CN101812058A - Indometacin 2-arylmorpholine ethyl, preparation method and application thereof - Google Patents
Indometacin 2-arylmorpholine ethyl, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses indometacin 2-arylmorpholine ethyl or a salt thereof has a structural formula in the specification. The preparation method for the indometacin 2-arylmorpholine ethyl (I) comprises the following steps: dissolving indometacin chloride into tetrahydrofuran to obtain solution; adding the solution of 4-hydroxyethyl-2-arylmorpholine tetrahydrofuran into the solution dropwise with stirring; and after finishing reaction, distilling for recovering the tetrahydrofuran so as to obtain the indometacin 2-arylmorpholine ethyl. The preparation method for the salt of the indometacin 2-arylmorpholine ethyl comprises the following steps: dissolving the indometacin 2-arylmorpholine ethyl into absolute ethyl ether or ethanol; and introducing dry HCl gas or performing a reaction with acid (HY) to obtain the salt of the indometacin 2-arylmorpholine ethyl (II). The indometacin 2-arylmorpholine ethyl or the salt thereof is applied to preparing anti-inflammatory analgesics.
Description
Technical field
The present invention relates to new compound of a class and its production and application, specifically is Indometacin 2-arylmorpholine ethyl or its salt and its production and application.
Background technology
Traditional non-steroid antiinflammatory drug (non-steroidal anti-inflammatory drugs, NSAIDs) COX-1 and COX-2 there is restraining effect, effective therapeutic action of NSAIDs comes from its inhibition to COX-2, and untoward reaction belongs to the inhibition to COX-1.The whole world has 3,000 ten thousand to 4,000 ten thousand patient taking NSAIDs the every day, and annual untoward reaction that is caused by this class medicine or complication be up to 200,000 examples, wherein case fatality rate＞20%.The untoward reaction of NSAIDs appears clinically.
Traditional non-steroid antiinflammatory drug suppresses cyclooxygenase-1 (COX-1) and COX-2 simultaneously, and gastrointestinal side effect is arranged.By comparison, the COX-2 selective depressant keeps anti-inflammatory and analgesia effect, but avoids or reduced GI toxic side effect.The difference of COX-2 and COX-1 structure is the basis of design COX-2 selective depressant, the volume ratio COX-1 in COX-2 catalytic activity chamber is big by about 25%, and have the unexistent side of a COX-1 pocket, this mainly is because the difference of a key amino acid residue causes.Yang Cuifen etc. have described with compounds such as indomethacin and halohydrocarbon, nitrobenzyl alcohol, nitrobenzyl chlorides and have carried out condensation and nitric acid esterification, prepare 4 kinds of indomethacin derivatives.Its antiphlogistic activity apparently higher than indomethacin (Chinese Journal of New Drugs, 2004,13:818-820).Can improve the selectivity that COX-2 is suppressed by traditional non-steroid antiinflammatory drug being carried out structure of modification, design and to be replaced by the compound (A, Bioorg.Med.Chem.Lett.2001,11,1325) of substituted thiazolyl to the indomethacin carboxyl.Structural modification be the anti-ester of indomethacin (B, Bioorg.Med.Chem.2005,13:6810-6822) and the indomethacin phenethyl ester (C, Journal of Medicinal Chemistry, 2000,43:2860-2870).The Preliminary pharmacological test result of this analog derivative shows that compound is kept the restraining effect of COX-2 after transforming, and the restraining effect of COX-1 is disappeared, and has strengthened the selectivity that COX-2 is suppressed.
The structure activity relationship that the present invention is based on non-steroid antiinflammatory drug is carried out structural modification to its carboxyl, introduces morpholinyl in indomethacin phenethyl ester (C) structure, and indomethacin is designed to Indometacin 2-arylmorpholine ethyl (I).Expectation Compound I and II and phenylbenzene substituted pyrazolecarboxylic ring (three rings) class celecoxib (Celecoxib) has similar biological activity.
Summary of the invention
The object of the present invention is to provide Indometacin 2-arylmorpholine ethyl or its salt.It is characterized in that it has following chemical structural formula:
Wherein, R is selected from: hydrogen, C
1～C
4Alkyl; Ar is selected from: phenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 3,4-dichlorophenyl, 3,5-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 6-dichlorophenyl, 2,4-two chloro-5-fluorophenyls, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 3,5-two (trifluoromethyl) phenyl, the 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, the 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, the 2-ethoxyl phenenyl, 3-ethoxyl phenenyl, 4-ethoxyl phenenyl, the 3-isopropyl phenyl, 4-isopropyl phenyl, 3-isopentyloxy phenyl, 4-isopentyloxy phenyl, 3-benzyloxy phenyl, 4-benzyloxy phenyl, 4-methanesulfonamido phenyl, 4-sulfamoyl phenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 6-methoxyl group-2-naphthyl, 6-methoxyl group-5-chloro-2-naphthyl, 6-methoxyl group-5-bromo-2-naphthyl.HY is selected among the formula II: HCl, HBr, H
3PO
4, H
2SO
4, CH
3SO
3H, p-CH
3C
6H
4SO
3H.
The present invention also aims to provide chemistry 2-methyl isophthalic acid by name-(4-chlorobenzene formacyl)-5-methoxyl group-indole-3-acetic acid 2-(2-aryl morpholine base) ethyl ester of described Indometacin 2-arylmorpholine ethyl.
The present invention also aims to provide the preparation method of described Indometacin 2-arylmorpholine ethyl (I), it is characterized in that the indomethacin acyl chlorides is dissolved in the tetrahydrofuran (THF), stir and drip the 2-aryl-4-hydroxyethyl morpholine tetrahydrofuran solution that is equivalent to 1～2 times of molar weight of indomethacin acyl chlorides down, reaction finishes, tetrahydrofuran (THF) is reclaimed in distillation, and the oily matter that obtains gets Indometacin 2-arylmorpholine ethyl through column chromatography.
The present invention also aims to provide described indomethacin acyl chlorides preparation method, it is characterized in that the acid of indomethacin acid indomethacin is dissolved in the solvent, add the chlorizating agent that is equivalent to 1～4 times of molar weight of indomethacin acid consumption, stir and drip catalyst n, dinethylformamide, refluxed 5～8 hours, vacuum distillation recovered solvent gets solid, promptly gets the indomethacin acyl chlorides after the washing.
The present invention also aims to provide the preparation method of described Indometacin 2-arylmorpholine ethyl salt (II), it is characterized in that Indometacin 2-arylmorpholine ethyl is dissolved in anhydrous diethyl ether or ethanol, feed dry HCl gas or with respective acids reaction, obtain Indometacin 2-arylmorpholine ethyl salt.
Indometacin 2-arylmorpholine ethyl preparation method of the present invention is undertaken by following chemical equation:
The preparation method of Indometacin 2-arylmorpholine ethyl salt is undertaken by following chemical equation:
HY＝HCl，HBr，H
3PO
4，H
2SO
4，CH
3SO
3H，p-CH
3C
6H
4SO
3H
The present invention also aims to provide described Indometacin 2-arylmorpholine ethyl or the application of its salt in pharmacy.Described Indometacin 2-arylmorpholine ethyl or its salt have inhibition cyclooxygenase-2 (COX-2) active function, are used to prepare anti-inflammation and analgesic drugs.
The present invention compared with prior art has following advantage:
1, the present invention introduces morpholinyl in indomethacin phenethyl ester structure, and indomethacin is transformed into the Indometacin 2-arylmorpholine ethyl new compound.
2, the structure activity relationship that the present invention is based on non-steroid antiinflammatory drug is carried out structural modification to its carboxyl, introduces aryl on the morpholine ring, is designed to Indometacin 2-arylmorpholine ethyl (I or II).Compound I or II and phenylbenzene substituted pyrazolecarboxylic ring (three rings) class celecoxib (Celecoxib) has similar biological activity.
3, traditional non-steroid antiinflammatory drug such as indomethacin are transformed into the COX-2 selective depressant.Utilized Autodock process simulation indomethacin acid and COX-1 and COX-2 bonded conformation, and and the structure of COX-2 selective depressant SC-558 and COX-2 crystalline complex compare, find indomethacin acid heat to occupy the structure fragment of COX-2 side pocket, cause two isozyme non-selectivities, thus indomethacin is designed to Indometacin 2-arylmorpholine ethyl, in the hope of occupying the side pocket of COX-2, increase obtains the COX-2 selective depressant the keying action of COX-2.
Embodiment
Following examples are intended to illustrate the present invention rather than limitation of the invention further.
The preparation of embodiment 1 indomethacin 2-(2-phenylmorpholine base) ethyl ester and hydrochloride thereof
(1) preparation of indomethacin acyl chlorides
The 3mmol indomethacin is dissolved in the 8mL methylene dichloride, adds the 1mL oxalyl chloride, and ice bath stirs 3h, removes solvent under reduced pressure, separates remaining oxalyl chloride, gets yellow solid indomethacin acyl chlorides.
(2) preparation of indomethacin 2-(2-phenylmorpholine base) ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol 2-phenyl-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-(2-phenylmorpholine base) ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-(2-phenylmorpholine base) ethyl ester, feed dry hydrogen chloride and get indomethacin 2-(2-phenylmorpholine base) carbethoxy hydrochloride, yield 72%, fusing point: 184～186 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 2.35 (s, 3H, CH
3), 2.61 (br, 2H, C
4H
7NO 3,5-Ha), and 3.21 (bm, 2H, NCH
2), 3.35 (d, J=12Hz, 1H, C
4H
7NO 5-He), 3.49 (d, J=11.2Hz, 1H, C
4H
7NO 3-He), 3.80 (s, 2H, OCH
2), 3.85 (s, 3H, OCH
3), 3.93 (d, J=11.2Hz, 1H, C
4H
7NO 6-Ha), 4.38 (t, J=12.8Hz, 1H, C
4H
7NO 6-He), 4.68 (s, 2H, CH
2CO), 5.24 (d, J=10Hz, 1H, C
4H
7NO 2-H), 6.68～7.68 (m, 12H, C
6H
5, C
6H
4, C
6H
3), 13.76 (s, 1H, N-H).Meet constitutional features.
Embodiment 2 indomethacin 2-[2-(4-aminomethyl phenyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol 2-(4-aminomethyl phenyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(4-aminomethyl phenyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(4-aminomethyl phenyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(4-aminomethyl phenyl) morpholinyl] carbethoxy hydrochloride, yield 49%, fusing point: 170～172 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), 6:2.33 (s, 3H, phenyl ring CH
3), 2.35 (s, 3H, indole ring CH
3), 2.59 (br, 2H, C
4H
7NO 3,5-Ha), and 3.20 (bm, 2H, NCH
2), 3.34 (d, J=12.4Hz, 1H, C
4H
7NO 5-He), 3.46 (d, J=12Hz, 1H, C
4H
7NO 3-He), 3.80 (s, 2H, OCH
2), 3.85 (s, 3H, OCH
3), 3.91 (dd, J=3.2Hz, J=3.2Hz, 1H, C
4H
7NO 6-Ha), 4.38 (t, J=12.0Hz, 1H, C
4H
7NO6-He), 4.68 (s, 2H, CH
2CO), 5.19 (d, J=9.2Hz, 1H, C
4H
7NO 2-H), 6.68～7.68 (m, 11H, C
6H
5, C
6H
4, C
6H
3), 13.72 (s, 1H, N-H).Meet constitutional features.
Embodiment 3 indomethacin 2-[2-(4-ethylphenyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol 2-(4-ethylphenyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(4-ethylphenyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(4-ethylphenyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(4-ethylphenyl) morpholinyl] carbethoxy hydrochloride, yield 22%, fusing point: 186～189 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 1.21 (t, J=7.6Hz, 3H, CH
3), 2.35 (s, 3H, indoles 2-CH
3), 2.58～2.68 (m, 4H, PhCH
2, C
4H
7NO 3,5-Ha), and 3.22 (bm, 2H, NCH
2), 3.35 (d, J=10.8Hz, 1H, C
4H
7NO 5-He), 3.48 (d, J=10.8Hz, 1H, C
4H
7NO 3-He), 3.80 (s, 2H, OCH
2), 3.85 (s, 3H, OCH
3), 3.91 (d, J=12.4Hz, 1H, C
4H
7NO 6-Ha), 4.38 (t, J=12.4Hz, 1H, C
4H
7NO 6-He), 4.68 (s, 2H, CH
2CO), 5.20 (d, J=10.8Hz, 1H, C
4H
7NO 2-H), 6.68～7.68 (m, 11H, C
6H
5, C
6H
4, C
6H
3), 13.69 (s, 1H, N-H).Meet constitutional features.
Embodiment 4 indomethacin 2-[2-(4-p-methoxy-phenyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol 2-(4-p-methoxy-phenyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(4-p-methoxy-phenyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(4-p-methoxy-phenyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(4-p-methoxy-phenyl) morpholinyl] carbethoxy hydrochloride, yield 47%, fusing point: 185～187 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 2.36 (s, 3H, CH
3), 2.59 (br, 2H, C
4H
7NO 3,5-Ha), and 3.21 (br, 2H, NCH
2), 3.34 (d, J=11.2Hz, 2H, C
4H
7NO 5-He), 3.44 (d, J=11.2Hz, 2H, C
4H
7NO 3-He), 3.80 (s, 2H, OCH
2), 3.81 (s, 3H, phenyl ring OCH
3), 3.85 (s, 3H, indole ring OCH
3), 3.91 (d, J=11.6Hz, 1H, C
4H
7NO 6-Ha), 4.38 (t, J=8.8Hz, 1H, C
4H
7NO 6-He), 4.68 (s, 2H, CH
2CO), 5.17 (d, J=10.4Hz, 1H, C
4H
7NO 2-H), 6.86～7.68 (m, 11H, C
6H
4, C
6H
4, C
6H
3), 13.67 (s, 1H, N-H).Meet constitutional features.
Embodiment 5 indomethacin 2-[2-(4-isopropyl phenyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol 2-(4-isopropyl phenyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(4-isopropyl phenyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(4-isopropyl phenyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(4-isopropyl phenyl) morpholinyl] carbethoxy hydrochloride, yield 57%, fusing point: 218～219 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 1.32 (d, J=6Hz, 6H, 2CH
3), 2.37 (s, 3H, CH
3), 2.61 (br, 2H, C
4H
7NO 3,5-Ha), and 3.21 (br, 2H, NCH
2), 3.33 (d, J=11.2Hz, 2H, C
4H
7NO 5-He), 3.44 (d, J=11.6Hz, 2H, C
4H
7NO 3-He), 3.81 (s, 2H, OCH
2), 3.85 (s, 3H, OCH
3), 3.90 (dd, J=2.8Hz, J=2.8Hz, 1H, C
4H
7NO 6-Ha), 4.37 (t, J=12.4Hz, 1H, C
4H
7NO 6-He), 4.53 (7 heavy peaks, 1H, (CH
3)
2CHO), 4.68 (s, 2H, CH
2CO), 5.15 (d, J=10.8Hz, 1H, C
4H
7NO 2-H), 6.68～7.68 (m, 11H, C
6H
5, C
6H
4, C
6H
3), 13.69 (s, 1H, N-H).Meet constitutional features.
Embodiment 6 indomethacin 2-[2-(4-butoxy phenyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol 2-(4-butoxy phenyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(4-butoxy phenyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(4-butoxy phenyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(4-butoxy phenyl) morpholinyl] carbethoxy hydrochloride, yield 46%, fusing point: 179～180 ℃.Proton nmr spectra structural characterization data:
1HNMR (CDCl
3, 400MHz), δ: 0.97 (t, J=6.8Hz, 3H, CH
3(CH
2)
3), 1.48 (6 heavy peaks, 2H, CH
3CH
2), 1.75 (5 heavy peaks, 2H, CH
3CH
2CH
2), 2.36 (s, 3H, CH
3), 2.60 (br, 2H, C
4H
7NO 3,5-Ha), and 3.21 (br, 2H, NCH
2), 3.33 (d, J=12.0Hz, 1H, C
4H
7NO 5-He), 3.44 (d, J=11.6Hz, 1H, C
4H
7NO 3-He), 3.80 (s, 2H, C
3H
7CH
2O), 3.85 (s, 3H, indole ring OCH
3), 3.92 (s, 2H, OCH
2), 3.94 (d, J=10.8Hz, 1H, C
4H
7NO 6-Ha), 4.37 (t, J=12.4Hz, 1H, C
4H
7NO 6-He), 4.68 (s, 2H, CH
2CO), 5.15 (d, J=10.4Hz, 1H, C
4H
7NO 2-H), 6.68～7.22 (m, 11H, C
6H
4, C
6H
4, C
6H
3), 13.65 (s, 1H, N-H).Meet constitutional features.
Embodiment 7 indomethacin 2-[2-(2,4-two chloro-5-fluorophenyls) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, the tetrahydrofuran solution of dropping 2mmol 2-(2,4-two chloro-5-fluorophenyls)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, and reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(2,4-two chloro-5-fluorophenyls) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(2,4-two chloro-5-fluorophenyls) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(2,4-two chloro-5-fluorophenyls) morpholinyl] carbethoxy hydrochloride, yield 43%, fusing point: 171～174 ℃.Proton nmr spectra structural characterization data:
1H NMR (400MHz, CDCl
3), δ: 2.36 (s, 3H, CH
3), 2.59 (br, 2H, C
4H
7NO 3,5-Ha), and 3.21～3.37 (m, 4H, C
4H
7NO 3,5-He, NCH
2), 3.81 (s, 2H, OCH
2), 3.85 (s, 3H, phenyl ring OCH
3), 3.95 (d, J=12Hz, 1H, C
4H
7NO 6-Ha), 4.45 (s, 1H, C
4H
7NO 6-He), 4.69 (s, 2H, CH
2CO), 5.52 (d, J=8.0Hz, 1H, C
4H
7NO 2-H), 6.68～7.68 (m, 9H, C
6H
4, C
6H
3, C
6H
2), 14.06 (s, 1H, N-H).Meet constitutional features.
Embodiment 8 indomethacin 2-[2-(2-chloro-4-(4-chlorophenoxy) phenyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip 2mmol[2-chloro-4-(4-chlorophenoxy)] tetrahydrofuran solution of phenyl-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(2-chloro-4-(4-chlorophenoxy) phenyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(2-chloro-4-(4-chlorophenoxy) phenyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(2-chloro-4-(4-chlorophenoxy) phenyl) morpholinyl] carbethoxy hydrochloride, yield 33%, fusing point: 166～168 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 2.36 (s, 3H, CH
3), 2.51 (br, 2H, C
4H
7NO 3,5-Ha), and 3.21 (br, 2H, NCH
2), 3.35 (d, J=10.4Hz, 1H, C
4H
7NO 5-He), 3.65 (d, J=12.8Hz, 1H, C
4H
7NO 3-He), 3.81 (s, 2H, OCH
2), 3.85 (s, 3H, indole ring OCH
3), 3.94 (d, J=12.4Hz, 1H, C
4H
7NO 6-Ha), 4.45 (t, J=11.6Hz, 1H, C
4H
7NO 6-He), 4.69 (s, 2H, CH
2CO), 5.53 (d, J=10.4Hz, 1H, C
4H
7NO 2-H), 6.68～7.68 (m, 14H, C
6H
4, C
6H
4, C
6H
3, C
6H
3), 14.03 (s, 1H, N-H).Meet constitutional features.
Embodiment 9 indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol (6-methoxyl group-2-naphthyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] carbethoxy hydrochloride, yield 30%, fusing point: 101～102 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 500MHz), δ: 2.36 (s, 3H, CH
3), 2.47 (br, 2H, C
4H
7NO3,5-Ha), 2.92～3.28 (m, 4H, NCH
2, C
4H
7NO 5-He, 3-He), 3.73 (s, 2H, OCH
2), 3.83 (s, 3H, indole ring CH
3O), 3.91 (s, 3H, naphthalene nucleus CH
3O), 3.97 (d, J=8Hz, 1H, C
4H
7NO 6-Ha), 4.01 (br, 1H, C
4H
7NO 6-He), 4.48 (s, 2H, CH
2CO), 4.91 (m, 3H, OCH
2, C
4H
7NO 2-H), 6.64～7.72 (m, 13H, C
10H
6, C
6H
4, C
6H
3), 13.49 (s, 1H, N-H).Meet constitutional features.
Embodiment 10 indomethacin 2-[2-(5-chloro-6-methoxyl group-2-naphthyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol (5-chloro-6-methoxyl group-2-naphthyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(5-chloro-6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(5-chloro-6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(5-chloro-6-methoxyl group-2-naphthyl) morpholinyl] carbethoxy hydrochloride, yield 45%, fusing point: 229～230 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 2.37 (s, 3H, CH
3), 2.66 (br, 2H, C
4H
7NO 3,5-Ha), and 3.31～3.55 (bm, 4H, NCH
2, C
4H
7NO 5-He, 3-He), 3.81 (s, 2H, OCH
2), 3.85 (s, 3H, indole ring CH
3O), 3.99 (br, 1H, C
4H
7NO 6-Ha), 4.05 (s, 3H, naphthalene nucleus CH
3O), 4.46 (br, 1H, C
4H
7NO 6-He), 4.71 (br, 2H, CH
2CO), 5.44 (br, 1H, C
4H
7NO 2-H), 6.68～8.22 (m, 12H, C
10H
5, C
6H
4, C
6H
3), 13.78 (s, 1H, N-H).Meet constitutional features.
Embodiment 11 indomethacin 2-[2-(5-bromo-6-methoxyl group-2-naphthyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol (5-bromo-6-methoxyl group-2-naphthyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[2-(5-bromo-6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[2-(5-bromo-6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[2-(5-bromo-6-methoxyl group-2-naphthyl) morpholinyl] carbethoxy hydrochloride, yield 33%, fusing point: 225～227 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 2.36 (s, 3H, CH
3), 2.66 (br, 2H, C
4H
7NO 3,5-Ha), and 3.28～3.56 (m, 4H, NCH
2, C
4H
7NO 5-He, 3-He), 3.81 (s, 2H, OCH
2), 3.85 (s, 3H, indole ring CH
3O), 3.98 (br, 1H, C
4H
7NO 6-Ha), 4.04 (s, 3H, naphthalene nucleus CH
3O), 4.46 (br, 1H, C
4H
7NO 6-He), 4.71 (br, 2H, CH
2CO), 5.43 (br, 1H, C
4H
7NO 2-H), 6.68～8.22 (m, 12H, C
10H
5, C
6H
4, C
6H
3), 13.80 (s, 1H, N-H).Meet constitutional features.
Embodiment 12 indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] preparation of ethyl ester vitriol
Indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester is dissolved in the ethanol, adds the sulfuric acid stirring reaction, gets indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl through aftertreatment] ethyl ester vitriol.
Embodiment 13 indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] the phosphatic preparation of ethyl ester
Indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester is dissolved in the ethanol, adds the phosphoric acid stirring reaction, gets indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl through aftertreatment] the acetophos hydrochlorate.
Embodiment 14 indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] preparation of ethyl ester tosilate
Indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester is dissolved in the ethanol, adds the tosic acid stirring reaction, gets indomethacin 2-[2-(6-methoxyl group-2-naphthyl) morpholinyl through aftertreatment] the ethyl ester tosilate.
Embodiment 15 indomethacin 2-[3-methyl-2-(6-methoxyl group-2-naphthyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol (3-methyl-6-methoxyl group-2-naphthyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[3-methyl-2-(6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[3-methyl-2-(6-methoxyl group-2-naphthyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[3-methyl-2-(6-methoxyl group-2-naphthyl) morpholinyl] carbethoxy hydrochloride, yield 22%, fusing point: 145～147 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 1.27 (d, J=6.4Hz, 3H, CH
3), 2.44 (s, 3H, CH
3), 2.72 (br, 1H, C
4H
7NO 3-H), 3.08 (br, 2H, NCH
2), 3.31 (d, J=11.2Hz, 1H, C
4H
7NO 5-Ha), 3.67 (br, 1H, C
4H
7NO 5-He), 3.77 (dd, J=10.4, J=2.0Hz, 1H, C
4H
7NO 6-Ha), 3.81 (s, 2H, OCH
2), 3.86 (s, 3H, indole ring CH
3O), 3.93 (s, 3H, naphthalene nucleus CH
3O), 4.46 (br, 1H, C
4H
7NO 6-He), 4.66 (s, 2H, CH
2CO), 5.01 (br, 2H, C
4H
7NO 2-H), 6.69～7.75 (m, 13H, C
10H
6, C
6H
4, C
6H
3), 13.47 (s, 1H, N-H).Meet constitutional features.
Embodiment 16 indomethacin 2-[3-methyl-2-(4-benzyloxy phenyl) morpholinyl] preparation of ethyl ester and hydrochloride thereof
The indomethacin acyl chlorides that the dissolving of 8mL tetrahydrofuran (THF) makes, drip the tetrahydrofuran solution of 2mmol 3-methyl-2-(4-benzyloxy phenyl)-4-hydroxyethyl morpholine, the 1mL triethylamine is made acid binding agent, stirring at room reaction 6h, reaction finishes, filter, filtrate is through the removal of solvent under reduced pressure tetrahydrofuran (THF), with the unnecessary indomethacin of 1.0mol/L sodium hydroxide solution flush away, ethyl acetate extraction, get organic layer, steam and remove ethyl acetate, column chromatography gets indomethacin 2-[3-methyl-2-(4-benzyloxy phenyl) morpholinyl] ethyl ester.
With a small amount of anhydrous diethyl ether dissolving indomethacin 2-[3-methyl-2-(4-benzyloxy phenyl) morpholinyl] ethyl ester, feed dry hydrogen chloride and get indomethacin 2-[3-methyl-2-(4-benzyloxy phenyl) morpholinyl] carbethoxy hydrochloride, yield 17%, fusing point: 122～125 ℃.Proton nmr spectra structural characterization data:
1H NMR (CDCl
3, 400MHz), δ: 1.21 (br, 3H, CH
3), 2.43 (s, 3H, CH
3), 2.68 (br, 1H, C
4H
7NO 3-H), 2.95 (br, 2H, NCH
2), 3.15 (br, 1H, C
4H
7NO 5-Ha), 3.70 (br, 1H, C
4H
7NO 5-He), 3.83～3.86 (br, 5H, OCH
2, indole ring CH
3O), 3.93 (s, 1H, C
4H
7NO6-Ha), 4.41 (br, 1H, C
4H
7NO 6-He), 4.65 (s, 2H, CH
2CO), 4.82 (br, 1H, C
4H
7NO 2-H), 5.06 (s, 2H, PhCH
2O), 6.68～7.68 (m, 16H, C
6H
5, C
6H
4, C
6H
4, C
6H
3), 13.37 (s, 1H, N-H).Meet constitutional features.
Embodiment 17 Indometacin 2-arylmorpholine ethyls and hydrochloride thereof suppress active to people's cyclooxygenase-2 (COX-2)
Preferred compound indomethacin 2-[2-of the present invention (4-aminomethyl phenyl) morpholinyl] carbethoxy hydrochloride, indomethacin 2-[2-(4-ethylphenyl) morpholinyl] carbethoxy hydrochloride, indomethacin 2-[2-(4-p-methoxy-phenyl) morpholinyl] carbethoxy hydrochloride, indomethacin 2-[2-(4-isopropyl phenyl) morpholinyl] carbethoxy hydrochloride, indomethacin 2-[2-(4-butoxy phenyl) morpholinyl] carbethoxy hydrochloride and indomethacin 2-[2-(2,4-two chloro-5-fluorophenyls) morpholinyl] cyclo-oxygenase-1 (COX-1) and people's cyclooxygenase-2 (COX-2) model active suppression test of carbethoxy hydrochloride be as follows:
1) experiment purpose: cyclo-oxygenase generates prostaglandin(PG) and oxyradical (ROS) by metabolism arachidonic acid (AA).Cyclo-oxygenase (COX-2) is that one of key factor that develops takes place inflammation.Cyclo-oxygenase-1 (COX-1) is then mainly regulated physiological function.The COX-2 selective depressant avoids interference physiological function in anti-inflammatory, be the good target spot of anti-inflammatory treatment, and the inhibitor that screens it has tangible application scenario.
2) test philosophy: COX-2 metabolism arachidonic acid generates prostaglandin(PG) and ROS.Measure R OS fluorescence or PGE2 generate, to determine enzymic activity.
3) COX-1 and COX-2 are active detects
A. the acquisition of Turnover of Mouse Peritoneal Macrophages and cultivation
1ml/ only for C57BL/6J mouse peritoneal injection sodium thioglycollate substratum (preparation more than 1 month in advance, sterilization back room temperature keeps in Dark Place).Inject back 4 days with the mouse sacrificed by decapitation, drain blood, in 75% ethanol, soak 1～2min.Abdominal injection D-Hanks physiological buffer 6～8ml, fully liquid in the sucking-off abdominal cavity slowly after the massage repeats to wash the abdominal cavity 1 time again, merges the abdominal cavity washing lotion.The centrifugal 5min of 1000r/min, supernatant inclines.Add 1～2ml Tris-NH
4Cl solution shakes gently and treats brokenly to dilute the centrifugal 5min of 1000r/min with isopyknic D-Hanks physiological buffer immediately behind the red corpuscle, the supernatant that inclines, and with D-Hanks physiological buffer washing 2 times, cell is resuspended with RPMI 1640 substratum again.Measure cytoactive with trypan blue rejection method, the Giemsa staining checks that the scavenger cell percentage is greater than 95% in the gained cell.
B.COX-1 is active to be detected
Peritoneal macrophage is pressed 1 * 10
9Cells/L concentration is inoculated in 48 orifice plates.37 ℃, 5%CO
2Adherent culture 2h.The substratum that inclines with D-Hanks physiological buffer flushing 2 times, is removed not attached cell, and every hole adds the RPMI1640 substratum that contains 5%NCS and presses column split and handle: 1. DMSO negative control group (control); 2. A23187 organizes (final concentration 1 μ mol.L
-1); 3. A23187+I and II organize (5 μ mol.L
-1); 4. A23187+Celecoxib organizes (1 μ mol.L
-1).Every group 3 multiple hole, and repeat independent experiment 3 times.With above-mentioned 37 ℃ of Turnover of Mouse Peritoneal Macrophages in 48 orifice plates and medicine or solvents, the 5%CO of being inoculated in
2Temperature is incubated 1h, and adding the A23187 final concentration again is 1 μ mol.L
-1, 37 ℃, 5%CO
2Temperature is incubated 1h, collects supernatant, uses
125The 6-keto-PGF of I mark
1 αRadioimmunological kit is measured 6-keto-PGF in the cell culture supernatant
1 αContent.Make typical curve by test kit provider legal system, from typical curve, calculate respective concentration according to the testing sample measured value.
C.COX-2 is active to be detected
Peritoneal macrophage is pressed 1 * 10
9Cells/L concentration is inoculated in 48 orifice plates.37 ℃, 5%CO
2Adherent culture 2h.The substratum that inclines with D-Hanks physiological buffer flushing 2 times, is removed not attached cell, and every hole adds the RPMI1640 substratum that contains 5%NCS and presses column split and handle: 1. DMSO negative control group (control); 2. LPS organizes (final concentration 1mg/L); 3. LPS+I and II organize (10 μ mol.L
-1); 4. LPS+celecoxib organizes (1 μ mol.L
-1).With above-mentioned 37 ℃ of Turnover of Mouse Peritoneal Macrophages in 48 orifice plates and medicine or solvents, the 5%CO of being inoculated in
2Temperature is incubated 1h, and adding the LPS final concentration again is 1mg/L, and 37 ℃, 5%CO
2Temperature is incubated 9h, collects supernatant, uses
3The PGE of H mark
2Radioimmunological kit is measured PGE in the cell culture supernatant
2Content.
4) test-results
A. the calculating of peritoneal macrophage inhibiting rate:
According to formula
Inhibiting rate (%)=(Cs-Ct)/(Cs-Cc) * 100%
The computerized compound is to COX-2 and the active restraining effect of COX-1.Wherein Cs, Ct and Cc represent PGE in LPS or A23187 group, testing compound group and the cellular control unit culture supernatant respectively
2Or 6-keto-PGF
1 αConcentration.
B.IC
50Value is calculated
Sample solution concentration logarithmic value and inhibiting rate linear regression utilize the computed in software sample to peritoneal macrophage half-inhibition concentration IC
50Value.Preferred compound Indometacin 2-arylmorpholine ethyl or its salt are for the IC of COX-2 and COX-1
50List table 1 in.
Table 1 preferred compound of the present invention is to the IC of COX-2 enzyme and COX-1 enzyme
50
The active testing result shows that Compound I of the present invention or II have good people's cyclooxygenase-2 (COX-2) and suppress active.Wherein, indomethacin 2-[2-(4-ethylphenyl) morpholinyl] carbethoxy hydrochloride and indomethacin 2-[2-(2,4-two chloro-5-fluorophenyls) morpholinyl] activity of carbethoxy hydrochloride is strong than celecoxib.Compound shown in formula I or the formula II is used to prepare anti-inflammation and analgesic drugs, has no side effect.
Claims (3)
1. Indometacin 2-arylmorpholine ethyl (I) or its salt (II) is characterized in that it has following chemical structural formula:
Wherein, R is selected from: hydrogen, C
1～C
4Alkyl; Ar is selected from: phenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 3,4-dichlorophenyl, 3,5-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 6-dichlorophenyl, 2,4-two chloro-5-fluorophenyls, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 3,5-two (trifluoromethyl) phenyl, the 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, the 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, the 2-ethoxyl phenenyl, 3-ethoxyl phenenyl, 4-ethoxyl phenenyl, the 3-isopropyl phenyl, 4-isopropyl phenyl, 3-isopentyloxy phenyl, 4-isopentyloxy phenyl, 3-benzyloxy phenyl, 4-benzyloxy phenyl, 4-methanesulfonamido phenyl, 4-sulfamoyl phenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 6-methoxyl group-2-naphthyl, 6-methoxyl group-5-chloro-2-naphthyl, 6-methoxyl group-5-bromo-2-naphthyl; HY is selected among the formula II: HCl, HBr, H
3PO
4, H
28O
4, CH
3SO
3H, p-CH
3C
6H
4SO
3H.
2. the preparation method of the described Indometacin 2-arylmorpholine ethyl of claim 1 or its salt, it is characterized in that the indomethacin acyl chlorides is dissolved in the tetrahydrofuran (THF), stir and drip 4-hydroxyethyl-2-aryl morpholine tetrahydrofuran solution down, reaction finishes, tetrahydrofuran (THF) is reclaimed in distillation, obtains Indometacin 2-arylmorpholine ethyl (I); Indometacin 2-arylmorpholine ethyl is dissolved in anhydrous diethyl ether or the ethanol, feed dry HCl gas or with acid (HY) reaction, obtain Indometacin 2-arylmorpholine ethyl salt (II):
Wherein, the definition of Ar, R and HY according to claim 1.
3. the application of claim 1 described Indometacin 2-arylmorpholine base ethyl ester or its salt is characterized in that, compound shown in formula I or the formula II is as the application of preparation anti-inflammation and analgesic drugs.
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| JP2013503141A (en) * | 2009-08-31 | 2013-01-31 | アボツト・ヘルスケア・プロダクツ・ベー・ブイ | (Thio) morpholine derivatives as S1P modulators |
| CN102940639A (en) * | 2012-11-12 | 2013-02-27 | 湖南大学 | Application of indometacin2-aryl morpholine ethyl ester in preparing medicine capable of resisting breast cancer |
| US9662337B2 (en) | 2010-07-09 | 2017-05-30 | Abbvie B.V. | Bisaryl (thio)morpholine derivatives as S1P modulators |
| US9670220B2 (en) | 2010-07-09 | 2017-06-06 | Abbvie B.V. | Fused heterocyclic derivatives as S1P modulators |
| US9951084B2 (en) | 2010-07-09 | 2018-04-24 | Abb Vie B.V. | Spiro-cyclic amine derivatives as S1P modulators |
| US11535632B2 (en) | 2019-10-31 | 2022-12-27 | ESCAPE Bio, Inc. | Solid forms of an S1P-receptor modulator |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1970546A (en) * | 2006-11-30 | 2007-05-30 | 华南理工大学 | Naproxen-2-aryl morpholine ethyl ester and its preparation method and uses |
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Non-Patent Citations (1)
| Title |
|---|
| 《Medicinal Chemistry Research》 20070721 Parmeshwari K. Halen et al Substituted aminoalcohol ester analogs of indomethacin with reduced toxic effects 101-111 1-3 第16卷, 2 * |
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| JP2013503141A (en) * | 2009-08-31 | 2013-01-31 | アボツト・ヘルスケア・プロダクツ・ベー・ブイ | (Thio) morpholine derivatives as S1P modulators |
| US9045441B2 (en) | 2009-08-31 | 2015-06-02 | Abbvie Bahamas Limited | (Thio)morpholine derivatives as S1P modulators |
| US9273017B2 (en) | 2009-08-31 | 2016-03-01 | Abbvie Bahamas Limited | (Thio)morpholine derivatives as S1P modulators |
| KR101767882B1 (en) | 2009-08-31 | 2017-08-14 | 애브비 바하마스 리미티드 | (Thio)morpholine derivatives as S1P modulators |
| US9662337B2 (en) | 2010-07-09 | 2017-05-30 | Abbvie B.V. | Bisaryl (thio)morpholine derivatives as S1P modulators |
| US9670220B2 (en) | 2010-07-09 | 2017-06-06 | Abbvie B.V. | Fused heterocyclic derivatives as S1P modulators |
| US9951084B2 (en) | 2010-07-09 | 2018-04-24 | Abb Vie B.V. | Spiro-cyclic amine derivatives as S1P modulators |
| US10179791B2 (en) | 2010-07-09 | 2019-01-15 | Abbvie B.V. | Spiro-cyclic amine derivatives as S1P modulators |
| US10807991B2 (en) | 2010-07-09 | 2020-10-20 | Abbvie B.V. | Spiro-cyclic amine derivatives as S1P modulators |
| US11427598B2 (en) | 2010-07-09 | 2022-08-30 | AbbVie Deutschland GmbH & Co. KG | Spiro-cyclic amine derivatives as S1P modulators |
| CN102940639A (en) * | 2012-11-12 | 2013-02-27 | 湖南大学 | Application of indometacin2-aryl morpholine ethyl ester in preparing medicine capable of resisting breast cancer |
| US11535632B2 (en) | 2019-10-31 | 2022-12-27 | ESCAPE Bio, Inc. | Solid forms of an S1P-receptor modulator |
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