NO301006B1 - Analogifremgangsmåte for fremstilling av terapeutisk aktive pyrazolderivater - Google Patents
Analogifremgangsmåte for fremstilling av terapeutisk aktive pyrazolderivater Download PDFInfo
- Publication number
- NO301006B1 NO301006B1 NO904134A NO904134A NO301006B1 NO 301006 B1 NO301006 B1 NO 301006B1 NO 904134 A NO904134 A NO 904134A NO 904134 A NO904134 A NO 904134A NO 301006 B1 NO301006 B1 NO 301006B1
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- compound
- substituted
- formula
- salts
- Prior art date
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- 150000003217 pyrazoles Chemical class 0.000 title description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- -1 nitro, amino Chemical group 0.000 claims abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 111
- 238000000034 method Methods 0.000 claims abstract description 97
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 59
- 230000008569 process Effects 0.000 claims abstract description 56
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 55
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 39
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims abstract description 36
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 36
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 150000002367 halogens Chemical class 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 108
- 125000001589 carboacyl group Chemical group 0.000 claims description 59
- 125000003277 amino group Chemical group 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 239000007858 starting material Substances 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 14
- 125000003118 aryl group Chemical group 0.000 abstract description 7
- 125000002252 acyl group Chemical group 0.000 abstract description 5
- 125000004442 acylamino group Chemical group 0.000 abstract description 5
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 238000001819 mass spectrum Methods 0.000 description 229
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
- 239000000203 mixture Substances 0.000 description 120
- 238000006243 chemical reaction Methods 0.000 description 110
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 103
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000002904 solvent Substances 0.000 description 45
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- 239000000243 solution Substances 0.000 description 36
- 239000013078 crystal Substances 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 239000002253 acid Substances 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 17
- 230000002411 adverse Effects 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 235000011054 acetic acid Nutrition 0.000 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 101150041968 CDC13 gene Proteins 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000003638 chemical reducing agent Substances 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 239000002198 insoluble material Substances 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 150000002148 esters Chemical group 0.000 description 7
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 7
- 150000007524 organic acids Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229910017052 cobalt Inorganic materials 0.000 description 6
- 239000010941 cobalt Substances 0.000 description 6
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 6
- 229910052802 copper Inorganic materials 0.000 description 6
- 239000010949 copper Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 210000002683 foot Anatomy 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- 150000007522 mineralic acids Chemical class 0.000 description 6
- 125000004430 oxygen atom Chemical group O* 0.000 description 6
- 230000036407 pain Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- FEKUXLUOKFSMRO-UHFFFAOYSA-N (4-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(F)C=C1 FEKUXLUOKFSMRO-UHFFFAOYSA-N 0.000 description 5
- YMJLEPMVGQBLHL-UHFFFAOYSA-N 1h-pyrazole-5-carbonitrile Chemical compound N#CC1=CC=NN1 YMJLEPMVGQBLHL-UHFFFAOYSA-N 0.000 description 5
- 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 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 102000000503 Collagen Type II Human genes 0.000 description 5
- 108010041390 Collagen Type II Proteins 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 150000003973 alkyl amines Chemical class 0.000 description 5
- 239000002168 alkylating agent Substances 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
- JBXLGRLORITUHD-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylic acid Chemical compound C1=CC(SC)=CC=C1C1=CC(C(O)=O)=NN1C1=CC=C(F)C=C1 JBXLGRLORITUHD-UHFFFAOYSA-N 0.000 description 4
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 208000011231 Crohn disease Diseases 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 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 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 150000001342 alkaline earth metals Chemical class 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 238000010531 catalytic reduction reaction Methods 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
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- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
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- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- KLBIUKJOZFWCLW-UHFFFAOYSA-N thallium(iii) nitrate Chemical compound [Tl+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O KLBIUKJOZFWCLW-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- IDXKMSQUTCYDPK-UHFFFAOYSA-N 1-(4-aminophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carbonitrile Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C#N)=NN1C1=CC=C(N)C=C1 IDXKMSQUTCYDPK-UHFFFAOYSA-N 0.000 description 3
- TYWKFUDMIDTRSC-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-(4-methylsulfanylphenyl)pyrazol-3-amine Chemical compound C1=CC(SC)=CC=C1C1=CC(N)=NN1C1=CC=C(F)C=C1 TYWKFUDMIDTRSC-UHFFFAOYSA-N 0.000 description 3
- LNFNRNGMQNJFBJ-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazol-3-amine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(N)=NN1C1=CC=C(F)C=C1 LNFNRNGMQNJFBJ-UHFFFAOYSA-N 0.000 description 3
- NKBRWXWNSUIHNI-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carbonitrile Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C#N)=NN1C1=CC=C(F)C=C1 NKBRWXWNSUIHNI-UHFFFAOYSA-N 0.000 description 3
- RIJYNNRXDHFDSL-UHFFFAOYSA-N 1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylic acid Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C(O)=O)=NN1C1=CC=C(F)C=C1 RIJYNNRXDHFDSL-UHFFFAOYSA-N 0.000 description 3
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
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- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UETLMBWMVIQIGU-UHFFFAOYSA-N calcium azide Chemical compound [Ca+2].[N-]=[N+]=[N-].[N-]=[N+]=[N-] UETLMBWMVIQIGU-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 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
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000001 effect on platelet aggregation Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- AIOKIAZWWNBJMD-UHFFFAOYSA-N ethyl 1,5-bis(4-methoxyphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(OC)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(OC)C=C1 AIOKIAZWWNBJMD-UHFFFAOYSA-N 0.000 description 1
- RNNZKFBGFPFMGM-UHFFFAOYSA-N ethyl 1-(2,4-difluorophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=C(F)C=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 RNNZKFBGFPFMGM-UHFFFAOYSA-N 0.000 description 1
- OCSMGTCFOLPWBF-UHFFFAOYSA-N ethyl 1-(2,4-difluorophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=C(F)C=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 OCSMGTCFOLPWBF-UHFFFAOYSA-N 0.000 description 1
- YIKIRFTWMUZZMW-UHFFFAOYSA-N ethyl 1-(2,5-difluorophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C(F)=CC=C(F)C=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 YIKIRFTWMUZZMW-UHFFFAOYSA-N 0.000 description 1
- XQWPHMSYNMDDLF-UHFFFAOYSA-N ethyl 1-(2-chlorophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=CC=C(Cl)C=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 XQWPHMSYNMDDLF-UHFFFAOYSA-N 0.000 description 1
- POQDTIRCTFZUPA-UHFFFAOYSA-N ethyl 1-(2-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=CC=C(F)C=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 POQDTIRCTFZUPA-UHFFFAOYSA-N 0.000 description 1
- KXRXNYFFYCDSOB-UHFFFAOYSA-N ethyl 1-(3-fluorophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=CC(F)=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 KXRXNYFFYCDSOB-UHFFFAOYSA-N 0.000 description 1
- SUKLDHJAFNPBIA-UHFFFAOYSA-N ethyl 1-(4-aminophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(N)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 SUKLDHJAFNPBIA-UHFFFAOYSA-N 0.000 description 1
- SBLIXODXFQZINW-UHFFFAOYSA-N ethyl 1-(4-aminophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(N)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 SBLIXODXFQZINW-UHFFFAOYSA-N 0.000 description 1
- AXOAILUZUQLKKG-UHFFFAOYSA-N ethyl 1-(4-fluoro-2-nitrophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=C([N+]([O-])=O)C=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 AXOAILUZUQLKKG-UHFFFAOYSA-N 0.000 description 1
- IMDXNDZKCDCGSO-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-5-(4-formamidophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(NC=O)C=C1 IMDXNDZKCDCGSO-UHFFFAOYSA-N 0.000 description 1
- IOHSZJLGDJKSTG-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-5-(4-methoxyphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(OC)C=C1 IOHSZJLGDJKSTG-UHFFFAOYSA-N 0.000 description 1
- XGNJUXREQVAIEN-UHFFFAOYSA-N ethyl 1-(4-fluorophenyl)-5-[4-(2-oxoethylamino)phenyl]pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(NCC=O)C=C1 XGNJUXREQVAIEN-UHFFFAOYSA-N 0.000 description 1
- WDGXVSGGGVZQKU-UHFFFAOYSA-N ethyl 1-(4-formamidophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(NC=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(C)C=C1 WDGXVSGGGVZQKU-UHFFFAOYSA-N 0.000 description 1
- JOFOJUNBRCBGHF-UHFFFAOYSA-N ethyl 1-(4-formamidophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(NC=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 JOFOJUNBRCBGHF-UHFFFAOYSA-N 0.000 description 1
- RLGYJWJGGQSZQF-UHFFFAOYSA-N ethyl 1-(4-formamidophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(NC=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 RLGYJWJGGQSZQF-UHFFFAOYSA-N 0.000 description 1
- RUYZDIWQXAEKCP-UHFFFAOYSA-N ethyl 1-(4-methoxyphenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(OC)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 RUYZDIWQXAEKCP-UHFFFAOYSA-N 0.000 description 1
- ZYAQUOJLZMGRPV-UHFFFAOYSA-N ethyl 1-(4-methylphenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(C)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 ZYAQUOJLZMGRPV-UHFFFAOYSA-N 0.000 description 1
- MZHWVKVPHTWDLG-UHFFFAOYSA-N ethyl 1-(4-methylphenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(C)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MZHWVKVPHTWDLG-UHFFFAOYSA-N 0.000 description 1
- CMNIXUIZAMKHRW-UHFFFAOYSA-N ethyl 1-[4-(methylamino)phenyl]-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(NC)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 CMNIXUIZAMKHRW-UHFFFAOYSA-N 0.000 description 1
- YBMYJWYUJDAFQU-UHFFFAOYSA-N ethyl 2-(4-fluorophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound CCOC(=O)C1=CC(C=2C=CC(SC)=CC=2)=NN1C1=CC=C(F)C=C1 YBMYJWYUJDAFQU-UHFFFAOYSA-N 0.000 description 1
- KVZMKNKWVKCNPX-UHFFFAOYSA-N ethyl 2-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxylate Chemical compound CCOC(=O)C1=CC(C=2C=CC(=CC=2)S(C)(=O)=O)=NN1C1=CC=C(F)C=C1 KVZMKNKWVKCNPX-UHFFFAOYSA-N 0.000 description 1
- GTFQWMDAUWOOKN-UHFFFAOYSA-N ethyl 4-(3,5-ditert-butyl-4-hydroxyphenyl)-2,4-dioxobutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GTFQWMDAUWOOKN-UHFFFAOYSA-N 0.000 description 1
- KHEAMBUFZSDFDX-UHFFFAOYSA-N ethyl 4-(4-acetylphenyl)-2,4-dioxobutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=C(C(C)=O)C=C1 KHEAMBUFZSDFDX-UHFFFAOYSA-N 0.000 description 1
- QQMYOPVSVNPECO-UHFFFAOYSA-N ethyl 4-(4-methylphenyl)-2,4-dioxobutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=C(C)C=C1 QQMYOPVSVNPECO-UHFFFAOYSA-N 0.000 description 1
- XWLRUMMFRQBZRJ-UHFFFAOYSA-N ethyl 4-(5-methylsulfanylthiophen-2-yl)-2,4-dioxobutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=C(SC)S1 XWLRUMMFRQBZRJ-UHFFFAOYSA-N 0.000 description 1
- MEDKZHAHTKVICR-UHFFFAOYSA-N ethyl 5-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-fluorophenyl)pyrazole-3-carboxylate Chemical compound CCOC(=O)c1cc(-c2cc(c(O)c(c2)C(C)(C)C)C(C)(C)C)n(n1)-c1ccc(F)cc1 MEDKZHAHTKVICR-UHFFFAOYSA-N 0.000 description 1
- LDWPVWOOEXIMHD-UHFFFAOYSA-N ethyl 5-(4-acetylphenyl)-1-(4-fluorophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(C(C)=O)C=C1 LDWPVWOOEXIMHD-UHFFFAOYSA-N 0.000 description 1
- KWAPJRQIOBXGIV-UHFFFAOYSA-N ethyl 5-(4-aminophenyl)-1-(4-fluorophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(F)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(N)C=C1 KWAPJRQIOBXGIV-UHFFFAOYSA-N 0.000 description 1
- BGZQQRSUMCGUOP-UHFFFAOYSA-N ethyl 5-(4-fluorophenyl)-1-(4-methylsulfanylphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(SC)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(F)C=C1 BGZQQRSUMCGUOP-UHFFFAOYSA-N 0.000 description 1
- MIHJOENGEGDFRA-UHFFFAOYSA-N ethyl 5-(4-methoxyphenyl)-1-(4-nitrophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(OC)C=C1 MIHJOENGEGDFRA-UHFFFAOYSA-N 0.000 description 1
- OPGLXDJBUNQJPT-UHFFFAOYSA-N ethyl 5-(4-methylphenyl)-1-(4-nitrophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(C)C=C1 OPGLXDJBUNQJPT-UHFFFAOYSA-N 0.000 description 1
- WTMFFRPNRZBJCF-UHFFFAOYSA-N ethyl 5-(4-methylphenyl)-1-[4-(2-oxoethylamino)phenyl]pyrazole-3-carboxylate Chemical compound C=1C=C(NCC=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(C)C=C1 WTMFFRPNRZBJCF-UHFFFAOYSA-N 0.000 description 1
- GHUBNPKEBHNMJO-UHFFFAOYSA-N ethyl 5-(4-methylsulfanylphenyl)-1-(2-nitrophenyl)pyrazole-3-carboxylate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 GHUBNPKEBHNMJO-UHFFFAOYSA-N 0.000 description 1
- AUCGOWGTTJHPBC-UHFFFAOYSA-N ethyl 5-(4-methylsulfanylphenyl)-1-(4-nitrophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 AUCGOWGTTJHPBC-UHFFFAOYSA-N 0.000 description 1
- KYGARQAZKDKKAZ-UHFFFAOYSA-N ethyl 5-(4-methylsulfanylphenyl)-1-[4-(2-oxoethylamino)phenyl]pyrazole-3-carboxylate Chemical compound C=1C=C(NCC=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 KYGARQAZKDKKAZ-UHFFFAOYSA-N 0.000 description 1
- ZAXSDFNRCWBQTI-UHFFFAOYSA-N ethyl 5-(4-methylsulfanylphenyl)-1-phenylpyrazole-3-carboxylate Chemical compound C=1C=CC=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 ZAXSDFNRCWBQTI-UHFFFAOYSA-N 0.000 description 1
- AFHXGQTURAAQPY-UHFFFAOYSA-N ethyl 5-(4-methylsulfanylphenyl)-1-pyridin-4-ylpyrazole-3-carboxylate;hydrochloride Chemical compound Cl.C=1C=NC=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)C=C1 AFHXGQTURAAQPY-UHFFFAOYSA-N 0.000 description 1
- NPRYYJDTLCFEIF-UHFFFAOYSA-N ethyl 5-(4-methylsulfonylphenyl)-1-(4-nitrophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 NPRYYJDTLCFEIF-UHFFFAOYSA-N 0.000 description 1
- CYPCCEUPGDVQCQ-UHFFFAOYSA-N ethyl 5-(4-methylsulfonylphenyl)-1-[4-(2-oxoethylamino)phenyl]pyrazole-3-carboxylate Chemical compound C=1C=C(NCC=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 CYPCCEUPGDVQCQ-UHFFFAOYSA-N 0.000 description 1
- NLEXQJVBWZXMRU-UHFFFAOYSA-N ethyl 5-(4-methylsulfonylphenyl)-1-phenylpyrazole-3-carboxylate Chemical compound C=1C=CC=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 NLEXQJVBWZXMRU-UHFFFAOYSA-N 0.000 description 1
- CCMWYELBFYIUTB-UHFFFAOYSA-N ethyl 5-(4-methylsulfonylphenyl)-1-pyridin-4-ylpyrazole-3-carboxylate Chemical compound C=1C=NC=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 CCMWYELBFYIUTB-UHFFFAOYSA-N 0.000 description 1
- NLTDMJABXUBSQV-UHFFFAOYSA-N ethyl 5-(5-methylsulfanylthiophen-2-yl)-1-(4-nitrophenyl)pyrazole-3-carboxylate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1N1N=C(C(=O)OCC)C=C1C1=CC=C(SC)S1 NLTDMJABXUBSQV-UHFFFAOYSA-N 0.000 description 1
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- TVZISJTYELEYPI-UHFFFAOYSA-N hypodiphosphoric acid Chemical compound OP(O)(=O)P(O)(O)=O TVZISJTYELEYPI-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- QUIOHQITLKCGNW-ODZAUARKSA-L magnesium;(z)-but-2-enedioate Chemical compound [Mg+2].[O-]C(=O)\C=C/C([O-])=O QUIOHQITLKCGNW-ODZAUARKSA-L 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- OQJWFSVVBUCFMZ-UHFFFAOYSA-N methyl n-[1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazol-3-yl]carbamate Chemical compound C=1C=C(F)C=CC=1N1N=C(NC(=O)OC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 OQJWFSVVBUCFMZ-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- QWYWYBJSXUWMDD-UHFFFAOYSA-N n,n-dimethyl-5-(4-methylsulfonylphenyl)-1-[4-(2-oxoethylamino)phenyl]pyrazole-3-carboxamide Chemical compound C=1C=C(NCC=O)C=CC=1N1N=C(C(=O)N(C)C)C=C1C1=CC=C(S(C)(=O)=O)C=C1 QWYWYBJSXUWMDD-UHFFFAOYSA-N 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- WWKRAFMFFKHIMZ-UHFFFAOYSA-N n-[1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazol-3-yl]acetamide Chemical compound C=1C=C(F)C=CC=1N1N=C(NC(=O)C)C=C1C1=CC=C(S(C)(=O)=O)C=C1 WWKRAFMFFKHIMZ-UHFFFAOYSA-N 0.000 description 1
- GXYIPWUZFOGNCW-UHFFFAOYSA-N n-[1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazol-3-yl]methanesulfonamide Chemical compound C=1C=C(F)C=CC=1N1N=C(NS(=O)(=O)C)C=C1C1=CC=C(S(C)(=O)=O)C=C1 GXYIPWUZFOGNCW-UHFFFAOYSA-N 0.000 description 1
- ZMWVJZFYSRGJGK-UHFFFAOYSA-N n-[2-[3-cyano-5-(4-methylsulfonylphenyl)pyrazol-1-yl]phenyl]formamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C#N)=NN1C1=CC=CC=C1NC=O ZMWVJZFYSRGJGK-UHFFFAOYSA-N 0.000 description 1
- UEMJMCSPZMVNQU-UHFFFAOYSA-N n-[4-[3-(difluoromethyl)-5-(4-methylsulfanylphenyl)pyrazol-1-yl]phenyl]formamide Chemical compound C1=CC(SC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(NC=O)C=C1 UEMJMCSPZMVNQU-UHFFFAOYSA-N 0.000 description 1
- YNOYTUDGMVQLNJ-UHFFFAOYSA-N n-[4-[3-cyano-5-(4-methylsulfonylphenyl)pyrazol-1-yl]phenyl]methanesulfonamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1N1C(C=2C=CC(=CC=2)S(C)(=O)=O)=CC(C#N)=N1 YNOYTUDGMVQLNJ-UHFFFAOYSA-N 0.000 description 1
- UDUPHVJKFGCLBS-UHFFFAOYSA-N n-[4-[5-(4-methylsulfanylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl]formamide Chemical compound C1=CC(SC)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(NC=O)C=C1 UDUPHVJKFGCLBS-UHFFFAOYSA-N 0.000 description 1
- PVDPKOPOUALBSX-UHFFFAOYSA-N n-[4-[5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl]formamide Chemical compound C1=CC(S(=O)C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(NC=O)C=C1 PVDPKOPOUALBSX-UHFFFAOYSA-N 0.000 description 1
- MRPLJIYEXYMNBO-UHFFFAOYSA-N n-[4-[5-(4-methylsulfonylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl]formamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(NC=O)C=C1 MRPLJIYEXYMNBO-UHFFFAOYSA-N 0.000 description 1
- XKYJVVBOBYXAMI-UHFFFAOYSA-N n-[4-[5-cyano-2-(4-fluorophenyl)pyrazol-3-yl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=CC(C#N)=NN1C1=CC=C(F)C=C1 XKYJVVBOBYXAMI-UHFFFAOYSA-N 0.000 description 1
- SAMQWYYFDXOTNY-UHFFFAOYSA-N n-[[1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazol-3-yl]methyl]acetamide Chemical compound C=1C=C(F)C=CC=1N1N=C(CNC(=O)C)C=C1C1=CC=C(S(C)(=O)=O)C=C1 SAMQWYYFDXOTNY-UHFFFAOYSA-N 0.000 description 1
- SWTFBLUIBHXOAH-UHFFFAOYSA-N n-butylhydroxylamine Chemical compound CCCCNO SWTFBLUIBHXOAH-UHFFFAOYSA-N 0.000 description 1
- ZQMDPSKTPXNCAQ-UHFFFAOYSA-N n-cyclopropyl-1-(4-fluorophenyl)-5-(4-methylsulfanylphenyl)pyrazole-3-carboxamide Chemical compound C1=CC(SC)=CC=C1C1=CC(C(=O)NC2CC2)=NN1C1=CC=C(F)C=C1 ZQMDPSKTPXNCAQ-UHFFFAOYSA-N 0.000 description 1
- KNMLOUNDEXHHCP-UHFFFAOYSA-N n-cyclopropyl-1-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyrazole-3-carboxamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C(=O)NC2CC2)=NN1C1=CC=C(F)C=C1 KNMLOUNDEXHHCP-UHFFFAOYSA-N 0.000 description 1
- VDUIPQNXOQMTBF-UHFFFAOYSA-N n-ethylhydroxylamine Chemical compound CCNO VDUIPQNXOQMTBF-UHFFFAOYSA-N 0.000 description 1
- PXSXRABJBXYMFT-UHFFFAOYSA-N n-hexylhexan-1-amine Chemical compound CCCCCCNCCCCCC PXSXRABJBXYMFT-UHFFFAOYSA-N 0.000 description 1
- PNSPGDXUAVSINV-UHFFFAOYSA-N n-methyl-1-[4-(methylamino)phenyl]-5-(4-methylsulfonylphenyl)pyrazole-3-carboxamide Chemical compound C=1C=C(NC)C=CC=1N1N=C(C(=O)NC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 PNSPGDXUAVSINV-UHFFFAOYSA-N 0.000 description 1
- IJIAHCQQHKLMPR-UHFFFAOYSA-N n-methyl-4-[3-methylsulfonyl-5-(4-methylsulfonylphenyl)pyrazol-1-yl]aniline;hydrochloride Chemical compound Cl.C1=CC(NC)=CC=C1N1C(C=2C=CC(=CC=2)S(C)(=O)=O)=CC(S(C)(=O)=O)=N1 IJIAHCQQHKLMPR-UHFFFAOYSA-N 0.000 description 1
- PVFFRCROTRYYBP-UHFFFAOYSA-N n-methyl-4-[5-(4-methylsulfanylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]aniline Chemical compound C1=CC(NC)=CC=C1N1C(C=2C=CC(SC)=CC=2)=CC(C(F)(F)F)=N1 PVFFRCROTRYYBP-UHFFFAOYSA-N 0.000 description 1
- LQCVEYRPHXYHLO-UHFFFAOYSA-N n-methyl-4-[5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]aniline;hydrochloride Chemical compound Cl.C1=CC(NC)=CC=C1N1C(C=2C=CC(=CC=2)S(C)=O)=CC(C(F)(F)F)=N1 LQCVEYRPHXYHLO-UHFFFAOYSA-N 0.000 description 1
- ZEEHSVXYAFQCGT-UHFFFAOYSA-N n-methyl-4-[5-(4-methylsulfonylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]aniline;hydrochloride Chemical compound Cl.C1=CC(NC)=CC=C1N1C(C=2C=CC(=CC=2)S(C)(=O)=O)=CC(C(F)(F)F)=N1 ZEEHSVXYAFQCGT-UHFFFAOYSA-N 0.000 description 1
- NUSQNKMZMMOZHY-UHFFFAOYSA-N n-methyl-5-(4-methylsulfonylphenyl)-1-[4-(2-oxoethylamino)phenyl]pyrazole-3-carboxamide Chemical compound C=1C=C(NCC=O)C=CC=1N1N=C(C(=O)NC)C=C1C1=CC=C(S(C)(=O)=O)C=C1 NUSQNKMZMMOZHY-UHFFFAOYSA-N 0.000 description 1
- JACMPVXHEARCBO-UHFFFAOYSA-N n-pentylpentan-1-amine Chemical compound CCCCCNCCCCC JACMPVXHEARCBO-UHFFFAOYSA-N 0.000 description 1
- ODHYIQOBTIWVRZ-UHFFFAOYSA-N n-propan-2-ylhydroxylamine Chemical compound CC(C)NO ODHYIQOBTIWVRZ-UHFFFAOYSA-N 0.000 description 1
- OMXHKVKIKSASRV-UHFFFAOYSA-N n-propylhydroxylamine Chemical compound CCCNO OMXHKVKIKSASRV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([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
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- XWVKTOHUMPLABF-UHFFFAOYSA-N thallium(3+) Chemical class [Tl+3] XWVKTOHUMPLABF-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Foreliggende oppfinnelse angår fremgangsmåter for fremstilling av nye pyrazolderivater og farmasøytisk akseptable salter derav.
Mer spesielt angår den fremgangsmåter for fremstilling av nye pyrazolderivater og farmasøytisk akseptable salter derav, som har antiinflammatoriske, analgetiske og antitrombotiske virkninger. De nye forbindelsene kan inngå i farmasøytiske preparater og benyttes terapeutisk ved behandling og/eller forebyggelse av inflammatoriske tilstander, forskjellige typer smerte, bindevevs-sykdommer, autoimmune sykdommer,
forskjellige immunlidelser og trombose i mennesker og dyr, og særlig for behandling.og/eller forebyggelse av inflammasjon og smerte i ledd og muskler [f.eks. reumatoid artritt, reumatoid spondylitt, osteoartritt, urinsyregikt, etc], inflammatoriske hudlidelser [f.eks. solbrenthet, eksem, etc], inflammatoriske øyesykdommer [f.eks. konjunktivitt, etc], lungelidelser hvor det inngår inflammasjon [f.eks. astma, bronkitt, "pigeon fancier's disease", farmer's lung, etc],
inflammasjonstUstander i gastrointestinaltraktus [f.eks.
aftøs ulcus, Crohn's sykdom, atrofisk gastritt, gastritis variolaforme, ulcerøs colitt, bukhulebetennelse, regional ileitt, irritabel tarm, etc], gingivitt, inflammasjon, smerte og hevelse etter operasjon eller skade, pyrea, smerte og andre tilstander forbundet med inflammasjon, spesielt slike hvor lipoksygenase- og cyklooksygenase-produkter er en faktor, systemisk lupus erythematosus, scleroderma, polymyositis, periarteritis nodosa, giktfeber, Sjøgren's syndrome, Bechet's sykdom, tyroiditt, diabetes type-I, nefrotisk syndrom, aplastisk anemi, myastenia gravis, uveitt, kontakt-dermatitt, psoriasis, Kawasaki's sykdom, sarkoidose, Hodgkins sykdom, og lignende. De nye forbindelsene forventes dessuten å være egnet som terapeutiske og/eller forebyggende midler ved kardiovaskulære eller cerebrovaskulære sykdommer, samt sykdommer forårsaket av hyperglykemi og hyperlipidemi.
I henhold til foreliggende oppfinnelse kan det fremstilles nye pyrazolderivater og farmasøytisk akseptable salter derav, som har antiinflammatoriske, analgetiske og
antitrombotiske virkninger.
Basert på oppfinnelsen kan det fremstilles farmasøytiske preparater som inneholder de nevnte pyrazolderivater og farmasøytisk akseptable salter derav, som virkestoff.
Enkelte pyrazolderivater med antiinflammatoriske og analgetiske virkninger har vært kjent, og er beskrevet for eksempel i Kanadisk patent 1 13 0 808 og EP-patentpublikasjon No. 272 704 og 293 220.
Pyrazolderivatene fremstillet i henhold til oppfinnelsen er nye og kan gjengis med den følgende generelle formel [I].
hvor R<1> er fenyl som kan ha substituenter valgt blant lavere alkyl, halogen, lavere alkoksy, lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, hydroksy, lavere alkylsulfonyloksy, nitro, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, og lavere alkylamino substituert med lavere alkanoyl; eller pyridyl,
R<2> er hydrogen; metyl substituert med amino, lavere alkyl-amino, halogen eller lavere alkanoyloksy;
karboksy; forestret karboksy; lavere alkanoyl eventuelt substituert med lavere alkoksy; karbamoyl eventuelt substituert med substituent(er) valgt fra gruppen bestående av lavere alkyl,
cyklo(lavere)alkyl, fenyl og hydroksy; 1-pyrrolidinylkarbonyl; N-metylpiperazinylkarbonyl;
lavere alkylsulfonyl; amino substituert med lavere alkanoyl, forestret karboksy eller lavere alkylsulfonyl; cyano; halogen; lavere alkyltio;
lavere alkylsulfinyl; eller tetrazolyl; og
R<3> er fenyl substituert med lavere alkyl, lavere alkyltio, lavere alkylsulfinyl, halogen, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, lavere alkyl-amino substituert med lavere alkanoyl, lavere
alkoksy, cyano, hydroksy, lavere alkanoyl, eller lavere alkylsulfonyl; eller tienyl som kan være substituert med lavere alkyltio, lavere
alkylsulfinyl eller lavere alkylsulfonyl; forutsatt at når
R<2> er karboksy, forestret karboksy eller
tri(halogen)metyl, da er
R<3> fenyl substituert med lavere alkyltio, lavere alkylsulf inyl, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, lavere alkylamino substituert med lavere alkanyl, hydroksy, lavere alkanoyl eller lavere alkylsulf onyl,- eller tienyl substituert med lavere alkyltio, lavere alkylsulfinyl eller lavere alkylsulfonyl; eller
R<1> er fenyl substituert med substituent(er) valgt fra lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, hydroksy, lavere alkylsulfonyloksy, nitro, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, og lavere alkylamino substituert med lavere alkanoyl;
eller pyridyl;
eller farmasøytisk akseptable salter derav.
Forbindelsen med formel [I] eller salter derav, kan fremstilles etter følgende fremgangsmåter.
Prosess 1
Prosess 2
Prosess 3
Prosess 4 Prosess 5
Prosess 6
Prosess 7 Prosess 8
Prosess 9
Prosess 10 Prosess 11
Prosess 12
Prosess 13 Prosess 14
Prosess 15
Prosess 16 Prosess 17
Prosess 18
Prosess 19 Prosess 20
Prosess 21
hvor R<1>, R2 og R<3> er som ovenfor definert,
Ra3 er fenyl eller tienyl som begge er substituert med
lavere alkyltio,
Rb<3> er fenyl eller tienyl som begge er substituert med lavere alkylsulfinyl eller lavere alkylsulfonyl,
Ra2 er <f>orestret karboksy,
Rb<2> er karbamoyl som kan være substituert med lavere alkyl, fenyl, cyklo(lavere)alkyl og hydroksy; eller 1-pyrrolidinylkarbonyl; eller N-metylpiperazinylkarbonyl,
Rc2 er karbamoyl som kan være substituert med lavere
alkyl,
Rd2 er aminometyl som kan være substituert med lavere
alkyl,
R<4> er lavere alkyl,
Rg1 er fenyl som kan være substituert med lavere alkyl,
halogen, lavere alkoksy, lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, hydroksy, lavere alkylsulfonyloksy, nitro, lavere alkylamino,
amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, og lavere alkylamino substituert med lavere alkanoyl; eller pyridyl;
Rb<1> er fenyl substituert med lavere alkyltio^
Rj.<1> er fenyl substituert med lavere alkylsulf inyl eller
lavere alkylsulfonyl,
Rd<x> er fenyl substituert med nitro,
Rex er fenyl substituert med amino,
Rf<1> er fenyl som kan være substituert med lavere alkyl,
halogen, lavere alkoksy, lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, lavere alkylsulf onyloksy, nitro, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, eller lavere alkylamino substituert med lavere alkanoyl;
eller pyridyl,
Re2 er amino substituert med lavere alkanoyl, forestret
karboksy eller lavere alkylsulfonyl,
Rg<1> er fenyl substituert med amino eller amino substituert
med lavere alkanoyl,
Rh<1> er fenyl substituert med lavere alkylamino eller
lavere alkylamino substituert med lavere alkanoyl,
Rc3 er fenyl substituert med amino,
Rd3 er fenyl substituert med amino substituert med lavere
alkanoyl eller lavere alkylsulfonyl,
Ri<1> er fenyl substituert med amino,
Rj1 er fenyl substituert med amino substituert med lavere
alkanoyl eller lavere alkylsulfonyl,
Re3 er fenyl substituert med amino eller amino substituert
med lavere alkanoyl,
Rf<3> er fenyl substituert med lavere alkylamino eller
lavere alkylamino substituert med lavere alkanoyl,
Rk<1> er fenyl substituert med amino eller lavere alkyl-amino, som hver er substituert, med lavere alkanoyl,
Ri<1> er fenyl substituert med amino eller lavere
alkylamino,
Rg3 er fenyl substituert med amino eller lavere alkyl-amino, som hver er substituert med lavere alkanoyl,
Rh3 er fenyl substituert med amino eller lavere
alkylamino,
X er halogen, og
R6 er lavere alkyltio.
I denne sammenheng og for den etterfølgende beskrivelse er det i det følgende gitt passende eksempler på de forskjellige definisjoner som faller inn under oppfinnelsens ramme.
Betegnelsen "lavere" står for en gruppe som har 1 til 6
karbonatomer om intet annet er angitt.
"Lavere alkyl" og lavere alkyl-deler i betegnelsene "lavere alkyltio", "lavere alkylsulfonyl", "lavere alkyl(acyl)amino", "lavere alkylsulfinyl" og "lavere alkylsulfonyloksy" kan være rett eller forgrenet, så som metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, heksyl eller lignende, hvorav metyl er foretrukket.
"Lavere alkoksy" kan hensiktsmessig være metoksy, etoksy,
propoksy, isopropoksy, butoksy, isobutoksy, tert-butoksy og lignende, hvorav metoksy er foretrukket.
"Aryl" kan hensiktsmessig være fenyl, naftyl og lignende, hvorav fenyl er foretrukket.
Arylgruppen for R<1> kan være substituert med 1 til 5 substituenter i henhold til angivelsene ovenfor, og arylgruppen for R<3> er substituert med 1 til 5 substituenter som angitt ovenfor, hvor det foretrukne substituentantall er 1 til 3 .
"Heterocyklisk gruppe" kan hensiktsmessig innbefatte mettede eller umettede, monocykliske eller polycykliske grupper inneholdende minst ett heteroatom, så som et nitrogenatom, oksygenatom eller svovelatom.
De foretrukne eksempler på således definerte "heterocyklisk gruppe" kan være en umettet, 3- til 8-leddet, fortrinnsvis 5- eller 6-leddet, heteromonocyklisk gruppe inneholdende 1 til 4 nitrogenatomer, som pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl-N-oksyd, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.;
en mettet, 3- til 8-leddet, fortrinnsvis 5- eller 6-leddet heteromonocyklisk gruppe som inneholder 1 til 4 nitrogenatomer, som pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
en umettet, kondensert heterocyklisk gruppe som inneholder 1 til 5 nitrogenatomer, som indolyl, isoindolyl, indolizinyl, benzimidazolyl, kinolyl, isokinolyl, indazolyl, benzotriazolyl, etc;
en umettet, 3- til 8-leddet heteromonocyklisk gruppe inneholdende 1 til 2 oksygenatomer og 1 til 3 nitrogenatomer, som oksazolyl, isoksazolyl, oksadiazolyl, etc;
en mettet, 3- til 8-leddet heteromonocyklisk gruppe inneholdende 1 til 2 oksygenatomer og 1 til 3 nitrogenatomer, som morfolin, sydnonyl, etc: en umettet kondensert heterocyklisk gruppe inneholdende 1 til 2 oksygenatomer og 1 til 3 nitrogenatomer, som benzoksazolyl, benzoksadiazolyl, etc: en umettet, 3- til 8-leddet heteromonocyklisk gruppe
inneholdende 1 til 2 svovelatomer og 1 til 3 nitrogenatomer, som tiazolyl, isotiazolyl, tiadiazolyl, etc.;
en umettet, 3- til 8-leddet heteromonocyklisk gruppe inneholdende 1 til 2 svovelatomer, som for eksempel tienyl,-
en umettet kondensert heterocyklisk gruppe inneholdende 1 til 2 svovelatomer og 1 til 3 nitrogenatomer, som benzo-tiazolyl, benzotiadiazolyl, etc;
en umettet, 3- til 8-leddet heteromonocyklisk gruppe inneholdende et oksygenatom, som for eksempel furyl;
en umettet, kondensert heterocyklisk gruppe inneholdende
1 til 2 svovelatomer, som for eksempel benzotienyl;
en umettet, Kondensert heterocyklisk gruppe inneholdende
1 til 2 oksygenatomer, som for eksempel benzofuranyl; eller lignende.
Den nevnte "heterocykliske gruppe" kan være substituert med lavere alkyl som eksemplifisert ovenfor, hvorav pyrrolidinyl, N-metylpiperazinyl, tetrazolyl, tienyl eller pyridyl er foretrukket.
"Cyklo(lavere)alkyl" kan hensiktsmessig være cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl og lignende, hvorav cyklopropyl er foretrukket.
"Halogen" kan hensiktsmessig være fluor, klor, brom og jod, hvorav fluor er foretrukket.
"Lavere alkylamino(lavere)alkyl" kan hensiktsmessig være mono- eller di(laverealkyl)amino-substituert lavere alkyl, så som metylaminometyl, metylaminoetyl, metylaminopropyl, metyl-aminoheksyl, etylaminometyl, etylaminoetyl, etylaminopropyl, etylaminoheksyl, dimetylaminometyl, dimetylaminoetyl, dimetyl-aminopropyl, dimetylaminoheksyl, dietylaminometyl, dietylaminoetyl, dietylaminopropyl, dietylaminoheksyl eller lignende.
"Lavere alkylamino" og lavere alkylamino-deler i "lavere alkylaminometyl" kan være mono- eller di(lavere)alkylamino, så som metylamino, etylamino, dimetylamino, dietylamino eller lignende.
"Halogen(lavere)alkyl" kan hensiktsmessig være klormetyl, fluormetyl, brommetyl, difluormetyl, diklormetyl, trifluormetyl, triklormetyl, 2-fluoretyl og lignende.
"Acyl" og acyl-deler i "acyloksy", "acylamino" og "lavere alkyl(acyl)amino" kan hensiktsmessig være karboksy; forestret karboksy; karbamoyl som eventuelt er substituert med lavere alkyl, cyklo(lavere)alkyl, aryl og hydroksy; lavere alkanoyl som eventuelt er substituert med lavere alkoksy; heterocyklisk karbonyl; lavere alkylsulfonyl; og lignende.
Den forestrede karboksygruppe kan være substituert eller usubstituert lavere alkoksykarbonyl [f.eks. metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, butoksykarbonyl, heksyloksy-karbonyl, 2-jodetoksykarbonyl, 2,2,2-trikloretoksykarbonyl], substituert eller usubstituert aryloksykarbonyl [f.eks. fenoksykarbonyl, 4-nitrofenoksykarbonyl, 2-naftyloksykarbonyl], substituert eller usubstituert ar(lavere)alkoksykarbonyl [f.eks. benzyloksykarbonyl, fenetyloksykarbonyl, benzhydryloksykarbonyl, 4-nitrobenzyloksykarbonyl] og lignende.
Den lavere alkanoylgruppe kan være formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hensanoyl og lignende.
Den heterocykliske del i betegnelsen "heterocyklisk
karbonyl" kan være som angitt for "heterocyklisk gruppe".
"Heterocyklisk karbonyl" kan hensiktsmessig være N-holdig heterocyklisk karbonyl, så som pyrrolidinylkarbonyl, imidazolidinylkarbonyl, piperidinkarbonyl,
piperazinylkarbonyl, N-metylpiperazinylkarbonyl eller lignende, hvorav pyrrolidinylkarbonyl eller N-metylpiperazinylkarbonyl er foretrukket.
"Lavere alkylsulfonyl" kan hensiktsmessig være metylsulfonyl, etylsulfonyl, propylsulfonyl og» lignende, hvorav metylsulfonyl er foretrukket.
"Lavere alkylsulfinyl" kan hensiktsmessig være metylsulf inyl, etylsulfinyl, propylsulfinyl og lignende, hvorav metylsulfinyl er foretrukket.
Passende farmasøytisk akseptable salter av de nye forbindelser [I] er konvensjonelle ugiftige salter og innbefatter syreaddisjonssalter, så som uorganiske syreaddisjonssalter [f.eks. hydroklorid, hydrobromid, sulfat, fosfat, etc], et organisk syreaddisjonssalt [f.eks. formiat, acetat, trifluor-acetat, maleat, tartrat, metansulfonat, benzensulfonat, toluensulfonat, etc], et salt med en aminosyre [f.eks. argininsalt, asparaginsyresalt, glutaminsyresalt, etc], et metallsalt så som et alkalimetallsalt [f.eks. natriumsalt, kaliumsalt, etc] og et jordalkalimetallsalt [f.eks. kalsiumsalt, magnesiumsalt, etc], et ammoniumsalt, et addisjonssalt med en organisk base [f.eks. trimetylamin, trietylamin, etc] og lignende..
Fremgangsmåtene for fremstilling av de nye forbindelser [I] er forklart utførlig i det følgende.
Prosess 1
Forbindelsen [Ia] eller salter derav kan fremstilles ved å omsette en forbindelse [Ila] eller salter derav, med en forbindelse [III] eller salter derav.
Passende salter av forbindelsene [Ila] og [III] kan være slike som er angitt for forbindelse [I].
Reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel, så som alkohol (f.eks. metanol, etanol), dioksan, tetrahydrofuran, eddiksyre eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker reaksjonen.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen utføres vanligvis under oppvarming.
Prosess 2
Forbindelsen [Ih] eller salter derav, kan fremstilles ved å omsette forbindelsen [lg] eller salter derav, med et oksydasj onsmiddel.
Passende oksydasjonsmidler kan være hydrogenperoksyd, Jones reagens, persyre [f.eks. pereddiksyre, perbenzosyre, m-klorperbenzosyre, etc], kromsyre, kaliumpermanganat, alkali-metallperjodat [f.eks. natriumperjodat, etc] og lignende.
Reaksjonen utføres vanligvis i et oppløsningsmiddel som ikke ugunstig påvirker omsetningen, så som
eddiksyrediklormetan, aceton, etylacetat, kloroform, vann, en alkohol [f.eks. metanol, etanol, etc] eller en blanding derav.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen utføres vanligvis under avkjøling eller oppvarming.
Dersom forbindelsen [lg] med fenyl substituert med lavere alkyltio for R<1> og/eller lavere alkyltio for R<2> benyttes som utgangsforbindelse, kan forbindelsen [Ih] med fenyl substituert med lavere alkylsulfinyl eller lavere alkylsulfonyl for R<1> og/eller lavere alkylsulfinyl eller lavere alkylsulfonyl for R<2>, oppnås under disse reaksjonsbetingelsene. Disse tilfellene omfattes også av foreliggende oppfinnelse.
Prosess 3
Forbindelsen [Ij] eller salter derav, kan fremstilles ved å fjerne estergruppen i en forbindelse [li] eller salter derav.
Reaksjonen utføres etter en konvensjonell metode, så som hydrolyse, reduksjon eller lignende.
Hydrolysen utføres fortrinnsvis i nærvær av en base eller en syre, innbefattet Lewis-syrer. Egnede baser kan innbefatte uorganiske baser og organiske baser, så som et alkalimetall [f.eks. natrium, kalium, etc], et jordalkalimetall [f.eks. magnesium, kalsium, etc], hydroksydet eller karbonatet eller bikarbonatet derav, trialkylamin [f.eks. trimetylamin, trietylamin, etc], pikolin, 1,5-diazabicyklo[4,3,0]non-5-en, 1, 4-diazabicyklo[2,2,2]oktan, 1,8-diazabicyklo[5,4,0]undek-7-en, eller lignende. Egnede syrer kan innbefatte en organisk syre [f.eks. maursyre, eddiksyre, propionsyre, trikloreddiksyre, trifluoreddiksyre, etc], en uorganisk syre [f.eks. saltsyre, hydrogenbromidsyre, hydrogenjodidsyre, svovelsyre, etc] og en Lewis-syre [f.eks. bortribromid, etc.].
Reaksjonen utføres vanligvis i et oppløsningsmiddel, så som vann, en alkohol [f.eks. metanol, etanol, etc], metylenklorid, tetrahydrofuran, en blanding derav eller et annet oppløsningsmiddel som ikke ugunstig påvirker omsetningen. En flytende base eller syre kan også benyttes som oppløsnings-middel. Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen utføres vanligvis under avkjøling eller under oppvarming.
Reduksjonen anvendes fortrinnsvis for å fjerne ester-delen, så som 4-nitrobenzyl, 2-jodetyl, 2,2,2-trikloretyl eller lignende. Reduksjonsmetoden egnet for eliminasjonsreaksjonen kan innbefatte kjemisk reduksjon og katalytisk reduksjon.
Egnede reduksjonsmidler for bruk ved kjemiske reduksjoner er en kombinasjon av metall [f.eks. tinn, sink, jern, etc] eller en metallisk forbindelse [f.eks. kromklorid, kromacetat, etc] og en organisk eller uorganisk syre [f.eks. maursyre, eddiksyre, propionsyre, trifluoreddiksyre, p-toluensulfonsyre, saltsyre, hydrogenbromidsyre, etc.].
Egnede katalysatorer for den katalytiske reduksjon er konvensjonelle katalysatorer, så som platina [f.eks. platina-blikk, platina-svamp, platina-sort, kolloidalt platina, platina-oksyd, platina-tråd, etc], palladium [f.eks. palladium-svamp, palladium-sort, palladium-oksyd, palladium-på-kull, kolloidalt palladium, palladium-på-bariumsulfat, palladium-på-bariumkarbonat, etc], nikkel-katalysatorer [f.eks. redusert nikkel, nikkel-oksyd, Raney-nikkel, etc], kobolt-katalysatorer [f.eks. redusert kobolt, Raney-kobolt, etc], jern-katalysatorer [f.eks. redusert jern, Raney-jern, etc], kobber-katalysatorer [f.eks. redusert kobber, Raney-kobber, Ullman-kobber, etc] eller lignende.
Reduksjonen utføres vanligvis i et konvensjonelt opp-løsningsmiddel som ikke ugunstig påvirker omsetningen, så som vann, en alkohol [metanol, etanol, propanol, etc], N,N-dimetylformamid eller en blanding av disse. Dersom de ovennevnte syrer for den kjemiske reduksjon er flytende, kan også de benyttes som oppløsningsmiddel. Dessuten kan det benyttes andre konvensjonelle oppløsningsmidler, så som dietyleter, dioksan, tetrahydrofuran eller blandinger derav.
Reaksjonstemperaturen for denne reduksjon er ikke av avgjørende betydning, og omsetningen kan utføres under avkjøling eller under oppvarming.
Når en forbindelse [li] som har fenyl substituert med lavere alkoksy for R<1>, benyttes som utgangsforbindelse, kan forbindelsen [Ij] som for R<1> har fenyl substituert med oksy, oppnås gjennom disse reaksjonsbetingelsene. Dette tilfellet
omfattes også av foreliggende oppfinnelse.
Prosess 4
Forbindelsen [Ik] eller salter derav, kan fremstilles ved å omsette forbindelsen [Ij] eller dens reaktive derivat ved karboksygruppen, eller salter derav,, med et amin eller formamid og alkalimetall-alkoksyd.
Herunder kan "amin" være ammoniakk, lavere alkylamin, arylamin, cyklo(lavere)alkylamin, lavere alkylhydroksylamin, en aminosyre, N-holdig heterocyklisk forbindelse og lignende.
Det lavere alkylamin kan være mono- eller
di(lavere)alkylamin, så som metylamin, etylamin, propylamin, isopropylamin, butylamin, isobutylamin, pentylamin, heksylamin, dimetylamin, dietylamin, dipropylamin, dibutylamin, diisopropylamin, dipentylamin, diheksylamin eller lignende, fortrinnsvis metylamin eller dimetylamin.
Arylaminet kan være anilin, naftylamin og lignende. Cyklo(lavere)alkylamin kan være cyklopropylamin, cyklobutylamin, cyklopentylamin, cykloheksylamin og lignende, fortrinnsvis cyklopropylamin.
Det lavere alkylhydroksylamin kan være
metylhydroksylamin, etylhydroksylamin, propylhydroksylamin, butylhydroksylamin, isopropylhydroksylamin og lignende, fortrinnsvis metylhydroksylamin.
Aminosyren kan være glycin, alanin, S-alanin, isoleucin, tyrosin og lignende, fortrinnsvis glycin.
Den N-holdige heterocykliske forbindelse kan være en mettet 5- eller 6-leddet N-, eller N- og S-, eller N- og O-holdig heterocyklisk forbindelse, så som pyrrolidin, imidazolidin, piperidin, piperazin, N-(lavere)alkylpiperazin [f.eks. N-metylpiperazin, N-etylpiperazin, etc], morfolin, tiomorfolin eller lignende, fortrinnsvis pyrrolidin eller N-metylpiperazin.
"Alkalimetall-alkoksyd" kan hensiktsmessig være natriummetoksyd, natriumetoksyd, kalium-tert-butoksyd og lignende.
Egnede reaktive derivater ved karboksygruppen av forbindelsen [Ij] kan være en ester, et syrehalogenid, et syre-anhydrid og lignende. Passende eksempler på reaktive derivater kan være et syrehalogenid [f.eks. syreklorid, syrebromid, etc.] ;
et symmetrisk syre-anhydrid;
et blandet syre-anhydrid med 1,1'-karbonyl-diimidazol eller en syre, så som en alifatisk syre [f.eks. eddiksyre,_ pivalinsyre, etc], substituert fosforsyre [f.eks. dialkylfosforsyre, difenylfosforsyre, etc.]; en ester, så som en lavere alkylester [f.eks. metylester, etylester, propylester, heksylester, etc], substituert eller usubstituert ar(lavere)alkylester [f.eks. benzylester, benzhydrylester, p-klorbenzylester, etc], substituert eller usubstituert arylester [f.eks."fenylester, tolylester, 4-nitrofenylester, 2,4-dinitrofenylester, pentaklorfenylester, naftylester, etc], eller en ester med N,N-dimetylhydroksylamin, N-hydroksysuccinimid, N-hydroksyftalimid eller l-hydroksy-6-klor-lH-benzotriazol, eller lignende.
Reaksjonen foretas ,vanligvis i et konvensjonelt oppløsningsmiddel, så som vann, aceton, dioksan, kloroform, metylenklorid, etylenklorid, tetrahydrofuran, formamid, etylacetat, N,N-dimetylformamid, pyridin, eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen. Hydrofile oppløsningsmidler blant disse kan benyttes i blanding med vann.
Når forbindelsen [Ij] benyttes i fri syreform under omsetningen, foretas reaksjonen fortrinnsvis i nærvær av et konvensjonelt kondensasjonsmiddel, så som N,N'-dicykloheksyl-karbodiimid, N-cykloheksyl-N'-morfolinetylkarbodiimid, N-etyl-N'-(3-dimetylaminopropyl)karbodiimid, tionylklorid, oksalyl-klorid, lavere alkoksykarbonylhalogenid [f.eks. etylklorformiat, isobutyl-klorformiat, etc], 1-(p-klorbenzensulfonyloksy)-6-klor-lH-benzotriazol eller lignende. Reaksjonen foretas fortrinnsvis i nærvær av en konvensjonell base, så som trietylamin, pyridin, natriumhydroksyd eller lignende.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan foretas under avkjøling eller under oppvarming.
Prosess 5
Forbindelsen [Im] eller salter derav, kan fremstilles ved å omsette en forbindelse [II] eller salter derav, med et dehydratiseringsmiddel.
Egnede dehydratiseringsmidler kan være fosforforbindelser [f.eks. fosforpentoksyd, fosforpentaklorid, fosforoksyklorid, etc], tionylklorid, syre-anhydrid [f.eks. eddiksyre-anhydrid, etc], fosgen, arylsulfonylklorid [f.eks. benzensulfonylklorid, p-toluensulfonylklorid, etc. ], metansulfonylklorid, sulfaminsyre, ammoniumsulfamat, N,N'-dicykloheksylkarbodiimid, lavere alkoksykarbonyl-halogenid [f.eks. etylklorformiat, etc] og lignende.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel, så som acetonitril, metylenklorid, etylenklorid, benzen, N,N-dimetylformamid, pyridin, eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen.
Dersom ovennevnte dehydratiseringsmiddel er flytende, kan også det benyttes som oppløsningsmiddel.
Reaksjonstemperaturen er ikke av avgjørende betydning, men omsetningen foretas fortrinnsvis under oppvarming eller koking.
Når det i denne reaksjon benyttes metylsulfonylklorid som dehydratiseringsmiddel og en forbindelse [II] som har fenyl substituert med hydroksy for R<1> og/eller fenyl substituert med amino for R<3>, som utgangsforbindeIse, kan forbindelsen [Im] som har fenyl substituert med metylsulfonyloksy for R<1> og/eller fenyl substituert med metylsulfonylamino for R<3>, oppnås under disse reaksjonsbetingelsene. Disse tilfeller omfattes også av foreliggende oppfinnelse.
Prosess 6
Forbindelsen [Io] eller salter derav, kan fremstilles ved å omsette en forbindelse [In] eller salter derav, med et reduksjonsmiddel.
Egnede reduksjonsmidler kan være diboran,
litiumaluminiumhydrid og lignende.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel, så som dietyleter, tetrahydrofuran eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan foretas under avkjøling eller under oppvarming.
Prosess 7
Forbindelsen [lp] kan fremstilles etter følgende metoder. 1) Forbindelsen [Ij] eller dens reaktive derivat ved karboksygruppen, eller salter derav, omsettes først med en forbindelse [IV], hvorpå 2) det resulterende produkt underkastes en hydrolysereaksjon.
Egnede reaktive derivater ved karboksygruppen av forbindelsen [Ij] kan være et syre-halogenid [f.eks. syreklorid, syrebromid, etc] og lignende.
I det første trinn utføres reaksjonen fortrinnsvis i nærvær av en base, så som et alkalimetall [f.eks. litium, natrium, kalium, etc], jordalkalimetall [f.eks. kalsium, magnesium, etc], alkalimetallhydrid [f.eks .natriumhydrid, etc], jordalkalimetallhydrid [f.eks. kalsiumhydid, etc], alkalimetallalkoksyd [f.eks. natriummetoksyd, natriumetoksyd, kalium-tert-butoksyd, etc], jordalkalimetallalkoksyd [f.eks. magnesiummetoksyd, magnesiunretoksyd, etc] og lignende.
Reaksjonen utføres vanligvis i et oppløsningsmiddel som ikke ugunstig påvirker omsetningen, så som dietyleter, tetrahydrofuran, dioksan og lignende.
Reaksjonstemperaturen er ikke avgjørende, og omsetningen kan utføres under avkjøling eller under oppvarming.
Ved denne reaksjon oppnås en forbindelse med formel:
eller salter derav
hvor R<1>, R3 og R<4> hver er som definert ovenfor.
Forbindelsen [Iz] eller salter derav, hydrolyseres ytterligere til forbindelsen [lp] eller salter derav.
Hydrolysen utføres fortrinnsvis i nærvær av en syre.
Egnede syrer kan være de samme som eksemplifisert under Prosess 3.
Hydrolysemetoden og reaksjonsbetingelsene kan være de samme som forklart under Prosess 3.
Prosess 8
Forbindelsen [Iq] eller salter derav, kan fremstilles ved å omsette en forbindelse [lp] eller salter derav, med en forbindelse [V].
Denne reaksjonen utføres fortrinnsvis i nærvær av et thallium(III)salt [f.eks. thallium(III)nitrat, etc] og lignende.
Reaksjonen utføres vanligvis i et oppløsningsmiddel så som dioksan, tetrahydrofuran eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen.
Reaksjonstemperaturen er ikke av avgjørende betydning, men omsetningen foretas fortrinnsvis ved romtemperatur eller under oppvarming eller koking.
Prosess 9
Forbindelsen [Ir] eller salter derav, kan fremstilles ved å omsette en forbindelse [Via] eller salter derav, med en nitrittforbindelse.
Egnede salter av forbindelsen [Via] kan være de samme som for forbindelse [I].
Egnede nitrittforbindelser kan være alkalimetallnitritter [f.eks. natriumnitritt, kaliumnitritt, etc], alkylnitritter [f.eks. tert-butylnitritt, etc] og lignende.
Denne reaksjonen utføres vanligvis i nærvær av kobber(II)klorid, hypofosforsyre og lignende.
Reaksjonen utføres vanligvis i et oppløsningsmiddel, så som dioksan, tetrahydrofuran, acetonitril eller et annet organisk oppløsningsmiddel ikke ugunstig påvirker omsetningen. Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan foretas under avkjøling eller under oppvarming.
Prosess 10
Forbindelsen [It] eller salter derav, kan fremstilles ved å omsette en forbindelse [Is] eller salter derav, med et oksydasj onsmiddel.
Denne reaksjonen kan utføres i det vesentlige på samme måte som under Prosess 2, og reaksjonsmåte og reaksjonsbetingelser (f.eks. oppløsningmiddel, reaksjonstemperatur, etc.) er som forklart under Prosess 2.
Dersom forbindelsen [Is] med lavere alkyltio for R<2 >og/eller fenyl eller tienyl som begge er substituert med lavere alkyltio for R<3>, herunder benyttes som utgangsforbindelse, kan forbindelsen [It] med lavere alkylsulf inyl eller lavere alkylsulfonyl for R2 og/eller fenyl eller tienyl, som begge er substituert med lavere alkylsulfinyl eller lavere alkylsulfonyl for R<3>, oppnås under disse reaksjohsbetingelsene. Disse tilfellene faller også inn under rammen for foreliggende oppfinnelse.
Prosess 11
Forbindelsen [Iv] eller salter derav, kan fremstilles ved
å redusere en forbindelse [lu] eller salter derav.
Reaksjonen kan bestå i en kjemisk reduksjon eller en
katalytisk reduksjon, som utføres på konvensjonell måte.
Egnede reduksjonsmidler for den kjemiske reduksjon er et metall [f.eks. tinn, sink, jern, etc], en kombinasjon av et slikt metall og/eller en metallisk forbindelse [f.eks. kromklorid, kromacetat, etc] og en organisk eller uorganisk syre [f.eks. maursyre, eddiksyre, propionsyre, trifluoreddiksyre, p-toluensulfonsyre, saltsyre, hydrogenbromidsyre, etc], en kombinasjon av et slikt metall og/eller en metallisk forbindelse og en base [f.eks. ammoniakk, ammoniumklorid, natriumhydroksyd, etc], en metallhydridforbindelse, så som en aluminiumhydridforbindelse [f.eks. litiumaluminiumhydrid, natriumaluminiumhydrid, aluminiumhydrid, litiumtrimetoksy-aluminiumhydrid, litium-tri-t-butoksyaluminiumhydrid, etc], en borhydridforbindelse [f.eks. natriumborhydrid, litiumborhydrid, natriumcyanoborhydrid, tetrametylammonium-borhydrid, boran, diboran, etc], en fosforforbindelse [f.eks. fosfortriklorid, fosfortribromid, trifenylfosfin, trietylfosfin, etc.] og lignende.
Egnede katalysatorer for den katalytiske reduksjon er konvensjonelle katalysatorer, så som platina [f.eks. platina-blikk, platina-svamp, platina-sort, kolloidalt platina, platina-oksyd, platina-tråd, etc], palladium-katalysatorer [f.eks. palladium-svamp, palladium-sort, palladium-oksyd, palladium-på-kull, kolloidalt palladium, palladium-på-bariumsulfat, palladium-på-bariumkarbonat, etc], nikkel-katalysatorer [f.eks. redusert nikkel, nikkel-oksyd, Raney-nikkel, etc], kobolt-katalysatorer [f.eks. redusert kobolt, Raney-kobolt, etc], jern-katalysatorer [f.eks. redusert jern, Raney-jern, etc], kobber-katalysatorer [f.eks. redusert kobber, Raney-kobber, Ullman-kobber, etc] eller lignende.
Reduksjonen utføres vanligvis i et oppløsningsmiddel. Et passende oppløsningsmiddel for formålet kan være vann, en alkohol [f.eks. metanol, etanol, propanol, etc], acetonitril eller et annet konvensjonelt organisk oppløsningsmiddel, så som dietyleter, dioksan, tetrahydrofuran, etc. eller en blanding derav.
Reaksjonstemperaturen er ikke av avgjørende betydning, men reaksjonen utføres fortrinnsvis under oppvarming eller koking.
Prosess 12
Forbindelsen [Iw] kan fremstilles ved å omsette en forbindelse [VIb] eller salter derav, med et acyleringsmiddel.
Egnede salter av forbindelsen [VIb] kan være de samme som er eksemplifisert for forbindelse [I].
Acyleringsmidlet kan være en organisk syre representert ved formelen: R<5->OH, hvor R<5> er lavere alkanoyl, forestret karboksy eller lavere alkylsulfonyl som illustrert ovenfor, eller et reaktivt derivat derav.
Passende reaktive derivater av organiske syrer kan være et syrehalogenid [f.eks. syreklorid, syrebromid, etc], et syreazid, et syreanhydrid, et aktivert amid, en aktivert ester eller' lignende.
Når det som acyleringsmiddel benyttes en fri syre, kan acyleringsreaksjonen fortrinnsvis foretas i nærvær av et konvensjonelt kondensasjonsmiddel, så som N,N'-dicykloheksyl-karbodiimid eller lignende.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel, så som vann, aceton, dioksan, kloroform, metylenklorid, acetonitril, etylenklorid, tetrahydrofuran, etylacetat, N,N-dimetylformamid, pyridin eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen, eller en blanding derav.
Reaksjonen utføres fortrinnsvis i nærvær av en konvensjonell base, så som trietylamin, pyridin, natriumhydroksyd eller lignende.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan utføres under avkjøling eller under oppvarming.
Prosess 13
Forbindelsen [ly] eller salter derav, kan fremstilles ved å omsette en forbindelse [lx] eller salter derav, med et alkyleringsmiddel.
Egnede alkyleringsmidler kan være lavere alkylhalogenider [f.eks. metyljodid, etylbromid, etc], en kombinasjon av en karbonylforbindelse, så som et alifatisk keton [f.eks. aceton, etylmetylketon, etc], karbaldehyd [f.eks. formaldehyd, etanal, etc], ortokarboksylsyreester [f.eks. trietylortoformiat, etc] eller lignende, og et reduksjonsmiddel, herunder både kjemiske og katalytiske [f.eks. maursyre, natriumborhydrid, natriumcyanoborhydrid, palladium-på-kull, etc.].
Dersom et lavere alkylhalogenid benyttes som alkyleringsmiddel, foretas omsetningen fortrinnsvis i nærvær av en base, så som et alkalimetall [f.eks. natrium, kalium, etc], et jordalkalimetall [f.eks. magnesium, kalsium, etc], eller et hydrid-, hydroksyd-, karbonat- eller bikarbonat derav. Reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel som ikke ugunstig påvirker omsetningen, så som vann, dioksan, en alkohol [f-eks. metanol., etanol, etc], acetonitril, tetrahydrofuran, N,N-dimetylformamid eller en blanding derav. Dersom ovennevnte alkyleringsmiddel er flytende, kan også det benyttes som oppløsningsmiddel.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan foretas under avkjøling eller under oppvarming.
Dersom forbindelsen [lx] med aminometyl for R<2> og/eller fenyl substituert med amino eller amino substituert med lavere alkanoyl for R<3> benyttes som utgangsforbindelse, kan forbindelsen [ly] som har lavere alkylaminometyl for R<2> og/eller fenyl substituert med lavere alkylamino eller lavere alkyl-amino substituert med lavere alkanoyl for R<3>, oppnås under de her anvendte reaksjonsbetingelser. Disse tilfeller omfattes også av foreliggende oppfinnelse.
Prosess 14
Forbindelsen [1-2] eller salter derav, kan fremstilles ved å omsette en forbindelse [I-l] eller salter derav, med et acyleringsmiddel.
Omsetningen kan foretas i det vesentlige på samme måte som under prosess 12, og reaksjonsmåte og -betingelser (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc) er derfor som forklart under Prosess 12.
Dersom forbindelsen [I-l] med fenyl substituert med amino eller hydroksy for R<1>, benyttes som utgangsforbindelse, kan forbindelsen [1-2] som har fenyl substituert med amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, eller lavere alkanoyloksy for R<1>, oppnås under disse reaksjonsbetingelsene. Disse tilfeller omfattes også av foreliggende oppfinnelse.
Prosess 15
Forbindelsen [1-4] eller salter derav, kan fremstilles ved å omsette en forbindelse [1-3] eller salter derav, med et acyleringsmiddel.
Denne omsetning kan foretas i det vesentlige som under
Prosess 12 og reaksjonsmåte og -betingelser (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc.) for reaksjonen er derfor som forklart for Prosess 12.
Dersom forbindelsen [1-3] med fenyl substituert med amino eller hydroksy for R<3> benyttes som utgangsforbindelse, kan forbindelsen [1-4] med fenyl substituert med amino substituert med lavere alkanoyl eller lavere alkylsulfonyl eller acyloksy for R<3>, oppnås under disse reaksjonsbetingelsene. Disse tilfeller omfattes også av foreliggende oppfinnelse.
Prosess 16
Forbindelsen [1-6] eller salter derav, kan fremstilles ved å omsette en forbindelse [1-5] eller salter derav, med et alkyleringsmiddel.
Denne reaksjon kan foretas i det vesentlige som under Prosess 13, og reaksjonsmåte og -betingelser (f.eks. oppløsningsmiddel, reaksjonstemperatur, etc.) for denne reaksjon er derfor som forklart under Prosess 13.
Dersom forbindelsen [1-5] med aminometyl for R<2> og/eller fenyl substituert med amino eller amino substituert med lavere alkyl for R<1>, benyttes som utgangsforbindelse, kan forbindelsen [1-6] med lavere alkylaminometyl for R<2> og/eller fenyl substituert med lavere alkylamino eller lavere alkylamino substituert med lavere alkanoyl for R<1>, oppnås under disse reaksjonsbetingelsene. Disse tilfeller omfattes også av foreliggende oppfinnelse.
Prosess 17
Forbindelsen [1-8] eller salter derav, kan fremstilles ved deacylering av en forbindelse [1-7] eller salter derav.
Reaksjonen kan fortrinnsvis foretas i nærvær av en uorganisk syre [f.eks. saltsyre, hydrogenbromidsyre, etc], og en organisk syre [f.eks. trifluoreddiksyre, metansulfonsyre, toluensulfonsyre, etc].
Reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel, så som vann, en alkohol [f.eks. metanol, etanol, etc], tetrahydrofuran, dioksan eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker
reaksjonen, eller en blanding derav.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan foretas under avkjøling eller under oppvarming.
Dersom forbindelsen [1-7] med fenyl substituert med amino eller lavere alkylamino som hver er substituert med lavere alkanoyl for R<3>, benyttes som utgangsforbindelse, kan forbindelsen [1-8] med fenyl substituert med amino eller lavere alkylamino for R<3>, oppnås under de anvendte reaksjonsbetingelser. Dette tilfellet omfattes også av foreliggende oppfinnelse.
Prosess 18
Forbindelsen [1-10] eller salter derav, kan fremstilles ved deacylering av en forbindelse [1-9] eller salter derav.
Omsetningen kan foretas det vesentlige som for Prosess 17 og reaksjonsmåte og -betingelser (f. eks. oppløsningsmiddel, reaksjonstemperatur, etc.) for reaksjonen er som forklart under Prosess 17.
Dersom forbindelsen [1-9] med fenyl substituert med acylamino eller lavere alkylamino som hver er substituert med lavere alkanoyl for R<1>, benyttes som utgangsforbindelse, kan forbindelsen [1-10] med aryl substituert med amino eller lavere alkylamino for R<1>, oppnås under disse reaksjonsbetingelsene. Dette tilfellet omfattes også av foreliggende oppfinnelse.
Prosess 19
Forbindelsen [1-11] eller salter derav, kan fremstilles ved å omsette en forbindelse [Im] eller salter derav, med en azidforbindelse.
Egnede azidforbindelser kan være alkalimetall-azider [f.eks. natriumazid, kaliumazid, etc], jordalkalimetall-azider [f.eks. kalsiumazid, etc], hydrogenazid og lignende.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel, så som tetrahydrofuran, dioksan, N,N-dimetylformamid eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan foretas under oppvarming eller under koking.
Prosess 20
Forbindelsen [1-12] kan fremstilles etter de følgende fremgangsmåter. 1) Forbindelsen [VI] eller salter derav, omsettes først med en nitrittforbindelse, og deretter 2) det resulterende produkt omsettes med kobber(I)halogenid.
Egnede salter av forbindelse [VI] kan være de samme som eksemplifisert for forbindelse [I] .
Egnede nitrittforbindelser kan være alkalimetallnitritter [f.eks. natriumnitritt, kaliumnitritt, etc], alkylnitritt [f.eks. tert-butylnitritt, etc] og lignende.
Egnede kobber(I)halogenider kan være kobber(I)klorid, kobber(I)bromid og lignende.
I det første trinn utføres omsetningen fortrinnsvis i nærvær av en syre [f .eks. svovelsyre, etc] .
Reaksjonen utføres vanligvis i et oppløsningsmiddel så som vann, tetrahydrofuran, dioksan, acetonitril eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen, eller en blanding derav.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan foretas under avkjøling eller under oppvarming.
I det annet trinn foretas reaksjonen fortrinnsvis i nærvær av et alkalimetallhalogenid [f.eks. natriumbromid, etc] og en uorganisk syre [f.eks. hydrogenbromidsyre, etc].
Reaksjonen foretas vanligvis i et oppløsningsmiddel så som vann, tetrahydrofuran, dioksan eller et annet organisk oppløsningsmiddel som ikke ugunstig påvirker omsetningen.
Reaksjonstemperaturen er ikke av avgjørende betydning, og omsetningen kan utføres under oppvarming eller koking.
Prosess 21
Forbindelsen [Ia] eller salter derav og/eller forbindelsen [Ib] eller salter derav, kan fremstilles ved å omsette en forbindelse [VII] eller salter derav, med en
forbindelse [III] eller salter derav.
Egnede salter av forbindelsene [III] eller [VII] kan være de som er eksemplifisert for forbindelse [I].
Reaksjonen kan i det vesentlige utføres på samme måte som i Prosess 1, og reaksjonsmåte og -betingelser (f._eks. opp-løsningsmiddel, reaksjonstemperatur, etc.) for denne reaksjon er derfor som forklart under Prosess 1.
Forbindelsene oppnådd etter px-osessene ovenfor kan isoleres og renses etter konvensjonelle fremgangsmåter, så som bunnfelling, omkrystallisasjon, kolonnekromatografi, utfelling eller lignende.
Forbindelsen " [I] og farmasøytisk akseptable salter derav har sterk antiinflammatorisk, analgetisk og antitrombotisk aktivitet og er nyttige ved behandling eller forebyggelse av inflammatoriske tilstander, forskjellige typer smerte, bindevevs-sykdommer, autoimmune sykdommer, forskjellige immunlidelser og trombose i mennesker eller dyr, og særlig for behandling og/eller forebyggelse av inflammasjon og smerte i ledd og-muskler [f.eks. reumatoid artritt, reumatoid spondylitt, osteoartritt, urinsyregikt, etc], inflammatoriske hudlidelser [f.eks. solbrenthet, eksem, etc], inflammatoriske øyesykdommer [f.eks. konjunktivitt, etc], lungelidelser hvor det inngår inflammasjon [f.eks. astma, bronkitt, "pigeon fancier's disease", farmer's lung, etc], inflammasjonstilstander i gastrointestinaltraktus [f.eks. aftøs ulcus, Crohn's sykdom, atrofisk gastritt, gastritis variolaforme, ulcerøs colitt, bukhinnebetennelse, regional ileitt, irritabel tarm, etc], gingivitt, inflammasjon, smerte og hevelse etter operasjon eller skade, pyrea, smerte og andre tilstander forbundet med inflammasjon, spesielt slike hvor lipoksygenase- og cyklooksygenase-produkter er en faktor, systemisk lupus erythematosus, scleroderma, polymyositis, periarteritis nodosa, giktfeber, Sjøgren's syndrome, Bechet's sykdom, tyroiditt, diabetes type-I, nefrotisk syndrom, aplastisk anemi, myastenia gravis, uveitt, kontakt-dermatitt, psoriasis, Kawasaki's sykdom, sarkoidose, Hodgkins sykdom, og lignende. De nye forbindelsene forventes dessuten å være egnet som terapeutiske og/eller forebyggende midler ved kardiovaskulære eller cerebrovaskulære sykdommer, samt sykdommer forårsaket av hyperglykemi og hyperlipidemi.
For å illustrere fordelen ved omhandlede forbindelse [I], er farmakologiske forsøksdata for forbindelsene vist i det følgende.
[A] Antiinflammatorisk aktivitet;
Virkning på adjuvant artritt i rotter:
(i) Testmetode:
Ti Sprague-Dawley-hunnrotter ble benyttet per gruppe. En dose på 0,5 mg Mycobacterium tuberculosis (stamme Aoyama B) suspendert i 0,05 ml flytende paraffin ble injisert subkutant i høyre bakfot. Injeksjonen av myobakterielt bæremiddel førte til lokale inflammatoriske lesjoner (primærlesjoner) og deretter ca. 10 dager senere, sekundære lesjoner i både injisert og ubehandlet fot. Differansen i volum mellom begge føtter før og etter bæremiddelinjeksjon, utgjorde målet for artritt. Medikamentet ble gitt peroralt en gang per dag i 23 påfølgende dager fra dag 1.
[B] Analgetisk aktivitet:
Inflammatorisk hyperalgesi indusert av ølgjær i rotter:
(i) Testmetode:
Ti Sprague-Dawley hannrotter ble benyttet per gruppe.
0,1 ml 5% ølgjær suspendert i 0,5% metylcellulose ble injisert
i den høyre bakfot. Smerteterskelen ble bestemt 3 timer etter gjær-injeksjonen ved å utsette foten for trykk og avlese det trykk som fikk dyret til å trekke foten tilbake.
Medikamentene ble gitt peroralt 2 timer etter gjær-injeksjonen. Smerteterskelen i behandlede dyr ble sammenlignet med kontro11dyrenes.
(ii) Testresultater:
[C] Antireumatisk aktivitet:
Effekt på kollagen-indusert artritt i mus:
(i) Testmetode:
Åtte DBA/l hannmus ble benyttet per gruppe. Type-II-kollagen fra storfe ble løst opp i 0,1M eddiksyre og emulgert i komplett Freund's adjuvans (CFA). Musene ble tilført 0,2 mg type-II-kollagen i CFA intradermalt ved haleroten. Etter 21 dager ble musene på samme måte utsatt for irritamentet. Fra den 10. dag etter irritamentet, ble medikamentene gitt oralt en gang per dag i 3 uker, og dyrene ble inspisert ukentlig med henblikk på visuelle tegn på artritt. Til graderingen ble det benyttet en artritt-indeks på 0-3, tilsvarende leddhevelse og erytem (Grad 1), synlige leddforstyrrelser (Grad 2) og påvisbar leddankylose (Grad 3). (ii) Testresultater:
[D] Antitrombotisk aktivitet;
Effekt på blodplateaggregasjon indusert av kollagen:
(i) Testmetode:
Blodplaterikt plasma (PRP) som inneholdt 3 x IO<8> blod-plater/ml ble fremstillet fra humanblod. Til 245 /il PRP ble de tilsatt 5 ixl medikamentoppløsning<*>, hvorpå blandingen ble omrørt i 2 min. ved 37°C. Oppløsningen ble tilsatt 5 fil kollagen (0,5 ^g/ml) som aggregasjonsutløser. Aggregasjonen ble målt ved å benytte et aggregometer (NKK HEMA-TRACER 1). Virkningen av hemmerne (testforbindelsene) ble uttrykt som IC50-verdier, dvs. den nødvendige dose for å hemme responsen på blodplate-aggregasjonen med 50%. ;Medikamentoppløsning Testforbindelsene ble oppløst i dimetylsulfoksyd. ;(ii) Testresultat: ;;[E] Virkning på DTH (Delayed Type Hypersensitivity) ;Respons på bovint type-II-kollagen. ;(i) Testmetode: ;Syv DBA/1 hannmus ble benyttet i denne undersøkelse. Musene ble sensibilisert ved haleroten med 125 fig type-II-kollagen emulgert i komplett Freund's adjuvans inneholdende Mycabacterium tuberculosis, stamme H37Rv (Wako Pure Chemical Industries Ltd., Osaka, Japan). To uker senere ble en 0,04 ml dose 2,5 mg/ml type-II-kollagen i fosfatbufret saltvann (PBS) injisert i plantarområdet av den høyre bakfot, mens 0,04 ml PBS i venstre bakfot tjente som kontroll. 24 timer etter irritamentet ble volumet av begge bakføttene målt med et volumeter (Muromachi MK-550). ;Medikamentene ble gitt peroralt alle dager unntatt helligdager fra sensibiliseringen. Data for hver undersøkelse ble uttrykt i % hemming sammenlignet med bæremiddelkontrollen. ;(ii) Testresultater: ;;For terapeutiske formål kan forbindelsen [I] og farmasøytisk akseptable salter derav, benyttes i form av farmasøytiske preparater som inneholder en av de nye forbindelser som virkestoff i blanding med et farmasøytisk akseptabelt bæremiddel, så som et organisk eller uorganisk fast eller flytende hjelpestoff egnet for oral, parenteral eller lokal administrasjon. De farmasøytiske preparatene kan være kapsler, tabletter, drasjéer, granuler, inhalasjonsmidler, suppositorier, oppløsninger, suspensjoner, emulsjoner eller lignende. I preparatene kan det eventuelt innarbeides andre virkestoffer, stabiliseringsmidler, fukte- eller emulgeringsmidler, buffere og andre vanlig benyttede ;tilsetningsstoffer. ;Selv om doseringen av forbindelsen [I] vil variere med pasientens alder og tilstand, kan en gjennomsnittlig enkeltdose på ca. 0,1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, ;1000 mg av forbindelse [I] gi effektiv behandling_av de foran nevnte sykdommer. I alminnelighet kan det per dag gis mengder på mellom 0,1 mg og 1000 mg. ;De etterfølgende Fremstillinger og Eksempler er angitt for å gi en ytterligere belysning av oppfinnelsen. ;Fremstilling 1 ;En blanding av 4-(metyltio)acetofenon (1 g) og natriumhydrid (60%; 288 mg) i N,N-dimetylformamid (7 ml) ble omrørt ved romtemperatur i 30 minutter. Blandingen ble avkjølt til 0°C og dråpevis tilsatt dietyloksalat (0,98 ml). Den resulterende blanding ble omrørt ved romtemperatur i 3 timer, helt over i isv-vann og surgjort med fortynnet saltsyre. Bunnfallet ble frafUtrert, vasket med vann og tørket under redusert trykk for å gi et blekbrunt pulver av etyl 4-[4-(metyltio)fenyl]-2,4-dioksobutanoat (1,6 g) ;Smp.: 91-97°C ;IR (Nujol): 3420, 1735, 1620, 1595, 1515 cn<T1>;NMR (DMSO-d6, 6: 1,29 (3H, t, J=7Hz), 2,54 (3H, s), 4,25 ;(2H, q, J=7Hz), 6,78 (1H, s), 7,35 (2H, d, J=8,5Hz), 7,91 (2H, d, J=8,5Hz). ;Massespektrum (m/z) : 266 (M+) , 193 ;De følgende forbindelser (Fremstilling 2-1) til 2-7)) ble oppnådd etter en tilsvarende fremgangsmåte som i Fremstilling 1. ;Fremstillin<g> 2 ;1) 1-[4-(metyltio)fenyl]-4,4,4-trifluorbutan-l,3-dion. ;Smp.: 79-83°C ;IR (Nujol) : 1590 (bred) , 1490 cm"<1>;NMR (DMS0-d6, 5): 2,57 (3H, s) , 7,0 (1H, s) , 7,42 (2H, d, ;J=8,6Hz), 8,06 (2H, d, J=8,6Hz) ;Massespektrum (m/z) : 262 (M<+>) ;2) Etyl 4-[5-(metyltio)-2-tienyl]-2,4-dioksobutanoat. ;Smp.: 33-45°C ;IR (Nujol) : 1730, 1620, 1560, 1510 cm'<1>;NMR (CDC13, 6): 1,42 (3H, t, J=7Hz) , 2,64 (3H, s) , 4,38 (2H, q, J=7Hz), 6,81 (1H, s), 6,95 (1H, d, J=4Hz), 7,27 (1H, s), 7,63 (1H, d, J=4Hz) ;Massespektrum (m/z) : 272 (M<+>) ;3) Etyl 4-[4-(formylamino)fenyl]-2,4-dioksobutanoat. ;Smp.: 171-174°C (dekomp.) ;IR (Nujol) : 3300, 1730, 1700, 1600, 1525 cm"<1 >Massespektrum (m/z) : 263 (M<+>) ;4) Etyl 4-(4-acetylfenyl)-2,4-dioksobutanoat. ;Smp.: 81-82°C ;IR (Nujol) : 1725, 1690, 1600 cm'<1>;NMR (CDCI3, 6): 1,43 (3H, t, J=7Hz) , 2,67 (3H, s) , ;4,42 (2H, q, J=7Hz), 7,11 (1H, s), 8,0-8,2 (4H, m), 15,13 (1H, s) ;Massespektrum (m/z) : 262 (M<+>) ;5) Etyl 4-[3,5-di (t-butyl) -4-hydroksy.fenyl]-2,4-dioksobutanoat. ;Smp.: 128-131°C ;IR (Nujol) : 3600, 1730, 1630, 1595 cm"<1>;NMR (DMS0-d6, 6): 1,35 (3H, t, J=7Hz) , 1,43 (18H, s) , 4,32 (2H, q, J=7Hz), 6,99 (1H, s), 7,74 (2H, s) ;6) 4-fluor-1-[4-(metyltio)fenyl]butan-1,3-dion. ;Smp.: 64-68°C ;IR (Nujol) : 1675, 1595, 1550 cm'<1>;NMR (CDCI3, 6): 2,49 (3H, s) , 4,33 (1H, s) , 5,11 (1H, s) , ;6,38 (1H, d, J=3Hz), 7,17 (2H, d, J=9Hz), 7,74 ;(2H, d, J=9Hz) ;7) 4,4-difluor-1-[4-(metyltio)fenyl]butan-1,3-dion. ;IR (Nujol) : 1640, 1595 cm-<1>;Massespektrum (m/z) : 244 (M<+>) ;Fremstilling 3 ;En oppløsning av dietyl-cyanometylfosfonat (5,3 ml) i tetrahydrofuran (10 ml) ble dråpevis tilsatt til en is-avkjølt blanding av natriumhydrid (60%, 1,3 g) i tetrahydrofuran ;(4 0 ml) . Blandingen ble omrørt ved 5°C i 15 minutter. Den resulterende blanding ble tilsatt en oppløsning av 4-(metyltio)-benzaldehyd (5 g) i tetrahydrofuran (10 ml) ved 5 til 10°C. Blandingen ble omrørt ved romtemperatur i 5 timer, fortynnet med etylacetat og vasket med vann. Det organiske lag ble tørket og konsentrert under redusert trykk. Residuet ble vasket med litt eter og tørket for å gi blekbrune krystaller av 3- [4-(metyltio)fenyl]-akrylnitril (4,7 g). ;IR (Nujol) : 2220, 1615, 1590, 1490 cm"<1>;NMR (DMSO-d6, 5): 2,51 (3H, s), 6,40 (1H, d, J=16,7Hz), ;7,2-7,7 (5H, m) ;Massespektrum (m/z) : 175 (M<+>) ;Fremstilling 4 ;4-fluorfenylhydrazin-hydroklorid (4 g) ble tilsatt til en oppløsning av natrium (1,13 g) i etanol (50 ml) og blandingen tilbakeløpsbehandlet i 1 time. Den avkjølte blandingen ble tilsatt 3-[4-(metyltio)fenyl]akrylnitril (4,3 g), hvorpå den resulterende blanding ble tilbakeløpsbehandlet over natten. Etylacetat og vann ble tilsatt og det organiske lag fraskilt, tørket og konsentrert. Det oljeaktige residuum (7,6 g) ble renset ved kolonnekromatografi på silikagel (76 g) under eluering med en blanding av toluen og etylacetat (2:1) for å gi brune krystaller av 4,5-dihydro-l-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-amin (5 g). ;Smp.: 100-110°C ;Massespektrum (m/z) : 301 (M<+>) ;Fremstilling 5 ;En blanding av 4,5-dihydro-l-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-amin (1 g) og mangan(IV)oksyd (1,16 g) i diklormetan (100 ml) ble omrørt ved romtemperatur i 2 timer. Uoppløselig materiale ble frafiltrert og filtratet konsentrert til tørrhet. Residuet (1 g) ble renset ved kolonnekromatografi på silikagel (16 g) under eluering med en blanding av kloroform og etylacetat (5:1) for å gi et blekbrunt pulver av l-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-amin (0,64 g). ;IR (Nujol) : 3400, 1600, 1565, 1515 cm"<1>;NMR (DMS0-d6, 6): 2,46 (3H, s) , 4,97 (2H, s) , 5,82 ;(1H, s) 7,0-7,3 (8H, m) ;Massespektrum (m/z) : 299 (M<+>) ;Fremstilling 6 ;En oppløsning av natriumnitritt (3,6 g) i vann (18 ml) ble dråpevis tilsatt til en is/salt-avkjølt oppløsning av 4-fluor-2-nitroanilin (7 g) i kons. saltsyre (45 ml) i løpet av 30 minutter. Blandingen ble omrørt ved 0°C i 3 0 minutter. Deretter ble blandingen dråpevis tilsatt en oppløsning av tinn(II)klorid-dihydrat (18,6 g) i kons. saltsyre (24 ml) mens temperaturen ble holdt lavere enn 5°C i 1 time. Bunnfallet ble oppsamlet ved filtrering og vasket med eter for å gi krystaller av 4-fluor-2-nitrofenylhydrazin-hydroklorid (4,4 g). ;Smp. : >260°C ;Massespektrum (m/z) : 171 (M<+>) ;Fremstilling 7 ;En oppløsning av karbon-disulfid (4,6 g) i tetrahydrofuran (60 ml) ble i løpet av 1 time dråpevis tilsatt til en blanding av 4-(metyltio)acetofenon (10 g) og 60% natriumhydrid (4,8 g) i tetrahydrofuran (100 ml) ved romtemperatur. Blandingen ble omrørt ved 40°C i 2 timer og deretter tilsatt en oppløsning av jodmetan (17,1 g) i tetrahydrofuran (60 ml). Den resulterende blanding ble omrørt ved 4 0°C i 1 time og under tilbakeløpskoking i 1 time. Vann og kloroform ble tilsatt til blandingen. Det organiske lag ble vasket med vann, tørket og inndampet i vakuum. Residuet ble vasket med metanol for å gi krystaller av 1-[4- ;(metyltio)fenyl]-3,3-bis(metyltio)-2-propen-l-on (10,5 g) ;Smp.: 119-122°C ;IR (Nujol) : 1620, 1590, 1550, 1495 cm"<1>;NMR (CDC13, 6): 2,52 (3H, s), 2,53 (3H, s), 2,56 ;(3H, s) , 6,74 (1H, s) , 7,26 (2H, d, J=7Hz) , ;7,83 (2H, d, J=7Hz) ;Massespektrum (m/z) : 270 (M<+>) ;Fremstilling 8 ;En blanding av etyl 4-(4-tolyl)-2,4-dioksobutanoat (4,7 g) og 4-fluorfenylhydrazin-hydroklorid (3,6 g) i dioksan (3 5 ml) og etanol (35 ml) ble tilbakeløpsbehandlet i 5 timer. Blandingen ble filtrert og filtratet konsentrert i vakuum. Det oljeaktige residuum (8 g) ble renset ved kolonnekromatografi på silikagel (13 0 g) under eluering med kloroform for å gi en olje av etyl 1-(4-fluorfenyl)-5-(4-tolyl)pyrazol-3-karboksylat (2,7 g) . ;IR (Film) : 1720, 1610, 1510 cm"<1>;NMR (CDCI3, 5): 1,42 (3H, t, J=7Hz), 2,31 (3H, s), 4,40 ;(2H, q, J=7Hz), 6,8-7,4 (9H, m) ;De følgende forbindelser (Fremstilling 9-1) til 9-3)) ble oppnådd etter en tilsvarende fremgangsmåte som i Fremstilling 8. ;Fremstilling 9 ;1) Etyl 1-(4-fluorfenyl)-5-(4-metoksyfenyl)pyrazol-3-karboksylat. ;Smp.: 91-93°C ;IR (Nujol) : 1715, 1610, 1510 cm"<1>;NMR (CDCI3, 3): 1,38 (3H, t, J=7Hz), 3,81 (3H, s), ;4,45 (2H, q, J=7Hz), 6,8-7,4 (9H, m) ;Massespektrum (m/z) : 34 0 (M<+>) ;2) Etyl 1,5-bis(4-metoksyfenyl)pyrazol-3-karboksylat. ;IR (Film) : 1730, 1610, 1510 cm"<1 >3) Etyl 5-(4-cyanofenyl)-1-(4-fluorfenyl)pyrazol-3-karboksylat. ;Smp.: 147-148°C ;IR (Nujol) : 2230, 1735, 1610, 1510 cm"<1>;NMR (CDC13, 6): 1,43 (3H, t, J=7Hz] , 4,46 (2H, q, J=7Hz) , ;7,0-7,8 (9H, m) ;Massespektrum (m/z) : 335 (M<+>) ;Fremstilling 10 ;En blanding av etyl 1-(4-fluorfenyl)-5-(4-tolyl)-pyrazol-3-karboksylat (2,7 g) og kaliumhydroksyd (1,1 g) i metanol (40 ml) ble tilbakeløpsbehandlet i 3 0 minutter. Oppløsningsmidlet ble fordampet og residuet oppløst i vann og vasket med etylacetat. Det vandige lag ble surgjort med fortynnet saltsyre og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket og konsentrert, hvilket ga krystaller av 1-(4-fluorfenyl)-5-(4-tolyl)pyrazol-3-karboksylsyre (2,1 g). ;Smp.: 170-173°C ;IR (Nujol) : 2750, 2600, 1690, 1600, 1510 cm'<1>;Massespektrum (m/z) : 296 (M<+>) ;Eksempél 1 ;En blanding av etyl 4-[4-(metyltio)fenyl]-2,4-dioksobutanoat (1 g) og 4-fluorfenylhydrazin-hydroklorid (0,67 g) i etanol (10 ml) og dioksan (10 ml) ble tilbakeløpsbehandlet i 5 timer. Oppløsningsmidlet ble fordampet og residuet oppløst i kloroform og vasket med vann. Det organiske lag ble tørket over magnesiumsulfat og konsentrert. Residuet (1,6 g) ble renset ved kolonnekromatografi på silikagel (3 0 g) under eluering med en blanding av toluen og etylacetat (20:1) for å gi etyl 1-(4-fluorfenyl)-3-[4-(metyltio)fenyl]pyrazol-5-karboksylat (0,11 g) ;Smp.: 100-104°C ;IR (Nujol) : 1730, 1600, 1515 cm"<1>;NMR (CDCI3, 3): 1,29 (3H, t, J=7Hz) , 2,51 (3H, s) , ;4,27 (2H, q, J=7Hz), 7,1-7,9 (9H, m) ;Massespektrum (m/z): 356 (M<+>) ;Den andre fraksjon som ble eluert med det samme oppløsningsmiddel, ble konsentrert i vakuum for å gi blekbrune krystaller av etyl 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karboksylat (1,1 g). ;Smp.: 100-102°C ;IR (Nujol) : 1710, 1600, 1510 cm'<1>;NMR (CDC13, 6): 1,42 (3H, t, J=7Hz), 2,48 (3H, s), ;4,45 (2H, q, J=7Hz), 7,0-7,4 (9H, m) ;Massespektrum (m/z): 356 (M<+>) ;Eksempel 2 ;En oppløsning av etyl 1-(4-fluorfenyl)-5-[4-(metyltio)-fenyl]pyrazol-3-karboksylat (0,95 g) og 30% hydrogenperoksyd-oppløsning (0,79 ml) i eddiksyre (9,5 ml) ble omrørt ved 70°C i 3 timer. Blandingen ble avkjølt i et is/vann-bad, hvorpå bunnfallet ble frafiltrert g vasket med etanol for å gi farveløse krystaller av etyl 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksylat (0,94 g). ;Smp.: 210-212°C ;IR" (Nujol) : 1715, 1600, 1515 cm"<1>;NMR (DMSO-d6, 6): 1,32 (3H, t, J=7Hz) , 3,25 (3H, s) , ;4,35 (2H, q, J=7Hz), 7,3-7,6 (7H, m), 7,92 ;(2H, d, J=8,5Hz) ;Massespektrum (m/z): 338 (M<+>) ;Eksempel 3 ;En blanding av etyl 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karboksylat (4,4 g) og 4N natriumhydroksyd (5,7 ml) i tetrahydrofuran (20 ml), etanol (10 ml) og dioksan (20 ml) ble omrørt ved romtemperatur over natten. Vann (50 ml) ble tilsatt og blandingen surgjort med saltsyre. Bunnfallet ble frafiltrert og vasket med vann for å gi farveløse krystaller av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksyl-syre (4,1 g). ;Smp.: 232-234°C ;IR (Nujol) : 1695, 1600, 1510 cm'<1>;NMR (DMSO-d6, 3): 3,25 (3H, s) , 7,2-7,6 (7H, m) , ;7,92 (2H, d, J=8,3Hz), 13,1 (1H, s) ;Massespektrum (m/z) : 360 (M<+>) ;Eksempel 4 ;En blanding av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylsyre (1,1 g) og fosforpentaklorid (0,67 g) i toluen (16 ml) og tetrahydrofuran (9 ml) ble omrørt ved romtemperatur i 2 timer. Uoppløselig materiale ble frafiltrert og filtratet konsentrert for å gi en olje av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonylklorid (1,37 g). ;IR (Film) : 1760, 1605, 1510 cm"<1>;En blanding av 25% metylamin i vann (2 ml), is-vann (5 ml) og tetrahydrofuran (10 ml) ble tilsatt til syrekloridet ovenfor. Blandingen ble omrørt over natten. Bunnfallet ble frafiltrert og filtratet ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket og konsentrert. Residuet (0,21 g) og bunnfallet (0,83 g) ble kombinert og omkrystallisert fra en blanding av etylacetat og etanol for å gi farveløse krystaller av 1-(4-fluorfenyl)-N-metyl-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksamid (1,0 g). ;Smp.: 271-273°C ;IR-(Nujol): 3400, 1660, 1605, 1550, 1535, 1510 cm'<1>;NMR (DMSO-d6, 5): 2,78 (3H, d, J=4,6Hz), 3,25 (3H, s) , ;7,16 (1H, s), 7,3-7,6 (6H, m), 7,91 (2H, d, ;J=8,3Hz), 8,35 (1H, q, J=4,6Hz) ;Massespektrum (m/z): 373 (M<+>) ;De følgende forbindelser (Eksempel 5-1) til 5-12)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 4. ;Eksempel 5 ;1) 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksamid. Smp.: 215-217°C IR (Nujol) : 3470, 3200, 1680, 1600, 1515 CirT<1 >NMR (DMSO-d6, 6) : 3,25 (3H, s) , 7,16 (1H, s) , 7,2-7,6
(7H, m), 7,77 (1H, s), 7,91 (2H, d, J=8,5Hz) Massespektrum (m/z) : 359 (M+) , 341 2) 1-(4-(fluorfenyl)-N,N-dimetyl-3-[4-(metylsulfonyl)-fenyl]pyrazol-5-karboksamid. ;Smp.: 192-193°C ;IR (Nujol) : 1640, 1605, 1510 cm"<1>;NMR (DMS0-d6, 6): 2,95 (3H, s) , 2,96 (3H, s) , 3,27 ;(3H, s) , 7,3-8,3 (9H, ir) ;Massespektrum (m/z) : 387 (M<+>) ;3) 1-(4-fluorfenyl)-3-[4-(metylsulfonyl)fenyl]pyrazol-5 -karboksamid. Smp. : 270-271°C IR (Nujol) : 3380, 3200, 1670, 1625, 1605, 1510 cm"<1 >NMR (DMS0-ds, 5): 3,26 (3H, s) , 7,2-8,2 (11H, m) , Massespektrum (m/z) : 359 (M<+>) 4) 5-[3,5-di(t-butyl)-4-hydroksyfenyl]-1-(4-fluorfenyl)-pyrazol-3-karboksamid. ;Smp. : 247-249°C ;IR (Nujol) : 3650, 3500, 3350, 1660, 1510 cm"<1>;NMR (DMS0-d6, 6): 1,26 (18H, s) , 6,96 (3H, s) , ;7,2-7,7 (6H, m) ;Massespektrum (m/z) : 409 (M<+>) ;5) N-fenyl-1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksamid. ;Smp.: 200-205°C (dekomp.) ;IR (Nujol) : 3400, 1680, 1595, 1530, 1510 cm"<1>;NMR (DMS0-d6, 6): 2,46 (3H, s) , 7,0-7,6 (12H, m) , 7,83 ;(2H, d, J=8Hz), 10,19 (1H, s) ;Massespektrum (m/z) : 409 (M<+>) ;6) 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-3-(1-pyrrolidinylkarbonyl)pyrazol ;Smp.: 139-140°C ;IR (Nujol) : 1615, 1515 cm"<1>;NMR (CDC13, 5): 1,8-2,1 (4H, m) , 2,48 (3H, s) , 3,70 ;(2H, t, J=6Hz), 3,98 (2H, t, J=6Hz), 6,9-7,4 ;(9H, m) ;Massespektrum (m/z) : 381 (M<+>) ;7) N-cyklopropyl-1- (4-f luorf enyl) -5- [4- (metyltio) fenyl] - pyrazol-3-karboksamid. ;Smp.: 147-148°C ;IR (Nujol) : 3360, 1675, 1600, 1510 cm'<1>;NMR (CDC13, 5): 0,6-0,9 (4H, m) , 2,48 (3H, s)_, 2,8-3,0 ;(1H, m), 7,0-7,4 (9H, m) ;Massespektrum (m/z) : 367 (M<+>) ;8) 1-(4-fluorfenyl)-3-(4-metyl-l-piperazinylkarbonyl)-5-[4-(metylsulfonyl)fenyl]pyrazol. Smp.: 170-173°C IR (Nujol) : 1620, 1520, 1500 cm'<1 >NMR (CDCI3, a): 2,34 (3H, s) , 2,4-2,6 (4H, m) , 3,08 (3H, s) , 3,8-4,2 (4H, m), 6,9-7,5 (7H, m), 7,91 (2H, d, J=8Hz) Massespektrum (m/z) : 442 (M<+>) 9) N-hydroksy-N-metyl-1- (4-f luorf enyl) -5- [4- (metylsulf onyl) - fenyl]pyrazol-3-karboksamid. ;Smp.: 185-188°C (dekomp.) ;IR (Nujol) : 1630, 1605, 1510 cm"<1>;NMR (CDCI3, 3): 3,09 (3H, s) , 3,86 (3H, s) , 7,0-7,5 ;(7H, m), 7,91 (2H, d, J=8Hz) ;Massespektrum (m/z) : 389 (M<+>) ;10) N-{l-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-3-pyrazolylkarbonyl}glycin. ;Smp.: 258-260°C (dekomp.) ;IR (Nujol) : 3420, 1720, 1645, 1560, 1510 cm'<1>;NMR (DMS0-d6, 6) : 3,25 (3H, s) , 3,89 (2H, d, J=6Hz) , ;7,20 (1H, s), 7,3-7,6 (6H, m), 7,92 (2H, d, ;J=8Hz), 8,50 (1H, t, J=6Hz) ;Massespektrum (m/z) : 417 (M<+>) ;11) N-metyl-1- [4- (N-formylmetylamino) fenyl] -5- [4- (metylsulf onyl) fenyl]pyrazol-3-karboksamid. ;IR (Nujol) : 3350, 1660, 1605, 1550, 1515 cm"<1 >Massespektrum (m/z) : 412 (M<+>) 12) N,N-dimetyl-l-[4-(N-formylmetylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksamid. ;Massespektrum (m/z) : 426 (M+) ;Eksempel 6 ;En blanding av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksamid (2,7 g) og metansulfonylklorid (3,4 ml) i pyridin (25 ml) ble omrørt ved 50°C i 6 timer. Oppløsningsmidlet ble fordampet og etylacetat og vann tilsatt til residuet. Bunnfallet ble frafiltrert og vasket med vann og etylacetat. Filtratet ble fraskilt og det organiske lag vasket med fortynnet saltsyre, tørket og konsentrert til tørrhet. Residuet og de ovennevnte bunnfall ble kombinert og omkrystallisert fra en blanding av etanol og etylacetat for å gi farveløse krystaller av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonitril (2,4 g) ;Smp.: 194-196°C ;IR (Nujol) : 2240, 1600, 1515 cm'<1>;NMR (DMSO-d6, 5): 3,25 (3H, s) , 7,3-7,6 (7H, m) , ;7,95 (2H, d, J=6,7Hz) ;Massespektrum (m/z) : 341 (M<+>) ;De følgende forbindelser (Eksempel 7-1) til 7-4)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 3. ;Eksempel 7 ;1) 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karboksylsyre. IR (Nujol) : 3500, 1695, 1600, 1515 cm"<1 >2) 1-(4-fluorfenyl)-3-[4-(metylsulfonyl)fenyl]pyrazol-5-karboksylsyre. ;Smp.: 259-260°C (dekomp.) ;IR (Nujol) : 1705, 1605, 1515 cm"<1>;NMR (DMS0-d6, 6): 3,26 (3H, s) , 7,3-8,3 (9H, m) Massespektrum (m/z) : 360 (M<+>) 3) 5-[3,5-di(t-butyl)-4-hydroksyfenyl]-1-(4-fluorfenyl)-pyrazol-3-karboksylsyre. ;Smp.: 239-242°C ;IR (Nujol) : 3550, 1690, 1510 cm"<1>;NMR (DMS0-d6, 6): 1,25 (18H, s) , 6,96 (2H, s) , 7,03 ;(1H, s), 7,25-7,45 (4H, m) ;Massespektrum (m/z): 410 (M<+>), 395 ;4) 1-[4-(N-formyImetylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karboksylsyre. ;IR (Nujol) : 1720, 1665, 1605, 1520 cm"<1>;Massespektrum (m/z) : 399 (M<+>) ;Eksempel 8 ;En blanding av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylsyre (3 g) og 1,1'-karbonyldiimidazol (1,6 g) i tetrahydrofuran (39 ml) ble tilbakeløpsbehandlet i 1 time. Dimetylamin-hydroklorid (1,04 g) og kaliumkarbonat (1,33 g) ble tilsatt, hvorpå den resulterende blanding ble omrørt og tilbakeløpsbehandlet i 3 timer. Blandingen ble fortynnet med etylacetat, vasket suksessivt med vann, en vandig oppløsning av natriumbikarbonat, fortynnet saltsyre og vann, tørket og konsentrert for å gi en blekbrun olje av 1-(4-fluorfenyl)-N,N-dimetyl-5-[4-(metyltio)fenyl]pyrazol-3-karboksamid (2,6 g). ;IR (Film) : 1620, 1510 cm-<1>;Eksempel 9 ;En blandikng av 1-(4-fluorfenyl)-N,N-dimetyl-5-[4-(metyltio) fenyl]pyrazol-3-karboksamid (1 g) og m-klorperbenzosyre ;(1,8 g) i diklormetan (17 ml) ble omrørt ved romtemperatur over natten. Uoppløselig materiale ble frafiltrert og filtratet vasket med en vandig oppløsning av natriumbikarbonat, tørket og konsentrert til tørrhet. Den gjenværende olje (1,4 g) ble renset ved kolonnekromatografi på silikagel (30 g) under eluering med en blanding av kloroform og metanol (20:1). Den oppnådde olje (1,0 g) ble krystallisert fra eter for å gi farveløse krystaller av N,N-dimetyl-1-[4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksamid (0,69 g) . ;Smp.: 171-173°C ;IR (Nujol) : 162 0, 1510 cm"<1>;NMR (DMSO-d6/ 6): 3,02 (3H, s) , 3,25 (3H, s) , 3,32 ;(3H, s), 7,08 (1H, s), 7,2-8,0 (8H, m) ;Massespektrum (m/z) : 387 (M<+>) ;Eksempel 10 ;En blanding av 1-(4-f luorf enyl) -N,.N-dimetyl-5-[4-(metyltio) fenyl]pyrazol-3-karboksamid (1,6 g) og litiumaluminiumhydrid (0,34 g) i eter (8,5 ml) og benzen (13 ml) ble omrørt og tilbakeløpsbehandlet i 2 timer. 4N natriumhydroksyd (10 ml) og etylacetat (20 ml) ble dråpevis tilsatt til blandingen. Uopp-løselig materiale ble frafiltrert og filtratet fraskilt. Det organiske lag ble"vasket med vann, tørket og konsentrert. Residuet (1,2 g) ble renset ved kolonnekromatografi på silikagel (3 0 g) under eluering med en blanding av etylacetat og metanol (5:1) for å gi en blekbrun olje av 3-(N,N-dimetylaminometyl)-1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol (0,69 g). ;IR (Film) : 2820, 2770, 1600, 1560, 1510 cm-<1>;Massespektrum (m/z) : 341 (M+) , 298 ;De følgende forbindelser (Eksempel 11-1) til 11-3)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 9. ;Eksempel 11 ;1) 3-(N,N-dimetylaminometyl)-1-(4-fluorfenyl)-5- [4-(metylsulf onyl) fenyl]pyrazol-hydroklorid. ;Smp.: 157-160°C (dekomp.) ;IR (Nujol): 3350, 2580, 1600, 1510 cm"<1>;NMR (DMSO-d6, 6) : 3,25 (3H, s) , 3,54 (6H, s) , 4,99 (2H, s) , 7,07 (1H, s), 7,2-8,0 (8H, m), 12,9 (1H, s) ;Massespektrum (m/z) : 373 (M+) , 330 ;2) Etyl 1-(4-fluorfenyl)-3-[4-(metyl-sulfonyl)-fenyl]pyrazol-5-karboksylat. ;Smp.: 203-205°C ;IR (Nujol) : 1725, 1605, 1515 cm"<1>;NMR (DMSO-d6, 6): 1,21 (3H, t, J=7Hz) , 3,27 (3H, s) , ;4,23 (2H, q, J=7Hz); 7,3-8,3 (9H, m) ;Massespektrum (m/z) : 388 (M<+>) ;3) 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-3- (trifluormetyl)pyrazol ;Smp.: 210-212°C ;IR (Nujol) : 3150, 1605, 1520, 1505 cm"<1>;NMR (DMS0-d6, 6): 3,26 (3H, s) , 7,3-7,6 (7H,_m), 7,96 ;(2H, d, J=8,3Hz), ;Massespektrum (m/z) : 384 (M<+>) ;Eksempel 12 ;En blanding av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylsyre (6,4 g) og tionylklorid (3 0 ml) i tetrahydrofuran (60 ml) ble tilbakeløsbehandlet i 1 time og konsentrert under redusert trykk, hvilket ga 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonylklorid. ;En oppløsning av dietylmalonat (3,46 g) og etanol (1,96 ml) i eter (19,6 ml) ble dråpevis tilsatt til en omrørt blanding av magnesium (518 mg), etanol (0,785 ml) og karbontetraklorid (1,18 ml) i eter (19,6 ml) under nitrogenatmosfære. Den resulterende blanding ble omrørt ved romtemperatur i 100 minutter og tilbakeløpsbehandlet i 25 minutter. En oppløsning av det ovenfor oppnådde syreklorid i tetrahydrofuran (24 ml) ble porsjonsvis tilsatt til blandingen. Blandingen ble omrørt ved romtemperatur i 85 minutter og tilbakeløpsbehandlet i 70 minutter. Reaksjonsblandingen ble helt over i 10% svovelsyre (160 ml) og ekstrahert med etylacetat. Ekstraktet ble vasket med vann og tørket over magnesiumsulfat. Oppløsningsmidlet ble fordampet under redusert trykk for å gi 3-bis(etoksykarbonyl)-acetyl-1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol. ;En blanding av svovelsyre (3,9 ml), eddiksyre (23,6 ml) og vann (19,6 ml) ble tilsatt til 3-bis(etoksykarbonyl)acetyl-1-(4-fluorfenyl)-5- [4-(metylsulfonyl)fenyl]pyrazol. Blandingen ble tilbakeløpsbehandlet i 5 timer og konsentrert. Residuet ble oppløst i etylacetat og oppløsningen vasket med vann, tørket og konsentrert. Residuet ble renset ved kolonnekromatografi på silikagel (150 g) under eluering med en blanding av kloroform og etylacetat (3:1) for å gi blekbrune krystaller av 3-acetyl-l-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol (4,2 g). ;Smp.: 207-209°C ;IR (Nujol) : 1690, 1600, 1515 cm"<1>;NMR (DMS0-d6, 5): 2,57 (3H, s) , 3,25 (3H, s) , 7,2-8,0 ;(9H, m) ;Massespektrum (m/z) : 358 (M<+>) ;Eksempel 13 ;En blanding av 3-acetyl-l-(4-fluorfenyl)-5-[4-(metylsulf onyl)fenyl]pyrazol (1,1 g), thallium(III)nitrat-trihydrat (1,6 g) og perklorsyre (70%; 3,3 ml) i metanol (16 ml) og dioksan (8 ml) ble omrørt ved romtemperatur over natten. Uoppløselig materiale ble frafiltrert og filtratet fortynnet med kloroform, vasket"med vann, tørket og konsentrert. Residuet (1,6 g) ble renset ved kolonnekromatografi på silikagel (100 g) under eluering med en blanding av toluen og etylacetat (2:1) for å gi blekbrune krystaller av 1-(4-fluorfenyl)-3-(metoksyacetyl)-5-[4-(metylsulfonyl)fenyl]pyrazol (0,13 g). ;Smp.: 151-154°C ;IR (Nujol) : 1705, 1600, 1510 cm"<1>;NMR (DMSO-d6, 6): 3,25 (3H, s) , 3,39 (3H, s) , 4,81 ;(2H, s), 7,2-8,0 (9H, m) ;De følgende forbindelser (Eksempel 14-1) til 14-26)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 1. ;Eksempel 14 ;1) 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-3-
(trifluormetyl)pyrazol. ;IR (Film) : 1605, 1515, 1500 cm"<1>;NMR (CDC13, 6): 2,48 (3H, s), 6,72 (1H, s), 7,0-7,4 ;(8H, m) ;Massespektrum (m/z) : 352 (M<+>) ;2) Etyl 5-[4-(metyltio)fenyl]-1-(4-pyridyl)pyrazol-3-karboksylat-hydroklorid. ;Smp. : 181-186°C ;IR (Nujol) : 1720, 1630, 1600, 1510 cm-<1>;NMR (DMSO-d6, 6) : 1,34 (3H, t, J=7Hz) , 2,51 (3H, s) , ;4,37 (2H, q, J=7Hz), 7,21 (1H, s), 7,33 (4H, s), ;7,72 (2H, d, J=5Hz), 8,85 <2H, d, J=5Hz) Massespektrum (m/z) : 33 9 (M<+>) 3) Etyl 1-(2-fluorfenyl)-5-[4-(metyltio)fenyl]-3-karboksylat. IR (Film) : 1725, 1600, 1510 cm"<1 >NMR (CDC13, 5): 1,39 (3H, t, J=7Hz) , 2,42 (3H, s) , 4.42 (2H, q, J=7Hz), 6,9-7,6 (9H, m) 4) Etyl 1-(2,4-difluorfenyl)-5-[4-(metyltio)-fenyl]pyrazol-3-karboksylat. IR (Film) : 1720, 1605, 1515 cm"<1 >NMR (CDC13, 6): 1,40 (3H, t, J=7Hz) , 2,42 (3H, s) , 4.43 (2H, q, J=7Hz), 6,7-7,8 (8H, m) 5) Etyl 1-(3-fluorfenyl)-5-[4-(metyltio) fenyl]-pyrazol-3-karboksylat. IR (Film) : 1720, 1605, 1490 cm"<1 >NMR (CDCI3, 6): 1,42 (3H, t, J=7Hz), 2,44 (3H, s), 4,42 (2H, q, J=7Hz), 6,9-7,5 (9H, m) 6) Etyl 5-[4-(metyltio)fenyl]-1-fenylpyrazol-3-karboksylat. IR (Film) : 1705, 1600, 1560, 1500 cm"<1 >NMR (CDCI3, 6): 1,40 (3H, t, J=7Hz) , 2,45 (3H, s) , 4,42 (2H, q, J=7Hz), 6,9-7,5 (10H, m) 7) Etyl 1-(4-metoksyfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylat. IR (Film) : 1720, 1605, 1510 cm"<1 >NMR (CDCI3, 6): 1,42 (3H, t, J=7Hz) , 2,47 (3H, s) , 3,86 (3H, s), 4,45 (2H, q, J=7Hz), 6,8-7,4 (9H, m) 8) Etyl 1-(4-metylfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylat. ;IR (Film) : 1720, 1605, 1520 cm"<1>;NMR (CDCI3, 5): 1,42 (3H, t, J=7Hz) , 2,37 (3H, s) , ;2,47 (3H, s), 4,45 (2H, q, J=7Hz), 7,00 (1H, s), ;7,0-7,4 (8H, m) 9) Etyl 5-(4-fluorfenyl)-1-[4-(metyltio)fenyl]-pyrazol-3-karboksylat. ;Smp. : 95-96,5°C ;IR (Nujol) : 1710, 1610, 1545, 1495 cm'<1>;NMR (CDC13, 3): 1,42 (3H, t, J=7Hz), 2,49 (3H, s) , ;4,45 (2H, q, J=7Hz), 6,9-7,3 (9H, m) ;Massespektrum (m/z) : 356 (M<+>) ;10) Etyl 5-[4-(metyltio)fenyl]-1-(4-nitrofenyl)-pyrazol-3-karboksylat. Smp. : 157-159°C IR (Nujol) : 1695, 1655, 1590, 1510 cm'<1 >Massespektrum (m/z) : 383 (M<+>) 11) Etyl 1-(4-fluorfenyl)-5-[5-(metyltio)-2-tienyl] - pyrazol-3-karboksylat. IR" (Film) : 1720, 1600, 1510 cm"<1 >NMR (CDCI3, a): 1,39 (3H, t, J=7Hz), 2,44 (3H, s), 4.42 (2H, q, J=7Hz), 6,6-7,4 (7H, m) 12) Etyl 1-(4-fluorfenyl)-5-[4-(formylamino)fenyl] - pyrazol-3-karboksylat. Smp. : 184-188°C IR (Nujol) : 3300, 1730, 1720, 1690, 1600, 1510 cm"<1 >Massespektrum (m/z) : 353 (M<+>) 13) Etyl 5-[5-(metyltio)-2-tienyl]-1-(4-nitrofenyl) - pyrazol-3-karboksylat. IR (Film) : 1725, 1600, 1525, 1500 cm"<1 >14) Etyl 1-(4-nitrofenyl)-5-(4-tolyl)pyrazol-3-karboksylat. ;Smp.: 147-149°C ;IR (Nujol) : 1715, 1595, 1525, 1500 cm"<1>;NMR (CDCI3, a): 1,43 (3H, t, J=7Hz), 2,39 (3H, s), ;4.43 (2H, q, J=7Hz), 6,9-8,3 (9H, m) ;Massespektrum (m/z) : 351 (M<+>) ;15) Etyl 5-(4-metoksyfenyl)-1-(4-nitrofenyl)pyrazol-3-karboksylat. Smp.: 161-162°C IR (Nujol) : 1710, 1615, 1595, 1525, 1500 cm"<1 >Massespektrum (m/z) : 367 (M<+>) 16) Etyl 5-(4-acetylfenyl)-1-(4-fluorfenyl)pyrazol-3-karboksylat. ;Smp.: 220-222°C ;IR (Nujol) : 1710, 1610, 1510 cm"<1>;Massespektrum (m/z) : 352 (M<+>) ;17) Etyl 5-[3,5-di(t-butyl)-4-hydroksyfenyl] -1-(4-fluor-fenyl) pyrazol-3-karboksylat. ;Smp.: 173-174°C ;IR (Nujol) : 3550, 1730, 1605, 1510 cm"<1>;NMR (DMSO-d6, 6) : 1,25 (18H, s), 1,31 (3H, t, J=8Hz), ;4,32 (2H, q, J=8Hz), 6,96 (2H, s), 7,08 (1H, s), 7,2-7,5 (4H, m) ;Massespektrum (m/z) : 438 (M<+>) ;18) Etyl 1-(2, 5-difluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylat. ;Smp.: 81-84°C ;IR (Nujol) : 1730, 1600, 1510 cnf<1>;NMR (CDC13, 6): 1,43 (3H, t, J=7Hz), 2,47 (3H, s), ;4,46 (2H, q, J=7Hz), 7,0-7,4 (8H, m) ;Massespektrum (m/z) : 374 (M<+>) ;19) Etyl 5-[4-(metyltio)fenyl]-1-(2-nitrofenyl)-pyrazol-3 -karboksylat. ;Smp.: 155-157°C ;IR (Nujol) : 1715, 1605, 1535 cm"<1>;NMR (CDCI3, 5): 1,41 (3H, t, J=7Hz) , 2,45 (3H, s) , 4,44 ;(2H, q, J=7Hz), 7,0-8,1 (9H, m) ;Massespektrum (m/z) : 383 (M<+>) ;20) Etyl 1-(4-fluor-2-nitrofenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylat. ;IR (Film) : 1725, 1590, 1545, 1510 cm'<1>;NMR (CDC13, 5): 1,41 (3H, t, J=7Hz) ,. 2,46 (3H, s) , ;4,36 (2H, q, J=7Hz), 6,9-8,0 (8.H, m) ;Massespektrum (m/z) : 401 (M<+>) ;21) 5-[4-(metyltio)fenyl]-1-(4-nitrofenyl)-3-(trifluormetyl)pyrazol ;Smp.: 163-164°C ;IR (Nujol) : 1600, 1525 cm"<1>;22) 3-(fluormetyl)-1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol. IR (Film) : 1600, 1515 cm"<1 >NMR (CDCI3, 6): 2,44 (3H, s), 5,14 (1H, s), 5,67
(1H, s), 6,53 (1H, s), 6,8-7,3 (8H, m) Massespektrum (m/z): 316 (M<+>) 23) 3-(fluormetyl)-5-[4-(metyltio)fenyl] -1-(4-nitrofenyl)pyrazol. Smp.: 165-167°C IR (Nujol) : 1600, 1520, 1500 cm"<1 >NMR (CDCI3, 6): 2,50 (3H, s), 5,36 (1H, s), 5,60
(1H, s), 6,64 (1H, a), 7,1-8,3 (8H, m) Massespektrum (m/z) : 343 (M<+>) 24) 3-(difluormetyl)-1-(4-nitrofenyl)-5-[4-(metyltio) fenyl]pyrazol. ;Smp. : 124-12 9°C ;IR (Nujol) : 1600, 1520 cm"<1>;NMR (CDCI3, 6): 2,50 (3H, s) , 6,5-8,5 (10H, m) Massespektrum (m/z) : 361 (M<+>) 25) 3-(difluormetyl)-1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol. ;Smp.: 70-71°C ;IR (Nujol) : 1600, 1520 cm-<1>;NMR (CDCI3, 6): 2,48 (3H, s) , 6,7-7,4 (10H, m) Massespektrum (m/z) : 334 (M<+>) 26) Etyl 1-(2-klorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylat. ;Smp. : 119-120°C ;IR (Nujol) : 1715, 1605 cm-<1>;NMR (CDC13, 6): 1,42 (3H, t, J=7Hz) , 2,45 (3H, s) , ;4,45 (2H, q, J=7Hz), 7,0-7,6 (9H, m) ;Massespektrum (m/z): 372 (M<+>) , 344 ;De følgende forbindelser (Eksempel 15-1) til 15-29)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 6. ;Eksempel 15 ;1) 1-(4-fluorfenyl)-3-[4-(metylsulfonyl)fenyl]-pyrazol-5-karbonitril. Smp. : 200-202°C IR (Nujol) : 2240, 1600, 1515 cm"<1 >NMR (DMS0-d6, 6): 3,28 (3H, s) , 7,4-8,3 (9H, m) Massespektrum (m/z) : 341 (M<+>) 2) 1-(4-fluorfenyl)-5 - [4-(metyltio)fenyl]pyrazol-3-karbonitril. ;Smp. : 106-107°C ;IR (Nujol) : 2250, 1600, 1510 cm"<1>;NMR (CDCI3, 6): 2,48 (3H, s) , 6,84 (1H, s) , ;7,0-7,4 (8H, m) ;Massespektrum (m/z) : 309 (M<+>) ;3) 5-[4-(metylsulfonyl)fenyl]-1-(4-pyridyl)pyrazol-3-karbonitril. ;Smp.: 194-195°C ;IR (Nujol) : 2250, 1585, 1500 cm"<1>;NMR (DMSO-d6, 5): 3,27 (3H, s) , 7,3-8,1 (7H, m) , ;8,70 (2H, d, J=5Hz) ;Massespektrum (m/z) : 324 (M<+>) ;4) 5-[4-(metyltio)fenyl]-1-(4-pyridyl)pyrazol-3-karbonitril-hydroklorid. ;Smp.: 185-188°C ;IR (Nujol): 2350, 2250, 2120, 2020, 1630, 1510 cm"<1 >NMR (DMS0-d6, 6): 2,50 (3H, s) , 7,1-7,6 (7H, m) , ;8,75 (2H, d, J=6Hz) ;Massespektrum (m/z) : 292 (M<+>) ;5) 1-(2-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril. ;Smp. : 147-148°C ;IR (Nujol) : 2250, 1600, 1500 cm"<1>;NMR (CDC13, 6): 3,07 (3H, s) , 7,00 (1H, s) , ;7,0-8,0 (8H, m) ;Massespektrum (m/z) : 341 (M<+>) ;6) 1-(2,4-difluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril. ;Smp.: 129-130°C ;IR (Nujol) : 2250, 1610, 1520 cm"<1>;NMR (CDCI3, 6): 3,08 (3H, s), 6,8-8,0 (8H, m) ;Massespektrum (m/z) : 359 (M<+>) ;7) 1-(3-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril. Smp.: 167-168°C IR (Nujol) : 2250, 1600, 1495 cm"<1 >NMR (DMSO-d6, 6): 3,26 (3H, s) , 7,2-8,0 (9H, m) Massespektrum (m/z) : 341 (M<+>) 8) 5-(4-metylsulfonyl)fenyl]-1-fenyl-pyrazol-3-karbonitril. Smp.: 179-180°C IR (Nujol): 2250, 1600, 1500 cm'<1 >NMR (DMSO-ds, 6): 3,25 (3H, s) , 7,3-8,0 (10H, m) Massespektrum (m/z) : 323 (M<+>) 9) 1-(4-metoksyfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril. ;Smp.: 153-154°C ;IR (Nujol) : 2250, 1600, 1515 cm"<1>;NMR (DMSO-ds, 6): 3,25 (3H, s) , 3,80 (3H, s) , 7,0-8,0 (9H, m) ;Massespektrum (m/z) : 3 53 (M<T>) ;10) 1- (4-metylfenyl) -5- [4- (metylsulfonyl) fenyl] - pyrazol-3-karbonitril. Smp.: 210-211°C ;IR (Nujol) : 2250, 1600, 1515 cm"<1>;NMR (CDC13, 6): 2,41 (3H, s) , 3,08 (3H, s) , ;6,96 (1H, s), 7,1-8,0 (8H, m) 11) 5- (4-fluorfenyl)-1-[4-(metyltio)fenyl]-pyrazol-3-kafbonitril. ;Smp.: 82-83°C ;IR (Nujol): 2250, 1610, 1545, 1500 cm"<1 >Massespektrum (m/z) : 309 (M<+>) ;12) 5- [4-(metyltio)fenyl]-1-(4-nitrofenyl)pyrazol-3-karbonitril. Smp.: 165-166°C IR (Nujol) : 2250, 1600, 1520, 1480 cm"<1 >Massespektrum (m/z) : 336 (M<+>) 13) 1- (4-fluorfenyl)-5-[5-(metyltio)-2-tienyl] - pyrazol-3-karbonitril. IR (Film); 2250, 1600, 1510 cm"<1 >14) 5- [5-(metyltio)-2-tienyl]-1-(4-nitrofenyl) - pyrazol-3-karbonitril. IR (Film) : 2250, 1600, 1525, 1500 cm"<1 >15) 1-(4-fluorfenyl)-5-[4-(N-formylmetylamino)fenyl] - pyrazol-3-karbonitril. ;Smp.: 147-148°C ;IR (Nujol) : 2250, 1675, 1615, 1510 cm"<1>;NMR (DMSO-d6, 6): 3,19 (3H, s) , 7,2-7,7 (9H, m) ,, ;8,64 (1H, s) ;Massespektrum (m/z): 320 ;16) 5-[4-(acetamido)fenyl]-1-(4-fluorfenyl)pyrazol-3-karbonitril. ;Smp.: 96-98°C ;IR (Nujol) : 3340, 2250, 1670, 1600, 1535, 1510 cm"<1 >NMR (DMS0-d6, 5): 2,04 (3H, s) , 7,1-7,6 (9H,_m) ;10,10 (1H, s) ;Massespektrum (m/z) : 320 (M<+>) ;17) 1-[4-(N-formylmetylamino)fenyl]-5-(4-tolyl)-pyrazol-3-karbonitril. IR (Film) : 2250, 1680, 1610, 1515 cm-<1 >NMR (CDC13, 5) : 2,38 (3H, s) , 3,33 (3H, s) , 6,8-7,4 (9H, m), 8,55 (1H, s) 18) 1-(4-fluorfenyl)-5-(4-metoksyfenyl)pyrazol-3-karbonitril. Smp.: 122-123°C IR (Nujol) : 2250, 1610, 1500 cm'<1 >NMR (CDCI3, 5): 3,82 (3H, s), 6,8-7,4 (9H, m) Massespektrum (m/z) : 293 (M<+>) 19) 5-(4-metoksyfenyl)-1-(4-nitrofenyl)pyrazol-3-karbonitril. Smp.: 125-126°C IR (Nujol) : 2250, 1615, 1600, 1520, 1500 cm"<1 >Massespektrum (m/z) : 320 (M<+>) 20) 1,5-bis(4-metoksyfenyl)pyrazol-3-karbonitril. ;Smp. : 79-80°C ;IR (Nujol) : 2250, 1610, 1515 cm"<1>;NMR (CDCI3, 6): 3,81 (3H, s) , 3,83 (3H, s) , ;6,7-7,3 (9H, m) ;Massespektrum (m/z) : 305 (M<+>) ;21) 5-(4-cyanofenyl)-1-(4-fluorfenyl)pyrazol-3-karbonitril. ;Smp.: 154-156°C ;IR (Nujol) : 2250, 2230, 1615, 1510 cm'<1>;NMR (CDCI3, 5): 6,96 (1H, s) , 7,0-7,7 (8H, m) , Massespektrum (m/z): 288 (M<+>) ;22) 5-[3,5-di(t-butyl)-4-hydroksyfenyl]-1-(4-fluor-fenyl) pyrazol-3 -karbonitril . Smp.: 189-190°C ;IR (Nujol) : 3600, 2250, 1600, 1500 cm"<1>;NMR (DMSO-d6, 5): 1,24 (18H, s) , 6,96 (2H, s) , ;7,3-7,5 (5H, m) ;Massespektrum (m/z) : 391 (M<+>) , 376 ;23) 1-(2-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karbonitril. ;Smp.: 76-77°C ;IR (Nujol) : 2250, 1600, 1505 cm"<1>;NMR (CDCI3, 6): 2,46 (3H, s), 6,87 (1H, s), ;7,0-7,0 (8H, m) ;Massespektrum (m/z) : 309 (M<+>) ;24) 1-(2,4-difluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karbonitril. ;Smp.: 74-75°C ;IR (Nujol) : 2250, 1600, 1520 cm-<1>;NMR (CDCI3, 6): 2,47 (3H, s), 6,8-7,6 (8H, m) Massespektrum (m/z): 327 (M<+>) ;25) 1-(2,5-difluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karbonitril. IR (Film) : 2250, 1625, 1600, 1510 cm"<1 >26) 1- [4- (N-formylmetylamino) fenyl] -5- [4- (metyltio) - fenyl]pyrazol-3-karbonitril. Smp.: 132-134°C IR (Nujol) : 2250, 1670, 1600, 1515 cm"<1 >Massespektrum (m/z): 348 (M<+>) 27) 5-[4-(metyltio)fenyl]-1-(2-nitrofenyl)pyrazol-3-karbonitril. IR (Film) : 2250, 1605, 1535 cm"<1 >28) 1-(4-fluor-2-nitrofenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karbonitril. IR (Film) : 2250, 1590, 1550, 1510 cm"<1 >29) I-(2-klorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karbonitril. ;Smp.: 124-125°C ;IR (Nujol) : 2250, 1600 cm"<1>;NMR (CDC13, 6): 2,45 (3H, s) , 6,88 (1H, s) , ;7,0-7,5"(8H, m) ;Massespektrum (m/z) : 325 (M<+>) ;Eksempel 16 ;En blanding av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-amin (3 g) , kobber(II)klorid (1,6 g) og t-butylnitritt (1,14 g) i acetonitril (50 ml) og dioksan (20 ml) ble omrørt ved romtemperatur i 4 timer. Uoppløselig materiale ble frafiltrert og filtratet tilsatt etylacetat og vann. Det organiske lag ble fraskilt, vasket med fortynnet saltsyre, tørket og konsentrert. Det oljeaktige residuum (3,8 g) ble renset ved kolonnekromatografi på silikagel (40 g) under eluering med en blanding av toluen og etylacetat (10:1) for å gi en brun olje av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol (1,4 g). ;IR (Film) : 1600, 1510 cm"<1>;NMR (CDCI3, 3): 2,48 (3H, s) , 6,48 (1H, d, J=l,8Hz), ;6,9-7,4 (8H, m), 7,70 (1H, d, J=l,8Hz), ;Massespektrum (m/z) : 284 (M<+>) ;De følgende forbindelser (Eksempel 17-1) til 17-30)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 2. ;Eksempel 17 ;1) 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]- ;pyrazol ;Smp.: 110-112°C ;IR (Nujol) : 1600, 1515 cm"<1>;NMR (DMS0-d6, 5): 3,25 (3H, s) , 6,83 (1H, d, J=l,9Hz), ;7,2-8,0 (9H, m) ;Massespektrum (m/z): 316 (M<+>) ;2) 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril. ;Smp. : 197°C ;IR (Nujol) : 2240, 1600, 1515 cm"<1 >3) Etyl 5-[4-(metylsulfonyl)fenyl]-1-(4-pyridyl)-pyrazol-3-karboksylat. ;Smp.: 195-199°C ;IR (Nujol) : 1715, 1585, 1500 cm"<1>;NMR (DMS0-d6, 6): 1,33 (3H, t, J=7Hz) , 3,28 (3H, s) , ;4,37 (2H, q, J=7Hz), 7,2-7,4 (3H, m), 7,62 ;(2H, d, J=8,5Hz), 7,97 (2H, d, J=8,5Hz), ;8,68 (2H, bred s) ;Massespektrum (m/z) : 371 (M<+>) ;4) Etyl 1-(2-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylat. ;Smp.: 165-167°C ;IR (Nujol) : 1725, 1600, 1500 cm"<1>;NMR (CDC13, 5): 1,43 (3H, t, J=7Hz), 3,06 (3H, s), ;4,47 (2H, q, J=7Hz), 7,0-7,9 (9H, m) ;Massespektrum (m/z) : 388 (M+) , 316 ;5) Etyl 1-(2,4-difluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylat. ;Smp.: 184-185°C ;IR (Nujol) : 1730, 1605, 1520 cm"<1>;NMR (CDCI3, 5) : 1,40 (3H, t, J=7Hz) , 3,07 (3H, s) , ;4,47 (2H, q, J=7Hz), 6,8-8,0 (8H, m) ;Massespektrum (m/z): 406 (M<+>) ;6) Etyl 1-(3-fluorfen<y>l)-5-[4-(met<y>lsulfonyl)fenyl]-pyrazol-3-karboksylat. ;Smp.: 110-112°C ;IR (Nujol) : 1720, 1605, 1490 cm"<1>;NMR (CDC13, 6): 1,43 (3H, t, J=7Hz) , 3,09 (3H, s) , ;4,47 (2H, q, J=7Hz), 7,0-8,1 (1H, m) ;Massespektrum (m/z) : 388 (M<+>) ;7) Etyl 5-[4-(metylsulfonyl)fenyl]-1-fenylpyrazol-3-karboksylat. IR (Film) : 1720, 1600, 1500 cm'<1 >8) Etyl 1-(4-metoksyfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karboksylat. ;Smp.: 122-125°C ;IR (Nujol) : 1715, 1610, 1590, 1515 cm"<1>;Massespektrum (m/z): 400 (M<+>) ;9) Etyl 1- (4-metylfenyl) -5- [4- (metylsulfonyl) fenyl] - pyrazol-3-karboksylat. ;Smp.: 149-151°C ;IR (Nujol) : 1720, 1600, 1520 cm"<1>;Massespektrum (m/z) : 384 (M<+>) ;10) 5-[4-metylsulfonyl)fenyl]-1-(4-nitrofenyl)-pyrazol-3-karbonitril. Smp. : 199-200°C IR (Nujol) : 2250, 1600, 1530, 1500 cm"<1 >Massespektrum (m/z) : 368 (M<+>) 11) 1-(4-fluorfenyl)-5-[5-(metylsulfonyl)-2-tienyl]-pyrazol-3-karbonitril. ;Smp.: 131-132°C ;IR (Nujol) : 2250, 1510 cm"<1>;NMR (DMS0-d6< 5): 3,35 (3H, s) , 7,3-7,8 (7H, m) Massespektrum (m/z) : 347 (M<+>) ;12) 5-[5-(metylsulfonyl)-2-tienyl]-1-(4-nitrofenyl)-pyrazol-3-karbonitril. Smp.: 98-106°C IR (Nujol) : 2250, 1615, 1595, 1530 cm"<1 >Massespektrum (m/z): 374 (M<+>) 13) 1-(2,5-difluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril. Smp.: 139-140°C IR (Nujol) : 2250, 1620, 1605, 1505 cm"<1 >NMR (DMSO-d6, 6): 3,26 (3H, s) , 7,4-8,0 (8H, m) Massespektrum (m/z) : 359 (M<+>) 14) 1-[4-(N-formylmetylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonitril. ;Smp.: 170-173°C ;IR (Nujol) : 2250, 1610, 1520 cm"<1>;NMR (DMS0-d6, 6): 3,23 (3H, s), 3,26 (3H, s), 7,4-8,0 ;(9H, m), 8,68 (1H, s) ;Massespektrum (m/z) : 380 (M<+>) ;15) 5- [4- (metylsulfonyl) fenyl] -1- (2-nitrofenyl) - pyrazol-3-karbonitril. ;Smp.: 123-125°C ;IR (Nujol) : 2250, 1605, 1535 cm"<1>;Massespektrum (m/z) : 368 (M<+>) ;16) 1-(4-fluor-2-nitrofenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril. Smp.: 191-193°C IR (Nujol) : 2250, 1600, 1545, 1510 cm"<1 >Massespektrum (m/z): 386 (M<+>) 17) 5-[4-(metylsulfonyl)fenyl]-1-(4-nitrofenyl)-3-(trifluormetyl)pyrazol. ;Smp.: 163-164°C ;IR (Nujol) : 1600, 1535 cm"<1>;Massespektrum (m/z) : 411 (M<+>) ;18) 3-brom-1-(4-fluorfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol. ;Smp.: 185-186°C ;IR (Nujol) : 1600, 1515 cm"<1>;NMR (DMS0-d6, 6): 3,24 (3H, s) , 7,03 (1H, s)±;7,2-8,0 (8H, m) ;Massespektrum (m/z): 3 96, 3 94 ;19) N-cyklopropyl-1-(4-fluorfenyl)-5-[4-(metylsulfonyl) - fenyl]pyrazol-3-karboksamid. ;Smp. : 185-186°C ;IR (Nujol) : 3350, 1660, 1605, 1545, 1535, 1510 cm"<1 >NMR (CDC13, 6): 0,6-1,0 (4H, m) , 2,8-3,0 (1H, m) , ;3,08 (3H, s) , 7,0-7,5 (8H, m) , 7,90 (2H, d, J=8Hz) ;Massespektrum (m/z) : 3 99 (M<+>) ;20) Etyl 5- [4-(metylsulfonyl)fenyl]-1-[4-nitrofenyl] - pyrazol-3-karboksylat. Smp. : 209-210°C IR (Nujol) : 1710, 1600, 1525 cm"<1 >NMR (DMSO-d6, 6): 1,33 (3H, t, J=7Hz) , 3,26 (3H, s) , 4,37 (2H, q, J=7Hz), 7,36 (1H, s), 7,5-8,4 (8H, m) Massespektrum (m/z) : 415 (M<+>) 21) 3-(fluormetyl)-1-(4-fluorfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol. ;Smp.: 166-167°C ;IR (Nujol) : 1600, 1515 cm"<1>;NMR (DMS0-d6, 6): 3,25 (3H, s) , 5,35 (1H, s) , ;5,59 (1H, s), 6,9-8,0 (8H, m) ;Massespektrum (m/z): 348 ;22) 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-3-pyrazol-metylacetat. ;Smp.: 102-103°C ;IR (Nujol) : 1740, 1720, 1600, 1515 cm"<1>;NMR (CDCI3, 6) : 2,14 (3H, s) , 3,07 (3H, s) , 5,10 ;(2H, s), 6,66 (1H, s), 7,0-8,0 (8H, m) Massespektrum (m/z) : 388 (M*) , 345 23) 3-(klormetyl)-1-(4-fluorfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol.
Smp.: 155-156°C
IR (Nujol) : 1600, 1515 cm"<1>
NMR (DMS0-d6, 5) : 3,25 (3H, s) , 4,82 (2H, s) ,
6,91 (1H, s), 7,2-8,0 (8H, m)
Massespektrum (m/z): 364 (M<+>)
24) 3-(fluormetyl)-5-[4-(metylsulfonyl)fenyl]-1-(4-nitrofenyl)pyrazol.
Smp.: 152-153°C
IR (Nujol) : 1600, 1525 cm'<1>
Massespektrum (m/z) : 3 75 (M<+>)
25) 3-(difluormetyl)-1-[4-(metylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol.
Smp.: 175-176°C
IR (Nujol) : 3430, 1615, 1540 cm"<1>
NMR (CDCI3, a): 2,72 (3H, s) , 3,07 (3H, s) ,
3,97 (1H, s), 6,5-8,1 (10H, m)
Massespektrum (m/z): 377 (M<+>)
26) 3-(difluormetyl)-1-(4-fluorfenyl)-5-[4-(metylsulf onyl) fenyl]pyrazol.
Smp.: 190-191°C
IR (Nujol) : 1600, 1515 cm"<1>
NMR (CDCI3, 3): 3,08 (3H, s), 6,5-8,0 (10H, m) Massespektrum (m/z) : 366 (M<+>) 27) 4-brom-l-(4-fluorfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol.
Smp.: 169-170°C
IR (Nujol) : 1600, 1510 cm"<1>
NMR (CDCI3, a): 3,10 (3H, s) , 7,0-8,0 (9H, m)
Massespektrum (m/z): 396, 394
28) N-fenyl-1-(4-fluorfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karboksamid.
Smp.: 232-233°C
IR (Nujol) : 3350, 1680, 1595, 1535., 1505 cm"<1>
NMR (DMSO-d6, 5): 3,26 (3H, s) , 7,0-8,0 (14H, m) ,
10,26 (1H, s)
Massespektrum (m/z): 435
29) 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-3-(1-pyrrolidinylkarbonyl)pyrazol.
Smp. : 229-230°C
IR (Nujol) : 1615, 1515, 1500 cm"<1>
NMR (CDC13, a): 1,77-2,07 (4H, m) , 3,00 (3H, s) ,
3,67 (2H, t, J=6Hz), 3,97 (2H, t, J=6Hz),
6,9-7,5 (7H, m), 7,87 (2H, d, J=8Hz)
Massespektrum (m/z) : 413 (M<+>)
30) 1-(2-klorfenyl)-5-[4-(metylsulfonyl)fenyl]-
pyrazol-3-karbonitril.
Smp.: 151-152°C
IR (Nujol) : 2250, 1610, 1545, 1490 cm"<1>
NMR (CDCI3, a): 3,05 (3H, s) , 7,02 (1H, s) ,
7,3-8,0 (8H, m)
Massespektrum (m/z) : 357 (M<+>)
Eksempel 18
En blanding av etyl 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylat (3,6 g) og kaliumhydroksyd (2 g) i metanol (50 ml) ble tilbakeløpsbehandlet i 30 minutter. Oppløsningsmidlet ble fordampet. Residuet ble oppløst i vann og vasket med kloroform. Det vandige lag ble surgjort med fortynnet saltsyre og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket over magnesiumsulfat og konsentrert. Det oppnådde residuum ble omkrystallisert fra etanol for å gi krystaller av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karboksylsyre
(2 g) .
Smp.: 199-200°C
IR (Nujol) : 3550, 3300, 2500, 1710, 1680, 1600, 1515 cm'<1 >Massespektrum (m/z): 328 (M<+>)
De følgende forbindelser (Eksempel 19-1) til 19-11)) ble oppnådd etter en tilsvarende fremgangsmåte som i_Eksempel 18.
Eksempel 19
1) 5-[4-(metylsulfonyl)fenyl]-1-(4-pyridyl)pyrazol-3-karboksylsyre.
Smp.: 270-271°C (dekomp.)
IR (Nujol) : 1690, 1610, 1510 cm"<1>
NMR (DMSO-d6, 6): 3,28 (3H, s) , 7,2-8,0 (7H, m) ,
8,66 (2H, bred s), 13,25 (1H, s)
Massespektrum (m/z) : 343 (M<+>)
2) 5-[4-(metyltio)fenyl]-1-(4-pyridyl)pyrazol-3-karboksylsyre. Smp.: 225-227°C IR (Nujol) : 3400, 2400, 1700, 1600, 1510 cm"<1 >Massespektrum (m/z) : 311 (M<+>) 3) 1-(2-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylsyre.
Smp.: 228-229°C (dekomp.)
IR (Nujol) : 2600, 1700, 1600, 1500 cm"<1>
NMR (DMSO-d6, 6): 3,25 (3H, s) , 7,22 (1H, s) ,
7,3-8,0 (8H, m), 13,17 (1H, s)
Massespektrum (m/z) : 360 (M<+>)
4) 1-(2,4-difluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylsyre.
Smp.: 231-233°C (dekomp.)
IR (Nujol) : 2600, 1700, 1600, 1515 cm"<1>
NMR (DMSO-d6, 6): 3,25 (3H, s) , 7,3-8,0 (8H, m)
13,20 (1H, s)
Massespektrum (m/z) : 378 (M<+>)
5) 1-(3-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylsyre. IR (Nujol) : 2630, 1705, 1600, 1490 cm"<1 >NMR (DMS0-d6, å) : 3,26 (3H, s) , 7,1-8,0 (9H, m) Massespektrum (m/z) : 360 (M<+>) 6) 5-[4-(metylsulfonyl)fenyl]-1-fenylpyrazol-3-karboksylsyre. Smp.: 203-205°C IR (Nujol) : 2625, 1700, 1600, 1495 cm"<1 >Massespektrum (m/z) : 342 (M<+>) 7) 1-(4-(metoksyfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylsyre. Smp.: 197-199°C IR (Nujol) : 1700, 1600, 1515 cm"<1 >Massespektrum (m/z) : 372 (M<+>) 8) 1- (4-metylfenyl) - 5- [4- (metylsulfonyl) fenyl] - pyrazol-3-karboksylsyre. Smp.: 185-187°C IR (Nujol) : 2600, 1700, 1600, 1510 cm"<1 >Massespektrum (m/z): 356 (M<+>) 9) 5-(4-fluorfenyl)-1-[4-(metyltio)fenyl]-pyrazol-3-karboksylsyre. Smp.: 176-178°C IR (Nujol) : 3500, 1680, 1610, 1545, 1490 cm"<1 >Massespektrum (m/z) : 328 (M<+>) 10) 5-[4-(metyltio)fenyl]-1-(4-nitrofenyl)pyrazol-3 -karboksylsyre.
Smp.: 188-189°C
IR (Nujol) : 1690, 1595, 1520 cm"<1 >Massespektrum (m/z) : 355 (M<+>)
11) 1-(2,4-difluorfenyl)-5-[4-(metyltio)fenyl]-
pyrazol-3-karboksylsyre.
Smp.: 188-190°C
IR (Nujol) : 3300, 2500, 1705, 1680, 1600, 1520 cm"<1 >Massespektrum (m/z) : 346 (M<+>)
Eksempel 20
En blanding av etyl 1-(4-metoksyfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksylat (2 g) og hydrogenjodidsyre (57%, 5 ml) i eddiksyre (10 ml) ble tilbakeløpsbehandlet i 5 timer. Reaksjonsblandingen ble konsentrert og residuet utgnidd i en vandig oppløsning av natriumbisulfitt, hvilket førte til et pulver. Dette rå pulveret ble renset ved kolonnekromatografi på silikagel (80 g) under eluering med en blanding av kloroform og metanol for å gi et pulver av 1-(4-hydroksyfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksylsyre (0,86 g).
Smp.: 233-236°C (dekomp.)
IR (Nujol) : 3550, 3250, 1700, 1600, 1515 cm"<1>
Massespektrum (m/z) : 358 (M<+>)
Eksempel 21
En blanding av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksylsyre (13,5 g) og tionylklorid (10 ml) i diklormetan (30 ml) ble tilbakeløpsbehandlet i 1 time. Blandingen ble konsentrert til en olje av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karbonylklorid.
IR (Film) : 1760, 1605, 1510 cm"<1>
En oppløsning av kloridet ovenfor i tetrahydrofuran (50 ml) ble dråpevis tilsatt til en blanding av 28% ammoniakkvann og tetrahydrofuran (50 ml) ved 5 til 10°C. Blandingen ble omrørt i 1 time ved romtemperatur. Oppløsningsmidlet ble fordampet og residuet utgnidd med vann for å gi krystaller av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karboksamid (11,2 g) .
Smp.: 180-181°C
IR (Nujol) : 3500, 3425, 1670, 1600, 1510 cm"<1>
NMR (CDC13, 6): 2,48 (3H, s) , 5,70 (1H, s) , 6,87
(1H, s) , 7,0-7,4 (9H, m)
Massespektrum (m/z) : 327 (M<+>)
De følgende forbindelser (Eksempel 22-1) til 22-13)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 21.
Eksempel 22
1) 5-[4-(metylsulfonyl)fenyl]-1-(4-pyridyl)pyrazol-3-karboksamid.
Smp. : 286-288°C
IR (Nujol) : 3550, 3300, 3200, 1690, 1595, 1500 cm"<1>
NMR (DMSO-d6, 6): 3,28 (3H, s) , 7,18 {1H, s) ,
7,3-8,0 (8H, m), 8,66 (2H, d, J=5Hz)
Massespektrum (m/z) : 342 (M<+>)
2) 5-[4-(metyltio)fenyl]-1-(4-pyridyl)pyrazol-3-karboksamid. Smp. : 213-215°C IR (Nujol) : 3360, 3150, 1680, 1595 cm-<1 >3) 1- (2-f luorfenyl) -5- [4- (metylsulf onyl) f enyl] - pyrazol-3-karboksamid.
Smp.: 198-199°C
IR (Nujol) : 3500, 3150, 1690, 1600, 1510 cm"<1>
NMR (CDC13, 6): 3,06 (3H, s), 5,68 (1H, s),
6,86 (1H, s), 7,1-7,9 (9H, m)
Massespektrum (m/z) : 359 (M<+>)
4) 1-(2,4-difluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksamid.
Smp. : 213-214°C
IR (Nujol) : 3440, 3150, 1685, 1610, 1520 cm"<1>
NMR (DMSO-d6, 5) : 3,25 (3H, s) , 7,23 (1H, s) , 7,3-8,0
(7H, m)
Massespektrum (m/z) : 377 (M<+>)
5) 1-(3-fluorfenyl)-5- [4-(metylsulfonyl)fenyl]-pyrazol-3-karboksamid.
Smp. : 217-218°C
IR (Nujol) : 3460, 3220, 1680, 1600, 1490 cm"<1>
NMR (DMSO-d6, 6): 3,26 (3H, s) , 7,1-8,0 (11H, m) Massespektrum (m/z) : 359 (M<+>) 6) 5-[4-(metylsulfonyl)fenyl]-l-fenylpyrazol-3-karboksamid.
Smp.: 265-266°C
IR (Nujol) : 3475, 3200, 1680, 1600, 1495 cm"<1>
NMR (DMS0-d6, 5): 3,24 (3H, s), 7,16 (1H, s),
7,3-8,0 (11H, m)
Massespektrum (m/z) : 341 (M<+>)
7) 1-(4-metoksyfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksamid.
Smp.: 178-179°C
IR (Nujol) : 3480, 3310, 3230, 1675, 1590, 1515 cm"<1 >NMR (DMS0-ds, 6): 3,24 (3H, s), 3,79 (3H, s),
6,9-8,0 (11H, m)
Massespektrum (m/z) : 371 (M<+>)
8) 1-(4-hydroksyfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksamid. Smp.: 269-271°C IR (Nujol) : 3550, 3460, 3200, 1680, 1600, 1520 cm"<1 >Massespektrum (m/z) : 357 (M<+>) 9) 1- (4-metylfenyl) -5- [4- (metylsulfonyl) fenyl] - pyrazol-3-karboksamid.
Smp.: 125-130°C
IR (Nujol) : 3470, 3200, 1680, 1600, 1515 cm"<1>
NMR (DMSO-ds, 6): 2,35 (3H, s) , 3,24 (3H, s) ,
7,1-8,0 (11H, m)
Massespektrum (m/z) : 355 (M<+>)
10) 5-(4-fluorfenyl)-1-[4-(metyltio)fenyl]-pyrazol-3-karboksamid.
Smp.: 157-159°C
IR (Nujol): 3460, 3270, 1670, 1610, 1595, 1545, 1495 cm"<1 >Massespektrum (m/z) : 327 (M<+>) 11) 5-[4-(metyltio)fenyl]-1-(4-nitrofenyl)pyrazol-3-karboksamid.
Smp.: 192-194°C
IR (Nujol) : 3480, 3150, 1690, 1610, 1595, 1520 cm"<1 >Massespektrum (m/z) : 354 (M<+>)
12) 1-(4-fluorfenyl)-5-(4-tolyl)pyrazol-3-karboksamid.
Smp.: 183-186°C
IR (Nujol) : 3500, 3350, 3300, 1685, 1610, 1510 cm-<1>
NMR (DMS0-d6, 6): 2,29 (3H, s) , 6,8-7,5 {9H, m) ,
7,68 (2H, s)
Massespektrum (m/z) : 295 (M<+>)
13) 1-(2,4-difluorfenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksamid.
Smp.: 171-173°C
IR (Nujol) : 3440, 3200, 1665, 1600, 1515 cm-<1>
Massespektrum (m/z) : 345 (M<+>)
Eksempel 23
En blanding av 1-(4-hydroksyfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karboksamid (1,3 g) og metansulfonylklorid
(2,5 g) i pyridin (20 ml) ble omrørt ved 50°C i 5 timer. Oppløsningsmidlet ble fordampet, hvorpå fortynnet saltsyre og etylacetat ble tilsatt til residuet. Det organiske lag ble vasket med vann, tørket og konsentrert. Residuet ble renset ved kolonnekromatografi på silikagel (20 g) under eluering med en blanding av kloroform og metanol (20:1) for å gi krystaller av 5-[4-(metylsulfonyl)fenyl]-1-[4-(metylsulfonyloksy)fenyl]pyrazol-3-karbonitril (0,79 g).
Smp.: 195-196°C
IR (Nujol) : 2250, 1600, 1510 cm'<1>
NMR (DMSO-d6, 6): 3,10 (3H, s) , 3,45 (3H, s) ,
7,4-8,0 (9H, m)
Massespektrum (m/z) : 417 (M<+>)
Eksempel 24
En oppløsning av natriumperjodat (0,7 g) i vann (5 ml) ble tilsatt til en is-avkjølt oppløsning av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karbonitril (0,6 g) i metanol (50 ml). Den resulterende oppløsning ble omrørt ved romtemperatur i 8 timer. Uoppløselig materiale ble frafiltrert og filtratet konsentrert. Det oppnådde residuum ble oppløst i etylacetat og vasket med en vandig oppløsning av natriumhydrogensulfitt og vann. Det organiske lag ble tørket og konsentrert til et oljeaktig residuum (0,6 g). Residuet ble renset ved kolonnekromatografi på silikagel (13 g) under eluering med en blanding av kloroform og metanol (50:1). Det rensede produkt ble krystallisert fra en blanding av heksan og etanol for å gi krystaller av 1-(4-fluorfenyl)-5-[4-(metylsulfinyl)fenyl]pyrazol-3-karbonitril (0,45 g).
Smp.: 104-105°C
IR (Nujol) : 2250, 1600, 1515 cm"<1>
NMR (CDC13, 5) : 2,76 (3H, s) , 6,94 (1H, s) ;
7,0-7,7 (8H, m)
Massespektrum (m/z) : 325 (M<+>) , 310
Eksempel 25
En blanding av 5-(4-fluorfenyl)-1-[4-(metyltio)fenyl]-pyrazol-3-karbonitril (0,75 g) og 30% hydrogenperoksyd-oppløsning (1,4 ml) i eddiksyre (10 ml) ble omrørt ved 50°C i 4 timer. Reaksjonsblandingen ble konsentrert og residuet omkrystallisert fra etanol for å gi krystaller av 5-(4-fluorfenyl)-1-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonitril (0,66 g).
Smp.: 162-163°C
IR (Nujol): 3140, 2250, 1610, 1595, 1500 cm-<1>
NMR (CDCI3, 5): 3,09 (3H, s) , 6,89 (1H, s) ,
7,0-8,0 (8H, m)
Massespektrum (m/z) : 341 (M<+>)
Eksempel 2 6
En blanding av 5-[4-(metylsulfonyl)fenyl]-1-(4-nitrofenyl)-pyrazol-3-karbonitril (1,1 g), jernpulver (1,1 g) og ammoniumklorid (0,11 g) i etanol (20 ml) og vann (7 ml) ble tilbakeløps-behandlet i 1 time. Oppløsningsmidlet ble fordampet og residuet frafiltrert, vasket med vann og oppløst i varm etylacetat. Oppløsningen ble filtrert og filtratet konsentrert. Det oppnådde residuum ble omkrystallisert fra etylacetat for å gi krystaller av 1-(4-aminofenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonitril (0,83 g).
Smp.: 228-229°C
IR (Nujol): 3480, 3400, 3150, 2250, 1645, 1605, 1520 cm"<1 >NMR (DMSO-d6, 3): 3,25 (3H, s) , 5,57 (2H, s) ,
6,5-8,0 (9H, m)
Massespektrum (m/z) : 338 (M<+>)
Eksempel 27
En blanding av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-amin (0,7 g) og eddiksyre-anhydrid (0,22 ml) i diklormetan (15 ml) ble omrørt ved romtemperatur i 3 timer og konsentrert. Residuet ble renset ved kolonnekromatografi på silikagel (15 g) under eluering med en blanding av toluen og etylacetat (2:1). Det ønskede produkt (0,63 g) ble omkrystallisert fra etanol for å gi blekbrune krystaller av N-{l-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-3-pyrazolyl}acetamid
(0,52 g)
Smp.: 203-205°C
IR (Nujol) : 3350, 1690, 1580, 1510 cm"<1>
NMR (DMSO-d6, 6): 2,05 (3H, s) , 3,21 (3H, s) ,
6,98 (1H, s), 7,2-7,6 (6H, m), 7,89 (2H, d,
J=8Hz), 10,72 (1H, s)
Massespektrum (m/z) : 373 (M<+>) , 331
Eksempel 28
Metylklorformiat (0,163 ml) i acetonitril (0,7 ml) ble dråpevis tilsatt til en omrørt oppløsning av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl] pyrazol-3-amin (0,7 g) og pyridin (0,171 ml) i acetonitril (6 ml) og tetrahydrofuran (7 ml) ved
-2 0°C. Blandingen ble omrørt ved 5°C i 1 time, fortynnet med etylacetat, vasket med vann, tørket og konsentrert. Residuet (0,9 g) ble omkrystallisert fra en blanding av kloroform og etanol for å gi blekbrune krystaller av metyl N-{l-(4-fluor-fenyl) -5- [4- (metylsulf onyl) f enyl] -3 -pyrazolyl}karbamat (0,51 g)
Smp.: 225-227°C
IR (Nujol) : 3320, 1730, 1585, 1510 cm"<1>
NMR (DMS0-d6, 6): 3,16 (3H, s) , 3,62 (3H, s) ,
6,73 (1H, s) , 7,1-7,5 (6H, m), 7,84 (2H, d, J=8Hz) , 10,22 (1H, s)
Massespektrum (m/z): 3 89 (M<+>), 357
Eksempel 29
En blanding av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-amin (0,8 g) og metansulfonylklorid (0,224 ml) i pyridin (8 ml) ble omrørt ved romtemperatur i 2 timer. Pyridinet ble fordampet og residuet oppløst i etylacetat, vasket med vann og fortynnet saltsyre, tørket og konsentrert. Den gjenværende olje (1,1 g) ble renset ved kolonnekromatografi på silikagel
(20 g) under eluering med en blanding av toluen og etylacetat (2:1). Produktet (0,74 g) ble omkrystallisert fra etanol for å gi blekbrune krystaller av N-{l-(4-fluorfenyl)-5-[4-(metylsulf onyl)fenyl]-3-pyrazolyl}metansulfonamid (0,62 g).
Smp.: 186-187°C
IR (Nujol) : 3150, 1555, 1520 cm"<1>
NMR (DMSO-d6, 5): 3,17 (3H, s) , 3,24 (3H, s) ,
6,55 (1H, s), 7,2-7,6 (6H, m), 7,91 (2H, d,
J=8,5Hz), 10,37 (1H, s)
Massespektrum (m/z) : 409 (M<+>)
Eksempel 3 0
En blanding av 1-(4-aminofenyl)-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril (0,7 g) og maursyre (1 ml) i formalin (37%; 5 ml) ble tilbakeløpsbehandlet i 30 minutter. Kloroform ble tilsatt og blandingen vasket med vann, tørkete og konsentrert. Den gjenværende olje ble renset ved kolonnekromatografi på silikagel under eluering med en blanding av etylacetat og toluen (2:1). Det oppnådde produkt ble omkrystallisert fra etylacetat for å gi krystaller av 1-[4-(dimetylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonitril (0,46 g).
Smp.: 171-172°C
IR (Nujol) : 2240, 1610, 1530 cm'<1>
Massespektrum (m/z) : 3 66 (M<+>)
Eksempel 31
En blanding av 1- (4-aminofenyl) -5- [4- (metylsulfonyl) fenyl] - pyrazol-3-karbonitril (1 g), metyljodid (0,42 g) og kaliumkarbonat (0,6 g) i N,N-dimetylformamid (10 ml) ble omrørt ved romtemperatur i 1 time. Blandingen ble helt over i vann og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket og konsentrert. Residuet (1,2 g) ble renset ved kolonnekromatografi på silikagel (20 g) under eluering med kloroform for å gi krystaller av 1-[4-(metylamino)fenyl]-5-[4-(metylsulf onyl) f enyl] pyrazol-3 -karbonitril (0,31 g).
Smp.: 166-168°C
IR (Nujol) : 3450, 2240, 1610, 1530 cm"<1>
NMR (DMS0-d6, 6): 2,51 (3H, d, J=5Hz) , 3,25 (3H, s) ,
6,17 (1H, q, J=5Hz), 6,5-8,0 (9H, m)
Den følgende forbindelse (Eksempel 32) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 10.
Eksempel 32
1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-ylmetylamin.
IR (Film) : 3400, 3300, 1600, 1500 cm-<1>
NMR (CDC13, 6) : 1,85 (2H, s), 2,47 (3H, s), 2,96
(2H, s), 6,43 (1H, s), 7,0-7,4 (8H, m) Massespektrum (m/z): 313 (M<+>)
De følgende forbindelser (Eksempel 33-1) til 33-7)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 24.
Eksempel 33
1) 1-(2-fluorfenyl)-5-[4-(metylsulfinyl)fenyl]-pyrazol-3-karbonitril.
Smp.: 139-140°C
IR (Nujol) : 2250, 1600, 1500 cm"<1>
NMR (CDCI3, 5): 2,73 (3H, s), 6,96 (1H, s), 7,0-7,7
(8H, m)
Massespektrum (m/z) : 325 (M<+>) , 310
2) 1-(2,4-difluorfenyl)-5-[4-(metylsulfinyl)fenyl]-pyrazol-3-karbonitril. Smp.: 136-137°C IR (Nujol) : 2260, 1615, 1520 cm"<1 >NMR (CDCI3, 6): 2,74 (3H, s), 6,8-7,7 (8H, m) Massespektrum (m/z) : 343 (M<+>) , 328 3) 1- [4- (N-formylmetylamino) fenyl] -5- [4- (metylsulf inyl) fenyl]pyrazol-3-karbonitril. IR (Film) : 2250, 1680, 1610, 1515 cm"<1 >4) 5-[4-(metylsulfinyl)fenyl]-1-(4-nitrofenyl)-3-(trifluormetyl)pyrazol.
Smp.: 167-168°C
IR (Nujol) : 1600, 1530, 1495 cm"<1>
Massespektrum (m/z) : 3 95 (M<+>)
5) 3-(fluormetyl)-1-(4-fluorfenyl)-5-[4-(metyl-
sulfinyl)fenyl]pyrazol.
Smp. : 130-131°C
IR (Nujol) : 1600, 1515 cm"<1>
NMR (CDCI3, 5): 2,75 (3H, s) , 5,36 (1H, s) , 5,60
(1H, s), 6,69 (1H, s), 7,0-7,7 (8H, m) - Massespektrum (m/z) : 332 (M<+>) 6) 3-(klormetyl)-1-(4-fluorfenyl)-5-[4-(metylsulfinyl)fenyl]pyrazol.
Smp. : 96-97°C
IR (Nujol) : 1600, 1515 cm"<1>
NMR (CDCI3, 6): 2,75 (3H, s) , 4,70 (2H, s) ,
6,65 (1H, s), 7,0-7,7 (8H, m)
Massespektrum (m/z) : 348 (M<+>)
7) 3-(difluormetyl)-1-(4-fluorfenyl)-5-[4-
(metylsulfinyl)fenyl]pyrazol.
Smp. : 165-166°C
IR (Nujol) : 1600, 1515 cm"<1>
NMR (CDCI3, 6): 2,75 (3H, s) , 6,5-7,7 (10H, m) Massespektrum (m/z) : 350 (M<+>) , 335
De følgende forbindelser (Eksempel 34-1) til 34-13)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 26.
Eksempel 34
1) 1-(4-aminofenyl)-5-[5-(metylsulfonyl)-2-tienyl]-pyrazol-3-karbonitril. Smp.: 200-203°C IR (Nujol) : 3500, 3420, 2250, 1620, 1520 cm"<1 >Massespektrum (m/z) : 344 (M<+>) 2) Etyl 1-(4-aminofenyl)-5-(4-tolyl)pyrazol-3-karboksylat.
Smp. : 174-175°C
IR (Nujol) : 3460, 3380, 1730, 1700, 1635, 1520 cm"<1 >Massespektrum (m/z) : 321 (M<+>)
3) 1-(4-aminofenyl)-1-(4-metoksyfenyl)pyrazol-3-karbonitril. Smp.: 175-177°C IR (Nujol) : 3420, 3350, 2250, 1640, 1610, 1520 cm"<1 >Massespektrum (m/z): 290 (M<+>) _ 4) Etyl 1-(4-aminofenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karboksylat. Smp.: 153-155°C IR (Nujol): 3450, 3350, 3230, 1715, 1635, 1610, 1520 cm"<1 >Massespektrum (m/z) : 353 (M<+>) 5) 1- (2-aminofenyl) -5- [4- (metylsulfonyl) fenyl] - pyrazol-3-karbonitril. Smp.: 191-192°C IR (Nujol) : 3500, 3400, 2250, 1635, 1600, 1500 cm'<1 >Massespektrum (m/z) : 338 (M<+>) 6) 1-(2-amino-4-fluorfenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril. Smp.: 206-208°C IR (Nujol) : 3500, 3400, 2250, 1630, 1510 cm"<1 >Massespektrum (m/z) ; 356 (M<+>) 7) 1-(4-aminofenyl)-5-[4-(metyltio)fenyl]-3-(trifluormetyl)pyrazol. Smp.: 112-113°C IR (Nujol) : 3500, 3400, 1625, 1600, 1520, 1500 cm"<1 >Massespektrum (m/z) : 349 (M<+>) 8) 1-(4-aminofenyl)-5-[4-(metylsulfonyl)fenyl]-3-(trifluormetyl)pyrazol. Smp.: 250-251°C IR (Nujol) : 3500, 3400, 1640, 1600, 1520, 1500 cm"<1 >Massespektrum (m/z) : 381 (M<+>) 9) 1-(4-aminofenyl)-5-[4-(metylsulfinyl)fenyl]-3-(trifluormetyl)pyrazol. Smp.: 213-214°C IR (Nujol): 3500, 3380, 3250, 1645, 1610, 1525, 1505 cm"<1 >Massespektrum (m/z) : 365 (M<+>) 10) 1-(4-aminofenyl)-3-(metylsulfonyl)-5-[4-(metylsulfonyl)fenyl]pyrazol. Smp.: 208-210°C IR (Nujol) : 3500, 3400, 1635, 1605, 1520 cm"<1 >Massespektrum (m/z) : 391 (M<+>) 11) 1-(4-aminofenyl)-3- (fluormetyl)-5-[4-
(metylsulfonyl)fenyl]pyrazol. Smp.: 112-116°C IR (Nujol) : 3420, 3240, 1610, 1520 cm"<1 >12) 1-(4-aminofenyl)-3-(difluormetyl)-5-[4-(metyltio)fenyl]pyrazol. IR (Film) : 3500, 3380, 1625, 1520 cm"<1 >13) Etyl 1-(4-aminofenyl)-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karboksylat.
Smp.: 245-247°C
IR (Nujol) : 3450, 3350, 1740, 1645, 1605, 1520 cm-<1 >NMR (DMSO-d6, 5) : 1,32 (3H, t, J=7Hz) , 3,24 (3H, s) ,
4,33 (2H, q, J=7Hz), 5,51 (2H, s), 6,5-8,0 (9H, m) Massespektrum (m/z) ; 385 (M<+>)
De følgende forbindelser (Eksempel 35-1) og 35-2)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 27.
Eksempel 35
1) 5-[4-(acetamido)fenyl]-1-(4-fluorfenyl)pyrazol-3-karboksamid.
Smp.: 273-275°C
IR (Nujol) : 3500, 3200, 1670, 1600, 1550, 1510 cm"<1 >Massespektrum (m/z): 338 (M<+>) 2) 1-(4-acetamido)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril.
Smp.: 206-207°C
IR (Nujol): 3270, 2250, 1690, 1670, 1605, 1555, 1515 cm"<1 >NMR (DMSO-d6, 5): 2,07 (3H, s), 3,25 (3H, s),-
7,3-8,0 (9H, m), 10,21 (1H, s)
Massespektrum (m/z) : 380 (M<+>) , 338
Den følgende forbindelse (Eksempel 36) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 29.
Eksempel 3 6
1- [4-(metylsulfonylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karbonitril.
Smp.: 232-233°C
IR (Nujol): 3240, 2250, 1600, 1515 cm'<1>
NMR (DMSO-d6, 6): 3,09 (3H, s) , 3,26 (3H, s) ,
7,2-8,0 (9H, m), 10,17 (1H, s)
Massespektrum (m/z): 416 (M<+>)
De følgende forbindelser (Eksempel 37-1) til 37-4)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 31.
Eksempel 37
1) 1-[4-(dimetylamino)fenyl] - 5-[5-(metylsulfonyl)-2- tienyl]pyrazol-3-karbonitril.
Smp.: 168-169°C
IR (Nujol) : 2250, 1610, 1525 cm'<1>
NMR (DMSO-d6, 6) : 3,01 (6H, s) , 3,33 (3H, s) ,
6,7-7,8 (7H, m)
Massespektrum (m/z) : 372 (M<+>)
2) 1- [4-(etylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril.
Smp.: 167-168°C
IR (Nujol) : 3400, 2240, 1610, 1525 cm'<1>
NMR (CDC13, 6): 1,28 (3H, t, J=7Hz), 3,07 (3H, s),
3,13 (2H, q, J=7Hz), 6,5-8,0 (9H, m)
Massespektrum (m/z) : 366 (M+) , 351
3) 1-[4 -(dietylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril.
Smp. : 155-156°C
IR (Nujol) : 2240, 1610, 1520 cm"<1>
NMR (CDC13, 5) : 1,18 (6H, t, J=7Hz), 3,07 (3H, s),
3,37 (4H, q, J=7Hz), 6,5-8,0 (9H, m)
Massespektrum (m/z) : 394 (M+) , 379
4) 3-(fluormetyl)-1-[4-(metylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol.
Smp.: 151-153°C
IR (Nujol) : 3425, 1615, 1535 cm'<1>
NMR (CDCI3, 5) : 2,85 (3H, s), 3,06 (3H, s), 3,94 (1H, s),
5,36 (1H, s), 5,60 (1H, s), 6,5-8,0 (9H, m) Massespektrum (m/z) : 359 (M<+>)
Eksempel 38
En blanding av etyl 1-(4-fluorfenyl)-5-[5-(metyltio)-2-tienyl]pyrazol-3-karboksylat (2,1 g) og natriummetoksyd (895 mg) i formamid (10 ml) ble omrørt ved 100°C i 1 time. Vann ble tilsatt til reaksjonsblandingen, hvorpå bunnfallet ble oppsamlet, vasket med vann og tørket i vakuum for å gi krystaller av 1-(4-fluorfenyl)-5-[5-(metyltio)-2-tienyl]pyrazol-3-karboksamid (1,6 g).
Smp. : 132-140°C
IR (Nujol) : 3500, 3300, 3200, 1700, 1665, 1600, 1510 cm'<1 >Massespektrum (m/z) : 333 (M<+>)
De følgende forbindelser (Eksempel 39-1) til 39-16)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 38.
Eksempel 3 9
1) 5- [5-(metyltio)-2-tienyl]-1-(4-nitrofenyl)-pyrazol-3-karboksamid. IR (Nujol) : 3350, 3180, 1675, 1595, 1520 cm"<1 >2) 1-(4-fluorfenyl)-5-[4-(N-formyImetylamino)fenyl]-pyrazol-3-karboksamid. Smp.: 222-224°C IR (Nujol) : 3500, 3430, 3200, 1660, 1615,. 1510 cm"<1 >Massespektrum (m/z): 338 (M<+>) 3) 5-(4-aminofenyl)-1-(4-fluorfenyl)pyrazol-3-karboksamid. Smp. : 195-199°C IR (Nujol): 3500, 3360, 3200, 1675, 1630, 1610, 1510 cm"<1 >Massespektrum (m/z) : 296 (M<+>) 4) 1-[4-(N-formylmetylamino)fenyl]-5-(4-tolyl)-pyrazol-3-karboksamid. Smp.: 202-206° IR (Nujol) : 3400, 3200, 1665, 1610, 1520 cm'<1 >Massespektrum (m/z) : 334 (M<+>) 5) 1-(4-fluorfenyl)-5-(4-metoksyfenyl)pyrazol-3-karboksamid.
Smp.: 136-142°C
IR (Nujol): 3500, 3350, 3200, 1705, 1690, 1665, 1610,
1510 cm'<1>
Massespektrum (m/z): 311 (M+)
6) 5-(4-metoksyfenyl)-1-(4-nitrofenyl)pyrazol-3-karboksamid.
Smp. : 200-202°C
IR (Nujol) : 3400, 3170, 1680, 1610, 1595, 1520 cm'<1 >Massespektrum (m/z) : 338 (M<+>)
7) 1,5-bis(4-metoksyfenyl)pyrazol-3-karboksamid.
Smp.: 13 0-131°C
IR (Nujol): 3450, 3300, 3250, 1675, 1660, 1610, 1515 cm"<1 >NMR (DMS0-d6, 6): 3,75 (3H, s) , 3,78 (3H, s) ,
6,7-7,6 (11H, m) Massespektrum (m/z) : 323 (M"<1>) 8) 5-(4-acetylfenyl)-1- (4-fluorfenyl)pyrazol-3-karboksamid.
Smp. : >3 00°C
IR (Nujol) : 3500, 3420, 1675, 1590, 1510 cm"<1>
9) 5-(4-cyanofenyl)-1- (4-fluorfenyl)pyrazol-3-karboksamid. Smp.: 181-185°C IR (Nujol): 3500, 3350, 2240, 1660, 1600, 1510 cm"<1 >Massespektrum (m/z) ; 3 06 (M<+>) 10) 1-(2-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karboksamid. Smp.: 140-146°C IR (Nujol) : 3400, 3300, 1670, 1600, 1500 cm"<1 >Massespektrum (m/z) : 327 (M<+>) 11) 1-(2,5-difluorfenyl)-5- [4-(metyltio)fenyl]-pyrazol-3-karboksamid. Smp.: 185-187°C IR (Nujol) : 3450, 3300, 3150, 1690, 1610, 1510 cm"<1 >NMR (DMS0-ds, 5): 2,46 (3H, s), 7,0-7,8 (10H, m) Massespektrum (m/z) : 345 (M<+>) 12) l-[4-(N-formylmetylamino)fenyl]-5-[4-(metyltio)-fenyl]pyrazol-3-karboksamid.
Smp.: 183-189°C
IR (Nujol) : 3350, 3200, 1670, 1655, 1605, 1520 cm"<1 >NMR (DMS0-d6, 5): 2,47 (3H, s) , 3,23 (3H, s) ;
6,9-7,7 (11H, m), 8,65 (1H, s)
Massespektrum (m/z) : 366 (M<+>)
13) 5-[4-(metyltio)fenyl]-1-(2-nitrofenyl)-
pyrazol-3-karboksamid.
Smp.: 196-199°C (dekomp.)
IR (Nujol) : 3500, 3160, 1690, 1610, 1530 cm"<1>
Massespektrum (m/z) : 354 (M<+>)
14) 1-(4-fluor-2-nitrofenyl)-5-[4-(metyltio)fenyl]-pyrazol-3-karboksamid. IR (Nujol) : 3430, 3200, 1670, 1590, 1540, 1510 cm"<1 >15) 1-[4-(N-formylmetylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksamid.
Smp.: 278-283°C (dekomp.)
IR (Nujol) : 3350, 1665, 1600, 1520 cm'<1>
Massespektrum (m/z) : 3 98 (M<+>)
16) 1-(2-klorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-karboksamid.
Smp.: 195-201°C
IR (Nujol) : 3450, 3150, 1690, 1610, 1590 cm"<1>
Massespektrum (m/z) : 343 (M<+>)
Eksempel 4 0
En blanding av 1-(4-aminofenyl)-5-[5-(metylsulfonyl)-2-tienyl]pyrazol-3-karbonitril (1,1 g) og maursyre (5 ml) ble tilbakeløpsbehandlet i 30 minutter. Blandingen ble konsentrert og residuet utgnidd i vann for å gi krystaller av 1-[4-(formyl-amino)fenyl]-5-[5-(metylsulfonyl)-2-tienyl]pyrazol-3-karbonitril (1,1 g)•
Smp.: 152-158°C
IR (Nujol) : 3260, 2250, 1675, 1605, 1515 cm"<1 >Massespektrum (m/z) : 372 (M<+>)
De følgende forbindelser (Eksempel 41-1) til 41-11)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 40.
Eksempel 41
1) Etyl 1-[4-(formylamino)fenyl]-5-(4-tolyl)pyrazol-3-karboksylat. Smp.: 201-203°C IR (Nujol) : 3260, 1730, 1690, 1600, 1530 cm"^ 2) 1-[4-(formylamino)fenyl]-5-[4-(metoksyfenyl)-pyrazol-3-karbonitril. IR (Film) : 3300, 2250, 1690, 1610, 1515 cm-<1 >3) Etyl 1-[4-(formylamino)fenyl]-5-[4-(metyltio)-fenyl]pyrazol-3-karboksylat. Smp.: 190-192°C IR (Nujol) : 3250, 1730, 1690, 1605, 1520 cm"<1 >4) 1-[4-(formylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril.
Smp.: 195-197°C
IR (Nujol) : 3270, 2240, 1690, 1670, 1605, 1550, 1515 cm"<1 >NMR (DMSO-d6, 6): 3,26 (3H, s) , 7,2-8,0 (9H, m) ,
8,32 (1H, s), 10,48 (1H, s)
Massespektrum (m/z) : 366 (M<+>)
5) 1-[2-(formylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril. Smp.: 109-118°C IR (Nujol): 3330, 2250, 1700, 1600, 1520 cm"<1 >Massespektrum (m/z) : 366 (M+) , 338 6) 1-[4-(formylamino)fenyl]-5-[4-(metyltio)fenyl]-3-(trifluormetyl)pyrazol. Smp.: 134-135°C IR (Nujol) : 3370, 1700, 1605, 1530 cm"<1 >Massespektrum (m/z) : 377 (M<+>) 7) 1-[4-(formylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]-3-(trifluormetyl)pyrazol.
Smp.: 163-166°C
IR (Nujol) : 3270, 1680, 1610, 1550, 1520, 1500 cm"<1 >Massespektrum (m/z) : 409 (M<+>) 8) 1-[4-(formylamino)fenyl]-5-[4-(metylsulfinyl)-fenyl] -3-(trifluormetyl)pyrazol. IR (Film) : 3270, 1690, 1610, 1525, 1500 cm"<1 >9) 1-[4-(formlamino)fenyl]-3-(metylsulfonyl)-5-[4-(metylsulfonyl)fenyl]pyrazol.
Smp. : 193-195°C
IR (Nujol) : 3380, 1700, 1670, 1605, 1535 cm"<1>
Massespektrum (m/z) : 419 (M<+>)
10) 3-(difluormetyl)-1-[4-(formylamino)fenyl]-5-[4-(metyltio)fenyl]pyrazol.
Smp.: 127-131°C
IR (Nujol) : 3300, 1680, 1670, 1610, 1520 cm"<1>
Massespektrum (m/z) : 3 59 (M<+>)
11) Etyl 1-[4-(formylamino)fenyl]-5-[4-
(metylsulfonyl)fenyl]pyrazol-3-karboksylat.
Smp: 214-216°C
IR (Nujol) : 3270, 1740, 1670, 1605, 1555, 1510 cm"<1 >Massespektrum (m/z) : 413 (M<+>)
Eksempel 42
En oppløsning av 1-[4-(formylamino)fenyl]-5-[5-(metylsulfonyl)-2-tienyl]pyrazol-3-karbonitril (1,1 g) i N,N-dimetyl-formamid (3 ml) ble dråpevis tilsatt til en suspensjon av natriumhydrid (60%; 118 mg) i N,N-dimetylformamid (2 ml) . Blandingen ble omrørt ved 0°C i 30 minutter. Blandingen ble dråpevis tilsatt en oppløsning av jodmetan (0,84 g) i N,N-dimetyl f ormamid (2 ml) ved 0°C. Den resulterende blanding ble omrørt ved 0°C i 1 time, helt over i is-avkjølt fortynnet saltsyre og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket over magnesiumsulfat og inndampet i vakuum. Residuet ble omkrystallisert fra etanol for å gi krystaller av 1- [4-(N-(formylmetylamino)fenyl]-5-[5-(metylsulfonyl)-2-
tienyl]pyrazol-3-karbonitril (1 g).
Smp.: 170-173°C
IR (Nujol) : 2250, 1675, 1600, 1520 cm"<1>
Massespektrum (m/z) : 386 (M<+>)
De følgende forbindelser (Eksempel 43-1) til 43-12)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 42.
Eksempel 43
1) Etyl 1-(4-fluorfenyl)-5-[4-(N-formylmetylamino)-fenyl]pyrazol-3-karboksylat.
Smp.: 118-120°C
IR (Nujol) : 1715, 1680, 1610, 1515 cm'<1>
NMR (CDC13, 6): 1,43 (3H, t, J=7Hz), 3,32 (3H, s),
4,46 (2H, q, J=7Hz), 7,0-7,5 (9H, m), 8,55 (1H, s) Massespektrum (m/z) : 367 (M<+>) 2) Etyl 1-[4-(N-formylmetylamino)fenyl]-5-(4-tolyl)-pyrazol-3-karboksylat.
IR (Film) : 1720, 1675, 1610, 1515 cm'<1>
NMR (CDCI3, 6): 1,39 (3H, t, J=7Hz), 2,32 (3H, s),
3,28 (3H, s), 4,42 (2H, q, J=7Hz), 6,9-7,5
(9H, m), 8,42 (1H, s)
3) 1-[4-(N-formylmetylamino)fenyl] -5-(4-metoksy-fenyl)pyrazol-3-karbonitril. IR (Film) : 2250, 1680, 1610, 1515 cm"<1 >4) Etyl 1-[4-(N-formylmetylamino)fenyl]-5- [4-(metyltio)fenyl]pyrazol-3-karboksylat.
IR (Film) : 1720, 1680, 1605, 1520 cm"<1>
NMR (CDCI3, 6): 1,42 (3H, t, J=7Hz), 2,47 (3H, s),
3,28 (3H, s), 4,42 (2H, q, J=7Hz), 6,9-7,4
(9H, m), 8,37 (1H, S)
5) 1-[4-(N-formylmetylamino)fenyl] -5-[4-(metylsulf onyl) fenyl]pyrazol-3-karbonitril.
Massespektrum (m/z) : 380 (M<+>)
6) 1-[2-(N-formylmetylamino)fenyl]-5-[4-(metylsulf onyl) fenyl]pyrazol-3-karbonitril. Smp.: 172-173°C IR (Nujol) : 2250, 1670, 1600, 1500 cm"<1 >Massespektrum (m/z) : 380 (M<+>) , 352 7) 1-[4-(N-formylmetylamino)fenyl]-5-[4-(metyltio)-fenyl]-3 -(trifluormetyl)pyrazol. Smp.: 142-144°C IR (Nujol) : 1680, 1610, 1520, 1500 cm"<1 >Massespektrum (m/z): 3 91 8) 1-[4-(N-formylmetylamino)fenyl]-5-[4-(metylsulf onyl) f enyl] -3-(trifluormetyl)pyrazol. Smp.: 118-120°C IR (Nujol) : 1660, 1610, 1520, 1500 cm-<1 >Massespektrum (m/z): 423 (M<+>) 9) 1-[4-(N-formylmetylamino)fenyl]-5-[4-(metylsulf inyl) fenyl]-3-(trifluormetyl)pyrazol. IR (Film) : 1675, 1610, 1520, 1500 cm'<1 >10) 1-[4-(N-formylmetylamino)fenyl]-3-(metylsulf onyl) -5-[4-(metylsulfonyl)fenyl]pyrazol.
Smp.: 146-150°C
IR (Nujol) : 1675, 1605, 1520 cm"<1>
Massespektrum (m/z) : 433 (M<+>)
11) 3-(difluormetyl)-1-[4-(N-formylmetylamino)-fenyl]-5-[4-(metyltio)fenyl]pyrazol. Smp.: 109-115°C IR (Nujol) : 1680, 1605, 1520 cm"<1 >Massespektrum (m/z) : 373 (M<+>) 12) Etyl 1-[4-(N-formylmetylamino)fenyl] -5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksylat.
IR (Nujol) : 1745, 1725, 1680, 1600, 1520 cm"<1 >Massespektrum (m/z) : 427 (M<+>)
Eksempel 44
En blanding av 1-[4-(N-formylmetylamino)fenyl] - 5-[5-(metylsulfonyl)-2-tienyl]pyrazol-3-karbonitril (1 g) og 10%
saltsyre (3 ml) i metanol (15 ml) ble omrørt ved 60°C i 3 timer. Etter avkjøling ble blandingen filtrert og filtratet konsentrert i vakuum. Residuet ble vasket med etanol for å gi krystaller av 1-[4-(metylamino)fenyl]-5-[5-(metylsulfonyl)-2-tienyl]pyrazol-3-karbonitril-hydroklorid (0,89 g).
Smp. : 205-207°C
IR (Nujol) : 2600, 2450, 2250, 1510 cm"<1>
NMR (DMSO-d6, 6): 2,76 (3H, s) , 3,33 (3H, s) , 6,77
(2H, d, J=8Hz), 7,26 (2H, d, J=8Hz), 7,43
(1H, d, J=3Hz), 7,72 (1H, s), 7,78 (1H, d, J=3Hz) Massespektrum (m/z) : 358 (M<+>)
De følgende forbindelser (Eksempel 45-1) til 45-14)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 44.
Eksempel 45
1) 1-(4-fluorfenyl)-5-[4-(metylamino)fenyl]pyrazol-3-karbonitril-hydroklorid. Smp.: 189-191°C IR (Nujol) : 2650, 2450, 2250, 1510 cm'<1 >NMR (DMSO-d6/ 6): 2,73 (3H, s) , 6,8-7,5 (9H, m) Massespektrum (m/z) : 292 (M<+>) 2) l-[4-(metylamino)fenyl]-5-(4-tolyl)pyrazol-3-karbonitril-hydroklorid.
Smp. : 199-201°C
IR (Nujol) : 2600, 2450, 2250, 1610, 1520 cm"<1>
NMR (DMSO-d6, 6): 2,29 (3H, s) , 2,76 (3H, s) ,
6,9-7,4 (9H, m), 7,62 (2H, s)
Massespektrum (m/z) : 288 (M<+>)
3) 1-[4-(metylamino)fenyl]-5 - [4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril-hydroklorid.
Smp. : 218-221°C
IR (Nujol) : 3450, 2650, 2460, 2250, 1600, 1510 cm"<1>
NMR (DMSO-d6, 6): 2,70 (3H, s) , 3,25 (3H, s) ,
5,46 (2H, s), 6,5-8,0 (9H, m) Massespektrum (m/z) : 352 (M<+>) 4) 1-[4-(metylamino)fenyl]-5-[4-(metyltio)fenyl]-pyrazol-3-karbonitril-hydroklorid.
Smp.: 113-120°C
IR (Nujol) : 3400, 2650, 2450, 2250, 1600, 1515 cm'<1 >NMR (DMSO-d6, 6): 2,46 (3H, s) , 2,74 (3H, s) , 6,57
(2H, s), 6,5-7,4 (9H, m)
Massespektrum (m/z): 320 (M<+>)
5) 1-[4-(metylamino)fenyl]-5-[4-(metylsulfinyl)-fenyl]pyrazol-3-karbonitril-hydroklorid.
Smp.: 175-177°C (dekomp.)
IR (Nujol) : 2630, 2450, 2250, 1600, 1515 cm"<1 >NMR (DMSO-ds, 6): 2,74 (3H, s) , 2,76 (3H, s) ,
6,53 (2H, s), 6,7-7,8 (9H, m) Massespektrum (m/z) : 336 (M+) , 319 6) 1-[2-(metylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril.
Smp.: 192-193°C
IR (Nujol) : 3450, 2250, 1610, 1520 cm"<1>
NMR (DMS0-d6, 6): 2,66 (3H, d, J=5Hz) , 3,22 (3H, s) ,
5,33 (1H, q, J=5Hz), 6,5-8,0 (9H, m)
Massespektrum (m/z): 352 (M<+>)
7) 1-[4-(metylamino)fenyl]-5-[4-(metyltio)fenyl]-3-(trifluormetyl)pyrazol.
Smp.: 168-169°C
IR (Nujol) : 3400, 1610, 1535, 1500 cm"<1>
NMR (CDC13, 6): 2,47 (3H, s) , 2,84 (3H, s) ,
6,5-7,3 (9H, m)
Massespektrum (m/z) : 363 (M<+>)
8) 1-[4-(metylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]-3-(trifluormetyl)pyrazol-hydroklorid. Smp.: 200-202°C IR (Nujol): 2725, 2600, 2450, 1600, 1520, 1500 cm-<1 >NMR (DMS0-d6, 6): 2,75 (3H, s) , 3,26 (3H, s) , 6,8-8,0 (9H, m), 8,42 (2H, s) Massespektrum (m/z) : 395 (M<+>) 9) 1- [4- (metylamino) fenyl] -5- [4- (metylsulfinyl) - fenyl]-3-(trifluormetyl)pyrazol-hydroklorid. Smp.: 171-172°C IR (Nujol) : 2625, 2450, 1500 cm"<1 >NMR (DMS0-ds, 6): 2,76 (6H, s) , 6,8-7,8 (10H, m) Massespektrum (m/z) : 379 (M<+>) 10) 1-[4-(metylamino)fenyl]-3-(metylsulfonyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-hydroklorid.
Smp.: 209-211°C
IR (Nujol) : 2650, 2450, 1600, 1515 cm"<1>
NMR (DMSO-d6, 5) : 2,74 (3H, s), 3,26 (3H, s), 3,35
(3H, s) , 6,7-8,0 (9H, m)
Massespektrum (m/z): 405 (M<+>)
11) 3-(difluormetyl)-1-[4-(metylamino)fenyl] -5-[4-(metyltio)fenyl]pyrazol.
Smp.: 128-129°C
IR (Nujol) : 3360, 1610, 1530 cm"<1>
NMR (CDC13, 6): 2,47 (3H, s) , 2,84 (3H, s) , 6,4-7,2
(10H, m)
Massespektrum (m/z) : 345 (M<+>)
12) N-metyl-1-[4-(metylamino)fenyl]-5-[4-(metylsulf onyl) fenyl]pyrazol-3-karboksamid. Smp.: 187-188°C IR (Nujol): 3400, 1670, 1650, 1610, 1560, 1525 cm"<1 >NMR (CDCI3, 6): 2,86 (3H, s) , 2,92 (3H, d, J=5Hz), 3,06 (3H, s), 4,03 (1H, s), 6,5-8,0 (10H, m) Massespektrum (m/z) : 384 (M<+>) 13) N,N-dimetyl-l- [4- (metylamino) fenyl.] -5- [4- (metylsulf onyl) fenyl]pyrazol-3-karboksamid.
Smp.: 204-205°C
IR (Nujol) : 3420, 1620, 1530 ctrf1
NMR (CDC13, 6): 2,86 (3H, s) , 3,07 (3H, s) ,
3,14 (3H, s), 3,44 (3H, s), 4,00 (1H, s), 6,4-8,0
(9H, m)
Massespektrum (m/z) : 3 98 (M<+>)
14) 1-[4-(metylamino)fenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karboksamid.
Smp.: 215-216°C
IR (Nujol) : 3470, 3370, 3160, 1675, 1610, 1530 cm"<1>
NMR (DMSO-d6, 6): 2,69 (3H, d, J=5Hz) , 3,24 (3H, s) ,
6,07 (1H, q, J=5Hz), 6,55 (2H, d, J=9Hz),
7,0-8,0 (9H, m)
Massespektrum (m/z) : 370 (M<+>)
Eksempel 46
Etyl 1-[4-(metylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karboksylat, oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 44, ble omsatt etter en tilsvarende fremgangsmåte som i Eksempel 3 for å gi 1-[4-(metylamino)fenyl]-5-[4-(metylsulfonyl)fenyl]pyrazol-3-karboksylsyre.
Smp.: 235-240°C (dekomp.)
IR (Nujol) : 3400, 1715, 1610, 1530 cm'<1>
NMR (DMSO-d6, 6): 2,69 (3H, s) , 3,24 (3H, s) ,
6,09 (1H, s), 6,55 (2H, d, J=9Hz), 7,05 (2H, d, J=9Hz), 7,17 (1H, s), 7,53 (2H, d, J=8Hz),
7,89 (2H, d, J=8Hz)
Massespektrum (m/z) : 371 (M<+>)
Eksempel 47
En blanding av 1-(4-fluorfenyl)-5-[4-{metylsulfonyl)fenyl]-pyrazol-3-karbonitril (1 g), ammoniumklorid (0,25 g) og natriumazid (0,24 g) i N,N-dimetylformamid (10 ml) ble omrørt ved 105°C i 10 timer. Blandingen ble helt over i _is-vann og bunnfallet oppsamlet, vasket med vann og omkrystallisert fra en blanding av etanol og tetrahydrofuran for å gi krystaller av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]-3-(5-tetrazolyl)pyrazol (0,71 g).
Smp.: 278-279°C (dekomp.)
IR (Nujol) : 3150, 1655, 1620, 1600, 1510 cm'<1>
NMR (DMS0-d6, 5): 3,27 (3H, s) , 7,3-7,6 (7H, m) ,
7,95 (2H, d, J=8Hz)
Massespektrum (m/z) : 3 84 (M<+>)
De følgende forbindelser (Eksempel 48-1) og 48-2)) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 47.
Eksempel 48
1) 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-3-5- (tetrazolyl)pyrazol.
Smp.: 242-243°C (dekomp.)
IR (Nujol) : 1605, 1510 cm"<1>
NMR (DMSO-d6, 6): 2,48 (3H, s), 7,1-7,6 (9H, s) , Massespektrum (m/z): 352 (M<+>) 2) 1-(4-fluorfenyl)-5- [4-(metylsulfinyl)fenyl]-3-(5-tetrazolyl)pyrazol.
Smp.: 272-273°C (dekomp.)
IR (Nujol) : 1615, 1510 cm-<1>
NMR (DMSO-d6, 6): 2,79 (3H, s), 7,3-7,8 (9H, m) Massespektrum (m/z): 368 (M<+>)
Eksempel 49
En blanding av etyl 4-[4-(formylamino)fenyl]-2,4-diokso-butanoat (6 g) og 4-fluorfenylhydrazin-hydroklorid (4,1 g) i eddiksyre (30 ml) ble omrørt ved 100°C i 2 timer. Blandingen ble konsentrert og residuet behandlet med 10% saltsyre (10 ml) og metanol (4 0 ml) ved 60°C i 2 timer. Oppløsningsmidlet ble fordampet og residuet oppløst i vann. Den oppnådde oppløsningen ble nøytralisert og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket og konsentrert i vakuum. Residuet ble vasket med etanol for å gi krystaller av etyl 5-(4-aminofenyl)-1-(4-fluorfenyl)pyrazol-3-karboksylat (3,4 g).
Smp.: 158-160°C
IR (Nujol) : 3450, 3350, 3250, 1720, 1640, 1610, 1510 cm"<1 >NMR (CDC13, 5): 1,42 (3H, t, J=7Hz), 4,44 (2H, q, J=7Hz),
6,5-7,4 (9H, m)
Massespektrum (m/z) : 325 (M<+>)
Eksempel 50
En oppløsning av natriumnitritt (0,26 g) i vann (0,3 ml) ble tilsatt til en is/salt-avkjølt blanding av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-3-pyrazolamin (1 g), acetonitril (1 ml), svovelsyre (0,6 ml) og vann (1,6 ml). Blandingen ble omrørt ved 0°C i 30 minutter. Den resulterende blanding ble porsjonsvis tilsatt til en blanding av kobber(I)bromid (645 mg), natriumbromid (582 mg), hydrogenbromidsyre (1,7 ml) og vann (3 ml) ved 80°C. Blandingen ble omrørt ved 80°C i 30 minutter og ekstrahert med toluen. Ekstraktet ble vasket med vann, tørket og inndampet i vakuum. Det oppnådde residuet ble renset ved kolonnekromatografi på silikagel (10 g) for å gi krystaller av 3-brom-l-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol (0,35 g).
Smp.: 98-99°C
IR (Nujol): 1600, 1510, 1680 Cirf1
NMR (CDCI3, 6): 2,48 (3H, s) , 6,49 (1H, s) ,
6,9-7,3 (8H, m)
Massespektrum (m/z) : 364 (M<+>)
Eksempel 51
En blanding av 4-brom-1-(4-fluorfenyl)-5-[4-(metyltio)-fenyl]pyrazol (1,9 g) og kobber(I)cyanid (0,7 g) ble oppvarmet til 200°C i 6 timer. Blandingen ble ekstrahert med etylacetat og ekstraktet konsentrert i vakuum. Residuet (0,95 gj ble renset ved kolonnekromatografi på silikagel (20 g) under eluering med kloroform for å gi krystaller av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-4-karbonitril {0,95 g) .
Smp.: 122-123°C
IR (Nujol) : 2230, 1600, 1505 cm'<1>
NMR (CDC13, 6): 2,50 (3H, s), 7,0-7,8 (8H, m)
8,00 (1H, s)
Massespektrum (m/z) : 309 (M<+>)
Eksempel 52
En oppløsning av brom (0,9 g) i diklormetan (2 ml) ble dråpevis tilsatt til en is-avkjølt oppløsning av 1-(4-fluor-fenyl) -5- [4- (metyltio) f enyl] pyrazol (1,6 g) i diklormetan (10 ml) . Blandingen ble omrørt ved 5°C i 1 time, vasket med en oppløsning av natriumbisulfitt og vann, tørket og konsentrert i vakuum. Residuet (1,9 g) ble omkrystallisesrt fra etanol for å gi krystaller av 4-brom-l-(4-fluorfenyl)-5-[4-(metyltio)fenyl] - pyrazol (1,3 g).
Smp.: 85-87°C
IR (Nujol) : 1600, 1510 cm"<1>
Massespektrum (m/z): 364, 362
Eksempel 53
En blanding av 1-[4-(metyltio)fenyl]-3,3-bis(metyltio)-2-propen-l-on (2,7 g) og 4-fluorfenylhydrazin-hydrat (1,8 g) i eddiksyre (15 ml) ble omrørt ved 100°C i 7 timer. Oppløsnings-midlet ble fordampet og residuet oppløst i etanol. Uoppløselig materiale ble frafiltrert og filtratet konsentrert i vakuum. Residuet ble renset ved kolonnekromatografi på silikagel (25 g) under eluering med kloroform for å gi en olje av 1-(4-fluor-fenyl) -3- (metyltio) -5- [4- (metyltio) fenyl] pyrazol (0,73 g).
IR (Nujol) : 1590, 1510 cm"<1>
NMR (CDCI3, 6): 2,48 (3H, s) , 2,59 (3H, s) ,
6,40 (1H, s), 6,9-7,4 (8H, m)
Den følgende forbindelse (Eksempel 54) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 53.
Eksempel 54
3-(metyltio)-5-[4-(metyltio)fenyl]-1-[4-nitrofenyl)pyrazol.
Smp. : 71-73°C
IR (Nujol) : 1595, 1515, 1500 cm"<1>
Massespektrum (m/z) : 357 (M<+>)
Eksempel 55
En blanding av 5-(4-aminofenyl)-1-(4-fluorfenyl)pyrazol-3-karboksamid (0,27 g) og metansulfonylklorid (0,63 g) i pyridin (5 ml) ble omrørt ved 60°C i 5 timer. Oppløsningsmidlet ble fordampet og residuet oppløst i en blanding av etylacetat og vann. Det organiske lag ble fraskilt, vasket med vann, tørket og konsentrert i vakuum. Residuet ble krystallisert fra etanol for å gi 1-(4-fluorfenyl)-5-[4-metylsulfonylamino)fenyl]pyrazol-3-karbonitril (0,19 g).
Smp. : 202-205°C
IR (Nujol) : 3160, 2250, 1615, 1510 cm'<1>
NMR (DMSO-d6, 5): 3,05 (3H, s) , 7,1-7,5 (9H, m) , 10,06 (1H, s)
Massespektrum (m/z) : 356 (M+) , 277
Eksempel 56
En blanding av 1-(2-amino-4-fluorfenyl)-5-[4-(metylsulf onyl) f enyl] pyrazol-3 -karbonitril (0,87 g), metyljodid (0,69 g) og kaliumkarbonat (0,27 g) i N,N-dimetylformamid (5 ml) ble omrørt ved 45°C i 19 timer. Blandingen ble helt over i vann og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket og konsentrert i vakuum. Residuet (1 g) ble renset ved kolonnekromatografi på silikagel (15 g) under eluering med kloroform.
1-[2-(dimetylamino)-4-fluorfenyl]-5-[4-(metylsulfonyl)-fenyl]pyrazol-3-karbonitril (0,11 g) ble oppnådd fra det første
eluat.
Smp.: 200-202°C
IR (Nujol) : 2250, 1620, 1500 cm"<1>
NMR (DMS0-d6, 6): 2,11 (6H, s) , 3,21 (3H, s) ,
6,7-7,9 (8H, m) Massespektrum (m/z) : 384 (M<+>)
1-[4-fluor-2-(metylamino)fenyl] -5-[4-(metylsulfonyl)fenyl]-pyrazol-3-karbonitril (0,44 g) ble oppnådd fra det andre eluatet.
Smp.: 192-193°C
IR (Nujol) : 3450, 2250, 1620, 1530 cm'<1>
NMR (DMS0-ds, 6): 2,65 (3H, d, J=3Hz) , 3,23 (3H, s) ,
5,68 (1H, q, J=3Hz), 6,3-8,0 (8H, m)
Massespektrum (m/z) : 370 (M<+>)
Eksempel 57
En blanding av 1-(4-fluorfenyl)-3-(metyltio)-5-[4-(metyltio) f enyl] pyrazol (0,73 g), 30% hydrogenperoksyd (1,5 ml) og konsentrert svovelsyre (2 dråper) i eddiksyre (10 ml) ble omrørt ved 60°C i 4 timer. Oppløsningsmidlet ble fordampet og residuet oppløst i etylacetat. Oppløsningen ble vasket suksessivt med en vandig oppløsning av natriumbikarbonat og vann, tørket og konsentrert. Residuet ble omkrystallisert fra en blanding av etylacetat og etanol for å gi krystaller av 1-(4-fluorfenyl)-3-(metylsulfonyl)-5-[4-(metylsulfonyl)fenyl]pyrazol (0,54 g).
Smp.: 209-210°C
IR (Nujol) : 1600, 1515 cm'<1>
NMR (DMS0-d6/ 6): 3,26 (3H, s) , 3,38 (3H, s) ,
7,3-8,0 (9H, m)
Massespektrum (m/z) : 394 (M<+>)
Den følgende forbindelse (Eksempel 58) ble oppnådd etter en tilsvarende fremgangsmåte som i Eksempel 57.
Eksempel 58
3-(metylsulfonyl)-5-[4-(metylsulfonyl)fenyl]-1-(4-nitrofenyl)pyrazol.
Smp. : 187-189°C
IR (Nujol) : 1600, 1530, 1500 cm'<1>
Massespektrum (m/z): 421
Eksempel 59
En blanding av 4-fluor-1-[4-(metyltio)fenyl]butan-1,3-dion (2 g) og 4-fluorfenylhydrazin-hydroklorid (1,6 g) i eddiksyre (10 ml) ble tilbakeløpsbehandlet i 5 timer. Oppløsningsmidlet ble fordampet og residuet oppløst i etylacetat. Den resulterende oppløsning ble vasket med en vandig oppløsning av natriumbikarbonat, tørket og konsentrert i vakuum. Residuet (3 g) ble renset ved kolonnekromatografi på silikagel under eluering med kloroform. En olje av 3-(klormetyl)-1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol (1,3 g) ble oppnådd fra det første eluatet.
IR (Film) : 1600, 1510 cm"<1>
NMR (CDC13, 6): 2,44 (3H, s) , 4,64 (2H, s) ;
6,49 (1H, s), 6,8-7,3 (8H, m)
Massespektrum (m/z) : 332 (M<+>)
En olje av 1-(4-fluorfenyl)-5-[4-(metyltio)fenyl]-3-pyrazolylmetyl-acetat (0,6 g) ble oppnådd fra det andre eluatet.
IR (Film) : 1740, 1600, 1515 cm'<1>
NMR (CDC13, 6): 2,11 (3H, s) , 2,44 (3H, s) ,
5,14 (2H, s), 6,46 (1H, s), 6,8-7,3 (8H, m)
Eksempel 60
En oppløsning av acetylklorid (0,48 g) i etylacetat (10 ml) ble dråpevis tilsatt til en is-avkjølt oppløsning av l-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-ylmetylamin (1,6 g) og trietylamin (lg) i etylacetat (50 ml). Blandingen ble omrørt ved 5°C i 1 time, vasket suksessivt med fortynnet saltsyre, en oppløsning av natriumbikarbonat og vann, tørket og konsentrert i vakuum. En blanding av det ovenfor oppnådde residuum (2,5 g) inneholdende N-{l-(4-fluorfenyl)-5-[4-(metyltio)fenyl]pyrazol-3-
ylmetyljacetamid og m-klorperbenzosyre (2,8 g) i diklormetan
(50 ml) ble omrørt ved romtemperatur over natten. Blandingen ble vasket med en oppløsning av natriumbikarbonat og konsentrert i vakuum. Det gjenværende pulver (2,1 g) inneholdende N-{l-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-ylmetyl}acetamid ble tilsatt etanol (40 ml) og konsentrert saltsyre (15 ml). Blandingen ble tilbakeløpsbehandlet i 7 timer og konsentrert til tørrhet. Residuet ble oppløst i vann, hvorpå oppløsningen ble gjort basisk med natriumhydroksyd og ekstrahert med etylacetat. Ekstraktet ble vasket med vann, tørket og konsentrert i vakuum. Det oppnådde residuum (1,4 g) ble renset ved kolonnekromatografi på silikagel (10 0"g) under eluering med en blanding av kloroform og metanol (10:1) for å gi krystaller av 1-(4-fluorfenyl)-5-[4-(metylsulfonyl)fenyl]pyrazol-3-ylmetylamin (1,0 g).
Smp.: 150-152°C
IR (Nujol) : 3380, 3300, 1600, 1510 cm"<1>
NMR (CDC13, a): 1,85 (2H, s) , 3,07 (3H, s) ,
3,99 (2H, s), 6,57 (1H, s), 7,0-7,5 (6H, m),
7,87 (2H, d, J=8Hz)
Massespektrum (m/z) : 345 (M<+>)
Claims (5)
1. Analogifremgangsmåte for fremstilling av en terapeutisk forbindelse med formel:
hvor R<1> er fenyl som kan ha substituenter valgt blant lavere
alkyl, halogen, lavere alkoksy, lavere alkyltio,
lavere alkylsulfinyl, lavere alkylsulfonyl, hydroksy, lavere alkylsulfonyloksy, nitro, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, og lavere alkylamino substituert med lavere alkanoyl; eller pyridyl,
R<2> er hydrogen; metyl substituert med amino, lavere
alkyl-amino, halogen eller lavere alkanoyloksy; karboksy; forestret karboksy; lavere alkanoyl eventuelt substituert med lavere alkoksy; karbamoyl eventuelt substituert med substituent(er) valgt fra gruppen bestående av lavere alkyl, cyklo(lavere)alkyl, fenyl og hydroksy; 1-pyrrolidinylkarbonyl; N-metylpiperazinylkarbonyl; lavere alkylsulfonyl; amino substituert med lavere alkanoyl, forestret karboksy eller lavere alkylsulfonyl; cyano; halogen; lavere alkyltio; lavere alkylsulfinyl; eller tetrazolyl; og R<3> er fenyl substituert med lavere alkyl, lavere
alkyltio, lavere alkylsulfinyl, halogen, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, lavere alkylamino substituert med lavere alkanoyl, lavere alkoksy, cyano, hydroksy, lavere alkanoyl, eller lavere alkylsulfonyl; eller tienyl som kan være substituert med lavere alkyltio, lavere alkylsulfinyl eller lavere alkylsulfonyl;
forutsatt at når
R<2> er karboksy, forestret karboksy eller
tri(halogen)metyl, da er
R<3> fenyl substituert med lavere alkyltio, lavere alkyl
sulf inyl, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, lavere alkylamino substituert med lavere alkanyl, hydroksy, lavere alkanoyl eller lavere alkylsulfonyl; eller tienyl substituert med lavere alkyltio, lavere alkylsulfinyl eller lavere alkylsulfonyl; eller R<1> er fenyl substituert med substituent(er) valgt fra
lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, hydroksy, lavere alkylsulfonyloksy, nitro, amino, lavere alkylamino, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, og lavere alkylamino substituert med lavere alkanoyl; eller pyridyl;
eller farmasøytisk akseptable salter derav, karakterisert ved at a) en forbindelse med formel:
eller salter derav, omsettes med en forbindelse med formel:
eller salter derav, for å gi en forbindelse med formel:
eller salter derav,
hvor i formlene ovenfor,
R<1>, R<2> og R3 hver er som definert ovenfor, eller b) en forbindelse med formel:
eller salter derav, oksyderes for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1> og R<2> hver er som definert ovenfor,
R<3>a er fenyl eller tienyl som begge er substituert
med lavere alkyltio, og R<3>b er fenyl eller tienyl som begge er substituert
med lavere alkylsulfinyl eller lavere alkylsulfonyl, eller c) en forbindelse med formel:
eller salter derav, underkastes en de-forestringsreaksjon for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1> og R<3> hver er som definert ovenfor, og
R<2>a er forestret karboksy, eller d) en forbindelse med formel:
eller dets reaktive derivat ved karboksygruppen, eller salter derav, omsettes med et amin eller formamid og et alkali-metallalkoksyd for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1> og R<3> hver er som definert ovenfor, og
R<2>b er karbamoyl som kan være substituert med
substituenter valgt fra lavere alkyl, fenyl, cyklo-(lavere)alkyl og hydroksy; 1-pyrrolidinylkarbonyl; eller N-metylpiperazinylkarbonyl; eller e) en forbindelse med formel:
eller salter-derav, dehydratiseres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1> og R<3> hver er som definert ovenfor, eller f) en forbindelse med formel:
eller salter derav, reduseres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1> og R<3> hver er som definert ovenfor,
R<2>C er karbamoyl som kan være substituert med lavere
alkyl, og
R<2>d er aminometyl som kan være substituert med lavere
alkyl, eller g) en forbindelse med formel:
eller dets reaktive derivat ved karboksygruppen, eller salter derav, omsettes med en forbindelse med formel:
CH2(COOR<4>)2 [IV]
hvorpå det resulterende produkt hydrolyseres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1> og R<3> hver er som definert ovenfor, og
R<4> er lavere alkyl, eller h) en forbindelse med formel:
eller salter derav, omsettes med en forbindelse med formel:
R<4->OH [V] for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1>, R<3> og R<4> hver er som definert ovenfor, eller i) en forbindelse med formel:
eller salter derav, omsettes med en nitrittforbindelse for
å gi en forbindelse med formel:
hvor, i formlene ovenfor,
R<1>a er fenyl som kan være substituert med lavere alkyl,
halogen,- lavere alkoksy, lavere alkyltio, lavere alkyl-sulfinyl, lavere alkylsulfonyl, hydroksy, lavere alkyl-sulfonyloksy, nitro, lavere alkylamino, lavere alkylamino substituert med lavere alkanoyl, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl; eller pyridyl; og R<3> er som definert ovenfor, eller j) en forbindelse med formel:
eller salter derav, oksyderes for å gi en forbindelse med formel:
eller salter derav, hvor, i formlene ovenfor, F^t, er fenyl substituert med lavere alkyltio, R<x>c er fenyl substituert med lavere alkylsulfinyl
eller lavere alkylsulfonyl, og R<2> og R<3> hver er definert ovenfor, eller k) en forbindelse med formel:
eller salter derav, reduseres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<x>d er fenyl substituert med nitro, R<x>e er fenyl substituert med amino, og R<2> og R<3> hver er som definert ovenfor, eller
1) en forbindelse med formel:
eller salter derav, acyleres for å gi en forbindelse med
formel:
eller salter derav,
hvor, i formlene ovenfor,
R1 f er fenyl som kan være substituert med lavere alkyl,
halogen, lavere alkoksy, lavere alkyltio, lavere alkylsulfinyl, lavere alkylsulfonyl, lavere alkylsulfonyloksy, nitro, amino substituert med lavere alkanoyl eller lavere alkylsulfonyl, og lavere alkyl-amino substituert med lavere alkanoyl; eller pyridyl;
R<2>e er amino substituert méd lavere alkanoyl, forestret
karboksy eller lavere alkylsulfonyl, og R<3> er som ovenfor definert, eller m) en forbindelse med formel:
eller salter derav, alkyleres for å gi en forbindelse med formel:
eller salter derav, hvor, i formlene ovenfor,
R<1>g er fenyl substituert med amino eller amino
substituert med lavere alkanoyl,
R<x>h er fenyl substituert med lavere alkylamino
eventuelt substituert med lavere alkanoyl, og R<2> og R<3> hver er som definert ovenfor, eller n) en forbindelse med formel:
eller salter derav, acyleres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<3>C er fenyl substituert med amino,
R<3>d er fenyl substituert med amino substituert med
lavere alkanoyl eller lavere alkylsulfonyl, og R<1> og R<2> hver er som definert ovenfor, o) en forbindelse med formel:
eller salter derav, acyleres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1>i er fenyl substituert med amino,
R<X>j er fenyl substituert med amino substituert med
lavere alkanoyl eller lavere alkylsulfonyl, og R2 og R<3> hver er som definert ovenfor, eller p) en forbindelse med formel:
eller salter derav, alkyleres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<3>e er fenyl substituert med amino eller amino
substituert med lavere alkanoyl,
R<3>f er fenyl substituert med lavere alkylamino eller
lavere alkylamino substituert med lavere alkanoyl, og
R<1> og R<2> hver er som definert ovenfor, eller q) en forbindelse med formel;
eller salter derav, deacyleres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1>,,. er fenyl substituert med amino eller lavere
alkylamino, som hver er substituert med lavere alkanoyl, _ R<1>! er fenyl substituert med amino eller lavere
alkylamino, og
R<2> og R<3> hver er som definert ovenfor, eller r) en forbindelse med formel:
eller salter derav, deacyleres for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<3>g er fenyl substituert med amino eller lavere
alkylamino, som hver er substituert med lavere alkanoyl,
R<3>h er fenyl substituert med amino eller lavere
alkylamino, og
R<1> og R<2> hver er som definert ovenfor, eller s) en forbindelse med formel:
eller salter derav, omsettes med en azidforbindelse for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<1> og R<3> hver er som definert ovenfor, eller t) en forbindelse med formel:
eller salter derav, omsettes med en nitrittforbindelse, hvorpå det resulterende produkt omsettes med kobber(I)-halogenid for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
X er halogen, og
R<1> og R<3> hver er som definert ovenfor, eller u) en forbindelse med formel: - *
eller salter derav, omsettes med en forbindelse med formel:
eller salter derav, for å gi en forbindelse med formel:
eller salter derav,
hvor, i formlene ovenfor,
R<6> er lavere alkyltio, og
R<1>, R2 og R<3> hver er som definert ovenfor.
2. Fremgangsmåte ifølge krav 1 for fremstiling av en forbindelse med formel [I] hvor
R<2> er hydrogen; metyl substituert med amino, lavere alkylamino
eller lavere alkanoyloksy; karbamoyl som eventuelt er . substituert med lavere alkyl, cyklo(lavere)alkyl, fenyl og hydroksy; lavere alkanoyl eventuelt substituert med lavere alkoksy; 1-pyrrolidinylkarbonyl; N-metylpiperazinylkarbonyl; amino substituert med lavere alkanoyl eller lavere alkylsulfonyl; cyano; halogen; lavere alkyltio; lavere alkylsulfinyl; lavere alkylsulfonyl; eller tetrazolyl,
karakterisert ved bruk av tilsvarende utgangsmaterialer.
3. Fremgangsmåte ifølge krav 2 for fremstilling av en forbindelse med formel [I] hvor
R<3> er fenyl eller tienyl, som hver er substituert med lavere
alkyltio, lavere alkylsulfinyl eller lavere alkylsulfonyl, karakterisert ved bruk av tilsvarende utgangsmaterialer.
4. Fremgangsmåte ifølge krav 3 for fremstilling av en forbindelse med formel [I] hvor
R<3> er fenyl substituert med lavere alkyltio, lavere alkyl
sulf inyl, eller lavere alkylsulfonyl,
karakterisert ved bruk av tilsvarende utgangsmaterialer.
5. Fremgangsmåte ifølge krav 4 for fremstilling av en forbindelse med formel [I] hvor
R<1> er fenyl substituert med halogen,
R<2> er halogen og
R<3> er fenyl substituert med lavere alkyltio, lavere
alkylsulfinyl eller lavere alkylsulfonyl,
karakterisert ved bruk av tilsvarende utgangsmaterialer.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB898921466A GB8921466D0 (en) | 1989-09-22 | 1989-09-22 | Pyrazole derivatives,processes for preparation thereof and pharmaceutical composition comprising the same |
GB909008399A GB9008399D0 (en) | 1990-04-12 | 1990-04-12 | Pyrazole derivatives,processes for preparation thereof and pharmaceutical composition comprising the same |
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NO904134D0 NO904134D0 (no) | 1990-09-21 |
NO904134L NO904134L (no) | 1991-03-25 |
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Family
ID=26295958
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NO904134A NO301006B1 (no) | 1989-09-22 | 1990-09-21 | Analogifremgangsmåte for fremstilling av terapeutisk aktive pyrazolderivater |
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EP (1) | EP0418845B1 (no) |
JP (1) | JP2586713B2 (no) |
KR (1) | KR0182798B1 (no) |
CN (1) | CN1046506C (no) |
AT (1) | ATE126216T1 (no) |
AU (1) | AU637142B2 (no) |
CA (1) | CA2025599C (no) |
DE (1) | DE69021472T2 (no) |
DK (1) | DK0418845T3 (no) |
ES (1) | ES2088933T3 (no) |
FI (1) | FI102535B (no) |
GR (1) | GR3017100T3 (no) |
HU (2) | HU208122B (no) |
IE (1) | IE68857B1 (no) |
IL (1) | IL95675A (no) |
NO (1) | NO301006B1 (no) |
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AU616564B2 (en) * | 1988-09-29 | 1991-10-31 | Sumitomo Chemical Company, Limited | Novel pyrazole compounds, method for production thereof, use thereof and intermediates for production thereof |
DE4039733A1 (de) * | 1990-12-13 | 1992-06-17 | Basf Ag | Substituierte 5-aminopyrazole |
NO179282C (no) * | 1991-01-18 | 1996-09-11 | Rhone Poulenc Agrochimie | Nye 1-(2-pyridyl)pyrazolforbindelser til kontroll av skadeinsekter |
AU1988692A (en) * | 1991-04-24 | 1992-12-21 | E.I. Du Pont De Nemours And Company | Fungicidal pyrazoles, pyrazolines and tetrahydropyridazines |
FR2682379B1 (fr) * | 1991-10-09 | 1994-02-11 | Rhone Poulenc Agrochimie | Nouveaux phenylpyrazoles fongicides. |
IL104311A (en) * | 1992-02-05 | 1997-07-13 | Fujisawa Pharmaceutical Co | Pyrazole derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same |
US5550147A (en) * | 1992-02-05 | 1996-08-27 | Fujisawa Pharmaceutical Co., Ltd. | Pyrazole derivatives, processes for preparation thereof and pharmaceutical composition comprising the same |
FR2690440B1 (fr) * | 1992-04-27 | 1995-05-19 | Rhone Poulenc Agrochimie | Arylpyrazoles fongicides. |
FR2713225B1 (fr) * | 1993-12-02 | 1996-03-01 | Sanofi Sa | N-pipéridino-3-pyrazolecarboxamide substitué. |
FR2692575B1 (fr) * | 1992-06-23 | 1995-06-30 | Sanofi Elf | Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant. |
US6492413B2 (en) | 1993-01-15 | 2002-12-10 | G.D. Searle & Co. | 3.4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
GB9420616D0 (en) * | 1994-10-12 | 1994-11-30 | Merck Sharp & Dohme | Method, compositions and use |
US5380738A (en) * | 1993-05-21 | 1995-01-10 | Monsanto Company | 2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents |
US5840746A (en) * | 1993-06-24 | 1998-11-24 | Merck Frosst Canada, Inc. | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases |
US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
US5387602A (en) * | 1993-08-30 | 1995-02-07 | Ortho Pharmaceutical Corporation | 1.5-diphenyl-3-(N-hydroxycarbamoyloxyalkyl)pyrazoles |
FR2711140B1 (fr) * | 1993-10-12 | 1996-01-05 | Sanofi Sa | 1-Naphtylpyrazole-3-carboxamides substitués actifs sur la neurotensine, leur préparation, les compositions pharmaceutiques en contenant. |
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US4146721A (en) * | 1969-09-12 | 1979-03-27 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Pyrazol-4-acetic acid compounds |
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1990
- 1990-09-11 PH PH41179A patent/PH27357A/en unknown
- 1990-09-13 IL IL9567590A patent/IL95675A/en not_active IP Right Cessation
- 1990-09-14 US US07/582,358 patent/US5134142A/en not_active Expired - Lifetime
- 1990-09-18 IE IE337990A patent/IE68857B1/en not_active IP Right Cessation
- 1990-09-18 CA CA002025599A patent/CA2025599C/en not_active Expired - Fee Related
- 1990-09-19 DK DK90117983.8T patent/DK0418845T3/da active
- 1990-09-19 HU HU905970A patent/HU208122B/hu not_active IP Right Cessation
- 1990-09-19 FI FI904602A patent/FI102535B/fi not_active IP Right Cessation
- 1990-09-19 ES ES90117983T patent/ES2088933T3/es not_active Expired - Lifetime
- 1990-09-19 EP EP90117983A patent/EP0418845B1/en not_active Expired - Lifetime
- 1990-09-19 AT AT90117983T patent/ATE126216T1/de not_active IP Right Cessation
- 1990-09-19 DE DE69021472T patent/DE69021472T2/de not_active Expired - Fee Related
- 1990-09-20 JP JP2252319A patent/JP2586713B2/ja not_active Expired - Fee Related
- 1990-09-21 AU AU63072/90A patent/AU637142B2/en not_active Ceased
- 1990-09-21 PT PT95389A patent/PT95389B/pt not_active IP Right Cessation
- 1990-09-21 KR KR1019900015110A patent/KR0182798B1/ko not_active IP Right Cessation
- 1990-09-21 CN CN90107130A patent/CN1046506C/zh not_active Expired - Fee Related
- 1990-09-21 NO NO904134A patent/NO301006B1/no not_active IP Right Cessation
- 1990-09-21 RU SU4831230/04A patent/RU2021990C1/ru not_active IP Right Cessation
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1991
- 1991-12-02 RU SU915010250A patent/RU2059622C1/ru active
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1995
- 1995-06-22 HU HU95P/P00344P patent/HU211532A9/hu unknown
- 1995-08-10 GR GR950402078T patent/GR3017100T3/el unknown
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