cumarone or phenyl ring partly pass through R 4, R 5Form the compound that obtains after the adjacent phenyl ether structure with formaldehyde condensation.
Benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof structure optimization of the present invention comprises that 2 substituting group is thionaphthene or the benzofuran compound of 2--oxyl formyl radical or 2-alkyl acyl group.
Benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof structure optimization of the present invention comprises that 2 substituting group is thionaphthene, cumarone or the benzazolyl compounds of 2-(2 '-first sulfone or methyl sulfoxide ethanoyl) or 2-(2 '-first sulfone or methyl sulfoxide replace-1 '-hydroxyl) ethyl.
As the indefiniteness example, benzo five-membered unsaturated heterocycle compound of the present invention can be selected from following particular compound:
2-ethoxycarbonyl-thionaphthene
2-(2 '-methyl sulfoxide base)-phenyl methyl ketone thiophthene
2-(2 '-methylsulfonyl) acetyl-thionaphthene
2-ethoxycarbonyl-5,6-methylene radical dioxy-thionaphthene
2-(2 '-methyl sulfoxide base) acetyl-5,6-methylene radical dioxy-thionaphthene
2-(2 '-methylsulfonyl) acetyl-5,6-methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-cumarone
2-(2 '-methyl sulfoxide base)-acetyl cumarone
2-ethoxycarbonyl-4-chloro-thionaphthene
2-(1 '-hydroxyl-2 '-methyl sulfoxide base)-ethyl-thionaphthene
2-ethoxycarbonyl-4-methoxyl group-cumarone
2-ethoxycarbonyl-5-methoxyl group-cumarone
2-ethoxycarbonyl-6-methoxyl group-cumarone
2-ethoxycarbonyl-7-methoxyl group-cumarone
2-ethoxycarbonyl-5,6-dimethoxy-thionaphthene
2-ethoxycarbonyl-7-fluoro-cumarone
2-ethoxycarbonyl-5,7-two chloro-cumarones
2-ethoxycarbonyl-5-methoxycarbonyl-thionaphthene
2-acetyl-5-methoxycarbonyl-thionaphthene
2-ethoxycarbonyl-6-methoxycarbonyl-thionaphthene
2-acetyl-5-carboxyl-thionaphthene
2-acetyl-6-methoxycarbonyl-thionaphthene
2-acetyl-6-carboxyl-thionaphthene
2-(2 '-methyl sulfoxide base) acetyl-4-chloro-thionaphthene
2-(2 '-methyl sulfoxide base) acetyl-4-methoxyl group-cumarone
2-(2 '-methyl sulfoxide base) acetyl-5-methoxyl group-cumarone
2-(2 '-methyl sulfoxide base) acetyl-5,6-dimethoxy-thionaphthene
2-(2 '-methyl sulfoxide base) acetyl-6-methoxyl group-cumarone
2-(2 '-methyl sulfoxide base) acetyl-7-methoxyl group-cumarone
2-ethoxycarbonyl-6-diethylin-cumarone
(E)-2-[3 '-(4 "-anisole) acryloyl]-6-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(4 "-anisole) acryloyl]-5-ethoxycarbonyl-thionaphthene
2-(1 '-hydroxyl-2 '-methyl sulfoxide base) ethyl-5,6-methylene radical dioxy-thionaphthene
2-(1 '-hydroxyl) ethyl-5-methoxycarbonyl-thionaphthene
2-(1 '-hydroxyl) ethyl-6-methoxycarbonyl-thionaphthene
(E)-2-cinnyl-6-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(2 ", 3 ", 4 "-trimethoxy-benzene) acryloyl]-5-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(2 ", 3 ", 4 "-trimethoxy-benzene) acryloyl]-6-ethoxycarbonyl-thionaphthene (E)-2-meat
Osmanthus acyl-5-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-5-ethoxycarbonyl-thionaphthene (E)-2-[3 '-(2 "-chlorobenzene
Base) acryloyl]-5-methoxycarbonyl-thionaphthene
(E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-6-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(3 ", 4 "-dimethoxy benzene) acryloyl]-6-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(3 ", 4 "-dimethoxy benzene) acryloyl]-5-ethoxycarbonyl-thionaphthene
2-(2 '-methylsulfonyl) acetyl-5-methoxyl group-cumarone
2-(1 '-hydroxyl-2 '-methyl sulfoxide) ethyl-5-methoxyl group-cumarone
(E)-2-[3 '-(4 "-anisole) acryloyl]-5,6-dimethoxy-indoles
(E)-1-methyl-2-[3 '-(4 "-anisole) acryloyl]-5,6-dimethoxy-indoles
(E)-1-chloroethyl-2-[3 '-(4 "-anisole) acryloyl]-5,6-dimethoxy-indoles
(E)-1-ethanoyl-2-[3 '-(4 "-fluorobenzene) acryloyl]-5,6-dimethoxy-indoles
(E)-1-(2 '-hydroxyethyl)-2-[3 '-(4 "-fluorobenzene) acryloyl]-5-acetoxyl group-indoles
(E)-1-(2 '-amino-ethyl)-2-[3 '-(4 "-fluorobenzene) acryloyl]-5-acetoxyl group-indoles
(E)-1-(2 '-methoxy ethyl)-2-[3 '-(4 "-fluorobenzene) acryloyl]-5-acetoxyl group-indoles
2-ethoxycarbonyl-4-methyl-thionaphthene
2-oenanthyl-5,6-dimethyl-thionaphthene
2-penta oxygen formyl-5,6-diaminobenzene thiophthene
2-ketone acid-thionaphthene
2-(1 ', 2 '-dicarbapentaborane) amylbenzene thiophthene
2-(butyl sulfoxide group) acetyl-5,6-diamino-thionaphthene
2-(4 '-chlorine oxygen in heptan formyl)-5,6-dimethoxy-thionaphthene
2-(4 '-chlorine hexyl sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene
2-(6 '-hydroxyl hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene
2-(6 '-hydroxyl, penta sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene
2-(6 '-methoxyl group hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene
2-(6 '-methoxyl group amyl group sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene
2-ethoxycarbonyl-5,6-ethyl methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5,6-(2 '-chloroethyl) methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5,6-(1 '-hydroxyethyl) methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5,6-(1 '-aminoethyl) methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5,6-(1 '-methoxy ethyl) methylene radical dioxy-thionaphthene
2-phenyl methyl ketone thiophthene
(E)-2-(3 '-(4 "-anisole) acryloyl)-thionaphthene
2-acetyl-cumarone
The present invention also provides the synthetic method of formula (I) related compound.
A, the X in formula (I) are S, and Y represents CO or CR 1' OH, R 1Be CH 2S (O) nR 8Or R 9During substituted benzene propenyl structure, method at first obtains intermediate (IV) shown in employing route 1 or the route 2, wherein, and R 2, R 3, R 4, R 5, R 6, R 8, R 9, n, R 1' definition with claim 1, R 11Represent H, OH, contain alkyl, carboxyl, acyl group, alkoxyl group or the sulfonic group of 1-18 carbon;
Route 1:
Figure G2009102467099D00111
Synthetic method is: the Ortho Nitro Benzaldehyde (II) with replacement is starting raw material, under alkaline reagents catalysis, uses mercaptoethanol to carry out fragrant nucleophilic substitution reaction, the NO of raw material 2Replaced by ethylmercapto group, generate intermediate (III); Under alkaline reagents catalysis, halogenating agent (Z represents leavings group) with intermediate (III) reaction, obtains the derivative (IV) of 2-substituted acyl thionaphthene;
Route 2:
Synthetic method is: the Ortho Nitro Benzaldehyde (II) with replacement is starting raw material, under alkaline reagents catalysis, with sulfhydryl reagent Directly react the derivative (IV) of 2-substituted acyl thionaphthene;
Further, described intermediate (IV) can carry out following reaction respectively and obtains corresponding compound of Formula I:
A. work as R 3, R 4, R 5, R 6In one or more when being ester group, intermediate (IV) hydrolysis under alkaline condition obtains carboxylic acid derivative (V), wherein R 3', R 4', R 5', R 6' respectively corresponding to R 3, R 4, R 5, R 6Group after the hydrolysis
Figure G2009102467099D00121
B. intermediate (IV) obtains corresponding hydroxy derivatives (VI) through reduction
Figure G2009102467099D00122
C. work as R 11During for methyl, intermediate (IV) and R 9The phenyl formaldehyde intermediate (VII) that replaces carries out aldol condensation, obtains 2 and is R 9The compound of substituted benzene acryloyl (VIII)
Figure G2009102467099D00123
D. work as R 11During for alkoxyl group, intermediate (IV) can carry out following reaction and obtain corresponding compound of Formula I:
Figure G2009102467099D00124
Intermediate (IV) is under highly basic and heating, obtain compound 2-(2 '-substituent methyl sulfoxide) acyl group benzothiophene derivative (IX) with the reaction of sulfinyl methyl-derivatives, proceed oxidation and reduction and obtain compound 2-(2 '-replacement first sulfone ethanoyl) benzothiophene derivative (X) and 2-(2 '-replacement first sulfone or methyl sulfoxide-1 '-hydroxyl) ethyl benzothiophene derivative (XI) respectively;
B, the X in formula (I) are O, and Y represents CO or CR 1' OH, R 1Be CH 2S (O) nR 8The time, method obtains intermediate (XIII) shown in its synthetic employing route 3, wherein, and R 2, R 3, R 4, R 5, R 6, R 8, n, R 1' definition with claim 1, R 12Represent following group: H, OH, the alkyl that contains 1-18 carbon, carboxyl, acyl group, alkoxyl group, sulfonic group
Route 3:
Figure G2009102467099D00131
Synthetic method is: the salicylaldhyde (XII) with replacement is starting raw material, under alkaline reagents catalysis, with halogenating agent
Figure G2009102467099D00132
(Z represents leavings group) reacts, and generates 2-carbonyl class (XIII) compound;
Wherein, work as R 12During for alkoxyl group, intermediate (XIII) can carry out following reaction and obtain corresponding compound of Formula I:
Figure G2009102467099D00133
Intermediate (XIII) is again under highly basic and heating, obtain 2-(2 '-substituent methyl sulfoxide) acyl group benzofuran derivative (XIV) with the reaction of sulfinyl methyl-derivatives, (XIV) proceed oxidation and reduction and obtain compound 2-(2 '-replacement sulfuryl) phenyl methyl ketone benzofuran derivs (XV) and 2-(2 '-replacement first sulfone or methyl sulfoxide-1 '-hydroxyl) ethyl benzofuran derivative (XVI) respectively;
C, X is NR in formula (I) 7, Y represents CO, R 1Be R 9During substituted benzene propenyl structure, method shown in its synthetic employing route 4, wherein, R 2, R 3, R 4, R 5, R 6, R 7, R 9Definition with claim 1;
Route 4:
Figure G2009102467099D00141
Synthetic method is: with the N-R that replaces 7-2-acetyl indole (XVII) is starting raw material, under alkaline reagents catalysis, carries out aldol condensation with the phenyl formaldehyde intermediate (VII) that replaces, and obtains 2 and is R 9The phenylallene acyl target compound (XVIII) that replaces.
The present invention has found compound in the general formula (I), 2-carbalkoxyl-thionaphthene/furan derivatives (compound 3b, 5b, 6b, 7b, 9b, 10b, 11b, 12b, 13b, 16b, 18b, 21b, 22b, 23b etc.), 2-acetyl/hydroxyethylbenzene thiophthene/furan derivatives (compound G39,1c, 1e, 2c, 2e, 1f, 2f etc.), 2-substituted benzene acryloyl-thionaphthene/furan derivatives (compound S 25,1dA, 1dB1,1dC, 2dA, 2dB, 2dC, 2dD, G33-1, G33-2, G33-3, G33-4, G33-5, G33-6, G33-7 etc.), 2-(2-sulfoxide group/sulfuryl)-phenyl methyl ketone thiophthene/furan derivatives (compound 3c, 3d, 4c, 7c, 9c, 10c, 11d, 11e, 12c, 13c, 18c, 22c, 23c etc.), phenyl moiety R 4, R 5For the formaldehyde adjacent phenyl ether structural derivative (compound 8b, 8c, 8e, 24b, 25b, 26b, 27b, 28b etc.) etc. that contracts has remarkable rise bone morphogenetic protein BMP-2 expression activity.Function of resisting osteoporosis result of study in the body, (S25 G39) all has the effect of improving SAMP6 mouse osteoporosis symptom to the representation compound in the aforementioned classes of compounds for 8b, 3c, the invention provides their application aspect the treatment osteoporosis.
The present invention also provides the pharmaceutical composition that contains said compound, and can contain above-claimed cpd or its pharmaceutical salts for the treatment of significant quantity is activeconstituents, and contains one or more pharmaceutically acceptable carriers.
Formula I compound of the present invention and pharmaceutical composition can be used for preparing osteosporosis resistant medicament.
Pharmaceutical composition provided by the invention can be according to the various form of administration of the conventional production method preparation of pharmaceutical field, and activeconstituents is mixed with one or more carriers, is made into required formulation then.For example can be with the mixture of compound itself or itself and pharmaceutically acceptable vehicle, thinner etc. with the form oral administration of tablet, capsule, granule, powder or syrup or with the non-oral administration of the form of injection.Pharmaceutical composition of the present invention preferably contains the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contains the activeconstituents that weight ratio is 0.5%-99.5%.Above-mentioned preparation can be by conventional pharmaceutical methods preparation.The example of available medicinal adjuvant comprises vehicle (for example carbohydrate derivative such as lactose, sucrose, glucose, mannitol and Sorbitol Powder; Starch derivative such as W-Gum, potato starch, dextrin and carboxymethyl starch; Derivatived cellulose such as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine; Gum arabic; Dextran; Silicate derivative such as metasilicic acid magnalium; Phosphate derivative such as calcium phosphate; Carbonate derivative such as calcium carbonate; Sulfate-derivatives such as calcium sulfate etc.), tackiness agent (gelatin for example, polyvinylpyrrolidone and polyoxyethylene glycol), disintegrating agent (for example derivatived cellulose such as Xylo-Mucine, polyvinylpyrrolidone), lubricant (talcum for example, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.), correctives (Chang Yong sweeting agent for example, acidic flavoring agent and spices etc.), thinner and injection liquid are with solvent (water for example, ethanol and glycerine etc.).
Effect experiment
According to above said route and method, can stablize, repeatable synthesizing obtain The compounds of this invention.
Test an external BMP-2 and raise screening active ingredients
With the rise BMP-2 screening model that has built (specifically referring to Chinese patent application: 03104750.5 record content), plasmid PYJ transient transfection MC3T3E1 cell, detailed process is: the MC3T3E1 cell of an amount of concentration in 100 μ L/ holes is cultivated 8h in 96 hole aseptic plastic culture plates, dilute an amount of PYJ plasmid DNA in aseptic centrifuge tube with the unparalleled anti-DMEM substratum of 25 μ L/ hole serum-frees, in another aseptic centrifuge tube, dilute 0.5 μ L/ hole LF2000 Reagent with the unparalleled anti-DMEM substratum of 25 μ L/ hole serum-frees, within 5min, above-mentioned two pipes are merged mixing, hatch 20min under the room temperature again, mixed transfection suspension is added in above-mentioned 96 orifice plates, every hole 50 μ L, fully behind the mixing 96 orifice plates are placed in 37 ℃ of CO2gas incubator, carry out fluoroscopic examination again after cultivating the drug effect cell that certain hour adds an amount of concentration then; Concrete testing process is as follows: discard the substratum in 96 orifice plates, with the PBS (pH 7.0) in 200 μ L/ holes gently behind the rinsing cell, discard PBS fully, 1 * the PLB that adds 25 μ L/ holes, jolting 15min under the room temperature makes the complete cracking of cell, and lysate is sucked into fluorometric analysis fully with in the 96 hole blank respective aperture, the analytical reagent LAR II that adds 70 μ L/ holes is in analyzing with after in the blank, and (in the 5min) will analyze with blank and place in the Galaxy spectrophotometer immediately; Testing conditions is: no excitation wavelength, wavelength of transmitted light is empty, Positioning delay is 1.0, Number of intervals is 1, Interval time is 1.0s, will be the jolting pattern before instrument readings is set, and the jolting diameter is 1 millimeter, utilize the positive control, blank and relevant data and the calculation formula that arrange, the rise rate of calculation sample.The results are shown in Table 1.
Rise rate=(the luminous number of the luminous number-DMSO of the sample)/luminous number of DMSO * 100%
The present invention adopts above-mentioned BMP-2 screening model that the activity of the compound that synthesized is estimated.Select the negative contrast of 0.1%DMSO for use, the positive contrast of 0.4 μ M Lovastatin, trial drug concentration is 4 μ M, the determination of activity result is as shown in table 1.Table 1 has provided the structure of preferred compound of the present invention, but does not limit the present invention in any way.
The activity of the structure of table 1 The compounds of this invention and external rise BMP-2
Figure G2009102467099D00181
Figure G2009102467099D00201
Figure G2009102467099D00211
Figure G2009102467099D00221
Figure G2009102467099D00231
Figure G2009102467099D00241
Figure G2009102467099D00251
Repeatedly the active determination test result proves, The compounds of this invention all has the rise effect to bone morphogenetic protein-2.Wherein, compound 2dB in the table 1,7b, 5b, 1c, 6b, 1e, 2c, 2e, 2f, 2dA, 8b, 10b, 11b, 12b, G33-1, G33-2, G33-4, G33-5, G33-6, G33-7, the activity of 24b is better than the contrast medicine, compound 6b, 1e, 2e, 2c, the rise rate of 12b etc. about 100%, compound 1dB1,4c, 10c, 8e, 3c, the activity of 23c is suitable with the contrast medicine.
Activity experiment in the experimental example disome
On the basis of external activity The selection result, select this seminar synthetic compound G39, S25,3c and 8b to carry out the activity in vivo evaluation.Select SAMP6 (Senescence-accelleratedmouse, strain P6 purchase the Experimental Animal Center in the Department Of Medicine, Peking University) rapid ageing mouse as the activity in vivo screening model, 19 weeks are the SAMP6 mouse greatly, the SPF level.Totally 35,14 female mices, 21 male mices.Female mice body weight 25-35g, male mice body weight 30-38g.Positive control drug is lovastatin (Lovastatin, Lov is available from Zhejiang pharmaceutcal corporation, Ltd of auspicious group) and Strontium Ranelate (Strontium ranelate, Sr is available from skill company limited of Beijing Hua Fenglian Boke); The blank group is 0.5%MC (methylated cellulose aqueous solution).
Reagent: the used primary antibodie BMP-2 antibody of immunohistochemical methods is available from U.S. Abcam (article No. ab14933), and two is anti-available from U.S. Zymed (article No. PV6001). and mouse bone alkaline phosphatase (BAP) test kit and mouse (urine) Deoxypyridinoline (DPD) test kit are American ADL company product.The Bone Gla protein test kit is with blue rich Clinical Laboratory institute product in Beijing.Uric creatinine (Cr) test kit is that Bai Ding biotechnology (Beijing) company limited produces.
After buying the SAMP6 mouse, place this institute experimental animal room barrier system, normal diet is fed, and adapts to a week.Two in the every cage of female mouse, one in the every cage of male mouse.Room temperature 18-23 ℃, the drinking water abundance, water bottle and bedding and padding change twice weekly, body weight of average per 10 days titles.Measure the mouse bone density, according to bone density value SAMP6 male and female mouse is carried out random packet respectively, mouse is divided into 7 groups, every group of 2 female mouse, 3 male mouse.2 in female mouse 1 cage, 1 in male mouse 1 cage.
The Strontium Ranelate physiological saline solution, all the other medicines are all made suspension with 0.5%MC.The compound method of 0.5%MC (methylcellulose gum) solution: 5g MC is added in the 1000ml distilled water, stir.
The dosage of experiment medicine is set at: lovastatin and Strontium Ranelate dosage are respectively 10mg/kgd and 625mg/kgd, and the dosage of all the other compounds is 30mg/kgd, and blank group gives 0.5%MC solution.Administering mode is the filling stomach.Every morning 9 administrations, once a day, successive administration, administration 3 months, totally 13 weeks.Experimental result is as follows:
BMP-2 expression level in the mouse body: administration finishes to get mouse left side femur and cooks frozen section, carries out the BMP-2 immunohistochemical staining then, has measured the painted level of BMP-2 positive reaction cell cytosol.Concrete numerical value and statistics see Table 2.
BMP-2 positive cell area percentage in each administration group SAMP6 mouse body of table 2 (mean ± SD)
aCompare p＜0.05 (n=5) with blank MC group; bCompare p＜0.005 (n=5) with blank MC group.
Mouse femur BMP-2 immunohistochemical staining measurement result is compared with rapid ageing mouse model control group (MC), and the BMP-2 in all administration group mouse femur tissues expresses and all is significantly improved.Wherein, the BMP-2 of Lov, G39,3c and 8b group expresses has the significance raising, Sr and S25 group unknown significance difference.Trial drug G39 and 8b group mouse femur BMP-2 expression level are suitable with the Lov group, and 3c administration group mouse femur BMP-2 expression level is higher than Lov and Sr control group.
The mouse bone density: the digital cone-beam flash of light borne densitometers OSTEOCORE 3 that uses French MEDILINK company to produce measures the mouse bone densities, this borne densitometers belong to dual intensity X-ray borne densitometers (dual-energy X-ray absorptiometry, DXA).The animalcule analysis software (V6.14) that data analysis adopts instrument to carry under software environment, is manually filled the mouse bone, the bone density of computed in software filled band.Analyze bone density and selected 3 area-of-interests (ROIs:regions of interest): 1.total: whole body; 2.spine: backbone; 3.left hind leg: left side rear.Bone density acquisition time point is respectively the 0th week (19 ages in week of mouse) of administration, the 4th week (23 ages in week of mouse), the 8th week (27 ages in week of mouse), the 12nd week (31 ages in week of mouse).The bone density data of each time point see Table 3.
The BMD data of 3 ROIs of each time point of table 3 (mean ± SD)
Figure G2009102467099D00272
Figure G2009102467099D00281
aCompare p＜0.05 (n=5) with blank MC group;
13 week of successive administration, back bone densitometry result showed, compare with model control group: the whole body bone density of Lov, Sr, S25,3c and 8b administration group mouse all has increase, wherein, 3c and 8b group increase more obvious, and the whole body bone density of 8b group mouse increases the most obvious; The spinal bone density of Lov, Sr, 3c and 8b administration group mouse increases apparent in view, and the increase in density of Lov group mouse spinal bone is the most obvious; The left side rear bone density of S25,3c and 8b administration group mouse all is significantly increased, and contrast medicine Lov and Sr group change not obvious.
It can also be seen that mouse changes of bone mineral density trend from table 3, the spinal bone density of each test group mouse all is increase trend during the administration, and the increase trend of administration group is stronger than model control group; The left side rear bone density of each test group mouse all is attenuating trend during the administration, and the attenuating trend of administration group is slowed down to some extent than the model contrast.Mouse whole body bone density change curve more complicated during the administration, after 1 month, mouse whole body bone density is on a declining curve in administration, and being then increases trend gradually.The peak value of SAMP6 mouse bone density appeared at about 4 monthly ages, and bone density can reduce gradually afterwards.And after administration for some time, relatively the administration initial stage, the whole body bone density has been seen improvement.G39 group situation is more special, whole body bone density, spinal bone density and the increase of left side rear bone density of administration G39 group mouse after 2 months are the most obvious, but, not only not increasing appearance on the contrary again in the bone density of administration in the time of full 3 months and reduce phenomenon, its reason remains further to be studied.
Mouse osseous tissue morphometry: administration is got the right side of mice femur and is made the undecalcified bone slice after finishing, to measure osseous tissue morphometry data.Adopt Leica-Qwin image analysis instrument system, the undecalcified bone slice is carried out norphometry.Trabecula Bone Volume per-cent (TBV%): Trabecula Bone Volume accounts for the per-cent of tested medullary space cumulative volume, is to weigh the flat item key of bone water gaging; Bone trabecula absorbing surface per-cent (TRS%): irregular, rough bone trabecula surface accounts for the per-cent on bone trabecula surface, and it can judge the activity of osteoclast; Bone trabecula forms surface percentage (TFS%): the OS that has scleroblast to be covered accounts for the per-cent on bone trabecula surface, and it can judge osteoblastic activity; Cortex internal surface osteoid width average (OSW): the cortex internal surface has the width average of the osteoid of scleroblast lining.Each administration group detailed data sees Table 4.
Each administration group SAMP6 mouse osseous tissue morphometry data of table 4 (mean ± SD)
Figure G2009102467099D00291
aCompare p＜0.05 (n=5) with blank MC group; bCompare p＜0.005 (n=5) with blank MC group.
Trabecula Bone Volume per-cent (TBV%) measurement result, each administration group mouse femur TBV% all obviously improves than model control group, and wherein, the TBV% of Lov control group and G39, S25,8b medicine group mouse improves obviously.TBV% weighs the flat item key of bone water gaging, illustrates that the bone amount of each administration group mouse all raises to some extent than model control group (MC group).
Bone trabecula forms surface percentage (TFS%) measurement result, and each administration group mouse femur TFS% all obviously improves than model control group, and wherein, the TFS% level of Lov control group, G39, S25 group mouse is significantly increased than model control group.TFS% has the OS of scleroblast lining to account for the per-cent on bone trabecula surface, and it can judge osteoblastic activity.The result confirms that Lov group, G39 organize and the S25 group has obviously been improved the scleroblast activity of mouse.
Bone trabecula absorbing surface per-cent (TRS%) measurement result, TRS% and the model group of Sr control group mice are suitable, and the TRS% of other all administration group mouse all is lower than model control group.TRS% refers to, and irregular, rough bone trabecula surface accounts for the per-cent on bone trabecula surface, and it can judge the activity of osteoclast.Finally, except Sr, other drug all has the trend that reduces the mouse osteoclast activity, but there is no significant difference from statistics.
Cortex internal surface osteoid width average (OSW) measurement result, the OSW of Lov medicine control group mice compares with model control group and is significantly improved, and the OSW of other each administration group mouse compares with model group does not have notable difference.OSW is the important symbol of scleroblast active degree in the cortex bone, and therefore except Lov, other compounds are increasing the not effect of cortex bone scleroblast activity.
The band that mouse undecalcified bone slice photo Smalt river shape wriggles namely is bone trabecula, and what photo was got is the subregion, can not represent the situation of whole bone, but the bone trabecula of model control group (MC group) lacks than each administration group as can be seen.
It is flat that the measurement result of osseous tissue morphometry shows that Lov, G39, S25 and 8b can improve mouse bone water gaging; Lov, G39 and S25 have improved the activity of mouse bone-forming cell, but to the active not effect of cortex bone scleroblast; Each administration group is not obvious to the osteoclast activity effect of mouse.
The mouse body weight change: during the administration, in the body weight that took by weighing mouse in the 0th, 5,12,21,37,51,66,80 days of administration, these 8 body weight are non-empty stomach body weight.Detailed data and tendency see Table 5.
Each body weight of organizing mouse all slowly increases, and mouse is respectively organized in prompting does not all have serious toxicity.
Mouse body weight change during table 5 administration (non-empty stomach body weight)
Figure G2009102467099D00311
Embodiment
Following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.The equal warp of the structure of all compounds among the present invention 1H NMR determines.
Embodiment 1:2-ethoxycarbonyl-thionaphthene (3b)
Be cooled to ice bath under 0 ℃, contain Ortho Nitro Benzaldehyde (4.5g, 30mmol) and anhydrous K 2CO 3(5.0g, among DMF 36.2mmol) (60ml), slowly drip ethyl thioglycolate (3.29ml, 30mmol).Dropwise, 0 ℃ is stirred 30min, reacts 12h then in 60 ℃ of oil baths.Reaction solution is poured in the frozen water into solid collected by filtration, chloroform dissolved solids, anhydrous Na 2SO 4Drying is filtered, and is spin-dried for behind the solvent to obtain yellow solid 5.80g (94%) after separating with silica gel column chromatography.
1HNMR(CDCl 3)δ：1.42(t，J＝7.0Hz，3H)，4.42(q，J＝7.0Hz，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 11H 10O 2S：206.0397)。
Embodiment 2:2-(2 '-methyl sulfoxide base)-phenyl methyl ketone thiophthene (3c)
Under the nitrogen protection, (280mg) puts into three-necked bottle 60% sodium hydride, the give a baby a bath on the third day after its birth grease of time flush away embedding sodium hydride of sherwood oil.Add the constant pressure funnel that fills DMSO (8ml), the remaining a small amount of sherwood oil of decompressing and extracting.DMSO is added in the sodium hydride, and adding is dissolved with 2-ethoxycarbonyl-thionaphthene (3b) (200mg, THF 0.97mmol) (8ml) in constant pressure funnel rapidly.Take out most air rapidly, put into nitrogen, three times repeatedly.Above-mentioned reaction system is heated to 70-75 ℃, and solution is emitted a large amount of hydrogen.Put bubble, be chilled to and add the ice bath cooling after the room temperature, slowly the THF solution in the addition funnel.Finish stirring at room 30min.In 3 times of volumes of reaction solution impouring (60ml) frozen water.Transfer PH to 3～4 with 2N hydrochloric acid.With chloroform (80ml * 2) extractive reaction liquid, amalgamation liquid is washed with distilled water (160ml * 3).The chloroform anhydrous Na 2SO 4Dry.Filtering Na 2SO 4, the evaporate to dryness chloroform gets yellow solid 202mg (87%) mutually.
1HNMR(CDCl 3)δ：2.79(s，3H)，AB system(4.33，4.41，J＝13.2Hz，2H)，7.43(t，J＝7Hz，1H)，7.51(t，J＝7.0Hz，1H)，7.88(d，J＝7.0Hz，1H)，7.94(d，J＝7.0Hz，1H)，8.09(s，1H).MS(EI +)m/z：238[M] +.HRMS(EI +)：found238.0102[M] +，(Calcd for C 11H 10O 2S 2：238.0122)。
Embodiment 3:2-(2 '-methylsulfonyl) acetyl-thionaphthene (3d)
(50mg 0.21mmol) is dissolved in (2ml) in the Glacial acetic acid to 2-(2 '-methyl sulfoxide base) acetyl-thionaphthene (3c), and the ice bath cooling slowly adds 30%H down 2O 2(1ml).Finish stirring at room reaction 5-6h.Add methylene dichloride (3ml * 2) and extract product, be spin-dried for and obtain white solid 2-(2 '-methylsulfonyl) acetyl-thionaphthene 24mg (45%) after silica gel column chromatography separates behind the solvent.
1HNMR(CDCl 3)δ：3.17(s，3H)，4.60(s，2H)，7.45(t，J＝7.0Hz，1H)，7.53(t，J＝7.0Hz，1H)，7.89(d，J＝8.0Hz，1H)，7.96(d，J＝8.0Hz，1H)，8.11(s，1H).HRMS(EI +)：found 254.0074[M] +，(Calcd for C 11H 10O 3S 2：254.0071)。
Embodiment 4:2-ethoxycarbonyl-5,6-methylene radical dioxy-thionaphthene (8b)
Be raw material with 3,4-methylene radical dioxy-6 nitrobenzaldehyde and ethyl thioglycolate, according to the synthetic orange/yellow solid 2-ethoxycarbonyl-5,6-methylene radical dioxy-thionaphthene (68.5%) of obtaining of the method for embodiment 1.
1HNMR(CDCl 3)δ：1.39(t，J＝7.2Hz，3H)，4.37(q，J＝7.2Hz，2H)，6.04(s，1H)，7.19(s，1H)，7.20(s，1H)，7.89(s，1H).MS(EI +)m/z：250[M] +.HRMS(EI +)：found 250.0305[M] +，(Calcd for C 12H 10O 4S：282.0002)。
Embodiment 5:2-(2 '-methyl sulfoxide base) acetyl-5,6-methylene radical dioxy-thionaphthene (8c)
Be raw material with compound 8b, according to the synthetic faint yellow solid powder (90%) that obtains of the method for embodiment 2.
1HNMR(CDCl 3)δ：2.77(s，3H)，AB system(4.26，4.33，J＝13.2Hz，2H)，6.08(s，1H)，7.22(s，1H)，7.24(s，1H)，7.91(s，1H)。HRMS(EI +)：found282.0002[M] +，(Calcd for C 12H 10O 4S 2：282.0021)。
Embodiment 6:2-(2 '-methylsulfonyl) acetyl-5,6-methylene radical dioxy-thionaphthene (8d)
Be raw material with compound 8c, according to the synthetic faint yellow solid powder (80.0%) that obtains of the method for embodiment 3.
1HNMR(CDCl 3)δ：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 +)：found297.9967[M] +，(Calcd for C 12H 10O 5S 2：297.9970)。
Embodiment 7:2-ethoxycarbonyl-cumarone (9b)
In reaction flask, add DMF (5ml) successively, and bromoethyl acetate (118mg, 0.71mmol), salicylic aldehyde (146.6mg, 1.2mmol), Anhydrous potassium carbonate (166mg, 1.2mmol).100 ℃ of oil baths reaction 4h, return to room temperature after, steam except DMF earlier.With the chloroform dissolving, wash the chloroform phase again.During layering, a lot of insolubless appear in chloroform mutually.Suction filtration filtering insolubles, with chloroform filter wash cake repeatedly.Be spin-dried for that silica gel column chromatography obtains the faint yellow oily thing of 57mg (55.9%) after separating behind the solvent.
1HNMR(CDCl 3)δ：1.35(t，J＝7.2Hz，3H)，4.37(q，J＝7.2Hz，2H)，7.22(t，J＝7.6Hz，1H)，7.36(t，J＝7.6Hz，1H)，7.45(s，1H)，7.51(d，J＝8.0Hz，1H)，7.60(d，J＝8.0Hz，1H)。MS(ESI +)m/z：191.4[M+H] +.HRMS(EI +)：found297.9967[M] +，(Calcd for C 11H 10O 3：190.0630)。
Embodiment 8:2-(2 '-methyl sulfoxide base) acetyl cumarone (9c)
Be raw material with 9b, according to synthetic yellow solid 2-(the 2 '-methyl sulfoxide base) acetyl-cumarone (29.6%) that obtains of the method for embodiment 2.
1HNMR(CDCl 3)δ：2.85(s，3H)，AB system(4.30，4.39，J＝13.2Hz，2H)，7.35(t，J＝7.2Hz，1H)，7.54(t，J＝7.2Hz，1H)，7.61(d，J＝8.0Hz，1H)，7.68(s，1H)，7.75(d，J＝8.0Hz，1H)。MS(EI +)m/z：222[M] +.HRMS(EI +)：found222.0350[M] +，(Calcd for C 11H 10O 3S：222.0351)。
Embodiment 9:2-ethoxycarbonyl-4-chloro-thionaphthene (4b)
Sodium hydroxide (100mg, 2.5mmol) in water-soluble (0.2ml), slow adding ethyl thioglycolate under the ice bath (0.28ml, 2.5mmol), stirring at room 0.5h.(200mg, 1.26mmol) and dioxane (2ml), 7h are reacted in 70 ℃ of oil baths to add 2-chloro-6-fluoro-phenyl aldehyde.Filter chloroform filter wash cake.Obtain the light butter product after the full-automatic quick preparative chromatograph chromatographic separation, the cooling back is yellow solid.
1HNMR(CDCl 3)δ：1.43(t，J＝7.0Hz，3H)，4.43(q，J＝7.0Hz，2H)，7.35-7.41(m，2H)，7.73-7.75(m，1H)。MS(EI)：240. 1CNMR(CDCl 3)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[M] +，242[M+2] +.HRMS(EI +)：found240.0014[M] +，(Calcd for C 11H 9O 2SCl：240.0012)。
Embodiment 10:2-(1 '-hydroxyl-2 '-methyl sulfoxide base)-ethyl-thionaphthene (3e)
(100mg 0.42mmol) joins in the mixed solution of THF (2ml) and distilled water (2ml) stirring and dissolving to 2-(2 '-methyl sulfoxide base)-phenyl methyl ketone thiophthene (3c).Add sodium borohydride under the ice bath (20mg, 0.53mmol), stirring at room is reacted 0.5h in batches.Filter, filtrate is used chloroform extraction.Be spin-dried for that silica gel column chromatography obtains faint yellow solid 2-(1 '-hydroxyl-2 '-methyl sulfoxide base)-ethyl-thionaphthene 46mg (54.2%) after separating behind the solvent.
1HNMR(CDCl 3)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 forC 11H 12O 2S 2Na：263.01764)。
Embodiment 11:2-ethoxycarbonyl-4-methoxyl group-cumarone (10b)
Be raw material with 2-methoxyl group-6-hydroxy benzaldehyde and bromoethyl acetate, according to the synthetic yellowish solid 2-ethoxycarbonyl-4-methoxyl group-cumarone (100%) that obtains of the method for embodiment 7.
1HNMR(CDCl 3)δ：1.42(t，J＝7.2Hz，3H)，3.95(s，3H)，4.43(q，J＝7.2Hz，2H)，6.68(d，J＝8.0Hz，1H)，7.19(d，J＝8.0Hz，1H)，7.36(t，J＝7.2Hz，1H)，7.62(s，1H).MS(EI +)m/z：220[M] +.HRMS(EI +)：found 220.0732[M] +，(Calcd for C 12H 12O 4：220.0736)。
Embodiment 12:2-ethoxycarbonyl-5-methoxyl group-cumarone (11b)
Be raw material with 3-methoxyl group-6-hydroxy benzaldehyde and bromoethyl acetate, according to the synthetic white solid 2-ethoxycarbonyl-5-methoxyl group-cumarone (82%) that obtains of the method for embodiment 7.
1HNMR(CDCl3)δ：1.43(t，J＝7.2Hz，3H)，3.85(s，3H)，4.44(q，J＝7.2Hz，2H)，7.05(d，J＝2.4Hz，1H)，7.06(d×d，J＝8.2Hz，2.4Hz，1H)，7.46-7.49(m，2H).MS(EI+)m/z：220[M]+.HRMS(EI+)：found 220.0733[M]+，(Calcd for C12H12O4：220.0736)。
Embodiment 13:2-ethoxycarbonyl-6-methoxyl group-cumarone (12b)
Be raw material with 4-methoxyl group-2-hydroxy benzaldehyde and bromoethyl acetate, according to the synthetic white solid 2-ethoxycarbonyl-6-methoxyl group-cumarone (68%) that obtains of the method for embodiment 7.
1HNMR(CDCl 3)δ：1.42(t，J＝7.2Hz，3H)，3.87(s，3H)，4.42(q，J＝7.2Hz，2H)，6.94(d×d，J＝8.8Hz，2.0Hz，1H)，7.07(d，J＝2.0Hz，1H)，7.47(s，1H)，7.53(d，J＝8.8Hz，1H).MS(EI +)m/z：220[M] +.HRMS(EI +)：found220.0739[M] +，(Calcd for C 12H 12O 4：220.0736)。
Embodiment 14:2-ethoxycarbonyl-7-methoxyl group-cumarone (13b)
Be raw material with 3-methoxyl group-2-hydroxy benzaldehyde and bromoethyl acetate, according to the synthetic white solid 2-ethoxycarbonyl-7-methoxyl group-cumarone (58%) that obtains of the method for embodiment 7.
1HNMR(CDCl 3)δ：1.42(t，J＝7.2Hz，3H)，4.02(s，3H)，4.44(q，J＝7.2Hz，2H)，6.92(d，J＝7.6Hz，1H)，7.21(d，J＝7.6Hz，1H)，7.22(d×d，J＝7.6Hz，3.2Hz，1H)，7.52(s，1H).MS(EI +)m/z：220[M] +.HRMS(EI +)：found220.0733[M] +，(Calcd for C 12H 12O 4：220.0736)。
Embodiment 15:2-ethoxycarbonyl-5,6-dimethoxy-thionaphthene (7b)
In 25ml DMF, add 2-nitro-4, the 5-dimethoxy benzaldehyde (2.0g, 9.5mmol) and the NaOH of catalytic amount, ice bath is cooled under 0 ℃, slowly drip ethyl thioglycolate (1.25ml, 11.4mmol).Dropwise 0 ℃ of stirring reaction 30min, 100 ℃ of oil bath reaction 2h then.Reaction solution is poured in the frozen water into solid collected by filtration, chloroform dissolved solids, anhydrous Na 2SO 4Dried overnight.Be spin-dried for that silica gel column chromatography obtains white solid 2-ethoxycarbonyl-5,6-dimethoxy-thionaphthene 1.58g (62.6%) after separating behind the solvent.
1HNMR(CDCl 3)δ：1.405(t，J＝7.2Hz，3H)，3.95(s，3H)，3.98(s，3H)，4.38(q，J＝7.2Hz，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 C 13H 14O 4S：266.0631)。
Embodiment 16:2-ethoxycarbonyl-7-fluoro-cumarone (14b)
Be raw material with 3-fluoro-2-hydroxy benzaldehyde and bromoethyl acetate, obtain yellow oily 2-ethoxycarbonyl-7-fluoro-cumarone (47%) according to the method reaction of embodiment 7.
1HNMR(CDCl 3)δ：1.43(t，J＝7.2Hz，3H)，4.45(q，J＝7.2Hz，2H)，7.14-7.25(m，2H)，7.43(d，J＝8.0Hz，1H)，7.54(d，J＝2.8Hz，1H).MS(EI +)m/z：208[M] +.HRMS(EI +)：found 208.0531[M] +，(Calcd for C 11H 9O 3F：208.0536)。
Embodiment 17:2-ethoxycarbonyl-5,7-two chloro-cumarones (15b)
Be raw material with 3,5-, two chloro-2-hydroxy benzaldehydes and bromoethyl acetate, obtain white solid 2-ethoxycarbonyl-5,7-two chloro-cumarones (65%) according to the method reaction of embodiment 7.
1HNMR(CDCl 3)δ：1.44(t，J＝7.2Hz，3H)，4.46(q，J＝7.2Hz，2H)，7.46(d，J＝1.6Hz，1H)，7.48(s，1H)，7.57(d，J＝1.6Hz，1H).MS(EI +)m/z：258[M] +，260[M+2] +，262[M+4] +.HRMS(EI +)：found 257.9840[M] +，(Calcd for C 11H 8O 3Cl 2：257.9850)。
Embodiment 18:2-ethoxycarbonyl-5-methoxycarbonyl-thionaphthene (5b)
Be raw material with 2-nitro-5-methoxycarbonyl phenyl aldehyde and ethyl thioglycolate, obtain white solid 2-ethoxycarbonyl-5-methoxycarbonyl-thionaphthene (5b) (97%) according to the method reaction of embodiment 1.
1HNMR(CDCl 3)δ：1.43(t，J＝7.2Hz，3H)，3.97(s，3H)，4.43(q，J＝7.2Hz，2H)，7.91(d，J＝8.4Hz，1H)，8.10(d，J＝8.4Hz，1H)，8.12(s，1H)，8.58(s，1H).HRMS(EI +)：found 264.0452[M] +，(Calcd for C 13H 12O 4S：264.0456)。
Embodiment 19:2-acetyl-5-methoxycarbonyl-thionaphthene (1c)
Under the ice bath, add successively in the 60ml DMF 3-aldehyde radical-4-nitro-methyl benzoate (1.95g, 9.3mmol), anhydrous K 2CO 3(1.55g, 11.2mmol) and sulfur alcohol (0.70mg, 11.3mmol).After stirring 10min, stirring at room 1h.Elimination K 2CO 3, evaporate to dryness DMF, chloroform dissolving crude product, washing chloroform phase, chloroform is used anhydrous sodium sulfate drying mutually.Be spin-dried for that silica gel column chromatography obtains white solid 3-aldehyde radical 4-ethylmercapto group-methyl benzoate (1-b) 1.81g (86.5%) after separating behind the solvent.
1HNMR(CDCl 3)δ：1.44(t，J＝7.6Hz，3H)，3.05(q，J＝7.6Hz，2H)，3.94(s，3H)，7.42(d，J＝8.4Hz，1H)，8.12(dd，J＝8.6Hz，1.6Hz，1H)，8.44(d，J＝1.6Hz，1H)，10.25(s，1H)。
Add successively in the 20ml DMF 3-aldehyde radical 4-ethylmercapto group-methyl benzoate (1-b) (1.0g, 4.5mmol), calcium oxide (125mg, 2.2mmol), acetone dichloride (825mg, 8.9mmol).90 ℃ of oil bath reaction 10h.Filter the filtrate evaporate to dryness.Chloroform dissolving crude product, washing chloroform phase, chloroform is used anhydrous sodium sulfate drying mutually.Be spin-dried for that silica gel column chromatography obtains yellowish solid 2-acetyl-5-methoxycarbonyl-thionaphthene 0.929g (88.9%) after separating behind the solvent.
1HNMR(CDCl 3)δ：2.69(s，3H)，3.98(s，3H)，7.93(d，J＝8.4Hz，1H)，8.00(s，1H)，8.11(d，J＝8.4Hz，1H)，8.61(s，1H).HRMS(EI +)：found234.0339[M] +，(Calcd for C 12H 10O 3S：234.0351)。
Embodiment 20:2-ethoxycarbonyl-6-methoxycarbonyl-thionaphthene (6b)
Be raw material with 2-nitro-4-methoxycarbonyl phenyl aldehyde and ethyl thioglycolate, obtain white solid 2-ethoxycarbonyl-6-methoxycarbonyl-thionaphthene (6b) (97%) according to the method reaction of embodiment 1.
1HNMR(CDCl 3)δ：1.43(t，J＝7.2Hz，3H)，3.97(s，3H)，4.43(q，J＝7.2Hz，2H)，7.91(d，J＝8.4Hz，1H)，8.04(d，J＝8.4Hz，1H)，8.07(s，1H)，8.58(s，1H).HRMS(EI +)：found 264.0449[M] +，(Calcd for C 13H 12O 4S：264.0456)。
Embodiment 21:2-acetyl-5-carboxyl-thionaphthene (1e)
(133mg 0.57mmol) adds in the 5ml dioxane stirring and dissolving with 2-ethanoyl-5-methoxycarbonyl-thionaphthene (1c).(34mg, 2ml water 0.85mmol) add in the dioxane, stirring at room 2h being dissolved with NaOH.The evaporate to dryness reaction solution is used the water dissolution crude product, and 5% hydrochloric acid is transferred PH to 2, separates out solid.Filter, filter cake washes with water, dry 36mg brown solid product 2-acetyl-5-carboxyl-thionaphthene (29%).
1HNMR(CDCl 3)δ：2.66(s，3H)，8.01(dd，J＝8.4Hz，1.6Hz，1H)，8.15(d，J＝8.4Hz，1H)，8.48(s，1H)，8.61(s，1H)，13.1(s，1H).MS(ESI -)m/z：219[M-H] -.HRMS(ESI -)：found 219.01148[M-H] -，(Calcd for C 11H 7O 3S：219.01159)。
Embodiment 22:2-acetyl-6-methoxycarbonyl-thionaphthene (2c)
Be raw material with 3-aldehyde radical-4-nitro-methyl benzoate and sulfur alcohol, obtain yellow solid 2-ethylmercapto group-3-aldehyde radical-methyl benzoate (2-b) (101.2%) according to the method reaction of embodiment 19.
1HNMR(CDCl 3)δ：1.39(t，J＝7.6Hz，3H)，3.06(q，J＝7.6Hz，2H)，3.96(s，1H)，7.90(s，1H)，7.90(s，1H)，8.08(s，1H)，10.44(s，1H).
Be raw material with compound 2-b and acetone dichloride, obtain yellow solid (73%) according to the method reaction of embodiment 19. 1HNMR(CDCl 3)δ：2.69(s，3H)，3.97(s，3H)，7.94(d，J＝8.4Hz，1H)，7.96(s，1H)，8.05(d，J＝8.4Hz，1H)，8.59(s，1H).HRMS(EI +)：found 234.0343[M] +，(Calcd for C 12H 10O 3S：234.0351)。
Embodiment 23:2-acetyl-6-carboxyl-thionaphthene (2e)
Be raw material with compound 2c, obtain brown solid product 2-acetyl-6-carboxyl-thionaphthene (59%) according to the method reaction of embodiment 21.
1HNMR(CDCl 3)δ：2.67(s，3H)，7.97(dd，J＝8.4Hz，1.2Hz，1H)，8.10(d，J＝8.4Hz，1H)，8.40(s，1H)，8.65(s，1H)，13.2(s，1H).HRMS(ESI -)：found219.01326[M-H] -，(Calcd for C 11H 7O 3S：219.01159)。
Embodiment 24:2-(2 '-methyl sulfoxide base) acetyl-4-chloro-thionaphthene (4c)
Be raw material with compound 4b, obtain faint yellow solid 2-(2 '-methyl sulfoxide base) acetyl-4-chloro-thionaphthene (4c) (59%) according to the method reaction of embodiment 2.
1HNMR(CDCl 3)δ：2.83(s，3H)，AB system(4.38，4.45，J＝13.Hz，2H)，7.46(d，J＝4.5Hz，2H)，7.79(t，J＝4.5Hz，1H)，8.24(s，1H).HRMS(EI +)：found 271.9733[M] +，(Calcd for C 11H 9O 2S 2Cl：271.9733)。
Embodiment 25:2-(2 '-methyl sulfoxide base) acetyl-4-methoxyl group-cumarone (10c)
Be raw material with compound 10b, obtain yellow solid 2-(2 '-methyl sulfoxide base) acetyl-4-methoxyl group-cumarone (10c) (76%) according to the method reaction of embodiment 2.
1HNMR(CDCl 3)δ：2.80(s，3H)，3.98(s，3H)，AB system(4.26，4.39，J＝13.5Hz，2H)，6.71(d，J＝8.0Hz，1H)，7.19(d，J＝8.0Hz，1H)，7.47(t，J＝8.0Hz，1H)，7.79(s，1H).HRMS(EI +)：found 252.0437[M] +，(Calcd forC 12H 12O 4S：252.0456)。
Embodiment 26:2-(2 '-methyl sulfoxide base) acetyl-5-methoxyl group-cumarone (11c)
Be raw material with compound 11b, obtain yellow solid 2-(2 '-methyl sulfoxide base) acetyl-5-methoxyl group-cumarone (11c) (83%) according to the method reaction of embodiment 2.
1HNMR(CDCl 3)δ：2.79(s，3H)，3.86(s，3H)，AB system(4.27，4.37，J＝13.2Hz，2H)，7.10(d，J＝2.0Hz，1H)，7.15(d×d，J＝8.8Hz，2.0Hz，1H)，7.48(d，J＝8.8Hz，1H)，7.60(s，1H).HRMS(EI +)：found 252.0439[M] +，(Calcdfor C 12H 12O 4S：252.0456)。
Embodiment 27:2-(2 '-methyl sulfoxide base) acetyl-5,6-dimethoxy-thionaphthene (7c)
Be raw material with compound 7b, obtain yellow solid 2-(2 '-methyl sulfoxide base) acetyl-5,6-dimethoxy-thionaphthene (7c) (96%) according to the method reaction of embodiment 2.
1HNMR(CDCl 3)δ：2.78(s，3H)，3.96(s，3H)，3.99(s，3H)，AB system(4.28，4.35，J＝13.6Hz，2H)，7.25(s，1H)，7.28(s，1H)，7.96(s，1H).HRMS(EI +)：found 298.0306[M] +，(Calcd for C 13H 14O 4S 2：298.0334)。
Embodiment 28:2-(2 '-methyl sulfoxide base) acetyl-6-methoxyl group-cumarone (12c)
With compound 12b raw material, obtain yellow solid 2-(2 '-methyl sulfoxide base) acetyl-6-methoxyl group-cumarone (12c) (51%) according to the reaction of the method for embodiment 2.
1HNMR(CDCl 3)δ：2.79(s，3H)，3.89(s，3H)，AB system(4.23，4.33，J＝13.2Hz，2H)，6.97(d×d，J＝8.8Hz，2.0Hz，1H)，7.04(s，1H)，7.60(d，J＝8.8Hz，1H)，7.62(s，1H).HRMS(EI +)：found 252.0443[M] +，(Calcd forC 12H 12O 4S：252.0456)。
Embodiment 29:2-(2 '-methyl sulfoxide base) acetyl-7-methoxyl group-cumarone (13c)
Be raw material with compound 13b, obtain yellow solid 2-(2 '-methyl sulfoxide base) acetyl-7-methoxyl group-cumarone (13c) (66%) according to the method reaction of embodiment 2.
1HNMR(d6-DMSO)δ：2.73(s，3H)，3.97(s，3H)，AB system(4.46，4.57，J＝14.0Hz，2H)，7.17(d，J＝7.6Hz，1H)，7.30(t，J＝7.6Hz，1H)，7.41(d，J＝7.6Hz，1H)，8.08(s，1H).HRMS(EI +)：found 252.0459[M] +，(Calcd forC 12H 12O 4S：252.0456)。
Embodiment 30:2-ethoxycarbonyl-6-diethylin-cumarone (16b)
Be raw material with 4-diethylin salicylic aldehyde, obtain yellow oily 2-ethoxycarbonyl-6-diethylin-cumarone (16b) (36%) according to the method reaction of embodiment 7.
1HNMR(CDCl 3)δ：1.20(t，J＝6.8Hz，6H)，1.41(t，J＝7.2Hz，3H)，3.41(q，J＝6.8Hz，4H)，4.41(q，J＝7.2Hz，2H)，6.73(d，J＝8.8Hz，1H)，6.76(s，1H)，7.40(s，1H)，7.43(d，J＝8.8Hz，1H).MS(EI +)m/z：261[M] +.HRMS(EI +)：found 261.1365[M] +，(Calcd for C 15H 19NO 3：261.1365)。
Embodiment 31:(E)-2-[3 '-(4 "-anisole) acryloyl]-6-ethoxycarbonyl-thionaphthene (2dC)
Add according to this in the 10ml dehydrated alcohol 2-ethanoyl-6-methoxycarbonyl-thionaphthene (2c) (100mg, 0.43mmol), the sodium ethylate of catalytic amount, aubepine (87.2mg, 0.64mmol).Stirring at room 1.5h, evaporate to dryness ethanol, chloroform dissolving crude product filters.Washing chloroform phase, anhydrous sodium sulfate drying chloroform phase.Be spin-dried for that silica gel column chromatography obtains yellow-green colour solid 78mg (52%) after separating behind the solvent.
1HNMR(CDCl 3)δ：1.45(t，J＝7.2Hz，3H)，3.88(s，3H)，4.44(q，J＝7.2Hz，2H)，6.69(d，J＝8.4Hz，2H)，7.42(d，J＝15.2Hz，1H)，7.65(d，J＝8.4Hz，2H)，7.90(d，J＝15.2Hz，1H)，7.96(d，J＝8.4Hz，1H)，8.07(d，J＝8.4Hz，1H)，8.11(s，1H)，8.62(s，1H).HRMS(EI +)：found 366.0920[M] +，(Calcdfor C 21H 18O 4S：366.0926)。
Embodiment 32:(E)-2-[3 '-(4 "-anisole) acryloyl]-5-ethoxycarbonyl-thionaphthene (1dC)
Be raw material with compound 1c and aubepine, obtain yellow-green colour solid E according to the method reaction of embodiment 31)-2-[3 '-(4 "-anisole) acryloyl]-5-ethoxycarbonyl-thionaphthene (1dC) (34%).
1HNMR(CDCl 3)δ：1.45(t，J＝7.2Hz，3H)，3.88(s，3H)，4.44(q，J＝7.2Hz，2H)，6.97(d，J＝8.4Hz，2H)，7.42(d，J＝15.2Hz，1H)，7.65(d，J＝8.4Hz，2H)，7.89(d，J＝15.2Hz，1H)，7.94(d，J＝8.4Hz，1H)，8.12(d，J＝8.4Hz，1H)，8.15(s，1H)，8.64(s，1H).HRMS(EI +)：found 366.0916[M] +，(Calcd for C 21H 18O 4S：366.0926)。
Embodiment 33:2-(1 '-hydroxyl-2 '-methyl sulfoxide base) ethyl-5,6-methylene radical dioxy-thionaphthene (8e)
Be raw material with compound 8c, obtain white solid 2-(1 '-hydroxyl-2 '-methyl sulfoxide base) ethyl-5,6-methylene radical dioxy-thionaphthene (8e) (96%) according to the method reaction of embodiment 10.
1HNMR(CDCl 3)δ：2.74(s，3H)，2.03-3.30(m，2H)，5.68(d×d，J＝9.2Hz，2.8Hz)，6.01(s，1H)，7.12(s，1H)，7.13(s，1H)，7.20(s，1H).MS(ESI +)m/z：307[M+Na] +.HRMS(ESI +)：found 307.00916[M+Na] +，(Calcd forC 12H 12O 4S 2Na：307.00747)。
Embodiment 34:2-(1 '-hydroxyl) ethyl-5-methoxycarbonyl-thionaphthene (1f)
Be raw material with compound 1c, obtain pale pink solid 2-(1 '-hydroxyl) ethyl-5-methoxycarbonyl-thionaphthene (1f) (92%) according to the method reaction of embodiment 10.
1HNMR(CDCl 3)δ：1.67(d，J＝6.4Hz)，2.18(s，1H)，3.95(s，3H)，5.22(q，J＝6.4Hz，2H)，7.25(s，1H)，7.84(d，J＝8.4Hz，1H)，7.95(d，J＝8.4Hz，1H)，7.95(d，J＝8.4Hz，1H)，8.41(s，1H).MS(EI +)m/z：236[M] +.HRMS(EI +)：found 236.0498[M] +，(Calcd for C 12H 12O 3S：236.0507)。
Embodiment 35:2-(1 '-hydroxyl) ethyl-6-methoxycarbonyl-thionaphthene (2f)
Be raw material with compound 2c, obtain white solid 2-(1 '-hydroxyl) ethyl-6-methoxycarbonyl-thionaphthene (2f) (92%) according to the method reaction of embodiment 10.
1HNMR(CDCl 3)δ：1.67(d，J＝6.4Hz)，1.80(s，1H)，3.95(s，3H)，5.23(q，J＝6.4Hz，2H)，7.24(s，1H)，7.74(d，J＝8.4Hz，1H)，7.99(d，J＝8.4Hz，1H)，7.95(d，J＝8.4Hz，1H)，8.53(s，1H).MS(EI +)m/z：236[M] +.HRMS(EI +)：found 236.0507[M] +，(Calcd for C 12H 12O 3S：236.0507)。
Embodiment 36:(E)-2-cinnyl-6-ethoxycarbonyl-thionaphthene (2dA)
Be raw material with compound 2c and phenyl aldehyde, obtain faint yellow solid (E)-2-cinnyl-6-ethoxycarbonyl-thionaphthene (2dA) (17%) according to the method reaction of embodiment 31.
1HNMR(CDCl 3)δ：1.45(t，J＝7.2Hz，3H)，4.44(q，J＝7.2Hz，2H)，7.45-7.47(m，3H)，7.54(d，J＝15.6Hz，1H)，7.69-7.71(m，2H)，7.93(d，J＝15.6Hz，1H)，7.97(d，J＝8.4Hz，1H)，8.08(d，J＝8.4Hz，1H)，8.14(s，1H)，8.63(s，1H).MS(EI +)m/z：336[M] +.HRMS(EI +)：found 336.0793[M] +，(Calcd for C 20H 16O 3S：336.0820)。
Embodiment 37:(E)-2-[3 '-(2 ", 3 ", 4 "-trimethoxy-benzene) acryloyl]-5-ethoxycarbonyl-thionaphthene (1dE)
Be raw material with compound 1c and 2,3,4-TMB, according to the method reaction of embodiment 31 obtain yellow solid (E)-2-[3 '-(2 ", 3 " 4 "-trimethoxy-benzene) acryloyl]-5-ethoxycarbonyl-thionaphthene (1dE) (30%).
1HNMR(CDCl 3)δ：1.44(t，J＝7.2Hz，3H)，3.91(s，3H)，3.94(s，3H)，3.99(s，3H)，4.44(q，J＝7.2Hz，2H)，6.75(d，J＝8.8Hz，1H)，7.42(d，J＝8.8Hz，1H)，7.59(d，J＝15.6Hz，1H)，7.94(d，J＝8.4Hz，1H)，8.08(d，J＝15.6Hz，1H)，8.11-8.14(m，2H)，8.64(s，1H).HRMS(EI +)：found 426.1147[M] +，(Calcd for C 23H 22O 6S：426.1137)。
Embodiment 38:(E)-2-[3 '-(2 ", 3 ", 4 "-trimethoxy-benzene) acryloyl]-6-ethoxycarbonyl-thionaphthene (2dE)
Be raw material with compound 2c and 2,3,4-TMB,, according to the method reaction of embodiment 31 obtain yellow-green colour oily matter (E)-2-[3 '-(2 ", 3 ", 4 "-trimethoxy-benzene) acryloyl]-6-ethoxycarbonyl-thionaphthene (2dE) (32%).
1HNMR(CDCl 3)δ：1.44(t，J＝7.2Hz，3H)，3.91(s，3H)，3.94(s，3H)，3.99(s，3H)，4.44(q，J＝7.2Hz，2H)，6.75(d，J＝8.8Hz，1H)，7.42(d，J＝8.8Hz，1H)，7.59(d，J＝15.6Hz，1H)，7.96(d，J＝8.4Hz，1H)，8.09(d，J＝15.6Hz，1H)，8.09(s，1H)，8.10(d，J＝8.4Hz，1H)，8.63(s，1H).HRMS(EI +)：found 426.1125[M] +，(Calcd for C 23H 22O 6S：426.1137)。
Embodiment 39:(E)-2-cinnyl-5-ethoxycarbonyl-thionaphthene (1dA)
Be raw material with compound 1c and phenyl aldehyde,, obtain yellow solid (E)-2-cinnyl-5-ethoxycarbonyl-thionaphthene (1dA) (62%) according to the method reaction of embodiment 31.
1HNMR(CDCl 3)δ：1.44(t，J＝7.2Hz，3H)，4.44(q，J＝7.2Hz，2H)，7.54(s，3H)，7.59(d，J＝15.2Hz，1H)，7.68-7.69(m，2H)，7.91(d，J＝15.2Hz，1H)，7.94(d，J＝8.0Hz，1H)，8.10(d，J＝8.0Hz，1H)，8.15(s，1H)，8.64(s，1H).MS(EI +)m/z：336[M] +.HRMS(EI +)：found 336.0796[M] +，(Calcd forC 20H 16O 3S：336.0820)。
Embodiment 40:(E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-5-ethoxycarbonyl-thionaphthene (1dB1)
Be raw material with compound 1c and o-chlorobenzaldehyde, obtain yellow solid (E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl according to the method reaction of embodiment 31]-5-ethoxycarbonyl-thionaphthene (1dB1) (62%).
1HNMR(CDCl 3)δ：1.44(t，J＝7.2Hz，3H)，4.44(q，J＝7.2Hz，2H)，7.35-7.37(m，2H)，7.47(d，J＝8.8Hz，1H)，7.50(d，J＝15.6Hz，1H)，7.79(d×d，J＝8.0Hz，2.4Hz，1H)，7.95(d，J＝8.4Hz，1H)，8.13(d，J＝8.4Hz，1H)，8.17(s，1H)，8.30(d，J＝15.6Hz，1H)，8.65(s，1H).MS(EI +)m/z：370[M] +，372[M+2] +.HRMS(EI +)：found 370.0418[M] +，(Calcd forC 20H 15O 3SCl：370.0430)。
Embodiment 41:(E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-5-methoxycarbonyl-thionaphthene (1dB2)
Be raw material with compound 1c and o-chlorobenzaldehyde, obtain pale brown solid (E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl according to the method reaction of embodiment 31]-5-methoxycarbonyl-thionaphthene (1dB2) (25%):
1HNMR(CDCl 3)δ：3.97(s，3H)，7.34-7.39(m，2H)，7.47(d，J＝8.8Hz，1H)，7.50(d，J＝15.6Hz，1H)，7.79(d×d，J＝8.0Hz，2.4Hz，1H)，7.95(d，J＝8.4Hz，1H)，8.13(d，J＝8.4Hz，1H)，8.16(s，1H)，8.30(d，J＝15.6Hz，1H)，8.64(s，1H).MS(EI +)m/z：356[M] +，358[M+2] +.HRMS(EI +)：found356.0254[M] +，(Calcd for C 19H 13O 3SCl：356.0274)。
Embodiment 42:(E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-6-ethoxycarbonyl-thionaphthene (2dB)
Be raw material with compound 2c and o-chlorobenzaldehyde, react according to the method for embodiment 31 obtain pale brown look solid (E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-6-ethoxycarbonyl-thionaphthene (2dB) (20%).
1HNMR(CDCl 3)δ：1.44(t，J＝7.2Hz，3H)，4.44(q，J＝7.2Hz，2H)，7.35-7.37(m，2H)，7.47(d，J＝8.8Hz，1H)，7.51(d，J＝15.6Hz，1H)，7.79(d×d，J＝8.0Hz，2.0Hz，1H)，7.97(d，J＝8.4Hz，1H)，8.08(d，J＝8.4Hz，1H)，8.13(s，1H)，8.30(d，J＝15.6Hz，1H)，8.63(s，1H).MS(EI +)m/z：370[M] +.HRMS(EI +)：found 370.0420[M] +，(Calcd for C 20H 15O 3SCl：370.0430)。
Embodiment 43:(E)-2-[3 '-(3 ", 4 "-dimethoxy benzene) acryloyl]-6-ethoxycarbonyl-thionaphthene (2dD)
Be raw material with compound 2c and 3,4-dimethoxy benzaldehyde, according to the method reaction of embodiment 31 obtain brown oil (E)-2-[3 '-(3 ", 4 "-dimethoxy benzene) acryloyl]-6-ethoxycarbonyl-thionaphthene (2dD) (10%).
1HNMR(CDCl 3)δ：1.45(t，J＝7.2Hz，3H)，3.96(s，3H)，3.98(s，3H)，4.44(q，J＝7.2Hz，2H)，6.93(d，J＝8.4Hz，1H)，7.20(s，1H)，7.29(d，J＝8.4Hz，1H)，7.39(d，J＝15.6Hz，1H)，7.88(d，J＝15.6Hz，1H)，7.96(d，J＝8.4Hz，1H)，8.08(d，J＝8.4Hz，1H)，8.12(s，1H)，8.63(s，1H).MS(EI +)m/z：396[M] +.HRMS(EI +)：found 396.1015[M] +，(Calcd for C 22H 20O 5S：396.1031)。
Embodiment 44:(E)-2-[3 '-(3 ", 4 "-dimethoxy benzene) acryloyl]-5-ethoxycarbonyl-thionaphthene (1dD)
Be raw material with compound 1c and 3,4-dimethoxy benzaldehyde, according to the method reaction of embodiment 31 obtain yellow oil (E)-2-[3 '-(3 ", 4 "-dimethoxy benzene) acryloyl]-5-ethoxycarbonyl-thionaphthene (1dD) (10%).
1HNMR(CDCl 3)δ：1.44(t，J＝7.2Hz，3H)，3.94(s，3H)，3.98(s，3H)，4.45(q，J＝7.2Hz，2H)，6.93(d，J＝8.4Hz，1H)，7.20(s，1H)，7.29(d，J＝8.4Hz，1H)，7.40(d，J＝15.2Hz，1H)，7.88(d，J＝15.2Hz，1H)，7.95(d，J＝8.8Hz，1H)，8.12(d，J＝8.8Hz，1H)，8.17(s，1H)，8.65(s，1H).MS(EI +)m/z：396[M] +.HRMS(EI +)：found 396.1032[M] +，(Calcd for C 22H 20O 5S：396.1031)。
Embodiment 45:2-(2 '-methylsulfonyl) acetyl-5-methoxyl group-cumarone (11d)
Be raw material with compound 11c, according to synthetic faint yellow solid 2-(2 '-methylsulfonyl) acetyl-5-methoxyl group-cumarone (57.0%) that obtains of the method for embodiment 3.
1HNMR(CDCl 3)δ：3.16(s，3H)，3.86(s，3H)，4.58(s，2H)，7.10(d，J＝2.4Hz，1H)，7.17(d×d，J＝9.0Hz，2.4Hz，1H)，7.49(d，J＝9.0Hz，1H)，7.65(s，1H)。MS(EI +)m/z：268[M] +.HRMS(EI +)：found 268.0416[M] +，(Calcd for
C 12H 10O 5S：268.0405)。
Embodiment 46:2-(1 '-hydroxyl-2 '-methyl sulfoxide) ethyl-5-methoxyl group-cumarone (11e)
Be raw material with compound 11c, obtain yellowish solid 2-(1 '-hydroxyl-2 '-methyl sulfoxide) ethyl-5-methoxyl group-cumarone (11e) (89%) according to the method reaction of embodiment 10.
1HNMR(CDCl 3)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＝5.2Hz，1H)，6.88(d×d，J＝8.8Hz，2.4Hz，1H)，7.01(d，J＝2.4Hz，1H)，7.33(d，J＝8.8Hz，1H)。MS(ESI +)m/z：277.3[M+Na] +.HRMS(ESI +)：found 277.05280[M+Na] +，(Calcd for C 12H 14O 4SNa：277.05105)。
Embodiment 47:(E)-2-[3 '-(4 "-anisole) acryloyl]-5,6-dimethoxy-indoles (G33-1)
With 2-acetyl-5,6-dimethoxy indoles and aubepine are raw material, obtain solid (E)-2-[3 '-(4 "-anisole) acryloyl with the reaction of the method for embodiment 31]-5,6-dimethoxy-indoles (74.5%).
1H NMR(CDCl 3)δ：3.73(s，3H)，3.85(s，3H)，3.92(s，3H)，6.67(d，J＝15.2Hz，1H)，6.80(s，1H)，6.95(s，1H)，7.09(s，2H)，7.38(s，1H)，7.54(d，J＝15.2Hz，1H)，7.68(s，2H)，11.63(br，1H).MS(EI +)m/z：337[M] +.
Embodiment 48:(E)-1-methyl-2-[3 '-(4 "-anisole) acryloyl]-5,6-dimethoxy-indoles (G33-2)
With 1-methyl-2-acetyl-5,6-dimethoxy indoles and aubepine are raw material, obtain solid (E)-1-methyl-2-[3 '-(4 "-anisole) acryloyl with the reaction of the method for embodiment 31]-5,6-dimethoxy-indoles (77.1%).
1H NMR(CDCl 3)δ：3.60(s，3H)，3.73(s，3H)，3.85(s，3H)，3.92(s，3H)，6.67(d，J＝15.2Hz，1H)，6.57(s，2H)，7.09(s，2H)，7.41(s，1H)，7.54(d，J＝15.2Hz，1H)，7.68(s，2H).MS(EI +)m/z：351[M] +.
Embodiment 49:(E)-1-chloroethyl-2-[3 '-(4 "-anisole) acryloyl]-5,6-dimethoxy-indoles (G33-3)
With 1-chloroethyl-2-acetyl-5,6-dimethoxy indoles and aubepine are raw material, obtain solid (E)-1-chloroethyl-2-[3 '-(4 "-anisole) acryloyl with the reaction of the method for embodiment 31]-5,6-dimethoxy-indoles (70.2%).
1H NMR(CDCl 3)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＝15.2Hz，1H)，6.59(s，2H)，7.11(s，2H)，7.38(s，1H)，7.53(d，J＝15.2Hz，1H)，7.71(s，2H).MS(EI +)m/z：399[M] +.
Embodiment 50:(E)-1-ethanoyl-2-[3 '-(4 "-fluorobenzene) acryloyl]-5,6-dimethoxy-indoles (G33-4)
With 1,2-diacetyl-5,6-dimethoxy indoles and p-Fluorobenzenecarboxaldehyde are raw material, obtain solid (E)-1-ethanoyl-2-[3 '-(4 "-fluorobenzene) acryloyl with the reaction of the method for embodiment 31]-5,6-dimethoxy-indoles (72.6%).
1H NMR(CDCl 3)δ：2.19(m，3H)，3.73(s，3H)，3.94(s，3H)，6.68(d，J＝15.2Hz，1H)，6.81(s，2H)，7.11(s，2H)，7.43(s，1H)，7.53(d，J＝15.2Hz，1H)，7.69(s，2H).MS(EI +)m/z：367[M] +.
Embodiment 51:(E)-1-(2 '-hydroxyethyl)-2-[3 '-(4 "-fluorophenyl) acryloyl]-5-acetoxyl group-indoles (G33-5)
Be raw material with 1-(2 '-hydroxyethyl)-2-acetyl-5-acetoxy-indole and p-Fluorobenzenecarboxaldehyde, obtain solid (E)-1-(2 '-hydroxyethyl)-2-[3 '-(4 "-fluorophenyl) acryloyl with the method reaction of embodiment 31]-5-acetoxyl group-indoles (70.5%).
1H NMR(CDCl 3)δ：2.33(s，3H)，4.08(m，4H)，4.30(s，1H)，6.70(d，J＝15.2Hz，1H)，7.02(m，2H)，7.35(m，4H)，7.42(s，1H)，7.53(d，J＝15.2Hz，1H)，7.80(m，1H).MS(EI +)m/z：367[M] +.
Embodiment 52:(E)-1-(2 '-amino-ethyl)-2-[3 '-(4 "-fluorophenyl) acryloyl]-5-acetoxyl group-indoles (G33-6)
Be raw material with 1-(2 '-amino-ethyl)-2-acetyl-5-acetoxy-indole and p-Fluorobenzenecarboxaldehyde, obtain solid (E)-1-(2 '-amino-ethyl)-2-[3 '-(4 "-fluorophenyl) acryloyl with the method reaction of embodiment 31]-5-acetoxyl group-indoles (58.0%).
1H NMR(CDCl 3)δ：2.33(s，3H)，3.12(m，2H)，4.11(m，2H)，5.80(s，2H)，6.68(d，J＝15.2Hz，1H)，6.98(m，2H)，7.02(m，2H)，7.36(m，4H)，7.42(s，1H)，7.53(d，J＝15.2Hz，1H)，7.84(m，1H).MS(EI +)m/z：366[M] +.
Embodiment 53:E) 1-(2 '-methoxy ethyl)-2-[3 '-(4 "-fluorophenyl) acryloyl]-5-acetoxyl group-indoles (G33-7)
Be raw material with 1-(2 '-methoxy ethyl)-2-acetyl-5-acetoxy-indole and p-Fluorobenzenecarboxaldehyde, obtain solid E with the method reaction of embodiment 31)-1-(2 '-methoxy ethyl)-2-[3 '-(4 "-fluorophenyl) acryloyl]-5-acetoxyl group-indoles (70.5%).
1H NMR(CDCl 3)δ：2.32(s，3H)，3.24(s，3H)，3.85(m，2H)，4.08(m，2H)，6.68(d，J＝15.2Hz，1H)，7.02(m，2H)，7.36(m，4H)，7.41(s，1H)，7.53(d，J＝15.2Hz，1H)，7.82(m，1H).MS(EI +)m/z：381[M] +.
Embodiment 54:2-ethoxycarbonyl-4-methyl-thionaphthene (1g)
Be raw material with 6-methyl 2-nitrobenzaldehyde and ethyl thioglycolate, operate according to the method for embodiment 1, get solid particulate 2-ethoxycarbonyl-4-methyl-thionaphthene (69.3%).
1HNMR(CDCl3)δ：1.45(t，J＝7.2Hz，3H)，2.35(s，3H)，4.46(q，J＝7.2Hz，2H)，7.38(m，2H)，7.74(m，1H)，7.98(s，1H)。MS(EI +)m/z：220[M] +.
Embodiment 55:2-oenanthyl-5,6-dimethyl-thionaphthene (17)
Be raw material with 4,5-dimethyl-2-nitro-phenyl aldehyde, sulfur alcohol and 1-chloro octane-2-ketone, obtain solid 2-oenanthyl-5,6-dimethyl-thionaphthene (17) (50%) according to the method reaction of embodiment 19.
1HNMR(CDCl 3)δ：0.96(t，J＝7.2Hz，，3H)，1.30(m，6H)，1.48(m，2H)，2.35(s，6H)，2.89(m，2H)，7.54(s，2H)，7.86(s，1H).MS(EI +)m/z：274[M] +.
Embodiment 56:2-penta oxygen formyl-5,6-diaminobenzene thiophthene (18b)
Be raw material with 5,6-diamino-6 nitrobenzaldehyde and Thiovanic acid pentyl ester, according to synthetic solid 2-penta oxygen formyl-5, the 6-diaminobenzene thiophthene (61%) of obtaining of the method for embodiment 1.
1HNMR(CDCl 3)δ：0.90(t，J＝7.2Hz，，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，1H).MS(EI +)m/z：278[M] +.
Embodiment 57:2-ketone acid-thionaphthene (19)
Be raw material with 2-nitrobenzaldehyde and sulfydryl 2-carbonyl propionic acid, according to the synthetic solid 2-ketone acid-thionaphthene (51.5%) that obtains of the method for embodiment 1.
1HNMR(CDCl 3) 1HNMR(CDCl 3)δ：7.32(t，J＝7.0Hz，1H)，7.49(t，J＝7.0Hz，1H)，7.76(d，J＝7.0Hz，1H)，7.79(d，J＝7.0Hz，1H)，7.94(s，1H)，12.6(s，1H).MS(EI +)m/z：206[M] +.
Embodiment 58:2-(1 ', 2 '-dicarbapentaborane) amylbenzene thiophthene (20)
With 2-nitrobenzaldehyde and 1-mercapto hexyl-2, the 3-diketone is raw material, according to synthetic solid 2-(1 ', 2 '-dicarbapentaborane) the amylbenzene thiophthene (40.2%) that obtains of the method for embodiment 1.
1HNMR(CDCl 3) 1HNMR(CDCl 3)δ：0.96(t，J＝7.2Hz，，3H)，1.65(m，2H)，2.40(m，2H)，7.33(t，J＝7.0Hz，1H)，7.46(t，J＝8.0Hz，1H)，7.70(d，J＝7.0Hz，1H)，7.82(d，J＝8.0Hz，1H)，8.05(s，1H).MS(EI +)m/z：232[M] +.
Embodiment 59:2-(butyl sulfoxide group) acetyl-5,6-diamino-thionaphthene (18c)
Be raw material with compound 18b (2-penta oxygen formyl-5,6-diaminobenzene thiophthene), obtain solid 2-(butyl sulfoxide group) acetyl-5,6-diamino-thionaphthene (18c) (80%) according to the method reaction of embodiment 2.
1HNMR(CDCl 3)δ：0.90(t，J＝7.2Hz，3H)，1.33(m，4H)，1.78(m，2H)，AB system(4.28，4.36，J＝13.2Hz，2H)，5.80(s，4H)，6.72(s，1H)，6.78(s，1H)，7.88(s，1H).MS(EI +)m/z：306[M] +.
Embodiment 60:2-(4 '-chlorine oxygen in heptan formyl)-5,6-dimethoxy-thionaphthene (21b)
With compound 2-nitro-4,5-dimethoxy benzaldehyde and Thiovanic acid-4 '-chlorine heptyl ester is raw material, reacts according to the method for embodiment 15 to obtain solid 2-(4 '-chlorine oxygen in heptan formyl)-5,6-dimethoxy-thionaphthene (21b) (55%).
1HNMR(CDCl 3)δ：0.96(t，J＝7.2Hz，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，1H)，7.25(s，1H)，8.30(s，1H).MS(EI +)m/z：370[M] +.
Embodiment 61:2-(4 '-chlorine hexyl sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene (21c)
Be raw material with compound 21b, obtain solid 2-(4 '-chlorine hexyl sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene (21c) (85%) according to the method reaction of embodiment 2
1HNMR(CDCl 3)δ：0.96(t，J＝7.2Hz，3H)，1.33(m，4H)，1.56(m，4H)，3.46(m，1H)，3.73(s，3H)，3.95(s，3H)，AB system(4.30，4.39，J＝13.2Hz，2H)，7.19(s，1H)，7.26(s，1H)，8.25(s，1H).MS(EI +)m/z：398[M] +.
Embodiment 63:2-(6 '-hydroxyl hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene (22b)
With compound 2-nitro-4, the own ester of 5-dimethoxy benzaldehyde and Thiovanic acid-6 '-hydroxyl is raw material, reacts according to the method for embodiment 15 to obtain solid 2-(6 '-hydroxyl hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene (22b) (50%).
1HNMR(CDCl 3)δ：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，1H)，7.21(s，1H)，7.30(s，1H)，8.09(s，1H).MS(EI +)m/z：338[M] +.
Embodiment 63:2-(6 '-hydroxyl amyl group sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene (22c)
Be raw material with compound 22b, obtain solid 2-(6 '-hydroxyl amyl group sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene (22c) (81%) according to the method reaction of embodiment 2
1HNMR(CDCl 3)δ：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＝13.2Hz，2H)，5.16(s，1H)，7.29(s，1H)，7.32(s，1H)，8.16(s，1H).MS(EI +)m/z：366[M] +.
Embodiment 64:2-(6 '-methoxyl group hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene (23b)
With compound 2-nitro-4,5-dimethoxy benzaldehyde and Thiovanic acid-6 '-methoxyl group polyhexamethylene is raw material, reacts according to the method for embodiment 15 to obtain solid 2-(6 '-methoxyl group hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene (23b) (63%).
1HNMR(CDCl 3)δ：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，1H)，7.28(s，1H)，8.19(s，1H).MS(EI +)m/z：352[M] +.
Embodiment 65:2-(6 '-methoxyl group amyl group sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene (23c)
Be raw material with compound 23b, obtain solid 2-(6 '-methoxyl group amyl group sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene (23c) (86%) according to the method reaction of embodiment 2
1HNMR(CDCl 3)δ：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＝13.2Hz，2H)，7.18(s，1H)，7.26(s，1H)，7.91(s，1H).MS(EI +)m/z：380[M] +.
Embodiment 66:2-ethoxycarbonyl-5,6-ethyl methylene radical dioxy-thionaphthene (24b)
Be raw material with 3,4-ethyl methylene radical dioxy-6 nitrobenzaldehyde and ethyl thioglycolate, according to the synthetic solid 2-ethoxycarbonyl-5,6-ethyl methylene radical dioxy-thionaphthene (68.5%) of obtaining of the method for embodiment 1.
1HNMR(CDCl 3)δ：0.96(m，3H)，1.42(t，J＝7.2Hz，3H)，2.13(m，2H)，4.37(q，J＝7.2Hz，2H)，6.04(m，1H)，7.21(s，1H)，7.26(s，1H)，7.91(s，1H).MS(EI +)m/z：278[M] +.
Embodiment 67:2-ethoxycarbonyl-5,6-(2 '-chloroethyl) methylene radical dioxy-thionaphthene (25b)
Be raw material with 3,4-(2 '-chloroethyl) methylene radical dioxy-6 nitrobenzaldehyde and ethyl thioglycolate, according to the synthetic solid 2-ethoxycarbonyl-5,6-(2 '-chloroethyl) methylene radical dioxy-thionaphthene (25b) (62.0%) of obtaining of the method for embodiment 1.
1HNMR(CDCl 3)δ：1.43(t，J＝7.2Hz，3H)，1.59(d，J＝5.0Hz，3H)，4.38(q，J＝7.2Hz，2H)，4.63(m，1H)，6.23(m，1H)，7.18(s，1H)，7.23(s，1H)，7.96(s，1H).MS(EI +)m/z：312[M] +.
Embodiment 68:2-ethoxycarbonyl-5,6-(1 '-hydroxyethyl) methylene radical dioxy-thionaphthene (26b)
Be raw material with 3,4-(1 '-hydroxyethyl) methylene radical dioxy-6 nitrobenzaldehyde and ethyl thioglycolate, according to the synthetic solid 2-ethoxycarbonyl-5,6-(1 '-hydroxyethyl) methylene radical dioxy-thionaphthene (26b) (68.0%) of obtaining of the method for embodiment 1.
1HNMR(CDCl 3)δ：1.42(t，J＝7.2Hz，3H)，2.28(m，2H)，3.53(m，2H)，4.38(q，J＝7.2Hz，2H)，5.16(s，1H)，5.96(m，1H)，7.18(s，1H)，7.25(s，1H)，7.98(s，1H).MS(EI +)m/z：294[M] +.
Embodiment 69:2-ethoxycarbonyl-5,6-(1 '-aminoethyl) methylene radical dioxy-thionaphthene (27b)
Be raw material with 3,4-(1 '-aminoethyl) methylene radical dioxy-6 nitrobenzaldehyde and ethyl thioglycolate, according to the synthetic solid 2-ethoxycarbonyl-5,6-(1 '-aminoethyl) methylene radical dioxy-thionaphthene (26b) (68.0%) of obtaining of the method for embodiment 1.
1HNMR(CDCl 3)δ：1.42(t，J＝7.2Hz，3H)，2.35(m，2H)，2.65(m，2H)，4.12(s，1H)，4.38(q，J＝7.2Hz，2H)，5.98(m，1H)，7.16(s，1H)，7.27(s，1H)，8.02(s，1H).MS(EI +)m/z：293[M] +.
Embodiment 70:2-ethoxycarbonyl-5,6-(1 '-methoxy ethyl) methylene radical dioxy-thionaphthene (28b)
With 3,4-(1 '-methoxy ethyl) methylene radical dioxy-6 nitrobenzaldehyde and ethyl thioglycolate are raw material, according to the synthetic solid 2-ethoxycarbonyl-5,6-(1 '-methoxy ethyl) methylene radical dioxy-thionaphthene (26b) (68.0%) of obtaining of the method for embodiment 1.
1HNMR(CDCl 3)δ：1.42(t，J＝7.2Hz，3H)，2.26(m，2H)，3.24(s，3H)，3.37(m，2H)，4.38(q，J＝7.2Hz，2H)，5.98(m，1H)，7.18(s，1H)，7.25(s，1H)，8.03(s，1H).MS(EI +)m/z：308[M] +.

Claims (8)

1. the benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof that has structure shown in formula I,
In the formula,
One, X represents O:
Y represents CO or CR 1' OH; R wherein 1' representative following group: H, methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl;
R 1Represent CH 2S (O) nR 8, R wherein 8Represent methylidene, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n=2;
R 2Representative: H;
R 3Represent following group: H, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy;
R 4Represent following group: H, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy;
R 5Represent following group: H, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy;
R 6Represent following group: H, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy;
And R4, R5 are not H simultaneously;
Two, X represents S, and following five kinds of replacement situations are arranged:
(1) Y represents CO or CR 1' OH; R wherein 1' representative following group: H, methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl;
R 1Represent CH 2S (O) nR 8R wherein 8Representative contains alkyl, halo alkyl or the hydroxy alkylene of 1-18 carbon, n=1-2;
R 2Representative: H;
R 3Representative: H, halogen;
R 4Represent alkoxyl group, carboxyl, methanoyl, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, the isoamyl acyloxy of following group: H, a 1-18 carbon;
R 5Represent alkoxyl group, carboxyl, methanoyl, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, the isoamyl acyloxy of following group: H, a 1-18 carbon;
R 6Representative: H;
And R4, R5 are not H simultaneously;
(2) Y represents CR 1' OH,
Wherein R1 ' represents following group: H, methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl;
R 1Represent following group: the alkyl that contains 1-18 carbon;
R 2Representative: H;
R 3Representative: H;
R 4, R 5Represent following group: H, methanoyl, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, isoamyl acyloxy; And R 4And R 5Be not H simultaneously;
R 6Representative: H;
(3) Y represents CO,
R 1Represent following group: the alkyl that contains 1-18 carbon;
R 2Representative: H;
R 3Representative: H;
R 4, R 5Represent following group: H, carboxyl; And R 4And R 5Be not H simultaneously;
R 6Representative: H;
(4) Y represents CO;
R 1Represent following group: R 9The substituted phenylethylene base; R wherein 9Represent H, halogen;
R 2Representative: H;
R 3Representative: H, halogen;
R 4Represent following group: H, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, isoamyl acyloxy;
R 5Represent following group: H, carboxyl, methanoyl, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, isoamyl acyloxy;
And R 4And R 5Be not H simultaneously;
R 6Representative: H;
(5) Y represents CO;
R 1Be methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy; R 2Be H; R 3Be H;
R 4Be methanoyl, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, isoamyl acyloxy, positive hexylyloxy, dissident's acyloxy;
R 5Represent H; R 6Represent H;
And work as R 1During for methoxyl group; R 4It is not acetoxyl group;
Three, X represents NR 7:
R wherein 7Represent H, alkyl, halo alkyl, carbonyl alkyl, hydroxy alkylene, hydrocarbyl amino or-oxyl;
Y represents CO;
R 1Representative: R 9The substituted phenylethylene base; R 9Represent H, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy, halogen;
R 2Representative: H;
R 3Representative: H;
R 4Represent following group: H, methanoyl, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, isoamyl acyloxy;
R 5Represent following group: H, methanoyl, acetoxyl group, isopropyl acyloxy, positive propionyloxy, positive butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy, positive penta acyloxy, isoamyl acyloxy;
R 6Representative: H;
And R 4And R 5Be not H simultaneously;
Above-described " alkyl " refers to that carbonatoms is at the alkyl or cycloalkyl of the straight or branched of 1-18.
2. benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof, it comprises:
2-(2 '-methylsulfonyl) acetyl-5-methoxyl group-cumarone
2-(2 '-methyl sulfoxide base) acetyl-5,6-methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5-methoxycarbonyl-thionaphthene
2-acetyl-5-methoxycarbonyl-thionaphthene
2-acetyl-5-carboxyl-thionaphthene
2-acetyl-6-methoxycarbonyl-thionaphthene
2-acetyl-6-carboxyl-thionaphthene
2-(2 '-methyl sulfoxide base) acetyl-5,6-dimethoxy-thionaphthene
(E)-2-[3 '-(4 "-anisole) acryloyl]-6-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(4 "-anisole) acryloyl]-5-ethoxycarbonyl-thionaphthene
2-(1 '-hydroxyl-2 '-methyl sulfoxide base) ethyl-5,6-methylene radical dioxy-thionaphthene
2-(1 '-hydroxyl) ethyl-5-methoxycarbonyl-thionaphthene
2-(1 '-hydroxyl) ethyl-6-methoxycarbonyl-thionaphthene
(E)-2-cinnyl-6-ethoxycarbonyl-thionaphthene
(E)-2-cinnyl-5-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-5-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(2 "-chloro-phenyl-) acryloyl]-6-ethoxycarbonyl-thionaphthene
(E)-2-[3 '-(3 ", 4 "-dimethoxy benzene) acryloyl]-6-ethoxycarbonyl-thionaphthene
2-(4 '-chlorine oxygen in heptan formyl)-5,6-dimethoxy-thionaphthene
2-(4 '-chlorine hexyl sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene
2-(6 '-hydroxyl hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene
2-(6 '-hydroxyl, penta sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene
2-(6 '-methoxyl group hexyl) oxygen formyl-5,6-dimethoxy-thionaphthene
2-(6 '-methoxyl group amyl group sulfoxide group) acetyl-5,6-dimethoxy-thionaphthene
2-ethoxycarbonyl-5,6-(2 '-chloroethyl) methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5,6-(1 '-hydroxyethyl) methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5,6-(1 '-aminoethyl) methylene radical dioxy-thionaphthene
2-ethoxycarbonyl-5,6-(1 '-methoxy ethyl) methylene radical dioxy-thionaphthene
(E)-1-(2 '-hydroxyethyl)-2-[3 '-(4 "-fluorobenzene) acryloyl]-5-acetoxyl group-indoles
(E)-1-(2 '-amino-ethyl)-2-[3 '-(4 "-fluorobenzene) acryloyl]-5-acetoxyl group-indoles
(E)-1-(2 '-methoxy ethyl)-2-[3 '-(4 "-fluorobenzene) acryloyl]-5-acetoxyl group-indoles.
3. have the method for the benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof of structure shown in the logical formula I in the preparation claim 1, it is characterized in that:
A, the X in formula (I) are S, and Y represents CO or CR 1' OH, R 1Be CH 2S (O) nR 8Or R 9During the substituted phenylethylene based structures, method at first obtains intermediate (IV) shown in employing route 1 or the route 2, wherein, and R 2, R 3, R 4, R 5, R 6, R 8, R 9, n, R 1' definition with claim 1, R 11Represent H, OH, contain alkyl, carboxyl, acyl group, alkoxyl group or the sulfonic group of 1-18 carbon;
Route 1:
Figure FDA00002903604000061
Synthetic method is: the Ortho Nitro Benzaldehyde (II) with replacement is starting raw material, under alkaline reagents catalysis, uses mercaptoethanol to carry out fragrant nucleophilic substitution reaction, the NO of raw material 2Replaced by ethylmercapto group, generate intermediate (III); Under alkaline reagents catalysis, halogenating agent
Figure FDA00002903604000062
(Z represents leavings group) with intermediate (III) reaction, obtains the derivative (IV) of 2-substituted acyl thionaphthene;
Route 2:
Figure FDA00002903604000063
Synthetic method is: the Ortho Nitro Benzaldehyde (II) with replacement is starting raw material, under alkaline reagents catalysis, with sulfhydryl reagent
Figure FDA00002903604000064
Directly react the derivative (IV) of 2-substituted acyl thionaphthene;
Further, described intermediate (IV) can carry out following reaction respectively and obtains corresponding generalformula:
A. work as R 3, R 4, R 5, R 6In one or more when being ester group, intermediate (IV) hydrolysis under alkaline condition obtains carboxylic acid derivative (V), wherein R 3', R 4', R 5', R 6' respectively corresponding to R 3, R 4, R 5, R 6Group after the hydrolysis
Figure FDA00002903604000071
B. intermediate (IV) obtains corresponding hydroxy derivatives (VI) through reduction
C. work as R 11During for methyl, intermediate (IV) and R 9The phenyl formaldehyde intermediate (VII) that replaces carries out aldol condensation, obtains 2 and is R 9The compound of substituted benzene acryloyl (VIII)
Figure FDA00002903604000073
D. work as R 11During for alkoxyl group, intermediate (IV) can carry out following reaction and obtain corresponding generalformula:
Figure FDA00002903604000081
Intermediate (IV) is under highly basic and heating, obtain compound 2-(2 '-substituent methyl sulfoxide) acyl group benzothiophene derivative (IX) with the reaction of sulfinyl methyl-derivatives, proceed oxidation and reduction and obtain compound 2-(2 '-replacement first sulfone ethanoyl) benzothiophene derivative (X) and 2-(2 '-replacement first sulfone or methyl sulfoxide-1 '-hydroxyl) ethyl benzothiophene derivative (XI) respectively;
B, the X in formula I are O, and Y represents CO or CR 1' OH, R 1Be CH 2S (O) nR 8The time, method obtains intermediate (XIII) shown in its synthetic employing route 3, wherein, and R 2, R 3, R 4, R 5, R 6, R 8, n, R 1' definition with claim 1, R 12Represent following group: H, OH, the alkyl that contains 1-18 carbon, carboxyl, acyl group, alkoxyl group, sulfonic group
Route 3:
Figure FDA00002903604000082
Synthetic method is: the salicylaldhyde (XII) with replacement is starting raw material, under alkaline reagents catalysis, with halogenating agent (Z represents leavings group) reacts, and generates 2-carbonyl class (XIII) compound;
Wherein, work as R 12During for alkoxyl group, intermediate (XIII) can carry out following reaction and obtain corresponding generalformula:
Figure FDA00002903604000091
Intermediate (XIII) is again under highly basic and heating, obtain 2-(2 '-substituent methyl sulfoxide) acyl group benzofuran derivative (XIV) with the reaction of sulfinyl methyl-derivatives, (XIV) proceed oxidation and reduction and obtain compound 2-(2 '-replacement sulfuryl) phenyl methyl ketone benzofuran derivs (XV) and 2-(2 '-replacement first sulfone or methyl sulfoxide-1 '-hydroxyl) ethyl benzofuran derivative (XVI) respectively;
C, X is NR in formula I 7, Y represents CO, R 1Be R 9During the substituted phenylethylene based structures, method shown in its synthetic employing route 4, wherein, R 2, R 3, R 4, R 5, R 6, R 7, R 9Definition with claim 1;
Route 4:
Figure FDA00002903604000092
Synthetic method is: with the N-R that replaces 7-2-acetyl indole (XVII) is starting raw material, under alkaline reagents catalysis, carries out aldol condensation with the phenyl formaldehyde intermediate (VII) that replaces, and obtains 2 and is R 9The phenylallene acyl target compound (XVIII) that replaces.
4. the application of benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof in the medicine of preparation treatment osteoporosis illness that has structure shown in the formula I in the claim 1.
5. pharmaceutical composition that is used for osteoporosis, it is characterized in that, contain the described benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof of the claim 1 for the treatment of significant quantity in this pharmaceutical composition, and contain one or more pharmaceutically acceptable pharmaceutical adjuvants.
6. pharmaceutical composition as claimed in claim 5, wherein, described benzo five-membered unsaturated heterocycle compound or pharmaceutically acceptable salt thereof is as activeconstituents, and the weight content in this pharmaceutical composition is 0.1%-99.5%.
7. pharmaceutical composition as claimed in claim 5 wherein, contains the activeconstituents that weight ratio is 0.5%-99.5% in this pharmaceutical composition.
8. as the application of composition as described in the claim 5 in the preparation osteosporosis resistant medicament.
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