CN105001212A - Fused ring compound, preparation method and applications thereof - Google Patents
Fused ring compound, preparation method and applications thereof Download PDFInfo
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- CN105001212A CN105001212A CN201410152162.7A CN201410152162A CN105001212A CN 105001212 A CN105001212 A CN 105001212A CN 201410152162 A CN201410152162 A CN 201410152162A CN 105001212 A CN105001212 A CN 105001212A
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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
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Abstract
The present invention relates to a series of fused ring compounds represented by a general formula (I) and having a novel structure, a pharmaceutically-acceptable salt, a prodrug or a compound-containing drug composition, and a preparation method thereof, wherein each symbol is as defined in the specification, and the compound or the salt, the prodrug thereof has a GPR40 receptor regulating function, and can be adopted as the insulin secretagogue and the drugs for prevention or treatment of diabetes and the like. The formula I is defined in the specification.
Description
Technical field
The fused ring compound that the present invention relates to a series of novel structures of GPR40 target spot with and its preparation method and application, they are that to can be used for GPR40 such as treatment diabetes B and metabolic disorder etc. diseases related.
Background technology
The current whole world has diabetic subject about 3.71 hundred million, and wherein II diabetes mellitus type accounts for 90 ~ 95% of diabetic subject's sum, simultaneously to continue to rise higher than the rate of increase of 6%.Current diabetes mellitus in China patient has reached 1.14 hundred million, accounts for 11.6% of Chinese adult population, and total patient's number accounts for 1/3rd of global diabetics's sum, and becomes quick ascendant trend.Diabetes mellitus in China sickness rate belongs to one of the highest country in Asia, and absolute number is that the whole world is maximum.Wherein II diabetes mellitus type accounts for more than 90% of whole diabetic population, and its main manifestations is insulin resistant (target organ declines to the susceptibility of Regular Insulin) and insulin secretion quantity not sufficient.Oral or injectable drug is the most efficient manner of current treating diabetes.Medicine for the treatment of II patients with type Ⅰ DM mainly contains: hypoglycemic class, as N1,N1-Dimethylbiguanide, reduces the decomposition of liver starch; Promote insulin secretion class, as sulfonylurea, DPP-4 inhibitor and GLP-1 analogue etc., increase the secretory volume of pancreatic beta cell Regular Insulin; Alpha-glucosidase inhibitor, suppresses the generation of glucose in enteron aisle; Peroxisome proliferators activated receptor γ (PPAR-γ) activator, improves body to the susceptibility of Regular Insulin.But, all there is certain side effect in these medicines, such as, cause the increase of hypoglycemia, body weight, gastrointestinal side effect, drug resistance etc.
GPR40 acceptor (g protein coupled receptor 40) is typical seven transmembrane receptors, is a kind of G-protein linked receptor (GPCR) being expressed in islet cells.Research display, this receptor and various diseases, especially diabetes are closely related.Free fatty acids is as important signaling molecule a kind of in insulin secretion process, its promoting insulin secretion depends on glucose and receptor-mediated by GPR40, it can play the insulin secretion effect of amplifying glucose and stimulating, so GPR40 can become the Novel submarine for the treatment of diabetes at target spot.In addition, GPR40 is also considered to neural class disease and some related to cancer with some.
The promoter action of GPR40 to insulin secretion has glucose dependency: namely when low concentration glucose, and GPR40 is very little to the promoter action of insulin secretion, thus blood sugar concentration can not be caused to continue to reduce; And when high density, comparatively strong to the promoter action of insulin secretion, can blood sugar concentration be effectively reduced.Therefore, GPR40 agonist, while treatment II patients with type Ⅰ DM, can prevent hypoglycemic risk.Based on above feature, GPR40 agonist can be used for treating II patients with type Ⅰ DM and relevant indication, such as fat, metabolism syndrome, atherosclerosis, hyperlipidemia etc.Therefore, discovery and transformation take GPR40 as the agonist of target spot, have very important value for scientific research and clinical application.
Disclose the patent application of a series of GPR40 agonist at present, comprising WO2005086661, WO2008001931, WO2010045258, WO2012072691, WO2012011125, WO2012004269, WO2011161030, US2011313008, US2011312995, US2012004234 and US2012035196 etc.
Although disclosed the GPR40 agonist of a series for the treatment of diabetes and metabolic disease etc. at present, not yet there is corresponding marketed drug at present.Therefore still need continuous research, develop the new compound with better drug effect.Through continuous effort, the present invention's design has the compound of structure shown in general formula (I), and finds that the compounds exhibit with this class formation goes out excellent GPR40 agonistic effects and effect.
Summary of the invention
The invention provides the new compound and uses thereof of a class as GPR40 agonist.
The present invention relates to the compound shown in following formula, or its pharmacy acceptable salt, and optical isomer
Wherein R
5r
8-SO
2-, the wherein R8 alkyl that is hydrogen or is optionally substituted, or the hydroxyl be optionally substituted, or the amino be optionally substituted, or the sulfydryl be optionally substituted;
Z is key or bivalent hydrocarbon radical;
R
3, R
4, R
6, R
7for identical or different, and separately independent be hydrogen atom, halogen atom, the alkyl that is optionally substituted, or the hydroxyl be optionally substituted, or the amino be optionally substituted, or the sulfydryl be optionally substituted;
Ring C is 5 to 7 rings; Y is the alkyl of key or 1-6 carbon;
R
1for the hydroxyl be optionally substituted;
Ring A is 5 to 7 yuan of aromatic nucleus or aromatic heterocycle;
Ring B is 5 to 7 rings;
Ring A and ring B condenses arbitrary key that key can be aromatic nucleus A or aromatic heterocycle A;
Wherein X is the atom such as key or oxygen, sulphur, nitrogen, carbon;
Except as otherwise noted, as " alkyl be optionally substituted " in this specification sheets, mention such as, 1 to the straight or branched alkane of multiple carbon atom, and this alkane can by halogen, and the atomic radicals such as oxygen, nitrogen, sulphur replaced; Or 3 to the naphthenic hydrocarbon of multiple carbon atom, and this naphthenic hydrocarbon can by halogen, and the atomic radicals such as oxygen, nitrogen, sulphur replaced; Or 2 to the straight or branched alkene of multiple carbon atom, and this alkene can by halogen, and the atomic radicals such as oxygen, nitrogen, sulphur replaced; Or 2 to the straight or branched alkynes of multiple carbon atom, and this alkynes can by halogen, and the heteroatom groups such as oxygen, nitrogen, sulphur replaced; Or C
7-16aralkyl, and this aryl can by halogen, and the heteroatom groups such as oxygen, nitrogen, sulphur replaced; Or C
7-16virtue to mix alkyl, and this aryl can by halogen, and the heteroatom groups such as oxygen, nitrogen, sulphur replaced;
Except as otherwise noted, as " aralkyl " in this specification sheets, mention such as, phenylmethane, phenylethane, the benzene alkyl such as phenylpropyl alcohol alkane, wherein phenyl ring can by by halogen, and the heteroatom groups such as alkane or the oxygen be optionally substituted, nitrogen, sulphur replaced;
Except as otherwise noted, comprise alkyl as " alkyl be optionally substituted " in this specification sheets, can mention such as, methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, isopentyl etc., preferable methyl, ethyl;
Except as otherwise noted, comprise alkylene as " alkyl be optionally substituted " in this specification sheets, described alkylene can be mentioned such as, vinyl, propenyl, pseudoallyl, 2-butylene-1-base, 4-amylene-1-base, 5-hexene-1-base etc.
Except as otherwise noted, comprise alkynes base as " alkyl be optionally substituted " in this specification sheets, described alkynes base can be mentioned such as, 2-butyne-1-base, 4-pentyne-1-base, 5-hexin-1-base etc.
Except as otherwise noted, as " hydroxyl be optionally substituted " in this specification sheets, can mention such as, " hydroxyl ", " the C1-6 alkoxyl group be optionally substituted ", " cycloalkyloxy be optionally substituted ", " the C7-14 aralkoxy be optionally substituted " etc.;
Except as otherwise noted, as " hydroxyl be optionally substituted " in this specification sheets, comprise " the C1-6 alkoxyl group be optionally substituted ", can mention such as, methoxyl group, oxyethyl group, propoxy-, isopropoxy, isobutoxy, pentyloxy, isopentyloxy etc., preferred methoxyl group, oxyethyl group;
Except as otherwise noted, as " hydroxyl be optionally substituted " in this specification sheets, comprise " cycloalkyl oxy be optionally substituted ", can mention such as, pentamethylene methoxyl group, pentamethylene oxyethyl group, hexanaphthene methoxyl group, hexanaphthene oxyethyl group, suberane methoxyl group, suberane oxyethyl group etc.
Except as otherwise noted, as " C7-14 aralkoxy " in this specification sheets, can mention such as, benzyloxy, styroyl oxygen base etc.
Except as otherwise noted, as " amino be optionally substituted, the sulfenyl be optionally substituted " in this specification sheets, basically identical with the implication of " hydroxyl be optionally substituted " described in specification sheets, wherein the amino alkyl that optionally can be substituted by two replace;
Except as otherwise noted, as " halogen " in this specification sheets, can mention such as, fluorine, chlorine, bromine, iodine etc.;
Except as otherwise noted, as " alkyl of 1-6 carbon " in this specification sheets, C is included but are not limited to
1-6straight-chain paraffin, alkene, alkynes, C
1-6branched paraffin, alkene, alkynes, C
3-6naphthenic hydrocarbon etc.;
Except as otherwise noted, as " 5 to 7 ring " in this specification sheets, the C be optionally substituted can be mentioned
5-7naphthenic hydrocarbon, comprises pentamethylene, hexanaphthene, suberane, the C be optionally substituted
5-7ring is mixed alkane, comprises tetrahydrofuran (THF) ring, amylene oxide ring, oxepane, Pyrrolidine ring, piperidine ring, azepan, tetramethylene sulfide ring, tetrahydric thiapyran ring, thia suberane etc., the C be optionally substituted
5-7aromatic nucleus, comprise ring penta-1,3-diene, phenyl ring etc., the C be optionally substituted
5-7fragrant heterocycle, such as thienyl (such as, 2-thienyl, 3-thienyl), furyl (such as, 2-furyl, 3-furyl), pyridyl (such as, 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (such as, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (such as, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazinyl, pyrimidyl (such as, 2-pyrimidyl, 4-pyrimidyl), pyrryl (such as, 1-pyrryl, 2-pyrryl, 3-pyrryl), imidazolyl (such as, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (such as, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (such as, 1-triazolyl, 2-triazolyl), tetrazyl, pyridazinyl (such as, 3-pyridazinyl, 4-pyridazinyl), isothiazolyl (such as, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), isoxazolyl (such as, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), indyl (such as, 1-indyl, 2-indyl, 3-indyl),
Except as otherwise noted, as " aromatic nucleus or aromatic heterocycle " in this specification sheets, aromatic alkyl is included but are not limited to, containing heteroatomic aromatic heterocycle such as one or more O, N, S etc.; Structure example is basically identical as previously mentioned for the concrete structure example of described fragrant alkane and aromatic heterocycle;
Except as otherwise noted, as " ring A and ring B condenses arbitrary key that key can be fragrance or aromatic heterocycle A " in this specification sheets; Multiplely mode is condensed including but not limited to following;
Or
Compound of the present invention, prepares approach by suitable and obtain, specifically see embodiment.
As the salt of compound (I), such as, salt metal-salt, ammonium salt can be mentioned, forming with organic bases, the salt formed with mineral acid, the salt formed with organic acid, and the salt etc. that formed of alkaline or acidic amino acid.The preferred embodiment of metal-salt comprises an alkali metal salt such as sodium salt, sylvite etc.; Alkaline earth salt is calcium salt, magnesium salts, barium salt, aluminium salt etc. such as.
The preferred embodiment of the salt formed with organic bases, comprises the salt formed with Trimethylamine 99, triethylamine, pyridine, picoline, 2,6-lutidine, DIPEA, thanomin, diethanolamine, trolamine, hexahydroaniline, dicyclohexylamine etc.
As the preferred embodiment of the salt formed with mineral acid, comprise the salt formed with hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, sulphur hydracid, nitric acid, phosphoric acid, phosphorus hydracid etc.
As the preferred embodiment of the salt formed with organic acid, comprise the salt formed with acetate, propionic acid, vinylformic acid, propanedioic acid, butyric acid, oxalic acid, lactic acid, citric acid, acid citrate, tartrate, hydrogen tartrate, succsinic acid, toxilic acid, fumaric acid, styracin, vanillic acid, oxysuccinic acid, glucose saccharic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, phenylformic acid, tosic acid etc.
As the preferred embodiment of the salt formed with basic aminoacids, comprise the salt formed with Methionin, arginine, Histidine etc.
As the preferred embodiment of the salt formed with acidic amino acid, comprise the salt formed with aspartic acid, L-glutamic acid etc.
In above-mentioned salt, the acceptable salt of preferred pharmacology.
The present invention can be taken to following compounds:
。
Specific embodiment
Embodiment 1:[6-(the synthesis of { 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-7-base-phenyl-2,3-dihydrobenzopyrans-2-base }-2,3-dihydro-1-cumarones-3-guanidine-acetic acid (E1)
Experimentation:
The first step: (
e) synthesis of-2-(6-(3-(the bromo-2-hydroxy phenyl of 4-)-3-oxo propylene-1-base)-2,3-Dihydrobenzofuranes-3-bases) acetic acid (A1)
By bromo-for 4-2-hydroxy acetophenone (2.6g; 12mmol), 2-(6-formyl radical-2; 3-Dihydrobenzofuranes-3-base) methyl acetate (2.2g, 10mmol), barium hydroxide octahydrate (7.6g, 24mmol), anhydrous methanol 500mL be placed in 1L eggplant type bottle.Stir, be heated to backflow, reaction 24h.After reaction terminates, concentrated removing organic solvent, 6N hydrochloric acid soln is acidified to pH=1 ~ 2, separates out a large amount of solid.Filter, obtain 2.8g off-white color solid after filtration cakes torrefaction, yield: 69%.[M-H]
-: 402.2。
Second step: (
e) synthesis of-2-(6-(3-(the bromo-2-hydroxy phenyl of 4-)-3-oxo propylene-1-base)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate (A2)
Will (
e)-2-(6-(3-(the bromo-2-hydroxy phenyl of 4-)-3-oxo propylene-1-base)-2,3-Dihydrobenzofuranes-3-base) acetic acid (A1) (2.02g, 5mmol), vitriol oil 5d, anhydrous methanol 150mL adds in 250mL eggplant type bottle, be heated with stirring to backflow, TLC detects (methylene dichloride: methyl alcohol=20:1) extremely without raw material A 1.Concentrated removing methyl alcohol, saturated NaHCO
3alkalization is to pH=7 ~ 8.Ethyl acetate (100mL*3) extracts, and organic phase, after anhydrous sodium sulfate drying, concentrates to obtain off-white color solid 1.98g, yield: 95%.[M+2H]
+: 419.5。
The synthesis of the 3rd step: 2-(6-(7-bromo-4-oxo-benzo-γ-pyrans-2-base)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate (A3)
Will (
e)-2-(6-(3-(the bromo-2-hydroxy phenyl of 4-)-3-oxo propylene-1-base)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (A2) (1.66g, 4mmol), iodine (0.76g, 6mmol) add in 15mL DMSO, be heated with stirring to backflow, reaction 6h.After reaction terminates, reaction solution is cooled to room temperature, pours in frozen water, and ethyl acetate (100mL*3) extracts, and organic phase column chromatography for separation after anhydrous magnesium sulfate drying obtains solid 1.25g, productive rate 75%.[M+2H]
+: 417.3;
1H-NMR(300MHz，CDCl
3)；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)。
The synthesis of the 4th step: 2-(6-(7-bromine look alkane-2-base)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate (A4)
By 2-(6-(7-bromo-4-oxo-benzo-γ-pyrans-2-base)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (A3) (1.25g, 3mmol), platinum dioxide (0.34g, 1.5mmol) add in 50mL anhydrous tetrahydro furan, nitrogen atmosphere room temperature reaction 2h.Reacting liquid filtering, filtrate to be purified to obtain solid 0.72g through column chromatography, productive rate: 60%.
The synthesis of the 5th step: 2-(6-(7-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-base) look alkane-2-base)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate (A5)
By 2-(6-(7-bromine look alkane-2-base)-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 ethanoate (0.29g; 3mmol) be added in 15mL anhydrous dioxane; nitrogen protection, stirs and is warming up to 100 DEG C, reaction 2h.Reaction solution obtains compound A-45 0.20g through column chromatography, productive rate: 30%.[M+H]
+:451.3.
The 6th step: [6-(synthesis of { 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-7-base-phenyl-2,3-dihydrobenzopyrans-2-base }-2,3-dihydro-1-cumarones-3-acetic acid methyl ester (A6)
By [1; two (diphenylphosphine) ferrocene of 1'-] palladium chloride (0.07g; 0.1mmol); salt of wormwood (0.12g; 0.9mmol); 2-(6-(7-(4,4,5; 5-tetramethyl--1; 3,2-dioxaborolan-2-base) look alkane-2-base)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate (A5) (0.20g; 0.45mmol) add in 10mL anhydrous dioxane; nitrogen protection, stirs and is warming up to 100 DEG C, reaction 2h.Reaction solution obtains compound 0.20g through column chromatography, yield: 80%.[M+H]
+:566.1.
The 7th step: [6-(synthesis of { 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-7-base-phenyl-2,3-dihydrobenzopyrans-2-base }-2,3-dihydro-1-cumarones-3-guanidine-acetic acid (E1)
By [6-({ 2'; 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-7-base-phenyl-2; 3-dihydrobenzopyrans-2-base }-2; 3-dihydro-1-cumarone-3-acetic acid methyl ester (A6) (0.20g; 0.035mmol); methyl alcohol 1mL adds in 1N NaOH 5mL, stirring at room temperature 24h.6N hcl acidifying, to pH=1 ~ 2, filters, and obtains target compound E 0.17g, yield 90% after filter cake vacuum-drying.[M+H]
+: 551.7;
1H-NMR(300MHz，CDCl
3)；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 compound can be prepared.
Embodiment 2
[6-({ 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-6-base-phenyl-2,3-Dihydrobenzofuranes-2-base }-2,3-dihydro-1-cumarones-3-guanidine-acetic acid (E2).
Embodiment 3
[6-({ 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-7-base-phenyl-1,2,3,4-tetrahydric quinoline group-2-base }-2,3-dihydro-1-cumarones-3-guanidine-acetic acid (E3).
Embodiment 4
[6-({ 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-7-base-phenyl-2,3-indoline-2-base }-2,3-dihydro-1-cumarones-3-guanidine-acetic acid (E4).
Embodiment 5
[6-({ 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-7-base-phenyl-2,3-dihydrobenzo imidazoles-2-base }-2,3-dihydro-1-cumarones-3-guanidine-acetic acid (E5).
Embodiment 6:
[6-(the synthesis of { 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-5-base-phenyl-1,2,3,4-tetrahydric quinoline group-1-base } methyl-2,3-dihydro-1-cumarone-3-guanidine-acetic acid
Experimentation:
The first step: the 2-(synthesis of 6-((bromo-3,4-dihydroquinoline-1 (the 2H)-Ji of 5-) methyl)-2,3-dihydro-1-cumarones-3-acetic acid methyl ester (B2)
By bromo-for 5-1; 2; 3; 4-tetrahydroquinoline (2.12g, 10mmol), 2-(6-(brooethyl)-2,3-dihydro-1-cumarone-3-acetic acid methyl ester (2.86g; 10mmol), salt of wormwood (6.91g; 50mmol) be added in 200mL dry DMF, nitrogen protection, stir and be warming up to 80 DEG C of reaction 12h.After reaction terminates, reaction solution analyzes to obtain B2 2.91g through column chromatography, yield: 70%.
Second ~ four step: with reference to embodiment 1 the five ~ seven step.Obtain target compound [6-({ 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-5-base-phenyl-1,2,3,4-tetrahydric quinoline group-1-base } methyl-2,3-dihydro-1-cumarone-3-guanidine-acetic acid.[M+H]
+: 564.7;
1H-NMR(300MHz，CDCl
3)；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 compound can be prepared:
Embodiment 7
[6-({ 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-5-base-phenyl-benzo ring hexyl-1-base } oxygen base-2,3-dihydro-1-cumarone-3-guanidine-acetic acid
Embodiment 8
[6-({ 2', 6'-dimethyl-4'-[3-(methyl sulphonyl) propoxy-]-5-base-phenyl-benzocyclopentane base-1-base } oxygen base-2,3-dihydro-1-cumarone-3-guanidine-acetic acid
Embodiment 9 test case
The agonism of compound of the present invention to GPR40 is investigated with external CHO-K1/GPR40 cell.
In 96 orifice plates, inoculum density is the CHO-K1/GPR40 cell in 25000/hole.37 DEG C, 5%CO
2cultivate 24 hours.Discard cell culture fluid, cell damping fluid is washed once, in every hole, add 100 μ L Fluo-4 calcium ion dyestuffs, and hatch 30 minutes 37 DEG C of lucifuges, then continue to hatch 30 minutes in room temperature.During mensuration, first read every hole baseline value, in hole, then add different concns medicine (50 μ L/ hole), continue to read fluorescent value.Obtain every porocyte responsiveness=(maximum fluorescence value-minimum fluorescent value)/minimum fluorescent value, computerized compound EC
50value.Result is as follows:
Embodiment 10 pharmacodynamics detects
The ICR mouse fed with high lipid food, for animal subject, observes the administration of the compounds of this invention single single oral dose to the impact of glucose load Mouse oral glucose tolerance (OGTT).
The male mouse that high lipid food is fed, overnight fast 16 hours.Measuring basal plasma glucose value after weighing, is Blank group, the compounds of this invention group according to blood sugar height random packet.
Dosage be 20mg/kg, Blank group to 5%DMSO-physiological saline.Gastric infusion, administration gives the glucose solution (every mouse gives 0.4mL) of 20% after 15 minutes.Measure blood glucose value (-15 minutes).And 0,15,30,45,60 and 120 minute time, use Instrument for Measuring Blood Sugar to measure the blood glucose value of each mouse.
AUC calculation formula:
AUC=(t
15min+t
0min)×0.25/2+(t
30min+t
15min)×0.25/2+(t
45min+t
30min)×0.25/2+(t
60min+t
45min)×0.25/2+(t
120min+t
60min)×1/2
Wherein t0min, t15min, t30min, t45min, t60min, t120min are the blood glucose value that different time points records.
Test-results
Conclusion: the compounds of this invention qf oral administration dosage is have obvious hypoglycemic activity to mouse under 20mg/kg.
Claims (14)
1. the compound shown in following formula or its pharmacy acceptable salt, and optical isomer
。
2. compound or its salt as claimed in claim 1, and optical isomer, R
5r
8-SO
2-, the wherein R8 alkyl that is hydrogen or is optionally substituted, or the hydroxyl be optionally substituted, or the amino be optionally substituted, or the sulfydryl be optionally substituted; Z is key or bivalent hydrocarbon radical; R
3, R
4, R
6, R
7for identical or different, and separately independent be hydrogen atom, halogen atom, the alkyl that is optionally substituted, or the hydroxyl be optionally substituted, or the amino be optionally substituted, or the sulfydryl be optionally substituted; Ring C is 5 to 7 rings; Y is the alkyl of key or 1-6 carbon; R
1for the hydroxyl be optionally substituted; Ring A is 5 to 7 yuan of aromatic nucleus or aromatic heterocycle; Ring B is 5 to 7 rings; Ring A and ring B condenses arbitrary key that key can be aromatic nucleus A or aromatic heterocycle A; Wherein X is the atom such as key or oxygen, sulphur, nitrogen, carbon.
3. as claimed in claim 2, wherein ring B is saturated rings, is made up of to multiple N, O, S atom carbon atom or 1, or the above-mentioned ring be optionally substituted.
4. as claimed in claim 2, aromatic nucleus or aromatic heterocycle A optionally have following substituted radical: halogen atom, the alkyl be optionally substituted, the hydroxyl be optionally substituted, the sulfydryl be optionally substituted and the amino be optionally substituted; Aromatic heterocycle is for containing 1 to multiple N, O, S heteroatoms.
5. as claimed in claim 2: R
8for the alkyl of C1-C5.
6. as claimed in claim 2: R
3, R
4, R
6, R
7be hydrogen atom separately, or halogen atom, or the alkyl of C1-C3, or the alkoxyl group of C1-C3.
7. as claimed in claim 2: ring B for except with ring A condense and ring except, the substituting group contained is hydrogen, or halogen atom, or the alkyl of C1-C3.
8. with described in claim 2: the mode that condenses of ring A and ring B mainly condenses mode including but not limited to following two kinds
Or
Wherein X is the atom such as carbon or oxygen, sulphur, nitrogen.
9. as claimed in claim 8: ring B is five yuan or hexa-atomic saturated rings alkane, or saturated heterocyclic alkane, and contained heteroatoms is O, N, S etc.
10. compound or its salt as claimed in claim 8, and optical isomer, comprise but be not limited only to following compounds:
。
11. preparations comprising the compound or its salt described in claim 1-10.
12. comprise the purposes of compound or its salt in the medicine for the preparation of prevention or treatment diabetes described in claim 1-10.
13. as the pharmaceutical preparation of claim 11, and it is the medicine of prevention or treatment diabetes.
14. as the pharmaceutical preparation of claim 11, the application in the treatment diabetes B preparation medicine that preparation GPR40 target spot produces.
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| CN114163408A (en) * | 2020-09-10 | 2022-03-11 | 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110300755A (en) * | 2017-02-08 | 2019-10-01 | 勃林格殷格翰国际有限公司 | Indanyl amino azepine Dihydrobenzofuranes acetic acid, the pharmaceutical composition for treating diabetes |
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| CN114163408A (en) * | 2020-09-10 | 2022-03-11 | 上海爱博医药科技有限公司 | Benzo-oxygen-containing heterocyclic compound and medical application thereof |
| CN114163426A (en) * | 2020-09-10 | 2022-03-11 | 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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| 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 |
| CN114163426B (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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| CN105001212B (en) | 2018-01-16 |
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