CN101544578B - phenylacetic acid derivatives, process for their preparation and their use in medicaments - Google Patents
phenylacetic acid derivatives, process for their preparation and their use in medicaments Download PDFInfo
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- CN101544578B CN101544578B CN2009103010697A CN200910301069A CN101544578B CN 101544578 B CN101544578 B CN 101544578B CN 2009103010697 A CN2009103010697 A CN 2009103010697A CN 200910301069 A CN200910301069 A CN 200910301069A CN 101544578 B CN101544578 B CN 101544578B
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- Prior art keywords
- dichlorophenyl
- amino
- oxyethyl group
- methyl
- toluylic acid
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- 239000003814 drug Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000000034 method Methods 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- CRZQGDNQQAALAY-UHFFFAOYSA-N Me ester-Phenylacetic acid Natural products COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 claims description 67
- 239000002253 acid Substances 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract description 10
- 102000004877 Insulin Human genes 0.000 abstract description 6
- 108090001061 Insulin Proteins 0.000 abstract description 6
- 229940125396 insulin Drugs 0.000 abstract description 5
- 239000008280 blood Substances 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003472 antidiabetic agent Substances 0.000 abstract description 3
- 229940127003 anti-diabetic drug Drugs 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 230000001235 sensitizing effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 235000019445 benzyl alcohol Nutrition 0.000 description 11
- 229960004217 benzyl alcohol Drugs 0.000 description 11
- 238000006482 condensation reaction Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 9
- 230000001610 euglycemic effect Effects 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 4
- 210000001789 adipocyte Anatomy 0.000 description 4
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 2
- MOOUWXDQAUXZRG-UHFFFAOYSA-N 4-(trifluoromethyl)benzyl alcohol Chemical compound OCC1=CC=C(C(F)(F)F)C=C1 MOOUWXDQAUXZRG-UHFFFAOYSA-N 0.000 description 2
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- 229940123464 Thiazolidinedione Drugs 0.000 description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 150000004283 biguanides Chemical class 0.000 description 2
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- 201000010099 disease Diseases 0.000 description 2
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
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- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
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- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000001467 thiazolidinediones Chemical class 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- HCEQQASHRRPQFE-UHFFFAOYSA-N 5-chloro-n-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxybenzamide;3-(diaminomethylidene)-1,1-dimethylguanidine;hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N.COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 HCEQQASHRRPQFE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 208000002177 Cataract Diseases 0.000 description 1
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- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
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- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
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- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a phenylacetic acid derivative with a general formula , a preparation method thereof and application thereof in medicines. The compound of the invention has insulin sensitizing activity, so the compound can be used for preparing antidiabetic drugs, reducing the blood sugar concentration of diabetes patients and inhibiting the generation of complications of the diabetes patients. The general formula is as follows:
Description
Technical field
The present invention relates to phenylacetic acid derivatives, its preparation method with and application in medicine, specifically be the application in the anti-diabetes B medicine of preparation.
Background technology
(Diabetesmellitus is the chronic secretion metabolic trouble of a kind of general that is associated with inherited genetic factors DM) to mellitus, is that the absolute or relative deficiency owing to insulin secretion in the body causes sugar, fat, proteinic metabolism disorder.Its principal feature is hyperglycemia and glucose in urine, clinically often with atherosclerotic cardiovascular and cerebrovascular diseases, diabetic nephropathy, nervous system lesion and eye pathology such as multiple complications such as cataract, retinopathy.In the whole world, it is 3,000 ten thousand that the number of mellitus is suffered from diagnosis in 1985 according to the World Health Organization (WTO) statistics, and nineteen ninety-five rises to 1.35 hundred million.The WHO prediction will have 300,000,000 people to suffer from this disease in 2025, and China diabetic subject has surpassed 3,000 ten thousand people, will reach 6,000 ten thousand people by 2010.Along with people's growth in the living standard, mellitus have become the 3rd fatal disease that is only second to cardiovascular diseases, cancer.Mellitus and complication thereof just China's people health and life security in serious harm.
Traditional anti-2 diabetes medicaments mainly contain sulfonylurea, biguanides, alpha-glucosidase inhibitor etc.But shortcomings such as there is weak curative effect in these medicines, and spinoff is big.Such as, sulfonylureas can cause hypoglycemic reaction; Biguanides can cause lacticemia; And alpha-glucosidase inhibitor equally also can cause gastrointestinal side effect.
Research shows that insulin resistant is to cause fat and a key factor of diabetes B.So after the nineties, world's Glucovance research and development emphasis has been transferred to and has been solved on the insulin resistant aspect.Euglycemic agent can improve the susceptibility of insulin action in the human body, thereby plays the effect that reduces diabetes B patient blood sugar.Euglycemic agent can also effectively stop or the generation of delaying complications of diabetes.First thiazolidinediones euglycemic agent of drugs approved by FDA troglitazone listing in 1997; U.S. FDA in 1999 ratify again to have gone on the market two other thiazolidinediones euglycemic agent rosiglitazone (rosiglitazone), U-721017E (pioglitazone); They all can effectively reduce insulin resistant; Control patient's blood sugar, and can resist and delay the generation of complication preferably.But several glitazone euglycemic agents of listing all can cause hepatotoxicity in various degree, and the glitazone euglycemic agent that has also can make patient's weight increase.Research thinks that the reason that causes hepatotoxicity possibly be the U 25560 group in the molecule, and weight increase maybe be relevant with the inhibition steatolysis with such compound promoted glyconeogenesis.For seeking the euglycemic agent that a new generation is efficient, toxic side effect is low, the novel insulin sensitizer of no U 25560 group becomes the important directions of antidiabetic medicine research.
Summary of the invention
Technical problem to be solved by this invention provides a kind of phenylacetic acid derivatives with insulin-sensitizing activity, and the preparation method and the application of this compounds in the anti-diabetes B medicine of preparation of this analog derivative are provided.
In order to address the above problem, the invention provides following compound and preparation method thereof and application:
Formula (I) compound:
Wherein, n=1～2; Substituent R
1-(CH
2)
n-O-is positioned at 4 or 5 of place phenyl ring; R
2Represent hydrogen or methyl; R
1Represent one of following groups:
Wherein said representation compound, as follows:
(1) 2-(2, the 6-dichlorophenyl is amino)-4-benzyloxy methyl phenylacetate;
(2) 2-(2, the 6-dichlorophenyl is amino)-4-benzyloxy toluylic acid;
(3) 2-(2, the 6-dichlorophenyl is amino)-4-(4-trifluoromethyl benzyloxy) methyl phenylacetate;
(4) 2-(2, the 6-dichlorophenyl is amino)-4-(4-trifluoromethyl benzyloxy) toluylic acid;
(5) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(2,4, the 5-trifluorophenyl) oxyethyl group] methyl phenylacetate;
(6) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-methyl-2-phenyl-4-oxazolyl) oxyethyl group] methyl phenylacetate;
(7) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] toluylic acid;
(8) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(1-indoles) oxyethyl group] methyl phenylacetate;
(9) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl phenylacetate;
(10) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-ethyl-2-pyridine) oxyethyl group] toluylic acid;
(11) 2-(2, the 6-dichlorophenyl is amino)-5-benzyloxy methyl phenylacetate;
(12) 2-(2, the 6-dichlorophenyl is amino)-5-benzyloxy toluylic acid;
(13) 2-(2, the 6-dichlorophenyl is amino)-5-(4-trifluoromethyl benzyloxy) methyl phenylacetate;
(14) 2-(2, the 6-dichlorophenyl is amino)-5-(4-trifluoromethyl benzyloxy) toluylic acid;
(15) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(2,4, the 5-trifluorophenyl) oxyethyl group] methyl phenylacetate;
(16) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-methyl-2-phenyl-4-oxazolyl) oxyethyl group] methyl phenylacetate;
(17) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-methyl-2-phenyl-4-oxazolyl) oxyethyl group] toluylic acid;
(18) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(1-indoles) oxyethyl group] methyl phenylacetate;
(19) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl phenylacetate;
(20) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-ethyl-2-pyridine) oxyethyl group] toluylic acid.
The structural formula such as the table 1 of above compound.
Table 1
The preparation method of wherein above-mentioned general formula (I) compound, concrete steps are following:
(1) be starting raw material with 4-hydroxyl-2-(2, the 6-dichlorophenyl is amino) toluylic acid or with 5-hydroxyl-2-(2, the 6-dichlorophenyl is amino) toluylic acid, methyl alcohol is solvent, and tosic acid is that catalyst reaction generates key intermediate (II)
Hydroxyl is positioned at 4 or 5 that belong to phenyl ring in the midbody (II).
(2) midbody (II) and corresponding pure R
1-(CH
2)
n-OH is through directly obtaining or after hydrolysis, obtain compound shown in (I) after the condensation reaction.
Do not contain the U 25560 group, therefore can avoid the relevant untoward reaction of this compounds recurring structure to greatest extent, for the higher anti-diabetic insulin sensitivity enhancing agent medicine of exploitation security has been established certain basic substance.
Embodiment
Embodiment 1:2-(2, the 6-dichlorophenyl is amino)-4-benzyloxy methyl phenylacetate (compound 1)
(1) 4-hydroxyl-2-(2, the 6-dichlorophenyl is amino) toluylic acid 1.0g (3.2mmol) is dissolved in the 30ml methyl alcohol, adds tosic acid 50mg; Reflux 3h; After TLC (thin-layer chromatography chromatogram) detection reaction was complete, the pressure reducing and steaming solvent added ETHYLE ACETATE 30ml dissolved residue; The 30ml washing is once used the saturated NaHCO of 30ml then successively
3Solution and 30ml saturated aqueous common salt are respectively washed once, through anhydrous Na
2SO
4Dry back decompression and solvent recovery is an eluent with petroleum ether-ethyl acetate (volume ratio 5: 1), and silica gel column chromatography obtains light yellow solid 0.68g, yield 65%.
1HNMR(CDCl
3)：δ＝3.73(s，2H)，3.78(s，3H)，4.69(br，1H)，5.99(d，J＝2.4Hz，2H)，6.39-6.42(dd，J＝2.8Hz，2.4Hz，1H)，6.92(s，1H)，7.02(t，1H)，7.06(d，1H)，7.33-7.36(d，2H)。
(2) above-mentioned midbody 0.4g (1.23mmol) is dissolved among the anhydrous diethyl ether 30ml, adds phenylcarbinol 0.2g (1.85mmol), triphenylphosphine 0.48g (1.85mmol); Under condition of ice bath, be added dropwise to azodicarboxy dimethyl phthalate 0.4ml (1.85mmol) then, stirring at room reaction 24h, stopped reaction; After boiling off ether; Residue is an eluent with petroleum ether-ethyl acetate (volume ratio 3: 1), and it is compound 10.36g that silica gel column chromatography obtains white solid, yield 57.6%.
1HNMR(CDCl
3)：δ＝3.74(s，2H)，3.77(s，3H)，4.92(s，2H)，6.14(s，1H)，6.43(d，J＝8.0Hz，1H)，6.56(d，J＝8.0Hz，1H)，6.92(s，1H)，6.99(t，1H)，7.12(d，J＝8.4Hz，1H)，7.32(s，7H)。
Embodiment 2:2-(2, the 6-dichlorophenyl is amino)-4-benzyloxy toluylic acid (compound 2)
Compound 10.2g (0.39mmol), absolute ethyl alcohol 2ml, 1mmol/LNaOH 2ml, behind the stirring at room 6h, pressure reducing and steaming ethanol, after the dilution of adding less water, 1mmol/L hydrochloric acid is transferred pH to 5, uses 5ml ethyl acetate extraction twice then, and organic layer is through anhydrous Na
2SO
4Dry back evaporate to dryness, petroleum ether-ethyl acetate-methyl alcohol (volume ratio 20: 20: 3) is eluent, it is compound 2 that silica gel column chromatography obtains white solid, yield 56%.
1HNMR(DMSO-d6)：δ＝3.59(s，2H)，4.91(s，2H)，5.78(t，1H)，6.49-6.52(dd，J＝2.4Hz，J＝4.4Hz，1H)，7.09(d，J＝7.2Hz，1H)，7.18-7.24(m，1H)，7.27-7.31(m，4H)，7.51(d，J＝8.0Hz，7H)。
Embodiment 3:2-(2, the 6-dichlorophenyl is amino)-4-(4-trifluoromethyl benzyloxy) methyl phenylacetate
Be similar among the embodiment 1 method in (2) step, and replace phenylcarbinol to carry out condensation reaction with the 4-trifluoromethyl benzyl alcohol obtaining title compound, yield 69%.
1H?NMR(CDCl
3)：δ＝3.73(s，2H)，3.74(s，3H)，4.98(s，2H)，6.08(d，J＝2.4Hz，1H)，6.53-6.56(dd，J＝2.0Hz，2.8Hz，1H)，6.94(br，1H)，7.00(t，1H)，7.12(d，J＝8.4Hz，1H)，7.32(s，1H)，7.33(s，1H)，7.43(d，J＝8.0Hz，2H)，7.57(d，J＝8.4Hz，2H)。
Embodiment 4:2-(2, the 6-dichlorophenyl is amino)-4-(4-trifluoromethyl benzyloxy) toluylic acid
Being similar to the method for embodiment 2, is that raw water is separated and obtained title compound, yield 52.3% with compound 3.
1HNMR(DMSO-d
6)：δ＝3.59(s，2H)，5.04(s，2H)，5.76(t，2H)，6.49-6.53(dd，J＝2.4Hz，2.4Hz，1H)，7.10(d，J＝8.4Hz，1H)，7.21(t，1H)，7.48-7.52(t，4H)，7.67(d，J＝8.0Hz，2H)。
Embodiment 5:2-(2, the 6-dichlorophenyl is amino)-4-[2-(2,4, the 5-trifluorophenyl) oxyethyl group) methyl phenylacetate
Be similar among the embodiment 1 method in (2) step, and replace phenylcarbinol to carry out condensation reaction with 2-(2,4, the 5-trifluorophenyl) ethanol obtaining title compound, yield 62.5%.
1H?NMR(CDCl
3)：δ＝2.97(t，J＝13.2Hz，2H)，3.73(s，2H)，3.74(s，3H)，4.02(t，J＝13.6Hz，2H)，6.05(d，J＝2.4Hz，1H)，6.46-6.49(dd，J＝2.0Hz，2.8Hz，1H)，6.84-6.90(m，1H)，6.95(m，1H)，6.99-7.03(m，2H)，7.08-7.12(d，1H)，7.35-7.37(d，2H).
Embodiment 6:2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] methyl phenylacetate (compound 6)
Be similar among the embodiment 1 method in (2) step, and replace phenylcarbinol to carry out condensation reaction with 2-(5-methyl-2-phenyl-4-oxazole) ethanol obtaining title compound, yield 70%.
1H?NMR(CDCl
3)：δ＝2.30(s，3H)，2.89(s，J＝13.6Hz，2H)，3.72(s，2H)，3.73(s，3H)，4.11(t，J＝13.6Hz，2H)，6.07(d，J＝2.0Hz，1H)，6.49-6.51(dd，J＝2.4Hz，2.0Hz，1H)，6.93(s，1H)，6.99(m，1H)，7.10(d，J＝8.4Hz，1H)，7.34(d，J＝8.4Hz，2H)，7.42(d，3H)，7.96(d，J＝8.0Hz，2H)，.
Embodiment 7:2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] toluylic acid
Being similar to embodiment 2, is that raw water is separated and obtained title compound, yield 76.5% with compound 6.
1HNMR(DMSO-d6)：δ＝2.30(s，3H)，2.93(s，J＝13.6Hz，2H)，3.59(s，2H)，4.00(t，J＝13.4Hz，2H)，6.10(d，J＝2.0Hz，1H)，6.49-6.51(dd，J＝2.4Hz，2.0Hz，1H)，6.93(s，1H)，6.99(m，1H)，7.18(d，J＝8.4Hz，1H)，7.35(d，J＝8.4Hz，2H)，7.52(d，3H)，7.96(d，J＝8.4Hz，2H).
Embodiment 8:2-(2, the 6-dichlorophenyl is amino)-4-[2-(1-indoles) oxyethyl group] methyl phenylacetate
Be similar among the embodiment 1 method in (2) step, and replace phenylcarbinol to carry out Mi Qu with 2-(1-indoles) ethanol spreading out condensation reaction and obtain title compound, yield 33.4%.
1H?NMR(CDCl
3)：δ＝3.72(s，2H)，3.73(s，3H)，4.14(t，2H)，4.42(t，J＝12Hz，2H)，6.05(d，J＝2.4Hz，1H)，6.42-6.48(m，1H)，6.95(s，1H)，7.00(m，1H)，7.07-7.013(m，2H)，7.18(m，1H)，7.30(s，1H)，7.33(s，1H)，7.36(s，1H)，7.62(d，J18.0Hz，2H)，.
Embodiment 9:2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl phenylacetate
Be similar among the embodiment 1 method in (2) step, and replace phenylcarbinol to carry out condensation reaction with 2-(5-ethyl-2-pyridine) ethanol obtaining title compound, yield 61.1%.
1H?NMR(CDCl
3)：δ＝1.24(t，3H)，2.62(q，2H)，3.18(t，J＝12.8Hz，2H)，3.72(s，2H)，3.73(s，3H)，4.22(t，J＝13.6Hz，2H)，6.08(d，J＝2.4Hz，1H)6.50(dd，2.4Hz，1H)，6.92(s，1H)，6.99(t，1H)，7.09-7.16(m，2H)，7.34(d，J＝8.0Hz，2H)，7.45(d，J＝7.6Hz，1H)，8.36(s，1H).
Embodiment 10:2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-ethyl-2-pyridine) oxyethyl group] toluylic acid
Being similar to embodiment 2, is that raw water is separated and obtained title compound, yield 85.6% with compound 9.
1H?NMR(CDCl
3)：δ＝1.18(t，3H)，2.58(q，2H)，3.03(t，J＝12.8Hz，2H)，3.61(s，2H)，4.16(t，J＝13.6Hz，2H)，5.72(d，J＝2.4Hz，1H)，6.45(dd，J＝2.0Hz，2.4Hz，1H)，6.42-6.48(m，1H)，7.08(d，J＝8.4Hz，1H)，7.16-7.26(m，2H)，7.51-7.54(m，3H)，8.32(s，1H).
Embodiment 11:2-(2, the 6-dichlorophenyl is amino)-5-benzyloxy methyl phenylacetate
Be similar to the method for embodiment 1, and replace 4-hydroxyl-2-(2, the 6-dichlorophenyl amino) toluylic acid of embodiment 1 in (1) step with 5-hydroxyl-2-(2, the 6-dichlorophenyl is amino) toluylic acid, prepare title compound, promptly compound 11, total recovery 35.2%.
1H?NMR(CDCl
3)：δ＝3.75(s，3H)，3.81(s，2H)，5.00(s，2H)，6.54(s，J＝8.8Hz，1H)，6.62(s，1H)，6.75-6.79(dd，J＝2.8Hz，8.8Hz，1H)，6.90(d，J＝2.8Hz，1H)，6.92(d，1H)，7.30(s，1H)，7.33(s，1H)，7.36(m，1H)，7.39-7.43(m，4H)。
Embodiment 12:2-(2, the 6-dichlorophenyl is amino)-5-benzyloxy toluylic acid
Being similar to embodiment 2, is that raw water is separated and obtained title compound, yield 68.5%. with compound 11
1HNMR (DMSO-d6): δ=3.68 (s, 2H), 5.00 (s, 2H), 6.32 (d, J=8.4Hz, 1H), 6.76 (dd; J=2.4Hz, J=8.8Hz, 1H), 6.89 (s, 1H), 6.95 (d, J=2.8Hz; 1H), 7.09 (t, 1H), 7.29-7.47 (m, 7H), 12.71 (br, 1H).
Embodiment 13:2-(2, the 6-dichlorophenyl is amino)-5-(4-trifluoromethyl benzyloxy) methyl phenylacetate
Be similar to the method for embodiment 1; And with 5-hydroxyl-2-(2; 6-dichlorophenyl amino) toluylic acid replaces the embodiment 1 4-hydroxyl-2-(2 in (1) step; The 6-dichlorophenyl is amino) toluylic acid, the phenylcarbinol in (2) step of 4-trifluoromethyl benzyl alcohol replacement embodiment 1 carries out condensation reaction and obtains title compound, yield 72.5%.
1HNMR(CDCl
3)：δ＝3.75(s，3H)，3.81(s，2H)，5.07(s，2H)，6.55(d，J＝8.8Hz，1H)，6.64(d，1H)，6.75(dd，J＝2.8Hz，J＝8.4Hz，1H)，6.90(d，J＝3.2Hz，1H)，6.94(t，J＝16.0Hz，1H)，7.31(s，1H)，7.33(s，1H)，7.54(dJ＝8.0Hz，2H)，7.64(d.J?8.0Hz，2H)。
Embodiment 14:2-(2, the 6-dichlorophenyl is amino)-5-(4-trifluoromethyl) benzyloxy toluylic acid
Being similar to embodiment 2, is that raw water is separated and obtained title compound, yield 68.3% with compound 13
1HNMR (DMSO-d6): δ=3.71 (s, 2H), 5.15 (s, 2H), 6.33 (d, J=8.8Hz, 1H), 6.78 (dd; J=2.8Hz, J=8.8Hz, 1H), 6.92 (s, 1H), 6.98 (d, J=2.8Hz, 1H); 7.11 (t, J=16.0Hz, 1H), 7.47 (s, 1H), 7.49 (s, 1H), 7.66 (d; J=8.0Hz, 2H), 7.76 (d, J=8.4Hz, 2H), 12.75 (br, 1H).
Embodiment 15:2-(2, the 6-dichlorophenyl is amino)-5-[2-(2,4, the 5-trifluorophenyl) oxyethyl group] methyl phenylacetate
Be similar to the method for embodiment 1; And with 4-hydroxyl-2-(2, the 6-dichlorophenyl amino) toluylic acid of 5-hydroxyl-2-(2, the 6-dichlorophenyl is amino) toluylic acid replacement embodiment 1 in (1) step; 2-(2; 4,5-trifluorophenyl) ethanol replaces the phenylcarbinol of embodiment 1 in (2) step to carry out condensation reaction obtaining title compound, yield 65.5%.
1H?NMR(CDCl
3)：δ＝3.04(t，J＝13.6Hz，2H)，3.75-3.80(m，5H)，4.09-4.13(m，2H)，5.30(s，1H)，6.54(t，J＝8.8Hz，1H)，6.65-6.68(dd，J＝2.8Hz，8.4Hz，2H)，6.78-6.81(dd，J＝2.8Hz，8.0Hz，1H)，6.87-6.97(m，2H)，7.11-7.17(m，1H)，7.30-7.33(m，2H).
Embodiment 16:2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] methyl phenylacetate
Be similar to the method for embodiment 1; And with 5-hydroxyl-2-(2; 6-dichlorophenyl amino) toluylic acid replaces the 4-hydroxyl-2-(2 of embodiment 1 in (1) step; The 6-dichlorophenyl is amino) toluylic acid, the phenylcarbinol in (2) step of 2-(5-methyl-2-phenyl-4-oxazole) ethanol replacement embodiment 1 carries out condensation reaction and obtains title compound, yield 62%.
1H?NMR(CDCl
3)：δ＝2.37(s，3H)，2.96(t，J＝13.2Hz，2H)，3.75(s，3H)，3.78(s，3H)，4.20(t，J＝13.2Hz，2H)，6.53(s，1H)，6.60(s，1H)，6.68(dd，J＝3.2Hz，8.8Hz，1H)，6.81(d，J＝2.8Hz，1H)，6.91(t，J＝16.0Hz，1H)，7.30(d，J＝8.0Hz，2H)，7.40-7.45(m，2H)，7.97-8.00(m，2H)。
Embodiment 17:2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] toluylic acid
With compound 16 is raw material, is similar to embodiment 2 and obtains title compound, yield 43%.
1H?NMR(DMSO-d6)：δ＝2.36(s，3H)，2.90(t，J＝13.2Hz，2H)，3.68(s，2H)，4.15(t，J＝12.8Hz，2H)，6.32(d，J＝8.8Hz，1H)，6.70(dd，J＝2.8Hz，8.8Hz，1H)，6.88(d，J＝13.2Hz，1H)，7.06-7.10(m，1H)，7.46-7.51(m，6H)，7.92(m，2H)，12.85(br，1H).
Embodiment 18:2-(2, the 6-dichlorophenyl is amino)-5-[2-(1-indoles) oxyethyl group] methyl phenylacetate
Be similar to the method for embodiment 1; And with 5-hydroxyl-2-(2; 6-dichlorophenyl amino) toluylic acid replaces the 4-hydroxyl-2-(2 of embodiment 1 in (1) step; The 6-dichlorophenyl is amino) toluylic acid, the phenylcarbinol in (2) step of 2-(1-indoles) ethanol replacement embodiment 1 carries out condensation reaction and obtains title compound, yield 36.5%.
1H?NMR(CDCl
3)：δ＝3.73(s，3H)，3.75(s，2H)，4.23(t，J＝11.2Hz，2H)，4.49(t，J＝11.2Hz，2H)，6.48-6.51(m，2H)，6.63(m，2H)，6.73(d，J＝2.8Hz，1H)，6.92(t，J＝16.4Hz，1H)，7.11-7.13(m，1H)，7.21-7.23(m，2H)，7.29(s，1H)，7.31(s，1H)，7.38-7.40(m，1H)，7.63(d，J＝8.0Hz，1H)
Embodiment 19:2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl phenylacetate
Be similar to the method for embodiment 1; And with 5-hydroxyl-2-(2; 6-dichlorophenyl amino) toluylic acid replaces the 4-hydroxyl-2-(2 of embodiment 1 in (1) step; The 6-dichlorophenyl is amino) toluylic acid, the phenylcarbinol in (2) step of 2-(5-ethyl-2-pyridine) ethanol replacement embodiment 1 carries out condensation reaction and obtains title compound, yield 64%.
1HNMR(CDCl
3)：δ＝1.26(t，3H)，2.63(q，2H)，3.22(t，J＝13.2Hz，2H)，3.74(s，3H)，3.78(s，2H)，4.21(t，J＝13.2Hz，2H)，6.51(d，J＝8.8Hz，1H)，6.60(s，1H)，6.69(dd，J＝3.2Hz，8.8Hz1H)，6.81(d，J＝2.8Hz1H)，6.92(t，J＝16.0Hz，1H)，7.20(d，J＝7.6Hz1H)，7.27-7.31(m，2H)，7.46(dd，J＝2.4Hz，8.0Hz，1H)，8.39(d，J＝10.0Hz1H).
Embodiment 20:2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-ethyl-2-pyridine) oxyethyl group] toluylic acid
Being similar to embodiment 2, is that raw water is separated and obtained title compound, yield 69.1% with compound 19.
1HNMR(CDCl
3)：δ＝1.20(t，3H)，2.63(q，2H)，2.98(t，J＝12.4Hz，2H)，3.61(s，2H)，4.26(t，J＝13.6Hz，2H)，5.73(d，J＝2.4Hz，1H)，6.45(dd，J＝2.0Hz，2.4Hz，1H)，6.42-6.48(m，1H)，7.18(d，J＝8.4Hz，1H)，7.24(m，2H)，7.51-7.54(m，H)，8.54(s，1H).
Test Example: biological activity determination
Adipocyte broke up to adipocyte before euglycemic agent can impel, and the differentiation situation of former adipocyte is an index, can specificly filter out euglycemic agent.Adipocyte is model before using 3T3-L1, with the index of triglyceride level growing amount in the cell as the reacting cells differentiation, can estimate the insulin-sensitizing activity of compound.
The 3T3-L1 cell inoculation in 96 orifice plates, is treated that cytogamy changes the high glycoform DMEM nutrient solution that contains 10%FBS (NBCS), 5 μ g/ml Regular Insulin, 1 μ mol/LDEX (dexamethasone) and 0.5mmol/L IBMX (isobutylmethylxanthine) (Dulbecco ' smodifiedEagle ' s medium) and the dosing of dividing into groups simultaneously after 2 days.Receive reagent and positive drug rosiglitazone all to establish 10
-9M, 10
-6Two concentration of M are established DMSO (DMSO 99.8MIN.) control group simultaneously.Change the DMEM nutrient solution that contains 10%FBS, 5 μ g/ml INS after 2 days and, change the DMEM nutrient solution and the dosing that only contain 10%FBS later on every other day with the method dosing.Break up the 8th day with content of triglyceride in the oil red O stain method mensuration cell.Key step be cell with 10% formaldehyde fixed 1h, use 0.2% oil red O solution-dyed 2h then, the unnecessary oil red O of distilled water flush away dyestuff, oil red O in the Virahol dissolved cell surveys 510nm OD value.Same experiment repetition 3～4 times.The increasing amount of the triglyceride level of each compound under different concns is seen table 2.
Increase percentage (x ± s, the n=3 or 4 of the interior lipid content of 3T3-L1 cell after the table 2. different concns compound effects
Can be known that by table 2 compound 2,7,3,14,17 and 20 etc. has stronger insulin-sensitizing activity, other compound also obviously increases content of triglyceride in the cell, has certain insulin-sensitizing effect.Therefore the formation that toluylic acid compounds involved in the present invention and salt thereof can be used for controlling the diabetes B blood glucose level in patients and suppresses complication is so these compounds might become novel treatment diabetes B medicine through development.
The above; It only is preferred embodiment of the present invention; Be not that the present invention is done any pro forma restriction; Anyly do not break away from technical scheme content of the present invention, to any simple modification, equivalent variations and modification that above embodiment did, all still belong in the scope of technical scheme of the present invention according to technical spirit of the present invention.
Claims (3)
1. formula (I) compound:
Wherein, n=1～2; Substituent R
1-(CH
2)
n-O-is positioned at 4 or 5 of place phenyl ring; R
2Represent hydrogen or methyl; R
1Represent one of following groups:
2. compound according to claim 1, as follows:
(1) 2-(2, the 6-dichlorophenyl is amino)-4-benzyloxy methyl phenylacetate;
(2) 2-(2, the 6-dichlorophenyl is amino)-4-benzyloxy toluylic acid;
(3) 2-(2, the 6-dichlorophenyl is amino)-4-(4-trifluoromethyl benzyloxy) methyl phenylacetate;
(4) 2-(2, the 6-dichlorophenyl is amino)-4-(4-trifluoromethyl benzyloxy) toluylic acid;
(5) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(2,4, the 5-trifluorophenyl) oxyethyl group] methyl phenylacetate;
(6) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-methyl-2-phenyl-4-oxazolyl) oxyethyl group] methyl phenylacetate;
(7) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] toluylic acid;
(8) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(1-indoles) oxyethyl group] methyl phenylacetate;
(9) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl phenylacetate;
(10) 2-(2, the 6-dichlorophenyl is amino)-4-[2-(5-ethyl-2-pyridine) oxyethyl group] toluylic acid;
(11) 2-(2, the 6-dichlorophenyl is amino)-5-benzyloxy methyl phenylacetate;
(12) 2-(2, the 6-dichlorophenyl is amino)-5-benzyloxy toluylic acid;
(13) 2-(2, the 6-dichlorophenyl is amino)-5-(4-trifluoromethyl benzyloxy) methyl phenylacetate;
(14) 2-(2, the 6-dichlorophenyl is amino)-5-(4-trifluoromethyl benzyloxy) toluylic acid;
(15) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(2,4, the 5-trifluorophenyl) oxyethyl group] methyl phenylacetate;
(16) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-methyl-2-phenyl-4-oxazolyl) oxyethyl group] methyl phenylacetate;
(17) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-methyl-2-phenyl-4-oxazolyl) oxyethyl group] toluylic acid;
(18) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(1-indoles) oxyethyl group] methyl phenylacetate;
(19) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl phenylacetate;
(20) 2-(2, the 6-dichlorophenyl is amino)-5-[2-(5-ethyl-2-pyridine) oxyethyl group] toluylic acid.
3. like the application of described each compound of claim 1～2 in the anti-diabetes B medicine of preparation.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1069022A (en) * | 1991-05-28 | 1993-02-17 | 帝国化学工业公司 | 4-[2-(2-hydroxyl-2-benzene ethylamino) oxyethyl group that is used for the treatment of obesity and correlation behavior] phenylacetic acid derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1069022A (en) * | 1991-05-28 | 1993-02-17 | 帝国化学工业公司 | 4-[2-(2-hydroxyl-2-benzene ethylamino) oxyethyl group that is used for the treatment of obesity and correlation behavior] phenylacetic acid derivatives |
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