CN105001212B - Fused ring compound and its preparation method and application - Google Patents
Fused ring compound and its preparation method and application Download PDFInfo
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- CN105001212B CN105001212B CN201410152162.7A CN201410152162A CN105001212B CN 105001212 B CN105001212 B CN 105001212B CN 201410152162 A CN201410152162 A CN 201410152162A CN 105001212 B CN105001212 B CN 105001212B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The present invention relates to a kind of a series of novel fused ring compound and its pharmaceutically useful salt of structures shown in logical formula (I), the prodrug or pharmaceutical composition containing it, and preparation method thereof, wherein each symbol is defined as in the description.The compound or its salt, prodrug have GPR40 regulation functions, and are used as Insulin secretagogues, and prevention or the medicine for treating diabetes etc. are useful.
Description
Technical field
The present invention relates to a series of novel fused ring compound of structures of GPR40 target spots with and its preparation method and application,
They are to can be used for treatment diabetes B and metabolic disorder etc. GPR40 diseases related.
Background of invention
The existing diabetic 3.71 hundred million or so in the whole world at present, wherein type 2 diabetes patient account for diabetic's sum
90~95%, while continue to rise with the growth rate higher than 6%.Diabetes mellitus in China patient accounts for China up to 1.14 hundred million at present
The 11.6% of adult population, total patient's number account for 1/3rd of global diabetes patient sum, and into the rapid increase impetus.China
Diabetes morbidity belongs to one of Asia highest country, and absolute number is whole world maximum.Wherein type 2 diabetes patient accounts for whole
More than the 90% of individual diabetic population, it is mainly shown as insulin resistance (target organ declines to the sensitiveness of insulin) and pancreas
Island element secretory volume deficiency.Oral or injection medicine is current treating diabetes most effective way.Treated for type ii diabetes
Medicine mainly have：Hypoglycemic class, such as melbine, reduce the decomposition of hepatic glycogen；Promotion insulin secretion class, such as sulfonylureas,
DPP-4 inhibitor and GLP-1 analogs etc., increase the secretory volume of pancreatic beta cell insulin；Alpha-glucosidase restrainer, suppression
The generation of glucose in enteron aisle processed；Peroxisome proliferators activated receptor γ (PPAR- γ) activator, body is improved to pancreas
The sensitiveness of island element.But, all there is certain side effect in these medicines, such as cause hypoglycemia, increased weight, intestines and stomach not
Good reaction, drug resistance etc..
GPR40 acceptors (g protein coupled receptor 40) are typical seven transmembrane receptors, for a kind of islet cells that is expressed in
G- G-protein linked receptors (GPCR).Studies have shown that this receptor and a variety of diseases, especially diabetes are closely related.Free-fat
Acid be used as a kind of important signaling molecule in insulin secretion process, its promoting insulin secretion depend on glucose and by
GPR40 is receptor-mediated, and it can play the insulin secretion effect that amplification glucose stimulates, so GPR40 can control as diabetes
The Novel submarine for the treatment of is in target spot.In addition, GPR40 be also believed to it is relevant with some neural class diseases and some cancers.
GPR40 has glucose dependency to the facilitation of insulin secretion：I.e. in low concentration glucose, GPR40
To the facilitation very little of insulin secretion, so as to which blood sugar concentration will not be caused to continue to reduce；And in high concentration, to insulin
The facilitation of secretion is stronger, can effectively reduce blood sugar concentration.Therefore, GPR40 activators are in treatment type ii diabetes
Meanwhile the risk of hypoglycemia can be prevented.Based on above feature, GPR40 activators can be used for treat type ii diabetes and
Related indication, such as fat, metabolic syndrome, atherosclerosis, high fat of blood etc..Thus, it is found that and transformation using GPR40 as
The activator of target spot, there is very important value for scientific research and clinical practice.
Disclose the patent application of a series of GPR40 activators at present, including WO2005086661,
WO2008001931、WO2010045258、WO2012072691、WO2012011125、WO2012004269、
WO2011161030, US2011313008, US2011312995, US2012004234 and US2012035196 etc..
Although the GPR40 activators of a series for the treatment of diabetes and metabolic disease etc. have been disclosed at present, at present
There has been no corresponding marketed drug.Therefore still need to constantly study, develop the new compound with more preferable drug effect.By constantly exerting
Power, compound of the present invention design with structure shown in logical formula (I), and it is excellent to find that the compound with this class formation is shown
GPR40 agonistic effects and effect.
The content of the invention
The invention provides a kind of noval chemical compound as GPR40 activators and application thereof.
The present invention relates to the compound shown in following formula, or its pharmaceutically acceptable salt, and optical isomer
Wherein R5It is R8-SO2-, wherein R8 is hydrogen or optionally substituted alkyl, or optionally substituted hydroxyl, or optionally
Substituted amino, or optionally substituted sulfydryl；
Z is key or bivalent hydrocarbon radical；
R3、R4、R6、R7To be identical or different, and hydrogen atom, halogen atom, optionally substituted alkyl are each stood alone as,
Or optionally substituted hydroxyl, or optionally substituted amino, or optionally substituted sulfydryl；
Ring C is 5 to 7 yuan of rings；Y is the alkyl of key or 1-6 carbon；
R1For optionally substituted hydroxyl；
Ring A is 5 to 7 yuan of aromatic rings or aromatic heterocycle；
Ring B is 5 to 7 yuan of rings；
Ring A and ring B fusion key can be aromatic rings A or aromatic heterocycle A any key；
Wherein X is the atom such as key or oxygen, sulphur, nitrogen, carbon；
Unless otherwise indicated, as " optionally substituted alkyl " in this specification, refer to for example, 1 arrives multiple carbon atoms
Straight or branched alkane, and the alkane can be substituted by the atomic radical such as halogen, oxygen, nitrogen, sulphur；Or 3 arrive multiple carbon atoms
Cycloalkane, and the cycloalkane can be substituted by the atomic radical such as halogen, oxygen, nitrogen, sulphur；Or 2 arrive multiple carbon atoms straight chain
Or branched-chain alkene, and the alkene can be substituted by the atomic radical such as halogen, oxygen, nitrogen, sulphur；Or 2 arrive multiple carbon atoms straight chain
Or branched alkyne, and the alkynes can be substituted by the heteroatom group such as halogen, oxygen, nitrogen, sulphur；Or C7-16Aralkyl, and
The aryl can be substituted by the heteroatom group such as halogen, oxygen, nitrogen, sulphur；Or C7-16Fragrant miscellaneous alkyl, and the aryl can quilt
The heteroatom group such as halogen, oxygen, nitrogen, sulphur is substituted；
Unless otherwise indicated, as " aralkyl " in this specification, refer to for example, the benzene such as phenylmethane, vinylbenzene, phenylpropyl alcohol alkane
Alkyl, wherein phenyl ring can be substituted by halogen, the heteroatom group such as alkane or optionally substituted oxygen, nitrogen, sulphur；
Unless otherwise indicated, alkyl is included as " optionally substituted alkyl " in this specification, it can be mentioned that for example,
Methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, isopentyl etc., preferably methyl, ethyl；
Unless otherwise indicated, alkylene is included as " optionally substituted alkyl " in this specification, the alkylene can
To refer to for example, vinyl, acrylic, isopropenyl, 2- butene-1s-base, 4- amylene -1- bases, 5- hexene -1- bases etc..
Unless otherwise indicated, alkynes base is included as " optionally substituted alkyl " in this specification, the alkynes base can
To refer to for example, 2- butine -1- bases, 4- pentyne -1- bases, 5- hexin -1- bases etc..
Unless otherwise indicated, as " optionally substituted hydroxyl " in this specification, it can be mentioned that for example, " hydroxyl ", " appoint
The substituted C1-6 alkoxies of choosing ", " optionally substituted cycloalkyloxy ", " optionally substituted C7-14 aralkoxies " etc.；
Unless otherwise indicated, as " optionally substituted hydroxyl " in this specification, including " optionally substituted C1-6 alkane
Epoxide ", it can be mentioned that for example, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, isobutoxy, amoxy, isoamoxy etc.,
It is preferred that methoxyl group, ethyoxyl；
Unless otherwise indicated, as " optionally substituted hydroxyl " in this specification, including " optionally substituted cycloalkyl
Epoxide ", it can be mentioned that for example, pentamethylene methoxyl group, pentamethylene ethyoxyl, hexamethylene methoxyl group, hexamethylene ethyoxyl, cycloheptane
Methoxyl group, cycloheptane ethyoxyl etc..
Unless otherwise indicated, as " the C7-14 aralkoxies " in this specification, it can be mentioned that for example, benzyloxy, benzene second
Base epoxide etc..
Unless otherwise indicated, as " optionally substituted amino, the optionally substituted sulfenyl " in this specification, with saying
The implication of " optionally substituted hydroxyl " is basically identical described in bright book, and wherein amino can be taken by two optionally substituted alkyl
Generation；
Unless otherwise indicated, as " halogen " in this specification, it can be mentioned that for example, fluorine, chlorine, bromine, iodine etc.；
Unless otherwise indicated, as " alkyl of 1-6 carbon " in this specification, C is included but are not limited to1-6Straight chain alkane
Hydrocarbon, alkene, alkynes, C1-6Branched paraffin, alkene, alkynes, C3-6Cycloalkane etc.；
Unless otherwise indicated, as " 5 to 7 yuan of rings " in this specification, it can be mentioned that optionally substituted C5-7Cycloalkanes
Hydrocarbon, including pentamethylene, hexamethylene, cycloheptane；Optionally substituted C5-7The miscellaneous alkane of ring, including tetrahydrofuran ring, oxinane
Ring, oxepane, nafoxidine ring, piperidine ring, azepan, thiophane ring, tetrahydric thiapyran ring, thia cycloheptane
Deng；Optionally substituted C5-7Aromatic rings, including amyl- 1, the 3- diene of ring, phenyl ring etc.；Optionally substituted C5-7Heteroaromatic,
Such as thienyl (for example, 2- thienyls, 3- thienyls), furyl (for example, 2- furyls, 3- furyls), pyridine radicals (example
Such as, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals), thiazolyl is (for example, 2- thiazolyls, 4- thiazolyls, 5- thiazolyl), oxazolyls
(for example, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls), pyrazinyl, pyrimidine radicals (for example, 2- pyrimidine radicals, 4- pyrimidine radicals), pyrroles
Base (for example, 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals), imidazole radicals (for example, 1- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals),
Pyrazolyl (for example, 1- pyrazolyls, 3- pyrazolyls, 4- pyrazolyls), triazolyl (for example, 1- triazolyls, 2- triazolyls), tetrazolium
Base, pyridazinyl (for example, 3- pyridazinyls, 4- pyridazinyls), isothiazolyl are (for example, 3- isothiazolyls, 4- isothiazolyls, the different thiophenes of 5-
Oxazolyl), isoxazolyls (for example, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls), indyl are (for example, 1- indyls, 2-
Indyl, 3- indyls)；
Unless otherwise indicated, as " aromatic rings or the aromatic heterocycle " in this specification, fragrant alkane is included but are not limited to
Base, containing the heteroatomic aromatic heterocycle such as one or more O, N, S；The concrete structure example of the fragrant alkane and aromatic heterocycle is such
The preceding structure example is basically identical；
Unless otherwise indicated, as in this specification " ring A and ring B fusion key can be fragrance or aromatic heterocycle A appoint
One key "；Including but not limited to following a variety of fusion modes：
Compound of the present invention, it can be obtained by appropriate preparation approach, referring specifically to embodiment.
As compound (I) salt, for example, it can be mentioned that metal salt, ammonium salt, the salt and inorganic acid formed with organic base
Salt that the salt of formation, the salt formed with organic acid and alkalescence or acidic amino acid are formed etc..The preferred embodiment of metal salt includes alkali
Metal salt such as sodium salt, sylvite etc.；Alkali salt such as calcium salt, magnesium salts, barium salt, aluminium salt etc..
With organic base formed salt preferred embodiment, including with trimethylamine, triethylamine, pyridine, picoline, 2,6- diformazans
The salt of the formation such as yl pyridines, N, N- diisopropylethylamine, monoethanolamine, diethanol amine, triethanolamine, cyclohexylamine, dicyclohexylamine.
As the preferred embodiment of the salt formed with inorganic acid, including with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulphur hydracid,
The salt of the formation such as nitric acid, phosphoric acid, phosphorus hydracid.
As the preferred embodiment of the salt formed with organic acid, including with acetate, propionic acid, acrylic acid, malonic acid, butyric acid,
Oxalic acid, lactic acid, citric acid, acid citrate, tartaric acid, hydrogen tartaric acid, butanedioic acid, maleic acid, fumaric acid, cinnamic acid, vanilla
The salt of the formation such as acid, malic acid, glucose saccharic acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid, benzoic acid, p-methyl benzenesulfonic acid
As the preferred embodiment of the salt formed with basic amino acid, including with the formation such as lysine, arginine, histidine
Salt.
As the preferred embodiment of the salt formed with acidic amino acid, including the salt with the formation such as aspartic acid, glutamic acid.
In above-mentioned salt, the preferred acceptable salt of pharmacology.
The present invention can use to following compounds：
Specific embodiment
Embodiment 1：[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -7- bases-phenyl -2,3- two
Hydrogen chromene -2- bases } -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids (E1) synthesis
Experimentation:
1) first step：(E) -2- (6- (3- (the bromo- 2- hydroxy phenyls of 4-) -3- oxo propylene -1- bases) -2,3- dihydrobenzos
Furans -3- bases) acetic acid (A1) synthesis
By the bromo- 2- hydroxy acetophenones (2.6g, 12mmol) of 4-, 2- (6- formoxyl -2,3- Dihydrobenzofuranes -3- bases) second
Sour methyl esters (2.2g, 10mmol), barium hydroxide octahydrate (7.6g, 24mmol), absolute methanol 500mL are placed in 1L eggplant type bottles.
Stirring, is heated to flowing back, and reacts 24h.After reaction terminates, concentration removes organic solvent, and 6N hydrochloric acid solutions are acidified to pH=1~2,
Separate out a large amount of solids.Filter, 2.8g off-white powders, yield are obtained after filtration cakes torrefaction：69%.[M-H]-:402.2。
2) second step：(E) -2- (6- (3- (the bromo- 2- hydroxy phenyls of 4-) -3- oxo propylene -1- bases) -2,3- dihydrobenzos
Furans -3- bases) methyl acetate (A2) synthesis
By (E) -2- (6- (3- (the bromo- 2- hydroxy phenyls of 4-) -3- oxo propylene -1- bases) -2,3- Dihydrobenzofuranes -3-
Base) acetic acid (A1) (2.02g, 5mmol), concentrated sulfuric acid 5d, absolute methanol 150mL are added in 250mL eggplant type bottles, are heated with stirring to back
Stream, TLC detection (dichloromethane：Methanol=20:1) to without raw material A 1.Concentration removes methanol, saturation NaHCO3Alkalize to pH=7
~8.Ethyl acetate (100mL*3) extracts, and organic phase is concentrated to give off-white powder 1.98g after anhydrous sodium sulfate drying, receives
Rate：95%.[M+2H]+:419.5。
3) the 3rd step：2- (6- (the bromo- 4- oxos-benzo-γ of 7--pyrans -2- bases) -2,3- Dihydrobenzofuranes -3- bases)
The synthesis of methyl acetate (A3)
By (E) -2- (6- (3- (the bromo- 2- hydroxy phenyls of 4-) -3- oxo propylene -1- bases) -2,3- Dihydrobenzofuranes -3-
Base) methyl acetate (A2) (1.66g, 4mmol), iodine (0.76g, 6mmol) added in 15mL DMSO, is heated with stirring to backflow, instead
Answer 6h.After reaction terminates, reaction solution is cooled to room temperature, pours into frozen water, and ethyl acetate (100mL*3) extraction, organic phase is through nothing
Column chromatography for separation obtains solid 1.25g, yield 75% after water magnesium sulfate is dried.[M+2H]+:417.3；1H-NMR (300MHz,
CDCl3)；δ(ppm)：7.57 (d, 1H), 7.37 (m, 2H), 7.27 (d, 1H), 7.02 (d, 1H), 6.84 (s, 1H), 6.71 (s,
1H), 4.35 (m, 1H), 4.15 (m, 1H), 3.91 (s, 1H), 3.60 (s, 3H), 2.45 (m, 2H), 2.20 (m, 2H).
4) the 4th step：The conjunction of 2- (6- (7- bromine color alkane -2- bases) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (A4)
Into
By 2- (6- (the bromo- 4- oxos-benzo-γ of 7--pyrans -2- bases) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate
(A3) (1.25g, 3mmol), platinum dioxide (0.34g, 1.5mmol) are added in 50mL anhydrous tetrahydro furans, and nitrogen atmosphere room temperature is anti-
Answer 2h.Reacting liquid filtering, filtrate purify to obtain solid 0.72g, yield through column chromatography：60%.
5) the 5th step：2- (6- (7- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) color alkane -2- bases) -
2,3- Dihydrobenzofuranes -3- bases) methyl acetate (A5) synthesis
By 2- (6- (7- bromine color alkane -2- bases) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (A4) (0.60g,
1.5mmol), connection boric acid pinacol ester (0.38g, 1.5mmol), palladium (0.07g, 0.3mmol), X-phos (0.17g,
0.36mmol), potassium acetate (0.29g, 3mmol) is added in 15mL anhydrous dioxanes, and nitrogen protection, stirring is warming up to 100 DEG C,
React 2h.Reaction solution obtains compound A-45 0.20g, yield through column chromatography：30%.[M+H]+:451.3.
6) the 6th step：[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -7- bases-phenyl -2,3- two
Hydrogen chromene -2- bases } -2,3- dihydro -1- benzofuran -3- acetic acid methyl esters (A6) synthesis
General [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride (0.07g, 0.1mmol), potassium carbonate (0.12g,
0.9mmol), 2- (6- (7- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- bases) color alkane -2- bases) -2,3- dihydros
Benzofuran -3- bases) methyl acetate (A5) (0.20g, 0.45mmol) added in 10mL anhydrous dioxanes, nitrogen protection, stirs
Mix and be warming up to 100 DEG C, react 2h.Reaction solution obtains compound 0.20g, yield through column chromatography：80%.[M+H]+:566.1.
7) the 7th step：[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -7- bases-phenyl -2,3- two
Hydrogen chromene -2- bases } -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids (E1) synthesis
By [6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -7- bases-phenyl -2,3- dihydrobenzos
Pyrans -2- bases } -2,3- dihydro -1- benzofuran -3- acetic acid methyl esters (A6) (0.20g, 0.035mmol), methanol 1mL adds to
In 1N NaOH 5mL, 24h is stirred at room temperature.6N hydrochloric acid is acidified to pH=1~2, filtering, and target chemical combination is obtained after filter cake vacuum drying
Thing E 0.17g, yield 90%.[M+H]+:551.7；1H-NMR (300MHz, CDCl3)；δ(ppm)：7.40 (m, 2H), 7.16 (s,
1H), 7.08 (m, 1H), 6.70 (s, 2H), 6.51 (m, 2H), 5.06 (m, 1H), 4.56 (t, 1H), 4.28 (dd, 1H), 4.13
(t, 2H), 3.81 (m, 1H), 3.58 (m, 2H), 2.85 (m, 2H), 2.98 (s, 3H), 2.47 (m, 6H), 2.08 (s, 6H).
By preparation method similar to Example 1, embodiment 2-5 title compounds can be prepared:
Embodiment 2
[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -6- bases-phenyl -2,3- dihydrobenzo furans
Mutter -2- bases -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids (E2)
Embodiment 3
[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -7- bases-phenyl -1,2,3,4- tetrahydrochysene quinolines
Quinoline base -2- bases } -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids (E3)
Embodiment 4
[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -7- bases-phenyl -2,3- indoline -2-
Base } -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids (E4)
Embodiment 5
[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -7- bases-phenyl -2,3- dihydrobenzo miaows
Azoles -2- bases } -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids (E5)
Embodiment 6：
[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -5- bases-phenyl -1,2,3,4- tetrahydrochysene quinolines
Quinoline base -1- bases } methyl -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids synthesis
Experimentation:
The first step：2- (6- ((bromo- 3,4- EEDQs -1 (the 2H)-yls of 5-) methyl) -2,3- dihydro -1- benzofurans -3-
The synthesis of acetic acid methyl ester (B2)
By the bromo- 1,2,3,4- tetrahydroquinolines (2.12g, 10mmol) of 5-, 2- (6- (bromomethyl) -2,3- dihydro -1- benzo furans
Mutter -3- acetic acid methyl esters (2.86g, 10mmol), potassium carbonate (6.91g, 50mmol) is added in 200mL dry DMFs, and nitrogen is protected
Shield, stirring are warming up to 80 DEG C of reaction 12h.After reaction terminates, reaction solution analyzes to obtain B2 2.91g, yield through column chromatography：70%.The
Two~the 4th step：With reference to the step of embodiment 1 the 5th~the 7th.Obtain target compound [6- ({ 2', 6'- dimethyl -4'- [3- (first
Base sulfonyl) propoxyl group] -5- bases-phenyl -1,2,3,4- tetrahydric quinoline group -1- bases } methyl -2,3- dihydro -1- benzofurans -
3- guanidine-acetic acids.[M+H]+:564.7；
1H-NMR (300MHz, CDCl3)；δ(ppm)：7.35 (m, 2H), 7.12 (d, 1H), 7.03 (m, 2H), 6.96 (s,
2H), 6.83 (m, 1H), 5.13 (s, 2H), 4.36 (t, 1H), 4.18 (dd, 1H), 4.12 (t, 2H), 3.73 (m, 1H), 3.38
(m, 2H), 3.38 (m, 2H), 2.98 (s, 3H), 2.77 (m, 2H), 2.41 (m, 2H), 2.15 (m, 4H), 2.08 (s, 6H).
By preparation method similar to Example 6, embodiment 7-8 title compounds can be prepared:
Embodiment 7
[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -5- base-phenyl-benzo ring hexyls -1-
Base } epoxide -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids
Embodiment 8
[6- ({ 2', 6'- dimethyl -4'- [3- (methyl sulphonyl) propoxyl group] -5- base-phenyl-benzocyclopentane bases -1-
Base } epoxide -2,3- dihydro -1- benzofuran -3- guanidine-acetic acids
The test case of embodiment 9
Agonism of the compound of the present invention to GPR40 is investigated with external CHO-K1/GPR40 cells.
Inoculum density is the CHO-K1/GPR40 cells in 25000/hole in 96 orifice plates.37 DEG C, 5%CO2It is small to cultivate 24
When.Cell culture fluid is discarded, after cell is washed once with buffer solution, 100 μ L Fluo-4 calcium ion dyestuffs are added in every hole,
And be incubated 30 minutes in 37 DEG C of lucifuges, then continue to be incubated 30 minutes in room temperature.During measure, first read per hole baseline value, then
Various concentrations medicine (50 μ L/ holes) is added in hole, continues to read fluorescent value.Obtain every hole cellular response rate=(maximum fluorescence
Value-minimum fluorescent value)/minimum fluorescent value, calculate compound EC50Value.As a result it is as follows：
| Compound number | EC50(CHO-K1/GPR40)/(nM) |
| Embodiment 1 | 8 |
| Embodiment 2 | 12 |
| Embodiment 3 | 108 |
| Embodiment 4 | 93 |
| Embodiment 5 | 55 |
| Embodiment 6 | 27 |
| Embodiment 7 | 69 |
| Embodiment 8 | 18 |
The pharmacodynamics of embodiment 10 detects
The ICR mouse fed using high lipid food is animal subjects, the single oral dose administration of observation the compounds of this invention single
Influence to glucose load Mouse oral glucose tolerance (OGTT).
The male mouse that high lipid food is fed, overnight fast 16 hours.After weighing determine basal plasma glucose value, according to blood glucose height with
Machine is grouped into Blank groups, the compounds of this invention group.
Dosage is 20mg/kg, and Blank groups give 5%DMSO- physiological saline.Gastric infusion, administration are given after 15 minutes
Give 20% glucose solution (every mouse gives 0.4mL).Determine blood glucose value (- 15 minutes).And in 0,15,30,45,60 and
The blood glucose value of each mouse is determined at 120 minutes using Instrument for Measuring Blood Sugar.
AUC calculation formula：
AUC=(t15min+t0min)×0.25/2+(t30min+t15min)×0.25/2+(t45min+t30min)×0.25/2+
(t60min+t45min)×0.25/2+(t120min+t60min)×1/2
Wherein t0min, t15min, t30min, t45min, t60min, t120min are the blood glucose that different time points measure
Value.
Result of the test
| Compound number | Dosage | AUC rates of descent (%) |
| Embodiment 1 | 20mg/kg | 42.3 |
| Embodiment 2 | 20mg/kg | 36.4 |
| Embodiment 3 | 20mg/kg | 22.3 |
| Embodiment 4 | 20mg/kg | 31.4 |
| Embodiment 5 | 20mg/kg | 48.3 |
| Embodiment 6 | 20mg/kg | 22.5 |
| Embodiment 7 | 20mg/kg | 34.8 |
| Embodiment 8 | 20mg/kg | 16.7 |
Conclusion：The compounds of this invention qf oral administration dosage is to have obvious hypoglycemic effect to mouse under 20mg/kg.
Claims (7)
1. compound or its pharmaceutically acceptable salt shown in following formula, and optical isomer
In formula:
R5It is R8-SO2-, wherein R8For hydrogen or methyl, and the methyl can be substituted by halogen；Or the cycloalkane of 3 carbon atoms,
And the cycloalkane can be substituted by halogen；Or the straight or branched alkene of 2 carbon atoms, and the alkene can be taken by halogen
Generation；Or the straight or branched alkynes of 2 carbon atoms, and the alkynes can be substituted by halogen；Or hydroxyl, methoxyl group, ethyoxyl,
Propoxyl group, isopropoxy, isobutoxy, amoxy, isoamoxy, pentamethylene methoxyl group, pentamethylene ethyoxyl, hexamethylene methoxy
Base, hexamethylene ethyoxyl, cycloheptane methoxyl group, cycloheptane ethyoxyl, benzyloxy, phenethyl epoxide；
Z is key or bivalent hydrocarbon radical；
R3、R4、R6、R7To be identical or different, and hydrogen atom, halogen atom, methyl are each stood alone as, and the alkane can be by halogen
Substituted；Or the cycloalkane of 3 carbon atoms, and the cycloalkane can be substituted by halogen；Or the straight or branched of 2 carbon atoms
Alkene, and the alkene can be substituted by halogen；Or the straight or branched alkynes of 2 carbon atoms, and the alkynes can be by halogen
Substituted；Or hydroxyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, isobutoxy, amoxy, isoamoxy, pentamethylene first
Epoxide, pentamethylene ethyoxyl, hexamethylene methoxyl group, hexamethylene ethyoxyl, cycloheptane methoxyl group, cycloheptane ethyoxyl, benzyloxy,
Phenethyl epoxide；
Ring C is 5 to 7 yuan of rings；Y is the alkyl of key or 1-6 carbon；
R1For hydroxyl or methoxyl group, ethyoxyl, propoxyl group, isopropoxy, isobutoxy, amoxy, isoamoxy；
Ring B is 6 yuan of saturation cycloalkane or heterocycloalkane, and contained hetero atom is X, and X is oxygen, sulphur, nitrogen-atoms.
2. as claimed in claim 1, R8For C1-C5 alkyl.
3. compound or its salt as claimed in claim 1, and optical isomer, selected from following compounds：
4. include the preparation of the compound or its salt any one of claim 1-3.
5. preparing the medicine for preventing or treating diabetes comprising the compound or its salt any one of claim 1-3
Purposes in thing.
6. preparation as claimed in claim 4, it is prevention or the medicine for the treatment of diabetes.
7. preparation as claimed in claim 4 answering in treatment diabetes B preparation medicine caused by GPR40 target spots is prepared
With.
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| CN114163408B (en) * | 2020-09-10 | 2024-03-19 | 上海爱博医药科技有限公司 | Benzo oxygen-containing heterocyclic compound and medical application thereof |
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| PL2646425T3 (en) * | 2010-12-01 | 2015-12-31 | Boehringer Ingelheim Int | Indanyloxydihydrobenzofuranylacetic acids useful for the treatment of metabolic syndrome |
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| Title |
|---|
| Progress in the discovery and development of small-molecule modulators of G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1): an emerging target for type 2 diabetes;Sandip B Bharate et al.;《Expert Opin. Ther. Patents》;20091231;第19卷(第2期);第237-264页 * |
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