AU2930392A - 3-pyridinol derivatives and their use as medicaments - Google Patents
3-pyridinol derivatives and their use as medicamentsInfo
- Publication number
- AU2930392A AU2930392A AU29303/92A AU2930392A AU2930392A AU 2930392 A AU2930392 A AU 2930392A AU 29303/92 A AU29303/92 A AU 29303/92A AU 2930392 A AU2930392 A AU 2930392A AU 2930392 A AU2930392 A AU 2930392A
- Authority
- AU
- Australia
- Prior art keywords
- compound
- formula
- group
- hereinbefore defined
- reacting
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
- 239000003814 drug Substances 0.000 title claims description 7
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical class OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 259
- -1 P (Z) (OH) (OR2.) Inorganic materials 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 17
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 239000002243 precursor Substances 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 229910006069 SO3H Inorganic materials 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 239000012025 fluorinating agent Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- UUSJZSSSJMSSSA-UHFFFAOYSA-N ethoxy-(3-hydroxy-5-naphthalen-2-ylpyridin-2-yl)phosphinic acid Chemical compound CCOP(=O)(C1=C(C=C(C=N1)C2=CC3=CC=CC=C3C=C2)O)O UUSJZSSSJMSSSA-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000004291 sulphur dioxide Substances 0.000 claims description 4
- 235000010269 sulphur dioxide Nutrition 0.000 claims description 4
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- IMRGDWGUNWSPCC-UHFFFAOYSA-N 5-(2,4-dipropoxyphenyl)-2-(2H-tetrazol-5-yl)pyridin-3-ol Chemical compound C(CC)OC1=C(C=CC(=C1)OCCC)C=1C=C(C(=NC1)C1=NN=NN1)O IMRGDWGUNWSPCC-UHFFFAOYSA-N 0.000 claims description 3
- ANRVSVSQGLWLHC-UHFFFAOYSA-N 5-(4-methoxy-3-propoxyphenyl)-3-(2h-tetrazol-5-yl)-2h-pyridin-3-ol Chemical compound C1=C(OC)C(OCCC)=CC(C=2C=NCC(O)(C=2)C2=NNN=N2)=C1 ANRVSVSQGLWLHC-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 3
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000005561 phenanthryl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 30
- 239000002585 base Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 239000003960 organic solvent Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- 229960004132 diethyl ether Drugs 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 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 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 230000008602 contraction Effects 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 4
- JJLIHTCEFNQHGH-UHFFFAOYSA-N (5-chloropyridin-3-yl) trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CN=CC(Cl)=C1 JJLIHTCEFNQHGH-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 206010007559 Cardiac failure congestive Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-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
- 150000001450 anions Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 150000005826 halohydrocarbons Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000002346 iodo group Chemical group I* 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical group [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- ZNGNDOSZRKWKJW-UHFFFAOYSA-N (2,4-dipropoxyphenyl)boronic acid Chemical compound CCCOC1=CC=C(B(O)O)C(OCCC)=C1 ZNGNDOSZRKWKJW-UHFFFAOYSA-N 0.000 description 2
- PGVBHBWAIOOUAA-UHFFFAOYSA-N (4-methoxy-3-propoxyphenyl)boronic acid Chemical compound CCCOC1=CC(B(O)O)=CC=C1OC PGVBHBWAIOOUAA-UHFFFAOYSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 2
- 229940035437 1,3-propanediol Drugs 0.000 description 2
- WRVKWDXNFSAJLZ-UHFFFAOYSA-N 1-methoxy-4-nitro-2-propoxybenzene Chemical compound CCCOC1=CC([N+]([O-])=O)=CC=C1OC WRVKWDXNFSAJLZ-UHFFFAOYSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
- DPMPVZBUODSGKE-UHFFFAOYSA-N 2-diethoxyphosphoryl-5-naphthalen-2-ylpyridin-3-ol Chemical compound C1=C(O)C(P(=O)(OCC)OCC)=NC=C1C1=CC=C(C=CC=C2)C2=C1 DPMPVZBUODSGKE-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- ZWBQQTMEEAZAEF-UHFFFAOYSA-N 3-chloro-5-(2,4-dipropoxyphenyl)pyridine Chemical compound CCCOC1=CC(OCCC)=CC=C1C1=CN=CC(Cl)=C1 ZWBQQTMEEAZAEF-UHFFFAOYSA-N 0.000 description 2
- JBWHPCNCXDHLET-UHFFFAOYSA-N 3-chloro-5-(4-methoxy-3-propoxyphenyl)pyridine Chemical compound C1=C(OC)C(OCCC)=CC(C=2C=C(Cl)C=NC=2)=C1 JBWHPCNCXDHLET-UHFFFAOYSA-N 0.000 description 2
- PSKQSAGJZQJLNG-UHFFFAOYSA-N 3-chloro-5-naphthalen-2-ylpyridine Chemical compound ClC1=CN=CC(C=2C=C3C=CC=CC3=CC=2)=C1 PSKQSAGJZQJLNG-UHFFFAOYSA-N 0.000 description 2
- XKCAARCUAAEMHG-UHFFFAOYSA-N 3-methoxy-5-naphthalen-2-ylpyridine Chemical compound COC1=CN=CC(C=2C=C3C=CC=CC3=CC=2)=C1 XKCAARCUAAEMHG-UHFFFAOYSA-N 0.000 description 2
- VDKBSHLNXWWHTE-UHFFFAOYSA-N 4-iodo-1-methoxy-2-propoxybenzene Chemical compound CCCOC1=CC(I)=CC=C1OC VDKBSHLNXWWHTE-UHFFFAOYSA-N 0.000 description 2
- ANOKHKHYCQIKGJ-UHFFFAOYSA-N 5-(2,4-dipropoxyphenyl)-3-phenylmethoxypyridine-2-carbonitrile Chemical compound CCCOC1=CC(OCCC)=CC=C1C1=CN=C(C#N)C(OCC=2C=CC=CC=2)=C1 ANOKHKHYCQIKGJ-UHFFFAOYSA-N 0.000 description 2
- PIKCOJUOTHTOAI-UHFFFAOYSA-N 5-(4-methoxy-3-propoxyphenyl)-3-phenylmethoxypyridine-2-carbonitrile Chemical compound C1=C(OC)C(OCCC)=CC(C=2C=C(OCC=3C=CC=CC=3)C(C#N)=NC=2)=C1 PIKCOJUOTHTOAI-UHFFFAOYSA-N 0.000 description 2
- TUIDQYRZDZRHPQ-UHFFFAOYSA-N 5-chloropyridin-3-ol Chemical compound OC1=CN=CC(Cl)=C1 TUIDQYRZDZRHPQ-UHFFFAOYSA-N 0.000 description 2
- FOXOPBOTUCTZLL-UHFFFAOYSA-N 5-naphthalen-2-ylpyridin-3-ol Chemical compound OC1=CN=CC(C=2C=C3C=CC=CC3=CC=2)=C1 FOXOPBOTUCTZLL-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Description
3-PYRIDINOL DERIVATIVES AND THEIR USE AS MEDICAMENTS.
The present invention relates to pyridinol derivatives, processes for their preparation, intermediates in their preparation, their use as medicaments and to pharmaceutical compositions comprising them.
The compounds of this invention are agonists of a cyclic AMP- dependent protein kinase (cA-PrK) (see J. Biol. Chem., 1989, 264, 8443 - 8446) and are of use in combatting such
conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, positive lusitropic, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of
cardiovascular diseases where there is a component of
diastolic failure, cancer, psoriasis, atheroschlerosis, thrombosis, re-stenosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome.
Accordingly the present invention provides compounds of the formula (1) :
or pharmaceutically acceptable salts thereof, wherein :
R0 is OH or a bioprecursor thereof,
R1 is A0CO2H, P(Z) (OH) (OR2), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof,
A0 is CH2, CHF, CF2, CR3(OR4), CO or C(OR5) (OR6),
R2 is phenyl, C3-5cycloalkyl, C3-5cycloalkylCι_4alkyl, or C1-8alkyl optionally substituted by C1-4alkoxy, R3 is H, methyl or ethyl,
R4 is H or C1-3alkyl,
R5 and R6 are each C1-3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group,
Z is O or S, and
Ar is phenyl optionally substituted by one to three groups independently selected from C1-6galkyl, C2-6 -lkenyl, C1-6alkoxy, C3-6alkenyloxy, C3-6cycloalkyl,
C3-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, N(R7)2 or NHCOR7 wherein R7 is H or C1-6alkyl, or -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or O and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy, C3-6cycloalkyl, N(R7)2, CO2R7 or CON(R7)2, or
Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or C1-6alkoxy,
3-phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl.
Bioprecursors of the groups R0 and R1 are derivatives thereof which are convertible in vivo into the groups R0 and R1. A suitable bioprecursor of the group R0 is OR8 wherein R8 is C1-4alkanoyl (for example acetyl), arylC1-4alkanoyl (for example phenyl C1-4alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or
toluenesulphonyl) or C1-4alkylsulphonyl
(for example methylsulphonyl) .
When R1 is A0CO2H a suitable bioprecursor is A0CO2R9 wherein R9 is an ester-forming group.
When R1 is P(Z) (OH) (OR2) a suitable bioprecursor is
P(Z) (OR2) 2 wherein Z and R2 are as hereinbefore defined or P(Z) (OR2) (OR10) wherein R10 is an O-protecting group.
Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.
When R1 is 5-tetrazolyl, a suitable bioprecursor is an
N-protected derivative thereof. Suitable N-protecting groups include pivalolyloxymethyl, propionyloxymethyl and
pivalolyloxycarbonyloxymethyl.
Alternatively bioprecursors of the groups R0 and R1 are those formed when R1 and R0 are linked together to form a cyclic structure such that R1-R0 is A1C02 or A2OCH2O, in which :
A1 is CH2, CHF, CF2, CR3(OR4), CO or C(OR5) (OR6),
A2 is P(Z)OR2 or CR3 (CO2R9), and R2 to R6, R9 and Z are as hereinbefore defined.
Suitably R0 is hydroxy or OR8, preferably hydroxy.
Suitably R1 is A0CO2H or A0CO2R9.
Suitably R1 is P(Z) (OH) (OR2) or P(Z) (OR2)2.
Suitably R1 is SO2H, SO3H or 5-tetrazolyl. Suitably R1 and R0 are linked together such that R1-R0 0s A1CO2.
Suitably R1 and R0 are linked together such that R1-R0 is A2OCH2O.
By the term alkyl is meant both straight- and branched- chain alkyl. By the term C1-6polyfluoroalkyl is meant a C1-6alkyl group having at least one hydrogen replaced with fluoro, e.g. CF3 or CF2CF2H.
Suitably R2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.
Suitably R3 is H, methyl or ethyl, preferably H or methyl. Suitably R4 is H, methyl, ethyl or propyl, preferably H or methyl.
Suitably R5 and R6 are independently methyl, ethyl or propyl, preferably together they form a 1,2-ethanediyl group.
Preferably Z is 0.
Suitably R9 is C1-4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or arylC1-4alkyl (for example
phenylC1-4alkyl such as benzyl).
Suitably Ar is phenyl optionally mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4
positions by C1-6alkyl, C1-6alkoxy, C3-6alkenyloxy,
C1-6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR7.
Suitably Ar is phenyl di-substituted by any groups as
hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4- or 2,5-, positions by groups independently selected from
C2-6alkenyl, C1-6alkoxy, C3-6cycloalkoxy, halo, -X(CH2)nY- or C1-6alkoxyC1-6 alkoxy.
Suitably Ar is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or 3,4,5-positions by groups independently selected from
C2-6alkenyl, C1-6alkoxy or halo.
Suitably Ar is 1-naρhthyl optionally substituted in the 4-position by hydroxy or C^-galkoxy. Suitably Ar is
2-naphthyl optionally substituted in the 1-position by hydroxy or C1-6alkoxy.
Suitably Ar is 3-phenanthryl or 9-phenanthryl.
Suitably Ar is 2-quinolinyl or 4-quinolinyl. Suitably Ar is 2-benzofuranyl or 3-thianaphthenyl.
Examples of C1-6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy. Examples of C1-6alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.
Examples of halo include fluoro, chloro, bromo or iodo. Particular compounds of this invention include : ethyl [5-(2-naphthyl)-3-hydroxy-2-pyridyl]phosphonate, 5-(2,4-dipropoxyphenyl)-2-(5-tetrazolyl)pyridin-3-ol, or
5-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-3-ol, and pharmaceutically acceptable salts thereof. This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula (1).
Compounds of the formula (1) can form pharmaceutically acceptable base addition salts with metal ions, such as
alkali metals for example sodium or potassium, or with an ammonium ion.
In order to use a compound of the formula (1) or a
pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in
accordance with standard pharmaceutical practice as a
pharmaceutical composition. Compounds of formula (1) and their pharmaceutically
acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration.
Compounds of formula (1) and their pharmaceutically
acceptable salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be
considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous
or non-aqueous carrier optionally containing a parenterally
acceptable oil or solubilising agent, for example
polyethylene glycol, polyvinylpyrrolidone, lecithin,
2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil. A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream,
ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably from 0.001 mg/Kg to 30 mg/Kg, and preferably from 0.005 mg/Kg to 15 mg/Kg, and each dosage unit for parenteral
administration contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid.
The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the
formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The active ingredient may be administered as required for example from 1 - 8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combatting such conditions where such agonism is thought to be beneficial. Such conditions can be treated by administration orally, sublingually topically, rectally, parenterally or by
inhalation. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1 - 5.0 mg of a compound of the formula (1) or a pharmaceutically acceptable salt thereof. The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently the compounds of this invention and the other active compound or compounds are formulated in a single pharmaceutical
composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula (1) are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example
theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine H1-antagonists, drugs used in the treatment of cancer such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, fluoracil, cisplatin, actinomycin D, anti- atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the treatment of psoriasis, for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin,
antithrombotics for example dipyridamole, or fibrinolytic agents.
In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or
pharmaceutically acceptable salts thereof, which process comprises : a) for compounds wherein R1 is A0CO2H or A0CO2R9 and : i) A0 is CR3(OR4),
reacting in the presence of a strong base a compound of the formula (2) :
wherein R11 is an O-protecting group and Ar is as
hereinbefore defined, with a compound of the formula (3) :
R3COCO2R9 (3) wherein R3 and R9 are as hereinbefore defined to form a compound of the formula (4) :
wherein R12 is CR3(OH)CO2R9 and R3, R9, R11, and Ar are as hereinbefore defined and thereafter optionally reacting with a C1-3alkylating agent to form the corresponding compound wherein R12 is CR3 (OC1-3alkyl) CO2R9,
ii) A0 is CO,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with a compound of the formula (5) :
R9O2CCO2R9 (5) wherein R9 is as hereinbefore defined to form a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11 and Ar are as hereinbefore defined, iii) A0 is CH(OH),
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R12 is CH(OH)CO2R9, iv) A0 is CH2,
reacting a compound of the formula (4) wherein R12 is COCO2H or COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R12 is CH2CO2H, v) A0 is C(OR5)(OR6),
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a
C1-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R12 is C(OR5) (OR6)CO2R9, vi) A0 is CF2,
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a
fluorinating agent to form the corresponding compound wherein R11 is CF2CO2R9, or vii) A0 is CHF,
reacting a compound of the formula (4) wherein R12 is
CH(OH)CO2R9 and R9, R11, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R12 is CHFCO2R9, and thereafter optionally : º converting the group OR11 into OH º converting the group A0CO2R9 into A0CO2H; or b) for compounds wherein R1 is CH2CO2H,
converting a compound of the formula (6) :
wherein R13 is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is CH2CO2H; or c) for compounds wherein R1 is CH(OR4)CO2H reacting a compound of the formula (4) wherein R12 is -CH(OH)CN with a C1-3alkylating agent and/or converting the group CN into CO2H, and optionally converting the group OR11 into OH; or d) for compounds wherein R1 is P (O) (OH) (OR2),
hydrolysing a compound of the formula (6) wherein R13 is P (O) (OR2)2 and R2, and Ar are as hereinbefore defined; or e) for compounds wherein R1 is P(S) (OH) (OR2), converting a compound of the formula (6) wherein R13 is P (O) (NHR14) (OR2) and R14 is phenyl or C1-4alkyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is
P(S) (OH) (OR2); or
f) for compounds where R1 is SO3H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR11 into OH; or g) for compounds wherein R1 is SO2H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide and optionally converting the group OR11 into OH; or h) for compounds wherein R1 is 5-tetrazolyl, reacting a compound of the formula (4) wherein R12 is cyano or a compound of the formula (6) wherein R13 is cyano with an azide salt and thereafter if necessary converting the group OR11 into OH; or i) for compounds wherein R1 is as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7):
wherein Rb is a group R1 as hereinbefore defined or a
precursor thereof and Ra is a group R0 as hereinbefore defined or a precursor thereof and L is a leaving group with a compound of the formula (8):
ArB(OH)2 (8) or a chemical equivalent thereof wherein Ar is as
hereinbefore defined and then, if necessary, converting a
precursor of R1 into R1 and/or converting a precursor of R0 into R0, and optionally thereafter :
° forming a bioprecursor of R0 and/or R1
° forming a pharmaceutically acceptable salt. Suitably a compound of the formula (2) is reacted with a strong base such as lithium diisopropylamide, or a C1 - 4alkyl lithium or aryl lithium such as mesityl lithium in an organic solvent such as tetrahydrofuran, diethylether or
dimethoxyethane with cooling (-100° - 0°C) to form the anion thereof. The strong base may be formed in situ, for example by the addition of a C1-4alkyl lithium e.g. methyllithium followed by a catalytic quantity of diisopropylamine.
The anion of a compound of the formula (2) is suitably reacted with, a compound of the formula (3) or a compound of the formula (5) in an organic solvent such as
tetrahydrofuran, diethylether or dimethoxyethane with cooling (-100° to 0°C) to form a compound of the formula (4) wherein R12 is CR3(OH)CO2R9 or COCO2R9 respectively. A suitable compound of the formula (3) is ethylpyruvate, or ethyl glyoxylate or a chemical equivalent thereof and a suitable compound of the formula (5) is diethyloxalate.
A compound of the formula (4) wherein R12 is CR3(OH)CO2R9 is suitably reacted with a Cι_3alkylating agent such as
iodomethane, iodopropane or dimethylsulphate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or
dimethylsulphoxide at elevated (e.g. 30 - 80°C) or preferably ambient temperature to form the corresponding compound
wherein R12 is CR3 (OC1-3alkyl) CO2R9. When potassium
hydroxide is used as base the CO2R9 group may be directly converted to carboxy.
A compound of the formula (4) wherein R12 is COCO2R9 is suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a C1-4alcohol e.g. ethanol, or acetic acid or mixtures thereof at ambient or elevated temperature (e.g. 30 - 80°C), or with cooling (e.g. 0 - 5°C) to form the corresponding compound wherein R12 is
CH(OH) CO2R9. A compound of the formula (4) wherein R12 is COCO2H or
COCO2R9 is suitably reacted with a reducing agent such as a zinc amalgam in hydrochloric acid in the absence of a solvent or in a solvent such as ethanol, acetic acid or dioxan and hydrogen chloride gas at ambient or elevated temperature (e.g. 40-100°C) to form the corresponding compound wherein R12 is CH2CO2H. Under these reaction conditions the CO2R9 group is converted to carboxy.
A compound of the formula (4) wherein R12 is COCO2R9 is suitably reacted with a C1-3alcohol, 1,2-ethanediol or 1,3- propanediol in the presence of an acid catalyst such as paratoluenesulphonic acid, concentrated sulphuric acid or anhydrous hydrogen chloride, at ambient or elevated
temperature to form the corresponding compound wherein R12 is C(OR5) (OR6)CO2R9.
A compound of the formula (4) wherein R12 is COCO2R9 or
CHOHCO2R9 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as a halohydrocarbon or an ether such as glyme, or THF at ambient or elevated temperature (e.g. 30-60°C) to form the corresponding compound where R12 is CF2CO2R9 or CHFCO2R9 respectively. Examples of O-protecting groups for R11 include methyl or benzyl. A compound of the formula (4) wherein OR11 is
methoxy can suitably be converted to the corresponding
compound wherein OR11 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such
as acetonitrile, or a halohydrocarbon e.g. dichloromethane or chloroform at elevated (e.g. 30 - 80°C) or preferably ambient temperature. This method is particularly suitable for preparing compounds of the formula (1) wherein R1 is A0CO2R9 since the ester-forming group R9 is not hydrolysed under the reaction conditions. Another method utilises sodium
thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature for example 40 - 120°C. The more forcing conditions of this method are suitable for preparing compounds of formula (1) wherein R1 is A0CO2H. Alternatively a compound of the formula (4) wherein OR11 is benzyloxy can be converted to the corresponding compound wherein OR11 is hydroxy in conventional manner, for example catalytic
hydrogenation on palladium on carbon or reacting with sodium in liquid ammonia.
A compound of the formula (4) wherein R12 is A0CO2R9 can suitably be converted to the corresponding compound wherein R12 is A0CO2H by reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature
(e.g. 40 - 120°). This method is particularly suitable for preparing compounds of the formula (1) wherein R0 is methoxy since the OR11 group is not hydrolysed. Another hydrolysis method utilises aqueous acid such as concentrated
hydrochloric acid at an elevated temperature (e.g. 40 ¬
120°C) which provides directly compounds of the formula (1) wherein R0 is hydroxy and R1 is A0CO2H.
Suitably a compound of the formula (6) wherein R13 is acetyl is converted to the corresponding compound where R13 is
CH2CO2H by reaction with sulphur and morpholine
at elevated temperature (e.g. 50 - 200°C), followed by
hydrolysis with an aqueous base such as sodium hydroxide at elevated temperature, preferably at the reflux temperature of the reaction mixture.
Suitably a compound of formula (4) where R12 is -CH(OH)CN is reacted with a C1-3alkylating agent as hereinbefore described followed by reaction with aqueous mineral acid such as
hydrochloric acid at ambient or elevated temperature, preferably at reflux in order to prepare the corresponding compound where R12 is CH(OC1-3alkyl) CO2H. The alkylation can be omitted if the corresponding compound where R12 is CH(OH)CO2H is desired. During the hydrolysis of the CN group the OR11 group may be converted to hydroxy. If not and if desired this group can be converted to hydroxy as
hereinbefore described. A compound of the formula (4) wherein R12 is -CH(OH)CN can be prepared by reacting the corresponding compound wherein R12 is -CHO with a source of cyanide such as potassium cyanide in the presence of acid such as hydrochloric acid, preferably at ambient temperature.
A compound of the formula (4) or (6) where R12 or R13 is CHO is suitably prepared by reacting the corresponding compound wherein R12 or R13 is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by aqueous acidic work-up.
Suitably a compound of the formula (6) wherein R13 is
P(O) (OR2)2 is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a C1-4alcohol at an elevated temperature (e.g. 40-100°C), preferably at the reflux temperature of the reaction mixture.
Suitably a compound of the formula (6) wherein R13 is
P (O) (NHR14) (OR2) is converted to the corresponding compound wherein R9 is P (S) (OH) (OR2) by reaction with a strong base such as sodium hydride in an organic solvent such as
dimethoxyethane at ambient or elevated temperature, (e.g. 40 - 100°C) followed by reaction with carbon disulphide. Suitably the anion of a compound of the formula (2) prepared as hereinbefore described is reacted with sulphuryl chloride or a chemical equivalent thereof or with sulphur dioxide in an organic solvent such as tetrahydrofuran with cooling (- 100° - 0°C) to form after aqueous work-up a compound of the
formula (4) wherein R12 is SO3H or SO2H respectively and OR11 is as hereinbefore defined which if desired can be converted to the corresponding compound wherein OR11 is hydroxy as hereinbefore described.
A compound of the formula (4) wherein R12 is cyano or a compound of the formula (6) wherein R13 is cyano is suitably reacted with an azide salt such as ammonium, sodium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone or
tetrahydrofuran at an elevated temperature e.g. 40-200°C, preferably at 100-150°C to form the corresponding
5-tetrazolyl compound. Preferably in a compound of the formula (4) OR11 is benzyloxy since this group is converted directly to hydroxy under the reaction conditions.
Suitably a compound of the formula (7) is reacted with a compound of the formula (8) in the presence of 1-50 mole %, preferably 2-10 mole %, of a palladium catalyst and a base such as triethylamine, sodium bicarbonate, or aqueous sodium carbonate and optionally lithium chloride in an organic solvent such as dimethylformamide, dimethoxyethane,
acetonitrile, toluene, tetrahydrofuran, ethanol, or mixtures thereof, at elevated temperature, (e.g. 30-150°C), preferably at the reflux temperature of the mixture. Suitably L1 is halo for example iodo, bromo or chloro, preferably L1 is a trifluoromethanesulphonate. Examples of palladium catalysts that can be used include: tetrakis(triphenylphosphine)palladium (Pd[PPh3]4),
bis(triphenylphosphine)palladium dichloride (Pd[PPh3]2CI2), [1,4-bis-(diphenylphosphine)butane]palladium dichloride
(Pd(dppb)Cl2),
[1,3-bis-(diphenylphosphine)propane]palladium dichloride
(Pd(dppp)Cl2),
[1,2-bis-(diphenylphosphine)ethane]palladium dichloride
(Pd(dppe)Cl2),
is (tri-o-tolylphosphine) palladium diacetate or dichloride
(Pd (totp) (OAc) 2 or Pd (totp) Cl2) , or
1,1 -bis(diphenylphosphine)ferrocinopalladium diacetate or dichloride (PdCdppf] (OAc)2 or Pd[dppf]Cl2).
By a chemical equivalent of a compound of the formula (8) is meant a reagent that can couple the Ar group onto the pyridyl ring of a compound of the formula (7). For example aryl stannanes can be used, such as ArSnMe3 which can suitably be prepared by reacting a suitable aryl halide (such as ArBr or Arl) with a base such as t-butyl lithium followed by reaction with a trimethyl tin halide (e.g. Me3SnCl). Alternatively the aryl halide can be reacted with Me3SnSnMe3 in the
presence of a palladium catalyst as hereinbefore described to prepare a suitable aryl stannane. When Ra is a group R0 as hereinbefore defined and Rb is a group R1 as hereinbefore defined, reaction of a compound of the formula (7) with a compound of the formula (8) results directly in compounds of the formula (1). An example of a precursor for R1 is when Rb is hydrogen.
Examples of a precursor for R0 is when Ra is halo, such as chloro, which can be converted to another precursor OR11, such as methoxy or benzyloxy by reaction with either sodium methoxide or benzyl alcohol and a base such as potassium tert butoxide preferably in the presence of a crown ether such as 18-crown-6 or 15-crown-5. Preferably a compound of the formula (7) wherein Ra is chloro, Rb is hydrogen and L1 is trifluoromethane sulphonate is reacted with a compound of the formula (8) or a chemical equivalent thereof, followed by conversion of Ra being chloro to Ra being OR11 to form a compound of the formula (2). Such a compound can then be converted into a compound of the formula (1) as herein
described. Other precursors for R1 include CN, CHO or COMe. Reaction of a compound of the formula (7) wherein Rb represents such a precursor and Ra is OH or OR11 with a compound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (4) or a compound of the formula (6) wherein R12
or R13 is CN, CHO or COMe. Such compounds can be converted to compounds of the formula (1) as herein described.
If desired a compound of the formula (1) wherein R1 is A0CO2 can be converted to the corresponding compound wherein R1 is A0CO2R9 by reaction with a compound R9OH wherein R9 is as hereinbefore defined.
A compound of the formula (1) wherein R^ is OH can be converted to the corresponding compound where R^ is OR^ by reaction with R8L2 wherein R8 is as hereinbefore defined an L2 is a leaving group such as halo e.g. bromo, chloro, iodo.
If desired a compound of the formula (1) wherein R1 is
P (Z) (OR2) (OH) can be converted to the corresponding compound wherein R1 is P(Z) (OR2) (OR10) by reaction with a suitable O-protecting agent in standard manner. For example the compound can be reacted with a pivalolyloxymethyl halide. A compound of the formula (1) wherein R1 is 5-tetrazole can be reacted with a suitable N-protecting agent in standard manner, for example with a pivalolyloxymethyl halide.
A compound of the formula (1) wherein R1-R0 is A1CO2 is suitably prepared by heating a compound of the formula (1) wherein R1 is A1CO2H and R0 is OH with a dehydrating agent such as acetic anhydride, at an elevated temperature (e.g. 40 - 200°C), preferably at the reflux temperature of the
reaction mixture .
A compound of the formula (1) wherein R1-R0 is A2OCH2O is suitably prepared by reacting a compound of the formula (1) wherein R1 is A2OH and R0 is OH with a dihalomethane such as diiodo- or dibromomethane in the presence of silver carbonate in an organic solvent such as dimethylformamide at an
elevated temperature (e.g. 40 - 120°C).
A compound of the formula (2) is suitably prepared by
reacting a compound of the formula (6) wherein R13 is
hydrogen with an O-methylating agent such as
dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (e.g. 40 - 120°C) or with iodomethane and silver carbonate in toluene or chloroform or with an O-benzylating agent such as benzyl bromide or chloride in the presence of a base such as
potassium carbonate or sodium hydride. This method can also be used for converting compounds of the formula (6) into corresponding compounds of the formula (4) and compounds of the formula (7) where Ra is hydroxy to corresponding
compounds wherein Ra is OR11.
A compound of the formula (6) wherein R13 is acetyl can also be prepared by reacting a compound of the formula (6) wherein R13 is cyano with methyl lithium followed by aqueous acidic work up with for example hydrochloric acid.
A compound of the formula (6) wherein R13 is hydrogen can be prepared by reacting a compound of the formula (6) wherein R13 is cyano with orthophosphoric acid at an elevated
temperature, e.g. 50 - 200°C.
A compound of the formula (6) wherein R13 is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R12 is cyano or acetyl and R11 and Ar are as hereinbefore defined with a demethylating agent or debenzylating agent as hereinbefore described. A compound of formula (4) wherein R12 is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein Ar and R11 are as hereinbefore defined with
dimethylformamide with cooling (e.g. -80 to 10°C), followed by ambient temperature and aqueous work-up. The resulting compound of formula (4) wherein R12 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature, e.g. 40-100°C, preferably at the reflux
temperature of the reaction mixture followed by dehydrating
the product obtained for example by heating with acetic anhydride.
A compound of the formula (4) where R12 is cyano is more suitably prepared by reacting a compound of the formula (9)
wherein Ar and R11 are as hereinbefore defined with a dimethyl carbamoyl halide such as the chloride folowed by reaction with trimethylsilylcyanide, conveniently at ambient temperature in a solvent such as dichloromethane.
A compound of the formula (9) is suitably prepared by reacting a compound of the formula (2) with an oxidising agent such as metachloroperbenzoic acid in an organic solvent such as dichloromethane.
A compound of the formula (6) wherein R13 is P (O) (OR2)2 can be prepared by treating a compound of the formula (2) wherein RH is P (O) (OR2)2 with a strong base such as lithium
diisopropylamide in an organic solvent such as
tetrahydrofuran with cooling (e.g. -100-0°C). A compound of the formula (2) wherein R11 is P (O) (OR2)2 is suitably prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (10):
L3P(0) (OR2)2 (10) wherein L3 is a leaving group and R2 is as hereinbefore defined with a base such as diisopropylethylamine.
Suitably L3 is halo, for example chloro or bromo.
A compound of formula (2) wherein R11 is P (O) (OR2)2 can also be prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (11): HP(O) (OR2)2 (11) wherein R2 is as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon tetrachloride. Alternatively, a compound of the formula (6) wherein R13 is P (O) (OR2)2 is suitably prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (10) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as
tetrahydrofuran with cooling (e.g. -100-0°C) without
isolation of the intermediate compound of the formula (2) wherein R11 is P (O) (OR2)2.
A compound of formula (6) wherein R13 is hydrogen is suitably prepared by demethylating or debenzylating a compound of formula (2) as hereinbefore defined. Suitably a compound of formula (2) wherein OR11 is methoxy is treated with boron tribromide in an organic solvent such as dichloromethane or toluene with cooling (e.g. -80 to 10°C) followed by ambient temperature and aqueous work-up. Or a compound of formula (2) is treated with sodium iodide and chlorotrimethylsilane at ambient or elevated temperature (e.g. 40-80°C)
conveniently ambient temperature in a solvent such as
acetonitrile or dichloromethane.
A compound of the formula (6) wherein R13 is P (O) (NHR14) (OR2) can be prepared by reaction of a compound of the formula (6) wherein R13 is P (O) (OH) (OR2) with carbon tetrachloride, triphenylphosphine and aniline or a Cι_4alkylamine in an organic solvent such as pyridine at ambient temperature or with cooling (e.g. -10 to 5°C). Alternatively a compound of the formula (6) where R13 is P (O) (OH) (OR2) can be reacted with dimethylformamide and oxalyl chloride in an organic solvent such as a halo hydrocarbon e.g. dichloromethane at
ambient temperature, followed by reaction with aniline or a C1-4alkylamine preferably with cooling (-10 to 5°C).
Compounds of the formula (7) are known or can be prepared in standard manner for example from a compound of the formula (12):
wherein Ra and L1 are as hereinbefore defined using similar methods to those described for preparing compounds of the formula (1). Thus, a compound of the formula (7) wherein Rb is P (O) (OR2)2 can be prepared by reacting a compound of the formula (12) wherein Ra is OH with a compound of the formula (10) or (11) in similar manner to the reaction of a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (10) or (11). If desired the group Ra can then be converted to OR11 as hereinbefore described.
Similarly, a compound of the formula (12) where Ra is OR11 can be treated in the presence of a strong base with a compound of the formula (3), a compound of the formula (5), sulphuryl chloride, sulphur dioxide or dimethylformamide to prepare a compound of the formula (7) wherein PP is
CR3(OR4)CO2R9, COCO2R9, SO3H, SO2H or CHO respectively in similar manner to the corresponding reaction with a compound of the formula (2) as hereinbefore described. Particularly suitable as a strong base is lithium tetramethyl piperidide.
A compound of the formula (12) wherein Ra is chloro and L1 is trifluoromethanesulphonate is suitably prepared by reacting 3-chloro-5-hydroxy pyridine with trifluoromethane sulphonic
anhydride in the presence of a suitable base, e.g. 4-N,N- dimethylaminopyridine in an organic solvent such as
dichloromethane. A compound of the formula (8) is suitably prepared by
reacting the organolithium or Grignard reagent, formed from a compound of the formula (13):
Ar-L4 (13) wherein L4 is bromo or iodo and Ar is as hereinbefore defined with a tri-C1-4alkylborate such as trimethyl, tri-isopropyl or tri-n-butyl borate in an organic solvent such as diethyl ether or tetrahydrofuran with cooling (e.g. - 80-10°C).
The Ar group in compounds of the formula (2), (4), (6) or (13) preferably (2) or (4) may be appropriately
functionalised by methods of aromatic substitution known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (eg. disubstituted in the 2- and 4-positions by electron-donating groups such as
C1-6alkoxy) by reaction with a brominating agent such as
N-bromosuccinimide or bromine in a solvent such as
dimethylformamide. Alternatively a nitro group can be
introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitronium tetrafluoroborate. Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR7 group by reaction with LCOR7 wherein L is a leaving group and R7 is as hereinbefore defined. Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR7).
Other suitable functionalisations include the introduction of an allyl group ortho to a hydroxy substituent on a phenyl ring by reaction with an allyl halide, eg. bromide, to form an allyloxy derivative which on heating undergoes a Claisen rearrangement to form an ortho allyl hydroxy derivative. The hydroxy group can in turn be functionalised, eg. by reaction
with a C1-6alkyl halide to form a C1-6alkoxy group. If desired, an allyl group can be converted to an E-1-propenyl group by reaction with a strong base, such as sodium
methoxide. An E-1-propenyl group can be cleaved to a formyl group by reaction with an oxidising agent such as
N-methylmorpholine-N-oxide in the presence of a catalyst suc as osmium tetroxide to form a 1,2,dihydroxypropyl group whic on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-1-propenyl grou can be converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group can in turn be further functionalised, for example it can be converted to a
hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a C1-6alkyl halide to form a C1-6alkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R15O)2P (O) CH2CO2R15 or Ph3P=CHCO2R15 wherein R15 is C1-4alkyl to form a CH=CHCO2R15 group which can be optionally hydrolysed to a -CH=CHCO2H group. A -CH=CHCO2R15 group can be converted to a -CH=CHC0N(R7) 2 group by reaction with an amine HN(R7)2 or a chemical equivalent thereof wherein R7 is as hereinbefore defined. Alternatively a
-CH=CHCO2H group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can then be reacted with an amine HN(R7)2 or a chemical
equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH=CHCONH2 group.
Pharmaceutically acceptable base addition salts of the compounds of the formula (1) may be prepared by standard methods, for example by reacting a solution of the compound of the formula (1) with a solution of the base.
The following biological test methods, data and Examples serve to illustrate this invention.
Cyclic-AMP Protein Kinase (cA-PrK) Agonist Activity
Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mis of 10 mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62). Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30°C for 5 minutes with
[γ-32P]-adenosine triphosphate and a suitable peptide
substrate such as malantide (Malencik et al., 1983, Anal.
Biochem., 132, 34-40). The reaction was terminated by the addition of hydrochloric acid and the [32P]-phosphoρeptide quantified by spotting the reaction mixture onto
phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC10 (μM). The compounds of Examples 1 to 3 had EC10 values in the range 1.8 to 100 μM.
Inhibition of Platelet Aggregation
Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 μM acetylsalicylic acid for 15 minutes at 37°C. A washed platelet suspension was then prepared in a Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5×108 cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37°C, then challenged with 1.0 μM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC50
(concentration to cause 50% inhibition of platelet
aggregation, μM). The compounds of Examples 1 to 3 had IC50 values in the range 6 to 109 μM.
Inhibition of Spontaneous Contraction in Guinea-Pig Colon
Segments of isolated guinea-pig colon (2 cm) were suspended under 2 g tension in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. On-line computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as % maximum inhibition of spontaneous contraction distance over 3 consecutive pre and post dose 2 minute readings. The concentration of compound which caused 50% inhibition of the spontaneous contraction is given as the EC50 (μM).
Bronchodilatation - In vitro
Spiral strips of guinea-pig trachea were suspended in
standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneously and concentrations of test compounds added in a cumulative, fashion. The concentration of compound which caused 50% inhibition of the spontaneously developed tension is given as the IC50 (μM). The compound of Example 1 had a IC50 value of 100 μM.
Measurement of cardiac muscle relaxation time in rabbit ventricle
Papillary muscles from the right ventricle of female Albino New Zealand rabbits are mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle is connected to an isometric transducer which allowed
recording of contractile force and its first derivative on chart recorders. Test compounds are added to the bath in a cumulative manner. Relaxation time is calculated as the time taken from peak tension to the end of the contraction.
Compounds which cause a decrease in the relaxation time indicate a positive lusitropic effect of use in the treatment of cardiovascular diseases where there is a component of diastolic failure such as congestive heart failure, angina, hypertension and cardiomyopathy.
Example 1
Ethyl [5-(2-Naphthyl)-3-hydroxy-2-pyridyl]phosphonate
(a) To an ice cooled solution of 3-chloro-5-hydroxypyridine (4.95g) and 4-N,N-dimethylaminopyridine (14g) in
dichloromethane (300mls), trifluoromethanesulphonic anhydride (10g) was added over 30 minutes. When the addition was complete the mixture was stirred for a further 2 hours and poured into 1M hydrochloric acid (300ml). The organic phase was separated, washed with water (2 × 100ml), dried (MgSO4) and solvent removed at reduced pressure to give 3-chloro-5trifluoromethanesulphonyloxypyridine (8.9g) as an oil that solidified on standing. 1H NMR δ (CDCI3) 7.69(m, 1H),
8.52 (m,1H) and 8.65 (m, 1H).
(b) From 2-naphthylboronic acid (2.33g) and 3-chloro-5- trifluoromethanesulphonyloxypyridine (3.4g), 3-chloro-5-(2- naphthyl)pyridine (2.5g) was prepared according to the method of A. Huth, I. Beetz and I. Schumann, Tetrahedron, 1989, 45, 6679. 1H NMR δ (CDCI3) 7.52-7.57 (m, 2H), 7.68(dd,1H), 7.84- 8.04(m,5H), 8.58(m,1H) and 8.85 (d, 1H).
(c) A mixture of 3-chloro-5-(2-naphthyl)pyridine (2.0g) and sodium methoxide in dimethylformamide (50ml) was heated at 130°C for 3.5 hours. The mixture was poured onto ice, stirred vigorously for one hour and extracted with diethyl ether
(200ml). The ether extract was washed with water (4 × 100ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel,
dichloromethane eluant) to give 3-methoxy-5-(2-naphthyl)pyridine (1.2g). 1H NMR δ (CDCI3) 4.12(s,3H), 7.51-7.62(m,3H), 7.82-8.04 (m, 5H), 8.19(dd,1H) and 8.53 (s, 1H).
(d) A solution of 3-methoxy-5-(2-naphthyl)pyridine (2.07g) in a mixture of acetic acid/hydrobromic acid (250ml, 2:3) was boiled for 65 hours. After cooling to room temperature
solvent was removed at reduced pressure and the residue triturated with water (100ml) to give 3-hydroxy-5-(2-
naphthyl)pyridine (1.75g) 1H NMR δ (DMSO-d6) 7.50-7.58 (m,3H), 7.86(d,1H), 7.95-8.08 (m,3H), 8.17(d,1H), 8.28(s,1H),
8.52 (d, 1H) and 10.15 (br. s, 1H).
(e) To a solution of 3-hydroxy-5-(2-naphthyl)pyridine (1.75g) in tetrahydrofuran (30ml), lithium diisopropylamide (prepared from n-butyl lithium 3.8mls of 2.5M solution in hexane and diisopropylamine 0.81g) was added at -78°C. When the addition was complete the reaction mixture was warmed to room
temperature stirred for 90 minutes, recooled to -78°C and treated with diethyl chlorophosphate (1.38g). The mixture was warmed to room temperature stirred for 15 minutes recooled to -78°C and treated with additional lithium diisopropylamide (from n-butyl lithium 3.8mls Of 2.5M in hexane and
diisopropylamine 0.81g). After stirring at -78°C for 15 minutes and at room temperature for 20 minutes the reaction mixture was poured into a mixture of ice (100g) and cone, hydrochloric acid (15ml) and stirred overnight.
Tetrahydrofuran was removed at reduced pressure and the aqueous residue extracted with dichloromethane (2 × 100ml). The combined organic extracts were washed with water (2 × 100ml) dried (MgSO4) and solvent removed at reduced pressure. The residual oil was column chromatographed (silica gel, dichloromethane followed by diethyl ether followed by ethyl acetate/ethanol 4:1 eluant) to give diethyl [3-hydroxy-5-(2- naphthyl)-2-pyridyl]phosphonate (1.86g). 1H NMR δ (CDCI3)
1.39(t,6H), 4.15-4.37 (m,4H), 7.53-7.62 (m,3H), 7.71(dd,1H), 7.87-7.95 (m,3H), 8.08(s,1H) and 8.69 (d, 1H). e) A mixture of diethyl [3-hydroxy-5-(2-naphthyl)-2-pyridyl]phosphonate (0.2g) and sodium hydroxide (0.5g) in water/ethanol (11ml, 10:1) was boiled for 12 hours. The solvent was removed at reduced pressure, the residue
dissolved in water (3ml) and acidified with cone,
hydrochloric acid (15ml). The precipitated material was
collected by filtration and recrystallised from ethanol to give the title compound (0.15g) m.p. 252-254°C. 1H NMR δ
(DMSO-d6) 1.15 (t,3H), 3.83-3.96 (m,2H), 7.56-7.62 (m,2H), 7.98-8.11(m,3H), 8.19(m,1H), 8.50(s,1H) and 8.73 (s, 1H).
Example 2
5-(2,4-Dipropoxyphenyl)-2-(5-tetrazolyl)pyridin-3-ol a) A mixture of 4-bromoresorcinol (25g) potassium carbonate and iodopropane in dimethylformamide was heated in
dimethylformamide at 90° for 18 hours. Solvent was removed at reduced pressure the residue triturated with diethyl ether, filtered, the filtrate adsorbed onto silica gel and column chromatographed (silica gel, petroleum ether/diethyl ether 9:1 eluant) to give l-bromo-2, 4-dipropoxybenzene (11g). 1H NMR δ (CDCl3) 1.03(t,3H), 1.06(t,3H), 1.71-1.94 (m, 4H),
3.89(q,2H), 3.92(q,2H), 6.37(dd,1H), 6.46(d,1H) and
7.37 (d, 1H). b) From 2,4-dipropoxyphenyl lithium [prepared by addition of 1-bromo-2,4-dipropoxy-benzene (11.0g) to tert-butyl lithium (48 mis of 1.7M in pentane], (2,4-dipropoxyphenyl)boronic acid (6.1g) was prepared according to the method of
W.J.Thompson and J.Gaudino J. Org. Chem., 1984, 49, 5237. 1H NMR δ (CDCI3) 1.14(t,3H), 1.16(t,3H), 1.84-2.04 (m, 4H),
4.06(q,2H), 4.19(q,2H), 6.55 (d,1H), 6.66(dd,1H) and
7.85(d,1H). c) From (2, 4-dipropoxyphenyl)boronic acid (5.0g) and 3- chloro-5-trifluoromethanesulphonyloxypyridine (5.5g), 3-chloro-5-(2,4-dipropoxyphenyl)pyridine (6.47g) was prepared according to the method of Example 1(b). 1H NMR δ (CDCI3) 0.99(t,3H), 1.06(t,3H), 1.72-1.89 (m, 4H), 3.93(t,2H),
3.96(q,2H), 6.55-6.59 (m, 2H) , 7.26(d,1H), 7.87(m,1H),
8.45 (d,1H) and 8.62 (d,1H). d) 3-Chloro-5-(2,4-dipropoxyphenyl)pyridine (3.9g), benzyl alcohol (20.0g), potassium tertbutoxide (4.0g) and 18-crown-6 (0.1g) were combined in N-methylpyrrolidinone (20mls) and heated at 130 °C for 48 hours. The mixture was poured into a mixture of ice (100g) and cone, hydrochloric acid (10ml) and extracted with dichloromethane (3 × 100ml). The combined
organic extracts were dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed
(silica gel, petroleum ether/diethyl ether 4:1 eluant) to give 3-benzyloxy-5-(2,4-dipropoxyphenyl)pyridine (1.6g). 1H NMR δ (CDCI3) 0.97(t,3H), 1.06(t,3H), 1.65-1.91 (m, 4H),
3.91(t,2H), 3.95 (t,2H), 5.13 (s,2H), 6.51-6.57 (m, 2H), 7.26- 7.49(m,7H), 8.27(d,1H) and 8.37 (d, 1H). e) 3-Chloroperbenzoic acid (2.0g) was added to a solution of 3-benzyloxy-5-(2,4-dipropoxyρhenyl)pyridine (1.6g) and the mixture was stirred for 3 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane/petroleum etherl:! eluant) to give 3-benzyloxy-5-(2,4-dipropoxyphenyl)pyridine-N-oxide (1.6g). 1H NMR δ (CDCI3) 0.99(t,3H), 1.06(t,3H), 1.74- 1.87(m,4H), 3.93(t,2H), 3.95(t,2H), 5.09(s,2H), 6.52- 6.59(m,2H), 7.16-7.20 (m,2H), 7.40(s,5H), 7.96(s,1H) and 8.13 (S,1H). f) From 3-benzyloxy-5-(2,4-diρropoxyphenyl)pyridine-N-oxide (1.6g), 3-benzyloxy-2-cyano-5-(2,4-dipropoxyphenyl)pyridine (0.8g) was prepared according to the method of W. K. Fife, Heterocycles, 1984, 22, 93. 1H NMR δ (CDCI3) 0.97 (t,3H), 1.06(t,3H), 1.68-1.91 (m,4H), 3.92(t,2H), 3.96(t,2H),
5.25(s,2H), 6.55(s,1H), 6.56(dd,1H), 7.20(d,1H), 7.33- 7.46(m,5H), 7.59(d,1H) and 8.44 (d, 1H). g) A mixture of 3-benzyloxy-2-cyano-5-(2,4- dipropoxyphenyl)pyridine (0.8g), sodium azide (0.54g) and ammonium chloride (1.0g) were heated together in N-methylpyrrolidinone (15ml) at 190°C for 6 hours. Solvent was removed at reduced pressure and the residue triturated with water. The crude product was collected by filtration and chromatographed (C18 reverse phase silica gel,
acetonitrile/0.1% aqueous trifluoroacetie acid 3:2 eluant) to give the title compound (0.13g) m.p. 179-180°C. 1H NMR δ (DMSO-d6) 0.95(t,3H), 1.00(t,3H), 1.67-1.84 (m, 4H), 3.99 (t,4H) 6.58-6.68(m,2H), 7.47(d,1H), 7.64(s,1H) and 8.44 (s, 1H).
Example 3
5-(4-Methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-3-ol a) From 3-hydroxy-4-methoxy-nitrobenzene (25g), 4-methoxy-1- nitro-3-propoxybenzene (31g) was prepared according to the method of Example 2(a). 1H NMR δ (CDCI3) 1.07 (t, 3H), 1.82- 1.97(m,2H), 3.97(s,3H), 4.05(t,2H), 6.91(d,1H), 7.74(d,1H) and 7.90 (dd, 1H).
(b) A solution of 4-methoxy-1-nitro-3-propoxybenzene (20g) in acetic acid (150ml) containing 10% palladium on charcoal (2g) was heated at 80°C under an atmosphere of hydrogen (60p.s.i) with shaking for 4 hours. The reaction mixture was filtered under nitrogen into 50% sulphuric acid (300ml) cooled to 0°C and treated with an aqueous solution of sodium nitrite (6.9g in 20ml water) at such a rate that the temperature did not rise above 5°C. When the addition was complete the mixture was stirred for a further 2 hours at 0°C and then poured into a solution of potassium iodide (200g) iodine (40g) and urea (1g) in water (300ml). Dichloromethane (300ml) was added and the mixture stirred vigorously at room temperature until gas evolution ceased (3 hours. Sodium metabisulphite (20g) was added, the organic phase was separated washed with water (2 × 100ml), dried (MgSO4) and solvent removed at reduced
pressure. The residue was column chromatographed (silica gel petroleum ether/dichloromethane 1:1 eluant) to give 1-iodo-4-methoxy-3-propoxybenzene (17g) 1H NMR δ (CDCI3) 1.03(t,3H), 1.77-1.95 (m, 2H) , 3.83(s,3H), 3.93(t,2H), 6.61(d,1H),
7.11 (d,1H) and 7.19 (dd, 1H).
(c) From 1-iodo-4-methoxy-3-propoxybenzene (16.9g), (4-methoxy-3-propoxyphenyl)boronic acid (10.0g) was prepared according to the method of Example 2 (b). 1H NMR δ (DMSO-d6) 0.98(t,3H), 1.65-1.79(m,2H), 3.76(s,3H), 3.89(t,2H),
6.91(d,1H), 7.32-7.37 (m,2H) and 7.86 (br.s, 2H).
(d) From (4-methoxy-3-propoxyphenyl)boronic acid (10.0g) and 3-chloro-5-trifluoromethanesulphonyloxypyridine (12.6g), 3-
chloro-5-(4-methoxy-3-propoxyphenyl)pyridine (11.0g) was prepared according to the method of Example 1 (b). 1H NMR δ (CDCl3) 1.07 (t,3H), 1.83-1.99 (m,2H), 3.92 (s,3H), 4.05 (t,2H), 6.97 (d,1H), 7.06(d,1H), 7.11(dd,1H), 7.81 (m,1H), 8.50 (d,1H) and 8.67 (d, 1H).
(e) From 3-chloro-5-(4-methoxy-3-propoxyphenyl)pyridine
(10.0g}, 3-benzyloxy-5-(4-methoxy-3-propoxyphenyl)pyridine was prepared according to the method of Example 2 (d). The crude material was treated with 3-chloroperbenzoic acid
(10.0g) according to the method of Example 2(e) to give 3- benzyloxy-5-(4-methoxy-3-propoxyphenyl)pyridine-N-oxide
(4.0g) 1H NMR 1.06 (t,3H), 1.82-1.97 (m,2H), 3.91(s,3H),
4.00(t,2H), 5.13(s,2H), 6.88-7.09 (m, 4H), 7.42(s,5H),
7.98(s,1H) and 8.14 (s,1H).
(f) From 3-benzyloxy-5-(4-methoxy-3-propoxyphenylpyridine-N- oxide (3.8g), 3-benzyloxy-2-cyano-5-(4-methoxy-3- propoxyphenyl)pyridine (2.3g) was prepared according to the method of Example 2(f). 1H NMR δ (CDCI3) 1.08 (t, 3H) , 1. 83- 1.98 (m, 2H) , 3.98 (s, 3H) , 4.01(t,2H), 6.94-6.98 (m, 2H),
7.07(dd,1H), 7.38-7.50 (m, 6H) and 8.45 (d, 1H).
(g) From 3-benzyloxy-2-cyano-5- (4-methoxy-3-propoxyphenyl)pyridine (1.55g), the title compound (0.6g) m.p. 229-230°C after reverse phase chromatography (water then 1% aqueous trifluoroacetie acid/acetonitrile 2:3 eluant) was prepared according to the method of Example 2 (g). 1H NMR 1.01(t,3H), 1.70-1.81 (m,2H), 3.83(s,3H), 4.05(t,2H),
7.10(d,1H), 7.30-7.38(m,2H), 7.77(s,1H) and 8.63(1H).
Example 4
Pharmaceutical compositions for oral administration are prepared by combining the following :
% w/w
Ethyl [5-(2-Naphthyl)-3- hydroxy-2-pyridyl]phosphonate 0.5 3.0 7.14
2% w/w Soya lecithin in soya
bean oil 90.45 88.2 84.41
Hydrogenated vegetable
shortening and beeswax 9.05 8.8 8.45
The formulations are then filled into individual soft gelatin capsules.
Example 5
A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 2
(0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (to 100 ml). The solution is then sterilised by
filtration through a 0.22 micron membrane filter and sealed in sterile containers.
Claims (9)
1. A compound of the formula (1) :
or a pharmaceutically acceptable salt thereof, wherein :
R0 is OH or a bioprecursor thereof,
R1 is A0CO2H, P (Z) (OH) (OR2.), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof,
A0 is CH2, CHF, CF2, CR3 (OR4), CO or C(OR5) (OR6),
R2 is phenyl, C3-5cycloalkyl, C3-5cycloalkylC1-4alkyl, or C1-8alkyl optionally substituted by C1-4alkoxy,
R3 is H, methyl or ethyl,
R4 is H or C1-3alkyl,
R5 and R6 are eachC1-3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group,
Z is O or S, and
Ar is phenyl optionally substituted by one to three groups independently selected from C1-6alkyl, C2-6alkenyl,
C1-6alkoxy, C1-6alkenyloxy, C3-6cycloalkyl,
C3-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C^-gpolyfluoroalkyl, C1-6polyfluoroalkoxy, halo, N(R7)2 or NHCOR7 wherein R7 is H or C1-6alkyl, or -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or O and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy, C3-6cycloalkyl, N(R7)2, CO2R7 or CON(R7)2; or
Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or C1-6alkoxy,
3_phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl.
2. A compound according to claim 1 wherein R1 is
A0CO2H or A0CO2R9 in which R9 is an ester-forming group.
3. A compound according to claim 1 wherein R1 is
P(Z) (OH) (OR2) or P(Z) (OR2)2.
4. A compound according to claim 1 wherein R1 is SO2H, SO3H or 5-tetrazolyl.
5. A compound according to claim 1 wherein Rl and R^ are linked together such that R1-R0 is A1CO2
in which A1 is CH2, CHF, CF2, CR3(OR4), CO or C(OR5) (OR6).
6. A compound according to claim 1 wherein R-- and R^ are linked together such that R1-R0 is A2OCH2O in which A2 is P(Z) (OR2) or CR3(CO2R9) and R9 is an ester-forming group.
7. A compound according to claim 1 which is : ethyl [5-(2-naphthyl)-3-hydroxy-2-pyridyl]phosphonate, 5-(2,4-dipropoxyphenyl)-2-(5-tetrazolyl)pyridin-3-ol, or 5-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-3-ol, or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 7 for use as a medicament.
9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.
10 A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises : a) for compounds wherein R1 is A0CO2H or A0CO2R9 and : i) A0 is CR3 (OR4),
reacting in the presence of a strong base a compound of the formula (2) :
wherein R11 is an O-protecting group and Ar is as defined in claim 1, with a compound of the formula (3) :
R3COCO2R9 (3) wherein R3 is as defined in claim 1 and R9 is an ester-forming group to form a compound of the formula (4) :
wherein R12 is CR3(OH)CO2R9 and R3, R9, R11, and Ar are as hereinbefore defined and thereafter optionally reacting with a C1-3alkylating agent to form the corresponding compound wherein R12 is CR3 (OC1-3alkyl) CO2R9, ii) A0 is CO,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with a compound of the formula (5) :
R9O2CCO2R9 (5) wherein R9 is as hereinbefore defined to form a compound of the formula (4) wherein R12 is C0C02R9 and R9, R11 and Ar are as hereinbefore defined, iii) A0 is CH(OH) ,
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R12 is CH(OH)CO2R9, iv) A0 is CH2,
reacting a compound of the formula (4) wherein R12 is COCO2H or COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R12 is CH2CO2H, v) A0 is C(OR5) (OR6),
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a
C1-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R12 is C(OR5) (OR6)CO2R9, vi) A0 is CF2,
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R11 is CF2CO2R9, or vii) A0 is CHF,
reacting a compound of the formula (4) wherein R12 is
CH(OH)CO2R9 and R9, R11, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R12 is CHFCO2R9, and thereafter optionally : º converting the group OR11 into OH º converting the group A0CO2R9 into A0CO2H; or b) for compounds wherein R1 is CH2CO2H,
converting a compound of the formula (6) :
(6)
wherein R13 is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is CH2CO2H; or c) for compounds wherein R1 is CH (OR4) CO2H reacting a compound of the formula (4) wherein R12 is -CH(OH)CN with a C1-3alkylating agent and/or converting the group CN into CO2H, and optionally converting the group OR11 into OH; or d) for compounds wherein R1 is P (O) (OH) (OR2), hydrolysing a compound of the formula (6) wherein R13 is P (O) (OR2)2, R2 is as defined in claim 1 and Ar is as hereinbefore defined; or e) for compounds wherein R1 is P(S) (OH) (OR2), converting a compound of the formula (6) wherein R13 is P (O) (NHR14) (OR2) and R14 is phenyl or C1-4alkyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is P(S) (OH) (OR2); or f) for compounds where R1 is SO3H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphury1 chloride or a chemical equivalent thereof and optionally converting the group OR11 into OH; or g) for compounds wherein R1 is SO2H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide and optionally converting the group OR11 into OH; or h) for compounds wherein R1 is 5-tetrazolyl, reacting a compound of the formula (4) wherein R12 is cyano or a compound of the formula (6) wherein R13 is cyano with an azide salt and thereafter if necessary converting the group OR11 into OH; or i) for compounds wherein R1 is as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7):
wherein Rb is a group R1 as defined in claim 1 or a precursor thereof and Ra is a group R0 or as defined in claim 1 or a precursor thereof and L1 is a leaving group with a compound of the formula (8):
ArB(OH)2 (8) or a chemical equivalent .thereof wherein Ar is as
hereinbefore defined and then, if necessary, converting a precursor of R1 into R1 and/or converting a precursor of R0 into OH, and optionally thereafter : º forming a bioprecursor of R0 and/or R1 º forming a pharmaceutically acceptable salt.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9124578 | 1991-11-20 | ||
GB919124578A GB9124578D0 (en) | 1991-11-20 | 1991-11-20 | Chemical compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2930392A true AU2930392A (en) | 1993-06-15 |
Family
ID=10704881
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Application Number | Title | Priority Date | Filing Date |
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AU29303/92A Abandoned AU2930392A (en) | 1991-11-20 | 1992-11-16 | 3-pyridinol derivatives and their use as medicaments |
Country Status (11)
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---|---|
EP (1) | EP0613476A1 (en) |
JP (1) | JPH07501070A (en) |
AU (1) | AU2930392A (en) |
CA (1) | CA2124002A1 (en) |
GB (1) | GB9124578D0 (en) |
MX (1) | MX9206710A (en) |
NZ (1) | NZ245167A (en) |
PT (1) | PT101072A (en) |
TW (1) | TW221990B (en) |
WO (1) | WO1993010114A1 (en) |
ZA (1) | ZA928893B (en) |
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AR036873A1 (en) | 2001-09-07 | 2004-10-13 | Euro Celtique Sa | PIRIDINAS ARIL REPLACED A, PHARMACEUTICAL COMPOSITIONS AND THE USE OF THE SAME FOR THE PREPARATION OF A MEDICINAL PRODUCT |
AR037233A1 (en) | 2001-09-07 | 2004-11-03 | Euro Celtique Sa | PIRIDINAS ARIL REPLACED, PHARMACEUTICAL COMPOSITIONS AND THE USE OF SUCH COMPOUNDS FOR THE PREPARATION OF A MEDICINAL PRODUCT |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
EP1781641A1 (en) | 2004-08-23 | 2007-05-09 | Wyeth | Pyrrolo-naphthyl acids as pai-1 inhibitors |
CN101044127A (en) | 2004-08-23 | 2007-09-26 | 惠氏公司 | Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1 |
CN101039936A (en) | 2004-08-23 | 2007-09-19 | 惠氏公司 | Oxazolo-naphthyl acids as plasminogen activator inhibitor type-1(pai-1) modulators useful in the treatment of thrombosis and cardiovascular diseases |
EP1853261B1 (en) * | 2005-03-03 | 2017-01-11 | Universität des Saarlandes | Selective inhibitors of human corticosteroid synthases |
WO2023240253A2 (en) | 2022-06-10 | 2023-12-14 | Forward Therapeutics, Inc. | Modulators of tnf-alpha activity |
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JPH06501254A (en) * | 1990-09-28 | 1994-02-10 | スミス・クライン・アンド・フレンチ・ラボラトリース・リミテッド | Pharmaceutical phenylpyridinol derivatives |
-
1991
- 1991-11-20 GB GB919124578A patent/GB9124578D0/en active Pending
-
1992
- 1992-11-16 CA CA002124002A patent/CA2124002A1/en not_active Abandoned
- 1992-11-16 WO PCT/GB1992/002118 patent/WO1993010114A1/en not_active Application Discontinuation
- 1992-11-16 JP JP5509094A patent/JPH07501070A/en active Pending
- 1992-11-16 AU AU29303/92A patent/AU2930392A/en not_active Abandoned
- 1992-11-16 EP EP92923524A patent/EP0613476A1/en not_active Withdrawn
- 1992-11-18 NZ NZ245167A patent/NZ245167A/en unknown
- 1992-11-18 PT PT101072A patent/PT101072A/en not_active Application Discontinuation
- 1992-11-18 ZA ZA928893A patent/ZA928893B/en unknown
- 1992-11-19 MX MX9206710A patent/MX9206710A/en unknown
- 1992-11-19 TW TW081109270A patent/TW221990B/zh active
Also Published As
Publication number | Publication date |
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GB9124578D0 (en) | 1992-01-08 |
NZ245167A (en) | 1995-08-28 |
WO1993010114A1 (en) | 1993-05-27 |
MX9206710A (en) | 1993-05-01 |
PT101072A (en) | 1994-02-28 |
EP0613476A1 (en) | 1994-09-07 |
CA2124002A1 (en) | 1993-05-27 |
ZA928893B (en) | 1994-05-18 |
JPH07501070A (en) | 1995-02-02 |
TW221990B (en) | 1994-04-01 |
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