WO1993011134A1 - [3H,7H]THIAZOLE[3,4-a]PYRIDINES HAVING ANTIASTHMATIC AND ANTIINFLAMMATORY ACTIVITIES ON THE RESPIRATORY TRACT - Google Patents
[3H,7H]THIAZOLE[3,4-a]PYRIDINES HAVING ANTIASTHMATIC AND ANTIINFLAMMATORY ACTIVITIES ON THE RESPIRATORY TRACT Download PDFInfo
- Publication number
- WO1993011134A1 WO1993011134A1 PCT/EP1992/002784 EP9202784W WO9311134A1 WO 1993011134 A1 WO1993011134 A1 WO 1993011134A1 EP 9202784 W EP9202784 W EP 9202784W WO 9311134 A1 WO9311134 A1 WO 9311134A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bis
- group
- pyrrolidin
- formula
- compounds
- Prior art date
Links
- 230000001088 anti-asthma Effects 0.000 title claims abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 4
- 239000000924 antiasthmatic agent Substances 0.000 title claims abstract description 4
- 210000002345 respiratory system Anatomy 0.000 title abstract description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title description 18
- RQMWVVBHJMUJNZ-UHFFFAOYSA-N 4-chloropyridin-2-amine Chemical compound NC1=CC(Cl)=CC=N1 RQMWVVBHJMUJNZ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- -1 pyrrolidino, piperidino, morpholino Chemical group 0.000 claims description 33
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910003827 NRaRb Inorganic materials 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000006323 alkenyl amino group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000006319 alkynyl amino group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 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 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 11
- 125000004076 pyridyl group Chemical group 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000003222 pyridines Chemical class 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 208000006673 asthma Diseases 0.000 description 6
- 239000011261 inert gas Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000035874 hyperreactivity Effects 0.000 description 4
- 229960003010 sodium sulfate Drugs 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 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 4
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 206010066091 Bronchial Hyperreactivity Diseases 0.000 description 3
- 241000700198 Cavia Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 230000036427 bronchial hyperreactivity Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 150000004885 piperazines Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 2
- 210000003979 eosinophil Anatomy 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229940092253 ovalbumin Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 0 **C1=C(*)C(*)C(I)=C(*)N1 Chemical compound **C1=C(*)C(*)C(I)=C(*)N1 0.000 description 1
- 125000004317 1,3,5-triazin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=N1 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XLHUBROMZOAQMV-UHFFFAOYSA-N 1,4-benzosemiquinone Chemical group [O]C1=CC=C(O)C=C1 XLHUBROMZOAQMV-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VINOSHDRVYFKLH-UHFFFAOYSA-N 2-n,2-n,5-n,5-n-tetraethyl-6-piperazin-1-ylpyridine-2,5-diamine Chemical compound CCN(CC)C1=CC=C(N(CC)CC)C(N2CCNCC2)=N1 VINOSHDRVYFKLH-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- SOLPCBZWYMXIRZ-UHFFFAOYSA-N [amino-[[3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridin-2-yl]methylsulfanyl]methylidene]azanium;chloride Chemical compound [Cl-].CCOC(=O)C1=C(CSC(N)=[NH2+])NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 SOLPCBZWYMXIRZ-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003897 fog Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- NPIJXCQZLFKBMV-YTGGZNJNSA-L pancuronium bromide Chemical compound [Br-].[Br-].C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 NPIJXCQZLFKBMV-YTGGZNJNSA-L 0.000 description 1
- 229960003379 pancuronium bromide Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003138 primary alcohols Chemical group 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to [3H,7H]thiazole[3,4-a]pyridines, a process for the preparation thereof and pharmaceutical compositions containing them.
- R is (C 1 -C 4 ) alkyl
- Ra is hydrogen, C 1 -C 6 alkyl, benzyl
- Rb is hydrogen or C 1 -C 6 alkyl, or Ra and Rb, together with the nitrogen atom, form a pyrrolidino, piperidino, morpholino, 4- thiomorpholino, (C 1 -C 4 ) alkylpiperazino group;
- R 2 is a (C 3 -C 7 )cycloalkyl group, ⁇ , ⁇ or ⁇ -pyridyl, optionally substituted phenyl or a bicyclic ring in which a benzene ring is fused to a 5- or 6-membered heterocycle containing one or more heteroatoms selected from O, S and N, said bicyclic ring being linked through the benzene ring;
- R 3 is a free or salified carboxy group or an alkoxycar- bonyl group
- D is a 5- or 6-membered heterocycle with 1-3 nitrogen atoms, optionally substituted with 1 or 2 amino, mono- (C 1 -C 6 )alkylamino, mono-(C 3 -C 7 )alkenyl or mono-(C 3 - C 7 ) alkynylamino, di-(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkyl (C 3 - C 7 )alkenylamino, piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl groups.
- phenyl as herein used, we mean a phenyl ring, containing from 1 to 3 substituents selected from C 1 -C 6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl; (C 1 - C 4 )alkoxy such as methoxy, ethoxy or propoxy; (C 1 - C 4 )alkylthio such as methylthio, ethylthio; phenoxy; 4- hydroxyphenoxy; phenylthio; 4-hydroxyphenylthio; halogen atoms (chlorine, bromine or fluorine); cyano, azido, nitro, amino groups; (C 1 -C 6 )acylamino; trihaloacetylamino such as trifluoroacetylamino; methane- or trifluoromethanesulfonamido; benzene- or para-toly
- Particularly preferred mono or poly-substituted phenyl groups are those bearing the following substituents: 2-chloro-, 3-chloro-, 4-chloro-, 2,3-dichloro-, 2-fluoro-, 2-fluoro-3-chloro-, 2-nitro-, 3-nitro-, 3- nitro-4-phenoxy-, 4-nitro-, 4-nitro-3-phenoxy-, 2- trif luoromethyl-, 3-trif luoromethyl-, 3-cyano-, 3- methoxy-, 2-amino-, 3-amino-, 4-amino-, 2- methanesulfonamido-, 3-methanesul fonamido-, 4-me- thanesulfonamido-, 3-methanesulfonamido-4-phenoxy-, 4- methanesulfonamido-3-phenoxy-, 4-fluoro-2,3-dichloro-, 3-carboxy-4-hydroxy-, 3-hydroxy-4-carbox
- R 2 is a (C 3 -C 7 )cycloalkyl group, this is preferably cyclopropyl, cyclopentyl or cyclohexyl.
- R 1 or R 3 are an alkoxycarbonyl group, this is preferably a (C 1 -C 4 ) alkyl, allyl, propargyl, benzyl, p- methoxybenzyl, benzhydryl, trityl or trichloroethyl ester.
- R 2 is a bicyclic ring in which a benzene ring is fused with a 5- or 6-membered heterocyclic ring
- this is preferably benzo-1,3-dioxolane-4-yl, 1,4- benzodioxolane-6-yl, 1,4-benzodioxolane-5-yl, benzo- furan-4-yl, benzofurazan-4-yl.
- D are: pyridin-2-yl, pyrimidin-4-yl, pyrimidin-2-yl or 1,3,5-triazin-2-yl, optionally substituted with 1 or 2 amino, monoalkylamino (methylamino, ethylamino), 2-pro- penylamino, 2-propynylamino, propylamino, isopro- pylamino or dialkylamino groups such as dime thy lamino, diethylamino, ethyl, 2-propenylamino and the like.
- D particularly preferred meanings for D are: pyri- din-2-yl, [2,6-bis(diethylamino)pyrimidin-4-yl], [2,6- bis (2-propenylamino)pyrimidin-4-yl], [2,6-bis(ami- no)pyrimidin-4-yl], [2,6-bis(pyrrolidin-1-yl)pyrimidin- 4-yl], [4,6-bis(2-propenylamino)-1,3,5-triazin-2-yl],
- Particularly preferred compounds (I) are those in which R 1 and R 3 are alkoxycarbonyl groups, particularly methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 2-propenyloxycarbonyl and tert-butoxycarbonyl groups, or those in which R 1 is a -CONH(CH 2 ) q -NRaRb group, with q, Ra and Rb as defined above, and R 3 is an alkoxycarbonyl group as defined above; R 2 is an optionally substituted phenyl group or a
- the compounds of formula (la) will be named hereinafter sin-[3H,7H] thiazole[3,4-a]pyridines or simply [3H,7H]thiazole[3,4-a]pyridines.
- Compounds of formula (lb) will be named anti-[3H,7H]thiazole[3,4- a . pyridines, whereas the diastereomeric mixtures will be indicated as (s,a)-[3H,7H]thiazole[3,4-a]pyridines.
- optically active compounds (la) will be defined (R)- or (S)-sin-[3H,7H]thiazole[3,4-a]pyridines or simply (R)- or (S)-[3H,7H]thiazole[3,4-a]pyridines; compounds (lb) will be named (R)- or ( S)-anti-[3H,7H]thiazole[3,4- a.pyridines.
- the compounds of the invention of formula (I) are prepared by a process which consists in reacting a Michael acceptor of formula (Ila) or (llb):
- Hal is a halogen atom (chlorine, bromine or iodine) and R 4 is a (C 1 -C 4 ) alkyl group, with a 1,4- dihydropyridine of formula (III):
- an inorganic or organic acid such as hydrochloric, hydrobromic, acetic, camphorsulfonic, mandelic, tartaric, O,O'-dibenzoyltartaric acids.
- hydrolysis of a carboxyester group to the corresponding carboxy group which in its turn can be transformed into the succinimido ester, the acid chloride, the mixed anhydride or other known reactive carboxy derivatives;
- conventional hydrolysis procedures comprise, for example, hydrolysis of an allyloxycarbonyl group with ammonium formate, Pd/C and triphenylphosphine; alkali hydrolysis of a methoxy- or ethoxycarbonyl group; hydrolysis of a tert- butoxycarbonyl group with trimethylsilyl iodide, and the like;
- suitable reducing agents comprise diborane or an alkali or alkaline-earth metal borohydride
- Michael acceptors of formula (II) are known or they can be prepared with conventional methods; some of them are also commercially available. Particularly, among the compounds of formula (II) the following ones are mentioned: a) propargyl acid esters; b) ⁇ - haloacrylesters (obtained from acryl esters by haloge addition and subsequent dehydrohalogenation).
- 1,4-Dihydropyridines of formula (III) are know from WO87/00836 (12.02.1987) or they can be prepare according to the methods described in sai international application. Said compounds of formula (III) can be used both in form of racemates and of pure enantiomers.
- An useful method for the preparation of pure enantiomers of compounds of formula (III) can comprise the optical resolution of the isothiouronium salts with optically active acids, according to the procedure described in EP 90102951.2 (15.02.1990).
- the compounds of the invention turned out to be effective in preventing and/or decreasing the hyper- reactivity of the respiratory tract and in curing the phlogistic conditions which are related to acute and sub-chronical inflammation of bronchial mucosa.
- Bronchial hyper-reactivity is a clinical symptom of asthma and it is believed to be a direct consequence of an abnormal and latent contractility and sensitivity of the bronchial mucosa.
- Bronchial hyper-reactivity can cause acute crisis of asthma after physical practice, and/or after exposure to external stimuli such as the inhalation of fog, pollutants, allergens and autacoids.
- the bronchial hyper-reactivity conditions may be simulated by an experimental model consisting in the PAF infusion (600 ⁇ g/1) in male guinea-pigs weighing 400-450 g, kept under forced ventilation under urethane and pancuronium bromide anesthesia.
- PAF which is one of the most important mediators involved in the inflammatory process of the airways, after infusion for 1 hour, causes an hyperreactivity reaction (bronchocostriction) to specific and different substances.
- the activity of the compounds of the invention, in the considered pharmacological model, is shown by the prevention of the PAF-induced hyper-reactivity, measured as increase of the pulmonary insufflatory pressure (measured according to the modified procedure of Konzett and Rossler, Naun. Schmied, Arch. Exper. Pathol. Pharmacol. 191, 71, 1970).
- the compounds of the invention which are administered 10 minutes before the PAF administration in dosages which vary between 2 and 50 ⁇ g/kg, demonstrate a protective action which lasts at least 4-6 hours and results in a reduction of the PAF-induced hyperreactivity. Such pharmacological effects are dose-related.
- the compounds of the invention are also tested according to another experimental model, namely the Late Phase Reaction on sensitized guinea pigs (P.A. Hutson et al., Am. Rev. Respir. Dis. 137; (1988); 548-577.
- the Late Phase Reaction is characterized by an increase in bronchoalveolar lavage (BAL) of the number of eosi- nophils in guinea pigs sensitized to ovalbumin aerosol.
- BAL bronchoalveolar lavage
- the compounds of the invention are effective in reducing the number of eosinophils in BAL, which was made 72 hours after the ovalbumin challenge.
- the compounds of the invention can be used in human therapy in the treatment of asthmatic and obstructive conditions of the respiratory tract, in the treatment of inflammatory phlogosis.
- the compounds of the invention will be administered in the form of pharmaceutical compositions which can be prepared with conventional excipients and techniques such as, for example, those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, 17th ed., 1985, adapted for administration by intramuscular, intravenous, oral, aerosol and rectal routes.
- the daily dose will depend on several factors such as the gravity of the pathology and the condition of the patient: it will normally consist of 1 to 50 mg of a compound of formula (I) for a patient weighing 70 kg, one or more times a day.
- PREPARATION 2 1 Litre of a sodium bicarbonate saturated aqueous solution is dropped into a suspension of 50 g of (7R)- S-[(6-methyl-5-methoxycarbonyl-3-ethoxycarbonyl-4-(3- nitrophenyl)-1,4-dihydropyridin-2-yl)methyl]isothiouro- nium-D(-)-mandelate in 1 1 of AcOEt, under strong stirring.
- the aqueous phase is removed, whereas the organic phase is dried over sodium sulfate and solvent is evaporated off under reduced pressure, keeping temperature below 40°C.
- reaction mixture is added with 0.65 ml of 2-(N-pyrrolidin)ethylamine and stirring is continued for 5 more hours, then the mixture is diluted with 15 ml of water and extracted with AcOEt (3x5 ml). The combined organic extracts are washed with water, dried over sodium sul- fate and solvent is evaporated off under reduced pressure.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI913269A IT1252626B (it) | 1991-12-06 | 1991-12-06 | ¬3h, 7h| tiazolo ¬3,4a| piridine ad attivita' antiasmatica ed antiinfiammatoria delle vie aeree |
| ITMI91A003269 | 1991-12-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993011134A1 true WO1993011134A1 (en) | 1993-06-10 |
Family
ID=11361270
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1992/002784 WO1993011134A1 (en) | 1991-12-06 | 1992-12-02 | [3H,7H]THIAZOLE[3,4-a]PYRIDINES HAVING ANTIASTHMATIC AND ANTIINFLAMMATORY ACTIVITIES ON THE RESPIRATORY TRACT |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU3084292A (enrdf_load_stackoverflow) |
| IT (1) | IT1252626B (enrdf_load_stackoverflow) |
| TW (1) | TW212801B (enrdf_load_stackoverflow) |
| WO (1) | WO1993011134A1 (enrdf_load_stackoverflow) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7622486B2 (en) | 2004-09-23 | 2009-11-24 | Reddy Us Therapeutics, Inc. | Pyridine compounds, process for their preparation and compositions containing them |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2210633A1 (de) * | 1972-03-06 | 1973-09-20 | Bayer Ag | Neue brueckenkopfheterocyclen, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| WO1987000836A1 (en) * | 1985-08-06 | 1987-02-12 | Boehringer Biochemia Robin S.P.A. | Pharmaceutically active 2-thiomethyl-substituted-1,4-dihydropyridines |
| WO1991018906A1 (en) * | 1990-06-08 | 1991-12-12 | Boehringer Mannheim Italia S.P.A. | [3H,7H]THIAZOLO[3,4-a]PYRIDINES WITH ANTIASTHMATIC AND ANTIINFLAMMATORY ACTIONS ON THE RESPIRATORY TRACT |
-
1991
- 1991-12-06 IT ITMI913269A patent/IT1252626B/it active IP Right Grant
-
1992
- 1992-12-02 AU AU30842/92A patent/AU3084292A/en not_active Abandoned
- 1992-12-02 WO PCT/EP1992/002784 patent/WO1993011134A1/en active Application Filing
- 1992-12-03 TW TW081109698A patent/TW212801B/zh active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2210633A1 (de) * | 1972-03-06 | 1973-09-20 | Bayer Ag | Neue brueckenkopfheterocyclen, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| WO1987000836A1 (en) * | 1985-08-06 | 1987-02-12 | Boehringer Biochemia Robin S.P.A. | Pharmaceutically active 2-thiomethyl-substituted-1,4-dihydropyridines |
| WO1991018906A1 (en) * | 1990-06-08 | 1991-12-12 | Boehringer Mannheim Italia S.P.A. | [3H,7H]THIAZOLO[3,4-a]PYRIDINES WITH ANTIASTHMATIC AND ANTIINFLAMMATORY ACTIONS ON THE RESPIRATORY TRACT |
Non-Patent Citations (1)
| Title |
|---|
| JOURNAL OF MEDICINAL CHEMISTRY. vol. 34, no. 7, July 1991, WASHINGTON US pages 2248 - 2260 I. SIRCAR ET AL. 'Calcium channel blocking and positive inotropic activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-((phenylsul fonyl)methyl)-4-aryl-3-pyridine-carboxylat e and analogues. Synthesis and structure-activity relationships' * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7622486B2 (en) | 2004-09-23 | 2009-11-24 | Reddy Us Therapeutics, Inc. | Pyridine compounds, process for their preparation and compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI913269A1 (it) | 1993-06-06 |
| ITMI913269A0 (it) | 1991-12-06 |
| AU3084292A (en) | 1993-06-28 |
| IT1252626B (it) | 1995-06-19 |
| TW212801B (enrdf_load_stackoverflow) | 1993-09-11 |
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