IL118664A

IL118664A - Pain-relieving compounds containing methylene-amino and oxy-linking groups, process for their preparation, pharmaceutical mixtures containing them and their uses for the preparation of pharmaceutical mixtures

Pain-relieving compounds containing methylene-amino and oxy-linking groups, process for their preparation, pharmaceutical mixtures containing them and their uses for the preparation of pharmaceutical mixtures

Info

Publication number: IL118664A
Authority: IL; Israel
Prior art keywords: alkyl; formula; compound; optionally substituted; hydrogen
Prior art date: 1995-06-20

Application number

IL11866496A

Other languages

English (en)

Hebrew (he)

Other versions

IL118664A0 (en

Original Assignee

Zeneca Ltd

Priority date

1995-06-20

Filing date

1996-06-16

Publication date

2001-12-23

1995-06-20 Priority claimed from GBGB9512476.4A external-priority patent/GB9512476D0/en

1996-01-25 Priority claimed from GBGB9601462.6A external-priority patent/GB9601462D0/en

1996-03-30 Priority claimed from GBGB9606831.7A external-priority patent/GB9606831D0/en

1996-06-16 Application filed by Zeneca Ltd filed Critical Zeneca Ltd

1996-10-31 Publication of IL118664A0 publication Critical patent/IL118664A0/xx

2001-12-23 Publication of IL118664A publication Critical patent/IL118664A/en

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 185
-1 methyleneamino Chemical group 0.000 title claims abstract description 107
208000002193 Pain Diseases 0.000 title claims abstract description 29
125000005647 linker group Chemical group 0.000 title claims abstract description 6
239000008194 pharmaceutical composition Substances 0.000 title claims description 12
238000004519 manufacturing process Methods 0.000 title claims description 10
238000002360 preparation method Methods 0.000 title description 3
239000001257 hydrogen Substances 0.000 claims abstract description 34
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 34
150000002148 esters Chemical class 0.000 claims abstract description 31
125000005843 halogen group Chemical group 0.000 claims abstract description 27
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 25
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 23
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 23
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
125000003282 alkyl amino group Chemical group 0.000 claims abstract description 14
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 14
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 14
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
229910052760 oxygen Inorganic materials 0.000 claims abstract description 14
239000001301 oxygen Substances 0.000 claims abstract description 14
239000002253 acid Substances 0.000 claims abstract description 13
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
125000001544 thienyl group Chemical group 0.000 claims abstract description 13
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 12
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 12
150000002431 hydrogen Chemical class 0.000 claims abstract description 12
125000004076 pyridyl group Chemical group 0.000 claims abstract description 12
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 11
125000000335 thiazolyl group Chemical group 0.000 claims abstract description 11
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 9
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
125000002971 oxazolyl group Chemical group 0.000 claims abstract description 8
125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 8
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
239000005864 Sulphur Chemical group 0.000 claims abstract description 7
125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 7
125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 7
125000006413 ring segment Chemical group 0.000 claims abstract description 7
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 6
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 6
125000000539 amino acid group Chemical group 0.000 claims abstract description 4
125000002883 imidazolyl group Chemical group 0.000 claims abstract description 4
125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 claims abstract description 3
125000005842 heteroatom Chemical group 0.000 claims abstract description 3
PEQJBOMPGWYIRO-UHFFFAOYSA-N n-ethyl-3,4-dimethoxyaniline Chemical compound CCNC1=CC=C(OC)C(OC)=C1 PEQJBOMPGWYIRO-UHFFFAOYSA-N 0.000 claims abstract description 3
NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims abstract 2
125000005115 alkyl carbamoyl group Chemical group 0.000 claims abstract 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
150000003839 salts Chemical class 0.000 claims description 23
125000001424 substituent group Chemical group 0.000 claims description 22
238000001727 in vivo Methods 0.000 claims description 19
125000006239 protecting group Chemical group 0.000 claims description 18
125000000217 alkyl group Chemical group 0.000 claims description 16
150000001408 amides Chemical class 0.000 claims description 13
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
239000003795 chemical substances by application Substances 0.000 claims description 7
230000003213 activating effect Effects 0.000 claims description 6
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
239000003814 drug Substances 0.000 claims description 4
229910052705 radium Inorganic materials 0.000 claims description 4
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
239000002243 precursor Substances 0.000 claims description 3
125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
IKNZBNHVVQIRTO-UHFFFAOYSA-N 2h-tetrazole-5-carboxylic acid Chemical group OC(=O)C=1N=NNN=1 IKNZBNHVVQIRTO-UHFFFAOYSA-N 0.000 claims description 2
GMMBETCEGBXFIY-UHFFFAOYSA-N 6-[(2-methoxyphenyl)methylamino]pyridine-3-carboxylic acid Chemical compound COC1=CC=CC=C1CNC1=CC=C(C(O)=O)C=N1 GMMBETCEGBXFIY-UHFFFAOYSA-N 0.000 claims description 2
241000124008 Mammalia Species 0.000 claims description 2
101001003232 Mus musculus Immediate early response gene 2 protein Proteins 0.000 claims description 2
150000001204 N-oxides Chemical class 0.000 claims description 2
125000005322 morpholin-1-yl group Chemical group 0.000 claims description 2
KDNIOKSLVIGAAN-UHFFFAOYSA-N 2-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC=CC=C1C(O)=O KDNIOKSLVIGAAN-UHFFFAOYSA-N 0.000 claims 1
FBEXNBDUERYLOP-UHFFFAOYSA-N 4-[(2-methoxyphenyl)methylamino]benzoic acid Chemical compound COC1=CC=CC=C1CNC1=CC=C(C(O)=O)C=C1 FBEXNBDUERYLOP-UHFFFAOYSA-N 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 claims 1
229960004889 salicylic acid Drugs 0.000 claims 1
125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 10
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 7
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 7
125000001589 carboacyl group Chemical group 0.000 abstract description 4
125000004356 hydroxy functional group Chemical group O* 0.000 abstract 4
125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 3
125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
125000002861 (C1-C4) alkanoyl group Chemical group 0.000 abstract 1
125000004423 acyloxy group Chemical group 0.000 abstract 1
125000005236 alkanoylamino group Chemical group 0.000 abstract 1
125000004466 alkoxycarbonylamino group Chemical group 0.000 abstract 1
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 150
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 130
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 127
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
239000000243 solution Substances 0.000 description 66
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 52
238000000034 method Methods 0.000 description 52
238000006243 chemical reaction Methods 0.000 description 50
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
239000000203 mixture Substances 0.000 description 46
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
239000007787 solid Substances 0.000 description 38
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
239000000047 product Substances 0.000 description 22
229910052799 carbon Inorganic materials 0.000 description 20
239000012044 organic layer Substances 0.000 description 19
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
229920006395 saturated elastomer Polymers 0.000 description 18
229910052943 magnesium sulfate Inorganic materials 0.000 description 17
239000011541 reaction mixture Substances 0.000 description 17
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
229960000583 acetic acid Drugs 0.000 description 16
238000000921 elemental analysis Methods 0.000 description 16
239000012267 brine Substances 0.000 description 15
RUUOPSRRIKJHNH-UHFFFAOYSA-N pyridazine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=N1 RUUOPSRRIKJHNH-UHFFFAOYSA-N 0.000 description 15
230000002829 reductive effect Effects 0.000 description 15
239000002904 solvent Substances 0.000 description 15
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
229910052786 argon Inorganic materials 0.000 description 13
239000002585 base Substances 0.000 description 13
229910000027 potassium carbonate Inorganic materials 0.000 description 13
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
238000003820 Medium-pressure liquid chromatography Methods 0.000 description 12
239000003921 oil Substances 0.000 description 12
235000019198 oils Nutrition 0.000 description 12
235000017557 sodium bicarbonate Nutrition 0.000 description 12
229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
238000012360 testing method Methods 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
230000015572 biosynthetic process Effects 0.000 description 11
125000001246 bromo group Chemical group Br* 0.000 description 11
235000011181 potassium carbonates Nutrition 0.000 description 11
DMYLUKNFEYWGCH-UHFFFAOYSA-N pyridazine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=N1 DMYLUKNFEYWGCH-UHFFFAOYSA-N 0.000 description 11
238000010992 reflux Methods 0.000 description 11
XIUVRDRLZYFQCI-UHFFFAOYSA-N 6-[[5-bromo-2-(cyclopropylmethoxy)phenyl]methyl-ethylamino]pyridazine-3-carboxylic acid Chemical compound C=1C=C(C(O)=O)N=NC=1N(CC)CC1=CC(Br)=CC=C1OCC1CC1 XIUVRDRLZYFQCI-UHFFFAOYSA-N 0.000 description 10
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
125000002252 acyl group Chemical group 0.000 description 10
125000001309 chloro group Chemical group Cl* 0.000 description 10
239000002244 precipitate Substances 0.000 description 10
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
229960004132 diethyl ether Drugs 0.000 description 9
230000000694 effects Effects 0.000 description 9
239000000284 extract Substances 0.000 description 9
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 9
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
235000019270 ammonium chloride Nutrition 0.000 description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
239000006260 foam Substances 0.000 description 8
210000003405 ileum Anatomy 0.000 description 8
239000000725 suspension Substances 0.000 description 8
238000003786 synthesis reaction Methods 0.000 description 8
238000004809 thin layer chromatography Methods 0.000 description 8
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
238000004587 chromatography analysis Methods 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
239000001117 sulphuric acid Substances 0.000 description 7
AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
NMCKZYHQHAZHIO-UHFFFAOYSA-N 6-chloropyridazine-3-carboxamide Chemical compound NC(=O)C1=CC=C(Cl)N=N1 NMCKZYHQHAZHIO-UHFFFAOYSA-N 0.000 description 6
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
241000282414 Homo sapiens Species 0.000 description 6
241001465754 Metazoa Species 0.000 description 6
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
239000005557 antagonist Substances 0.000 description 6
QGEIXOVZBMCRHR-UHFFFAOYSA-N butyl 6-[(5-bromo-2-hydroxyphenyl)methyl-ethylamino]pyridazine-3-carboxylate Chemical compound N1=NC(C(=O)OCCCC)=CC=C1N(CC)CC1=CC(Br)=CC=C1O QGEIXOVZBMCRHR-UHFFFAOYSA-N 0.000 description 6
125000001153 fluoro group Chemical group F* 0.000 description 6
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
229910000041 hydrogen chloride Inorganic materials 0.000 description 6
230000007062 hydrolysis Effects 0.000 description 6
238000006460 hydrolysis reaction Methods 0.000 description 6
239000010410 layer Substances 0.000 description 6
WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 6
239000012279 sodium borohydride Substances 0.000 description 6
229910000033 sodium borohydride Inorganic materials 0.000 description 6
238000003756 stirring Methods 0.000 description 6
235000011149 sulphuric acid Nutrition 0.000 description 6
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
ZWMUNUOJAOFVHX-UHFFFAOYSA-N 6-[[5-bromo-2-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl]methyl-ethylamino]pyridazine-3-carboxylic acid Chemical compound C=1C=C(C(O)=O)N=NC=1N(CC)CC1=CC(Br)=CC=C1OCC(O)C(F)(F)F ZWMUNUOJAOFVHX-UHFFFAOYSA-N 0.000 description 5
VZDUVYKVJJHFGC-UHFFFAOYSA-N 6-[[5-chloro-2-(cyclopropylmethoxy)phenyl]methyl-ethylamino]pyridazine-3-carboxamide Chemical compound C=1C=C(C(N)=O)N=NC=1N(CC)CC1=CC(Cl)=CC=C1OCC1CC1 VZDUVYKVJJHFGC-UHFFFAOYSA-N 0.000 description 5
YMUOLGNUZURDEW-UHFFFAOYSA-N 6-chloropyridazine-3-carbonitrile Chemical compound ClC1=CC=C(C#N)N=N1 YMUOLGNUZURDEW-UHFFFAOYSA-N 0.000 description 5
239000000010 aprotic solvent Substances 0.000 description 5
XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 5
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
201000008482 osteoarthritis Diseases 0.000 description 5
230000008569 process Effects 0.000 description 5
238000000746 purification Methods 0.000 description 5
239000007858 starting material Substances 0.000 description 5
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
QTYSIKBFSFIFOD-UHFFFAOYSA-N 6-[[5-chloro-2-(2-methylpropoxy)phenyl]methyl-ethylamino]pyridazine-3-carboxylic acid Chemical compound C=1C=C(C(O)=O)N=NC=1N(CC)CC1=CC(Cl)=CC=C1OCC(C)C QTYSIKBFSFIFOD-UHFFFAOYSA-N 0.000 description 4
101150041968 CDC13 gene Proteins 0.000 description 4
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
125000003435 aroyl group Chemical group 0.000 description 4
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 4
238000004440 column chromatography Methods 0.000 description 4
238000010511 deprotection reaction Methods 0.000 description 4
229960002986 dinoprostone Drugs 0.000 description 4
XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
239000005457 ice water Substances 0.000 description 4
CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
230000002401 inhibitory effect Effects 0.000 description 4
ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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