ZA200605023B - Antidiabetic compounds comprising benzofuran and benzothiophene derivatives - Google Patents

Antidiabetic compounds comprising benzofuran and benzothiophene derivatives Download PDF

Info

Publication number: ZA200605023B
Authority: ZA; South Africa
Prior art keywords: alk; ethyl; carboxylate; chosen; het
Prior art date: 2003-11-20

Application number

ZA200605023A

Other languages

English (en)

Inventor

Moinet Gurard

Kergoat Micheline

Leriche Caroline

Original Assignee

Merck Patent Gmbh

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2003-11-20

Filing date

2006-06-19

Publication date

2007-12-27

2006-06-19 Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh

2007-12-27 Publication of ZA200605023B publication Critical patent/ZA200605023B/en

Links

150000001875 compounds Chemical class 0.000 title claims description 54
IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title description 5
FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 4
230000003178 anti-diabetic effect Effects 0.000 title description 2
239000003472 antidiabetic agent Substances 0.000 title description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 73
150000003839 salts Chemical class 0.000 claims description 42
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 41
-1 -AlKAr Chemical group 0.000 claims description 37
125000005605 benzo group Chemical group 0.000 claims description 29
238000000034 method Methods 0.000 claims description 13
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
125000000753 cycloalkyl group Chemical group 0.000 claims description 8
125000005843 halogen group Chemical group 0.000 claims description 7
239000002798 polar solvent Substances 0.000 claims description 7
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 claims description 6
229910052757 nitrogen Inorganic materials 0.000 claims description 5
238000002360 preparation method Methods 0.000 claims description 5
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
125000004429 atom Chemical group 0.000 claims description 4
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
DYSJMQABFPKAQM-UHFFFAOYSA-M 1-benzothiophene-2-carboxylate Chemical compound C1=CC=C2SC(C(=O)[O-])=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-M 0.000 claims description 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
229910052760 oxygen Inorganic materials 0.000 claims description 3
229910052717 sulfur Inorganic materials 0.000 claims description 3
JBPCJVHNCPSANC-UHFFFAOYSA-N ethyl 3-(1-oxo-1-phenylpropan-2-yl)oxy-1-benzothiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC2=CC=CC=C2C=1OC(C)C(=O)C1=CC=CC=C1 JBPCJVHNCPSANC-UHFFFAOYSA-N 0.000 claims description 2
OKHSVALWXFKKNT-UHFFFAOYSA-N ethyl 3-[(3-cyanophenyl)methoxy]-1-benzothiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC2=CC=CC=C2C=1OCC1=CC=CC(C#N)=C1 OKHSVALWXFKKNT-UHFFFAOYSA-N 0.000 claims description 2
ILEBFFVFNKQJJV-UHFFFAOYSA-N ethyl 3-[2-(1-adamantyl)-2-oxoethoxy]-1-benzothiophene-2-carboxylate Chemical compound C1C(C2)CC(C3)CC2CC13C(=O)COC1=C(C(=O)OCC)SC2=CC=CC=C21 ILEBFFVFNKQJJV-UHFFFAOYSA-N 0.000 claims description 2
BDBFGZQZSYGIEB-UHFFFAOYSA-N ethyl 3-[2-oxo-2-(4-phenylphenyl)ethoxy]-1-benzothiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC2=CC=CC=C2C=1OCC(=O)C(C=C1)=CC=C1C1=CC=CC=C1 BDBFGZQZSYGIEB-UHFFFAOYSA-N 0.000 claims description 2
KRXONUVWZRBHQR-UHFFFAOYSA-N ethyl 3-hydroxy-1-benzothiophene-2-carboxylate Chemical compound C1=CC=C2C(O)=C(C(=O)OCC)SC2=C1 KRXONUVWZRBHQR-UHFFFAOYSA-N 0.000 claims description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
238000007363 ring formation reaction Methods 0.000 claims description 2
235000002639 sodium chloride Nutrition 0.000 claims 6
239000003814 drug Substances 0.000 claims 5
206010012601 diabetes mellitus Diseases 0.000 claims 3
239000008194 pharmaceutical composition Substances 0.000 claims 2
201000001320 Atherosclerosis Diseases 0.000 claims 1
208000032928 Dyslipidaemia Diseases 0.000 claims 1
206010054805 Macroangiopathy Diseases 0.000 claims 1
208000008589 Obesity Diseases 0.000 claims 1
235000010582 Pisum sativum Nutrition 0.000 claims 1
240000004713 Pisum sativum Species 0.000 claims 1
208000017442 Retinal disease Diseases 0.000 claims 1
206010038923 Retinopathy Diseases 0.000 claims 1
208000037849 arterial hypertension Diseases 0.000 claims 1
FMQSOQOSGLENFQ-UHFFFAOYSA-N ethyl 3-[(4-bromophenyl)methoxy]-1-benzothiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC2=CC=CC=C2C=1OCC1=CC=C(Br)C=C1 FMQSOQOSGLENFQ-UHFFFAOYSA-N 0.000 claims 1
UKTMSOFAZOGHOF-UHFFFAOYSA-N ethyl 3-[(4-methylphenyl)methoxy]-1-benzothiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC2=CC=CC=C2C=1OCC1=CC=C(C)C=C1 UKTMSOFAZOGHOF-UHFFFAOYSA-N 0.000 claims 1
PUMRBYFLANVISF-UHFFFAOYSA-N ethyl 3-[2-(4-cyanophenoxy)ethoxy]-1-benzothiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC2=CC=CC=C2C=1OCCOC1=CC=C(C#N)C=C1 PUMRBYFLANVISF-UHFFFAOYSA-N 0.000 claims 1
LZIGOSJCGDTENO-UHFFFAOYSA-N ethyl 3-[[2-(benzenesulfonylmethyl)phenyl]methoxy]-1-benzothiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC2=CC=CC=C2C=1OCC1=CC=CC=C1CS(=O)(=O)C1=CC=CC=C1 LZIGOSJCGDTENO-UHFFFAOYSA-N 0.000 claims 1
201000001421 hyperglycemia Diseases 0.000 claims 1
230000004054 inflammatory process Effects 0.000 claims 1
238000004519 manufacturing process Methods 0.000 claims 1
206010062198 microangiopathy Diseases 0.000 claims 1
201000001119 neuropathy Diseases 0.000 claims 1
230000007823 neuropathy Effects 0.000 claims 1
235000020824 obesity Nutrition 0.000 claims 1
208000033808 peripheral neuropathy Diseases 0.000 claims 1
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
208000001072 type 2 diabetes mellitus Diseases 0.000 claims 1
230000002792 vascular Effects 0.000 claims 1
235000013350 formula milk Nutrition 0.000 description 13
239000002253 acid Substances 0.000 description 9
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
230000006978 adaptation Effects 0.000 description 6
229910052500 inorganic mineral Inorganic materials 0.000 description 6
239000011707 mineral Substances 0.000 description 6
235000010755 mineral Nutrition 0.000 description 6
150000003254 radicals Chemical class 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
239000002585 base Substances 0.000 description 5
125000004432 carbon atom Chemical group C* 0.000 description 5
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
239000012458 free base Substances 0.000 description 4
239000000203 mixture Substances 0.000 description 4
239000000243 solution Substances 0.000 description 4
239000002904 solvent Substances 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
239000004475 Arginine Substances 0.000 description 3
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
239000004472 Lysine Substances 0.000 description 3
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 3
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
150000001412 amines Chemical class 0.000 description 3
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
229960003121 arginine Drugs 0.000 description 3
125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
229910052731 fluorine Inorganic materials 0.000 description 3
239000011737 fluorine Substances 0.000 description 3
230000004927 fusion Effects 0.000 description 3
229960003646 lysine Drugs 0.000 description 3
125000003373 pyrazinyl group Chemical group 0.000 description 3
125000002098 pyridazinyl group Chemical group 0.000 description 3
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
229910019142 PO4 Inorganic materials 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
230000002378 acidificating effect Effects 0.000 description 2
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
229910021502 aluminium hydroxide Inorganic materials 0.000 description 2
229910021529 ammonia Inorganic materials 0.000 description 2
150000005840 aryl radicals Chemical class 0.000 description 2
239000011668 ascorbic acid Substances 0.000 description 2
235000010323 ascorbic acid Nutrition 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
229910052794 bromium Inorganic materials 0.000 description 2
AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
239000000920 calcium hydroxide Substances 0.000 description 2
235000011116 calcium hydroxide Nutrition 0.000 description 2
229910001861 calcium hydroxide Inorganic materials 0.000 description 2
229940095643 calcium hydroxide Drugs 0.000 description 2
150000001768 cations Chemical class 0.000 description 2
238000006243 chemical reaction Methods 0.000 description 2
239000000460 chlorine Substances 0.000 description 2
229910052801 chlorine Inorganic materials 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
230000008878 coupling Effects 0.000 description 2
238000010168 coupling process Methods 0.000 description 2
238000005859 coupling reaction Methods 0.000 description 2
POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 2
MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
229940043264 dodecyl sulfate Drugs 0.000 description 2
125000002541 furyl group Chemical group 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
125000002883 imidazolyl group Chemical group 0.000 description 2
125000001041 indolyl group Chemical group 0.000 description 2
SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
125000005956 isoquinolyl group Chemical group 0.000 description 2
125000001786 isothiazolyl group Chemical group 0.000 description 2
125000000842 isoxazolyl group Chemical group 0.000 description 2
229940070765 laurate Drugs 0.000 description 2
VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
239000000347 magnesium hydroxide Substances 0.000 description 2
229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
229910052751 metal Chemical class 0.000 description 2
239000002184 metal Chemical class 0.000 description 2
125000002950 monocyclic group Chemical group 0.000 description 2
231100000252 nontoxic Toxicity 0.000 description 2
230000003000 nontoxic effect Effects 0.000 description 2
239000003960 organic solvent Substances 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
239000010452 phosphate Substances 0.000 description 2
239000000047 product Substances 0.000 description 2
125000006239 protecting group Chemical group 0.000 description 2
125000004076 pyridyl group Chemical group 0.000 description 2
125000000714 pyrimidinyl group Chemical group 0.000 description 2
125000000168 pyrrolyl group Chemical group 0.000 description 2
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
125000005493 quinolyl group Chemical group 0.000 description 2
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
239000011541 reaction mixture Substances 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
239000011734 sodium Substances 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
239000012312 sodium hydride Substances 0.000 description 2
229910000104 sodium hydride Inorganic materials 0.000 description 2
WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
125000001113 thiadiazolyl group Chemical group 0.000 description 2
125000001544 thienyl group Chemical group 0.000 description 2
125000004306 triazinyl group Chemical group 0.000 description 2
UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 2
229910021511 zinc hydroxide Inorganic materials 0.000 description 2
229940007718 zinc hydroxide Drugs 0.000 description 2
LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 1
BLDFSDCBQJUWFG-UHFFFAOYSA-N 2-(methylamino)-1,2-diphenylethanol Chemical compound C=1C=CC=CC=1C(NC)C(O)C1=CC=CC=C1 BLDFSDCBQJUWFG-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
125000005916 2-methylpentyl group Chemical group 0.000 description 1
229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
KRTGJZMJJVEKRX-UHFFFAOYSA-N 2-phenylethan-1-yl Chemical compound [CH2]CC1=CC=CC=C1 KRTGJZMJJVEKRX-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
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125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical class OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
229940086542 triethylamine Drugs 0.000 description 1
ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
229940070710 valerate Drugs 0.000 description 1
NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/64—Oxygen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Medicinal Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Diabetes (AREA)
Epidemiology (AREA)
Hematology (AREA)
Obesity (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Emergency Medicine (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Ophthalmology & Optometry (AREA)
Child & Adolescent Psychology (AREA)
Endocrinology (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Plural Heterocyclic Compounds (AREA)

ZA200605023A 2003-11-20 2006-06-19 Antidiabetic compounds comprising benzofuran and benzothiophene derivatives ZA200605023B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
FR0313612A FR2862645B1 (fr)	2003-11-20	2003-11-20	Composes antidiabetiques contenant des derives benzofuranes, benzothiophenes

Publications (1)

Publication Number	Publication Date
ZA200605023B true ZA200605023B (en)	2007-12-27

Family

ID=34531150

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ZA200605023A ZA200605023B (en)	2003-11-20	2006-06-19	Antidiabetic compounds comprising benzofuran and benzothiophene derivatives

Country Status (15)

Country	Link
US (1)	US7375130B2 (fr)
EP (1)	EP1685121B1 (fr)
JP (1)	JP4786545B2 (fr)
KR (1)	KR20060101491A (fr)
CN (1)	CN1882563A (fr)
AR (1)	AR046644A1 (fr)
AT (1)	ATE398116T1 (fr)
AU (1)	AU2004295029B2 (fr)
BR (1)	BRPI0416675A (fr)
CA (1)	CA2546647C (fr)
DE (1)	DE602004014401D1 (fr)
ES (1)	ES2308263T3 (fr)
FR (1)	FR2862645B1 (fr)
WO (1)	WO2005054225A1 (fr)
ZA (1)	ZA200605023B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
FR2862646B1 (fr) *	2003-11-20	2006-02-24	Merck Sante Sas	Nouveaux composes antidiabetiques contenant des derives benzofuranes, benzothiophenes
GB0506133D0 (en) *	2005-03-24	2005-05-04	Sterix Ltd	Compound
AU2011202542A1 (en)	2010-07-14	2012-02-02	Indian Institute Of Science	Benzothiophene carboxamide compounds, composition and applications thereof
CN104870429B (zh) *	2013-05-22	2017-05-03	四川海思科制药有限公司	苯并呋喃衍生物、其制备方法及其在医药上的应用

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3592907A (en) *	1968-03-06	1971-07-13	Dow Chemical Co	Substituted benzo(b)thiophene compositions
US3989718A (en) *	1975-05-06	1976-11-02	Eli Lilly And Company	[1]Benzothieno[3,2-b]furans
ZA858748B (en) *	1984-12-10	1987-06-24	Warner Lambert Co	Novel benzothiophenes and benzofurans having antiallergy activity
IE64995B1 (en) *	1987-07-14	1995-09-20	Warner Lambert Co	Novel benzothiophenes having antiallergic activity and both novel and other selected benzothiophenes having activity for treating acute respiratory distress syndrome
WO1995005170A1 (fr) *	1993-08-13	1995-02-23	Warner-Lambert Company	Methodes d'inhibition du vih et de son activation
US5350748A (en) *	1993-08-18	1994-09-27	Warner-Lambert Company	3-thio or amino substituted-benzo[b]thiophene-2-carboxamides and 3-oxygen, thio, or amino substituted-benzofuran-2-carboxamides as inhibitors of cell adhesion
US5908859A (en) *	1997-08-11	1999-06-01	Eli Lilly And Company	Benzothiophenes for inhibiting hyperlipidemia
CN1308621A (zh) *	1998-05-12	2001-08-15	美国家用产品公司	用于治疗胰岛素抗性和高血糖的苯基氧代－乙酸
HRP20000767A2 (en) *	1998-05-12	2001-10-31	American Home Prod	Benzothiophenes, benzofurans and indoles useful in the treatment of insulin resistance and hyperglycemia
US6436965B1 (en) *	2000-03-02	2002-08-20	Merck Frosst Canada & Co.	PDE IV inhibiting amides, compositions and methods of treatment
US20040259926A1 (en) *	2003-06-05	2004-12-23	Bruendl Michelle M.	3-Aryloxy and 3-heteroaryloxy substituted benzo[b]thiophenes as therapeutic agents
FR2862646B1 (fr) *	2003-11-20	2006-02-24	Merck Sante Sas	Nouveaux composes antidiabetiques contenant des derives benzofuranes, benzothiophenes

2003
- 2003-11-20 FR FR0313612A patent/FR2862645B1/fr not_active Expired - Fee Related
2004
- 2004-10-26 ES ES04790858T patent/ES2308263T3/es not_active Expired - Lifetime
- 2004-10-26 US US10/580,033 patent/US7375130B2/en not_active Expired - Fee Related
- 2004-10-26 BR BRPI0416675-2A patent/BRPI0416675A/pt not_active Application Discontinuation
- 2004-10-26 CA CA2546647A patent/CA2546647C/fr not_active Expired - Fee Related
- 2004-10-26 DE DE602004014401T patent/DE602004014401D1/de not_active Expired - Lifetime
- 2004-10-26 AU AU2004295029A patent/AU2004295029B2/en not_active Ceased
- 2004-10-26 AT AT04790858T patent/ATE398116T1/de not_active IP Right Cessation
- 2004-10-26 CN CNA2004800342573A patent/CN1882563A/zh active Pending
- 2004-10-26 JP JP2006540215A patent/JP4786545B2/ja not_active Expired - Fee Related
- 2004-10-26 WO PCT/EP2004/012075 patent/WO2005054225A1/fr not_active Ceased
- 2004-10-26 EP EP04790858A patent/EP1685121B1/fr not_active Expired - Lifetime
- 2004-10-26 KR KR1020067009679A patent/KR20060101491A/ko not_active Withdrawn
- 2004-11-19 AR ARP040104273A patent/AR046644A1/es unknown
2006
- 2006-06-19 ZA ZA200605023A patent/ZA200605023B/en unknown

Also Published As

Publication number	Publication date
KR20060101491A (ko)	2006-09-25
US7375130B2 (en)	2008-05-20
WO2005054225A1 (fr)	2005-06-16
JP2007511552A (ja)	2007-05-10
FR2862645B1 (fr)	2007-06-22
FR2862645A1 (fr)	2005-05-27
JP4786545B2 (ja)	2011-10-05
DE602004014401D1 (de)	2008-07-24
EP1685121B1 (fr)	2008-06-11
CA2546647A1 (fr)	2005-06-16
EP1685121A1 (fr)	2006-08-02
AU2004295029B2 (en)	2010-03-11
CN1882563A (zh)	2006-12-20
BRPI0416675A (pt)	2007-02-13
ES2308263T3 (es)	2008-12-01
CA2546647C (fr)	2013-02-12
ATE398116T1 (de)	2008-07-15
AR046644A1 (es)	2005-12-14
AU2004295029A1 (en)	2005-06-16
US20070078178A1 (en)	2007-04-05

Publication	Publication Date	Title
PL70430B1 (en)	1974-02-28	Phenylaminoethanol derivatives[gb1200886a]
RU2003134544A (ru)	2005-03-27	Амиды антраниловой кислоты, способы их получения, их применение в качестве антиаритмических средств, а также содержащие их фармацевтические композиции
GB2071088B (en)	1983-08-24	Indane derivatives
AU9233101A (en)	2002-04-15	5-amidino-2-hydroxybenzenesulfonamide derivatives, pharmaceutical compositions containing the same and intermediates for their preparation
BE905211A (nl)	1987-02-04	Farmaceutische preparaten met vaatverwijdende en anti-anoxische werking.
WO1999044624A3 (fr)	1999-10-21	Composition pharmaceutique pour la prophylaxie et la therapie de maladies associees a des modifications cytopathiques des tissus du fond de l'oeil
EP1685122B1 (fr)	2008-07-09	Benzofuranes et benzothiophenes
CA2546647C (fr)	2013-02-12	Composes antidiabetiques comprenant des derives de benzofurane et de benzothiophene
WO2019070709A1 (fr)	2019-04-11	Composés pour le traitement ou la prévention d'infections à flavivirus
JPS6110510A (ja)	1986-01-18	免疫抑制作用を有する新規な医薬組成物
EP0049814A3 (en)	1983-01-26	Cephalosporin derivatives, process for their preparation and pharmaceutical compositions containing them
RS57443B1 (sr)	2018-09-28	4-okso-n-(4-hidroksifenil)retinamid derivativi kao terapeutski agensi za lečenje kancera