NO180118B - Analogifremgangsmåte for fremstilling av terapeutisk aktive isoksazol-4-karboksylsyreamider og hydroksyalkylidencyaneddiksyreamider - Google Patents
Analogifremgangsmåte for fremstilling av terapeutisk aktive isoksazol-4-karboksylsyreamider og hydroksyalkylidencyaneddiksyreamider Download PDFInfo
- Publication number
- NO180118B NO180118B NO924433A NO924433A NO180118B NO 180118 B NO180118 B NO 180118B NO 924433 A NO924433 A NO 924433A NO 924433 A NO924433 A NO 924433A NO 180118 B NO180118 B NO 180118B
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- atoms
- stands
- bromine
- chlorine
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 27
- QBPXGTUBZXXKJO-UHFFFAOYSA-N 1,2-oxazole-4-carboxamide Chemical class NC(=O)C=1C=NOC=1 QBPXGTUBZXXKJO-UHFFFAOYSA-N 0.000 title abstract description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical class CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 125000004432 carbon atom Chemical group C* 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 55
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 55
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 55
- 229910052794 bromium Inorganic materials 0.000 claims description 55
- 229910052801 chlorine Inorganic materials 0.000 claims description 55
- 239000000460 chlorine Substances 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 53
- 229910052731 fluorine Inorganic materials 0.000 claims description 53
- 239000011737 fluorine Substances 0.000 claims description 53
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 53
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 53
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- -1 methylenedioxy Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- JJJXXHCDSQSIFQ-YFHOEESVSA-N (z)-2-cyano-3-hydroxy-n-[4-(trifluoromethoxy)phenyl]but-2-enamide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(OC(F)(F)F)C=C1 JJJXXHCDSQSIFQ-YFHOEESVSA-N 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
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- RXSNFDWFKNKMKV-UHFFFAOYSA-N n-(1h-indazol-5-yl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=C3C=NNC3=CC=2)=C1C RXSNFDWFKNKMKV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- XLWOZNBEEQLMKL-KTKRTIGZSA-N (z)-n-(1,3-benzodioxol-5-yl)-2-cyano-3-hydroxypent-2-enamide Chemical compound CC\C(O)=C(/C#N)C(=O)NC1=CC=C2OCOC2=C1 XLWOZNBEEQLMKL-KTKRTIGZSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 150000003951 lactams Chemical class 0.000 claims description 2
- NWOVTJSCRMZLMM-UHFFFAOYSA-N n-(1h-indazol-6-yl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=C3NN=CC3=CC=2)=C1C NWOVTJSCRMZLMM-UHFFFAOYSA-N 0.000 claims description 2
- NCJHFNRNOOGXMN-UHFFFAOYSA-N n-(1h-indol-5-yl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=C3C=CNC3=CC=2)=C1C NCJHFNRNOOGXMN-UHFFFAOYSA-N 0.000 claims description 2
- AFIFBOMOIFYWFT-UHFFFAOYSA-N n-(4,6-dimethylpyridin-2-yl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2N=C(C)C=C(C)C=2)=C1C AFIFBOMOIFYWFT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 34
- 239000007858 starting material Substances 0.000 claims 9
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- CIAYWDIOMYFBGQ-YFHOEESVSA-N (z)-2-cyano-3-hydroxy-n-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]but-2-enamide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(OC(F)(F)C(F)F)C=C1 CIAYWDIOMYFBGQ-YFHOEESVSA-N 0.000 claims 1
- MCQBBMWGWZVCPF-WJDWOHSUSA-N (z)-2-cyano-n-[4-(4-fluorobenzoyl)phenyl]-3-hydroxybut-2-enamide Chemical compound C1=CC(NC(=O)C(/C#N)=C(O)/C)=CC=C1C(=O)C1=CC=C(F)C=C1 MCQBBMWGWZVCPF-WJDWOHSUSA-N 0.000 claims 1
- YBLSBWHFPXDRHC-UHFFFAOYSA-N 3-methyl-1,2-oxazole-4-carboxylic acid Chemical compound CC1=NOC=C1C(O)=O YBLSBWHFPXDRHC-UHFFFAOYSA-N 0.000 claims 1
- VKXYORVLYJXLSK-UHFFFAOYSA-N 5-methyl-n-(4-methylsulfonylphenyl)-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)S(C)(=O)=O)=C1C VKXYORVLYJXLSK-UHFFFAOYSA-N 0.000 claims 1
- 150000003139 primary aliphatic amines Chemical class 0.000 claims 1
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- 230000035755 proliferation Effects 0.000 description 10
- RFXIFHIHWYTKIG-UHFFFAOYSA-N 5-ethyl-1,2-oxazole-4-carbonyl chloride Chemical compound CCC=1ON=CC=1C(Cl)=O RFXIFHIHWYTKIG-UHFFFAOYSA-N 0.000 description 9
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- 241001465754 Metazoa Species 0.000 description 6
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- RBKHNGHPZZZJCI-UHFFFAOYSA-N (4-aminophenyl)-phenylmethanone Chemical compound C1=CC(N)=CC=C1C(=O)C1=CC=CC=C1 RBKHNGHPZZZJCI-UHFFFAOYSA-N 0.000 description 4
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 4
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- UBNPYFRCAXBBPC-UHFFFAOYSA-N n-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(Cl)=CC=2)=C1C(F)(F)F UBNPYFRCAXBBPC-UHFFFAOYSA-N 0.000 description 1
- LAXQCXCWUSHHBG-UHFFFAOYSA-N n-(4-cyanophenyl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C#N)=C1C LAXQCXCWUSHHBG-UHFFFAOYSA-N 0.000 description 1
- RJWBPHKBPNRKGX-UHFFFAOYSA-N n-(4-fluorophenyl)-1,2-oxazole-4-carboxamide Chemical compound C1=CC(F)=CC=C1NC(=O)C1=CON=C1 RJWBPHKBPNRKGX-UHFFFAOYSA-N 0.000 description 1
- USIYWETWTBELJU-UHFFFAOYSA-N n-(4-fluorophenyl)-5-(trifluoromethyl)-1,2-oxazole-4-carboxamide Chemical compound C1=CC(F)=CC=C1NC(=O)C1=C(C(F)(F)F)ON=C1 USIYWETWTBELJU-UHFFFAOYSA-N 0.000 description 1
- YEPVJMPNKJNKBR-UHFFFAOYSA-N n-(4-fluorophenyl)-5-phenyl-1,2-oxazole-4-carboxamide Chemical compound C1=CC(F)=CC=C1NC(=O)C1=C(C=2C=CC=CC=2)ON=C1 YEPVJMPNKJNKBR-UHFFFAOYSA-N 0.000 description 1
- UINQKGBHZHDNAC-UHFFFAOYSA-N n-(4-hydroxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(O)=CC=2)=C1C UINQKGBHZHDNAC-UHFFFAOYSA-N 0.000 description 1
- YPWARVICKUQNMF-UHFFFAOYSA-N n-(5-bromopyridin-2-yl)-5-ethyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2N=CC(Br)=CC=2)=C1CC YPWARVICKUQNMF-UHFFFAOYSA-N 0.000 description 1
- ZINWLWNICFZQQO-UHFFFAOYSA-N n-(5-bromopyridin-2-yl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2N=CC(Br)=CC=2)=C1C ZINWLWNICFZQQO-UHFFFAOYSA-N 0.000 description 1
- KVRLDKHFSVWVID-UHFFFAOYSA-N n-(5-chloropyridin-2-yl)-1,2-oxazole-4-carboxamide Chemical compound N1=CC(Cl)=CC=C1NC(=O)C1=CON=C1 KVRLDKHFSVWVID-UHFFFAOYSA-N 0.000 description 1
- QHDXHVAUPGUMRX-UHFFFAOYSA-N n-(5-chloropyridin-2-yl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2N=CC(Cl)=CC=2)=C1C QHDXHVAUPGUMRX-UHFFFAOYSA-N 0.000 description 1
- KBLQZNWSRDESEY-UHFFFAOYSA-N n-(5-chloropyridin-2-yl)-5-phenyl-1,2-oxazole-4-carboxamide Chemical compound N1=CC(Cl)=CC=C1NC(=O)C1=C(C=2C=CC=CC=2)ON=C1 KBLQZNWSRDESEY-UHFFFAOYSA-N 0.000 description 1
- QOUZBIRERWEJLH-UHFFFAOYSA-N n-[4-(4-bromobenzoyl)phenyl]-5-ethyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(=O)C=2C=CC(Br)=CC=2)=C1CC QOUZBIRERWEJLH-UHFFFAOYSA-N 0.000 description 1
- ZTGRYIPJKFSGCO-UHFFFAOYSA-N n-[4-(4-bromobenzoyl)phenyl]-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(=O)C=2C=CC(Br)=CC=2)=C1C ZTGRYIPJKFSGCO-UHFFFAOYSA-N 0.000 description 1
- QFCDZZRSCHGPGS-UHFFFAOYSA-N n-[4-(4-chlorobenzoyl)phenyl]-5-ethyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(=O)C=2C=CC(Cl)=CC=2)=C1CC QFCDZZRSCHGPGS-UHFFFAOYSA-N 0.000 description 1
- SZNYSVWJORFIBB-UHFFFAOYSA-N n-[4-(4-chlorobenzoyl)phenyl]-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(=O)C=2C=CC(Cl)=CC=2)=C1C SZNYSVWJORFIBB-UHFFFAOYSA-N 0.000 description 1
- GVRDVSRITVRHRA-UHFFFAOYSA-N n-[4-(4-fluorobenzoyl)phenyl]-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(=O)C=2C=CC(F)=CC=2)=C1C GVRDVSRITVRHRA-UHFFFAOYSA-N 0.000 description 1
- WPODOZPYBLBFPV-UHFFFAOYSA-N n-[4-(4-methoxybenzoyl)phenyl]-5-methyl-1,2-oxazole-4-carboxamide Chemical compound C1=CC(OC)=CC=C1C(=O)C(C=C1)=CC=C1NC(=O)C1=C(C)ON=C1 WPODOZPYBLBFPV-UHFFFAOYSA-N 0.000 description 1
- LQFLWKPCQITJIH-UHFFFAOYSA-N n-allyl-aniline Chemical compound C=CCNC1=CC=CC=C1 LQFLWKPCQITJIH-UHFFFAOYSA-N 0.000 description 1
- ZARPPEQBQHAQLS-UHFFFAOYSA-N n-benzyl-4-(trifluoromethyl)aniline Chemical compound C1=CC(C(F)(F)F)=CC=C1NCC1=CC=CC=C1 ZARPPEQBQHAQLS-UHFFFAOYSA-N 0.000 description 1
- GRJMDUUPJRRRLU-UHFFFAOYSA-N n-benzyl-5-methyl-n-[4-(trifluoromethyl)phenyl]-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)N(CC=2C=CC=CC=2)C=2C=CC(=CC=2)C(F)(F)F)=C1C GRJMDUUPJRRRLU-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000001885 phytohemagglutinin Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
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- 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
- A61K31/275—Nitriles; Isonitriles
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- 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
- A61K31/42—Oxazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/40—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Air Conditioning Control Device (AREA)
- Photoreceptors In Electrophotography (AREA)
- Indole Compounds (AREA)
- Medicinal Preparation (AREA)
Description
Foreliggende oppfinnelse vedrører fremstillingen av terapeutisk aktive isoksazol-4-karboksylsyreamider og hydroksyalkylidencyaneddiksyreamider.
I litteraturen er det beskrevet en rekke fremgangsmåter for fremstilling av isoksazol-4-karboksylsyreamider (DE 25 24 959; DE 26 55 009; DE 34 05 727).
Fra det europeiske patentskriftet 13 376 er det kjent at 5—metylisoksazol-4-karboksylsyre-(4-trifluormetyl)-anilid på grunn av sine farmakologiske egenskaper kan anvendes som antireumatikum, antiflogistikum, antipyretikum og analgeti-kum, samt finne anvendelse for behandling av multippel sklerose. Det er også beskrevet fremgangsmåter for fremstilling av denne forbindelsen.
Det er nå funnet at isoksazol-4-karboksylsyreamider med formel I og hydroksyalkylidencyaneddiksyreamider med formel Ia oppviser antitumor aktivitet. Mange av de kjente antitumor-midlene fremkaller under behandlingen som bivirkninger kvalme, brekninger eller diaré, som også kan nødvendiggjøre legebehandling i sykehus. Videre forandrer disse legemidlene også veksthastigheten for andre kroppsegne celler som så fører til symptomer som eksempelvis håravfall eller blod-fattighet (anemi). Disse symptomene kunne ikke observeres ved behandling av mennesker og dyr med forbindelsene med formel I. Disse virksomme stoffene har i motsetning til de hittil kjente cytotoksiske antikreft-midlene ikke den egenskap at de påvirker immunsystemet (Bartlett, Int. J. Immunopharmac. , 1986, 8: 199 - 204). Dermed åpnes nye veier innen tumorterapien, fordi det kroppsegne forsvarssystemet ikke påvirkes, mens tumorcellenes vekst hindres. Over-raskende hemmes et stort antall tumorceller ved hjelp av dette virksomme stoffet, mens cellene av immunsystemet, som f.eks. T-lymfocyttene bare hemmes ved en inntil 50 ganger høyere konsentrasjon.
Oppfinnelsen vedrører følgelig fremstillingen av en terapeutisk aktiv forbindelse med formel (I) eller (Ia)
deres eventuelt stereoisomere former og/eller eventuelt minst ett av deres fysiologisk godtagbare salter, hvor
R1 står for
a) hydrogen,
b) alkyl med 1 til 6 C-atomer,
c) alkyl med 1 til 4 C-atomer, enkelt- eller flersubstituert med
1) halogen, som fluor, klor, brom eller jod,
d) fenyl,
R2 står for
a) hydrogen,
b) alkyl med 1 til 4 C-atomer,
c) fenyl-(C1-C2)-alkyl, spesielt benzyl,
d) alkenyl med 2 til 3 C-atomer,
r<3> står for
a) en pyridin—, indol—, indazol—, benzimidazol-, benz-tiazol-, pyrimidin- eller tiazolring,
usubstituert eller enkelt- eller flersubstituert med, 1) halogen, som fluor, klor, brom eller jod,
2) alkyl med 1 til 3 C-atomer,
3) nitro,
4 ) (C-L-C3 )-alkoksykarbonyl-(Ci-C3)-alkylgruppe ,
b) en rest med formel (II),
hvori R<4>, r<5> og R^ kan være like eller forskjellige og
står for
1) hydrogen,
3) alkyl med 1 til 3 C-atomer, enkelt- eller flersubstituert med
3.1 halogen, som fluor, klor, brom eller jod,
4) hvori R<4> står for hydrogen og R<5> og R<6> danner en metylendioksyrest, 5) alkoksy med 1 til 3 C-atomer, enkelt- eller flersubstituert med
5.1 halogen, som fluor, klor, brom eller jod,
6) halogen, som fluor, klor, brom eller jod,
7) nitro,
8) hydroksy,
9) karboksy,
10) (Cj-CsJ-alkylsulfonyl,
11) benzoyl,
12) benzoyl, enkelt- eller flersubstituert med 12.1 halogen, som fluor, klor, brom eller jod, 12.2 (C1-C3)-alkyl,
13) fenoksy,
14) fenoksy, enkelt- eller flersubstituert med
14.1 (C^-Cg)-alkyl, enkelt- eller flersubstituert med halogen, som fluor, klor, brom eller jod,
c) en rest med formel (III)
hvori R<10> står for
1) hydrogen,
2) alkyl med 1 til 4 C-atomer,
n står for et helt tall fra 1 til 12,
d) R<2> og R<3> danner sammen med nitrogenatomet som de er bundet til en piperidinring, eventuelt substituert med
C-L-Cs-alkyl
r''' står for
a) hydrogen,
b) alkyl med 1 til 4 C-atomer,
R<8> står for
a) hydrogen,
b ) metyl,
c) alkenyl med 2 til 3 C-atomer.
Blant disse forbindelsene foretrekkes forbindelsen 5-metylisoksazol-4-karboksylsyre(4-trifluormetyl)anilid (Forbindelse 1) og N-(4-trifluormetyl)-2-cyan-3-hydroksycrotonsyreamid (Forbindelse 2).
Egnede fysiologisk godtagbare salter av forbindelsen med formel I er eksempelvis alkali-, jordalkali- og ammonium-salter innbefattende slike av organiske ammoniumbaser.
Til de en-, to- eller trekjernede, innettede heterocykliske restene med 3 til 13 C-atomer hører eksempelvis tienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl , tiazolyl, tiazolinyl, oksazolyl, tiadiazolyl, benzoksazolyl, benzimidazolyl, kinolyl, pyrazolyl, akridinyl, indolyl, tetrazolyl eller indazolyl.
Forbindelsene med formel I og deres fysiologisk godtagbare salter egner seg spesielt for behandling av et stort antall kreftsykdommer. Til krefttypene som spesielt hemmes ved hjelp av disse forbindelsene hører eksempelvis leukemi, spesielt kronisk leukemi av T- og B-celletypen, lymfekjertel-kreft, f.eks. Hodgkin's eller ikke-Hodgkin's lymphom, karsinomer, sarkomer eller hudkreft. De virksomme stoffene kan enten administreres alene, eksempelvis i form av mikro-kapsler, i blandinger med hverandre eller i kombinasjon med egnede hjelpe- og/eller baerestoffer.
Fremstilling av forbindelsen med formel I eller Ia foregår på kjent måte (DE 2 524 959; DE 2 655 009; DE 3 405 727; DE 2 524 929; DE 2 555 789; DE 2 557 003).
Forbindelsene med formel (I) eller (Ia) fremstilles ifølge oppfinnelsen ved en fremgangsmåte som er kjennetegnet ved at man
a) omsetter en forbindelse med formel (V),
hvori X står for et halogenatom, fortrinnsvis klor eller brom og R<*> har den ved formel I angitte betydning, med aminet med formel (VI)
hvor R<2> og R<3> har betydningen angitt i formel I, eller
b) behandle en forbindelse med formel (VI)
hvor R<1> står for ( C^ C^ )-alkyl og R<4>, R<5> og R6 har
betydningen angitt ved formel I, med en hensiktsmessig ekvimolar mengde hydroksylamin i et organisk oppløsnings-middel, eller
c) omsetter en forbindelse med formel V, hvori X og R<1> har den ovenfor angitte betydningen, med et primært alifatisk
amin med formel (VII)
hvor n og R<10> har betydningen angitt i formel (I), eller
d) omsetter en forbindelse med formel (V), hvori X og R<1> har den ovenfor nevnte betydningen, med et laktam med formel
(VIII),
hvori m er et helt tall fra 1 til 6, eller
e) omsetter forbindelsen med formel I i nærvær av et basisk
middel til den tilsvarende forbindelsen med formel (Ia), og eventuelt omdannes en derved oppnådd forbindelse til et fysiologisk godtagbart salt. Ved fremgangsmåten ifølge oppfinnelsen fremstilles det nye forbindelser med formel (I)
dens eventuelt stereoisomere former og/eller eventuelt dens fysiologisk godtagbare salter, hvor
R<1> står for
a) hydrogen,
b) alkyl med 2 til 6 C-atomer,
c) alkyl med 1 til 4 C-atomer, enkelt- eller flersubstituert med
1) halogen, som fluor, klor, brom eller jod,
d) fenyl,
R<2> står for
a) hydrogen,
b) alkenyl med 2 til 3 C-atomer,
c) benzyl,
R<3> står for
a) pyridyl, enkelt- eller flersubstituert med
1) hydrogen,
2) halogen, som fluor, klor, brom eller jod,
3) nitro,
4) alkyl med 1 til 3 C-atomer, b) en rest med formel (II)
hvori R<4>, R<5>, R<6> kan være like eller forskjellige og
stå for
1) halogen, som fluor, klor, brom eller jod,
2) nitro,
3) hydrogen,
4) benzoyl, enkelt- eller flersubstituert med
4.1 halogen, som fluor, klor, brom eller jod,
4.2 metyl,
5) (C2-C3)-alkoksy, enkelt- eller flersubstituert med 5.1 halogen, som fluor, klor, brom eller jod, 6) (C1-C3)-alkyl, enkelt- eller flersubstituert med 6.1 halogen, som fluor, klor, brom eller jod,
7) hydroksy,
8) alkylsulfonyl, med 1 til 3 C-atomer i alkylkjeden, 9) R<4> står for hydrogen og R<5> og R<6> danner sammen en metylendioksyrest,
10) benzoyl.
Videre fremstilles det ifølge oppfinnelsen nye forbindelser med formel (Ia) deres eventuelt stereolsomere former og/eller eventuelt deres fysiologisk godtagbare salter, hvorved restene R<7>, R<8> og R<3 >under
a) med R<7> står for
1) alkyl med 1 til 4 C-atomer,
2) hydrogen,
med R<8> står for
1) hydrogen,
2) metyl,
3) alkenyl med 2 til 3 C-atomer,
med R<3> står for
1) pyridyl,
2) pyridyl, enkelt- eller flersubstituert med 2.1 halogen, som fluor, klor, brom eller jod, 2.2 alkyl med 1 til 3 C-atomer,
3) pyrimidinyl, substituert som ved 2)
4) tiazolyl, substituert som ved 2) og
4.1 alkoksykarbonyl, med 1 til 3 C-atomer i alkylkjeden,
5) benzotiazolyl, substituert som ved 2),
6) benzimidazolyl, substituert som ved 2),
7) indazolyl, substituert som ved 2),
b) med R<7> står for
1) hydrogen,
2) alkyl med 1 til 4 C-atomer,
med R<8> står for
1) hydrogen,
2 ) metyl,
med R<3> står for
1) en rest med formel (III),
hvor R 10 står for
1.1 hydrogen,
1.2 alkyl med 1 til 4 C-atomer,
c) med R<7> står for
1) hydrogen,
2) alkyl med 1 til 4 C-atomer,
R<®> og R<3> danner sammen med nitrogenet som de er bundet til en piperidinring,
eventuelt substituert med alkyl med 1 til 3 C-atomer.
Forbindelsene med formel (I) og (Ia) og/eller minst ett av deres fysiologisk godtagbare salter kan anvendes for fremstilling av legemidler for forebyggelse og/eller behandling av reumatiske sykdommer.
Disse legemidlene kan bestå av minst en forbindelse med formel (I) og/eller minst ett av dens fysiologisk godtagbare salter eller inneholde minst ett av disse virksomme stoffene ved siden av farmasøytisk egnede og fysiologisk godtagbare bærestoffer, fortynningsmidler og/eller andre hjelpestoffer.
Legemidlene kan anvendes oralt, topisk, rektalt eller eventuelt også parenteralt, hvorved den orale anvendelsen er foretrukket.
Egnede faste eller flytende galeniske preparatformer er eksempelvis granulater, pulvere, drageer, tabletter, (mikro)-kapsler, suppositorier, siruper, safter, suspensjoner, emulsjoner, dråper eller injiserbare oppløsninger samt preparater med forsinket frigivelse av virksomt stoff, ved hvis fremstilling det anvendes vanlige hjelpemidler, som bærestoffer, sprengmidler, bindemidler, overtrekksmidler, svellemidler, glide- eller smøremidler, smaksstoffer, søt-ningsmidler eller oppløsningsformidlere. Som hyppig anvendte hjelpestoffer skal nevnes f.eks. magnesiumkarbonat, titan-dloksyd, laktose, mannit og andre sukkertyper, talkum, melke-eggehvite, gelatin, stivelse, cellulose og dens derivater, animalske og vegetabilske oljer, polyetylenglykoler og oppløsningsmidler, som f.eks. sterilt vann og en- eller flerverdige alkoholer, f.eks. glycerol.
Fortrinnsvis fremstilles og administreres de farmasøytiske preparatene i doseringsenheter, hvorved hver enhet som aktiv bestanddel inneholder en bestemt dose av minst en av forbindelsene med formel I og/eller minst ett av deres fysiologisk godtagbare salter. Ved faste doseringsenheter, tabletter, kapsler, drageer eller suppositorier, kan denne dosen utgjøre inntil 300 mg, men fortrinnsvis 10 til 50 mg.
For behandlingen av en leukemisyk voksen pasient (70 kg) er, avhengig av virksomheten for forbindelsene med formel I og/eller deres fysiologisk godtagbare salter på mennesker, dagsdoser på 5 til 300 mg virksomt stoff indikert, fortrinnsvis 25 til 100 mg ved oral administrering. Under visse omstendigheter kan imidlertid også høyere og lavere dagsdoser være fordelaktig. Administreringen av dagsdosen kan foregå såvel ved enkelt tilførsel i form av en enkelt doseringsenhet eller ved flere mindre doseringsenheter som også flere tilførsler i oppdelte doser med béstemte intervaller.
Endelig kan forbindelsene med formel (I) og/eller minst ett av deres fysiologisk godtagbare salter ved fremstilling av de ovenfor nevnte galeniske preparatformene også administreres sammen med andre egnede virksomme stoffer, eksempelvis andre antitumormidler, immunglobuliner, monoklonale antistoffer, immunstimulerende agenser eller antibiotika. Disse forbindelsene kan også administreres ved siden av en stråle-terapi .
Farmakologiske undersøkelser og resultater.
Som virksomhetstest for kjemoterapeutika ble in vitro proliferasjonstesten for cellekulturer anvendt.
Eksempel 1
Prol iferasjonsforsøk
Clicks-/RPMI 1640 medium (50:50) med L-glutamin uten NaHC03 i pulverform for 10 1 (Seromed, Biochrom, Berlin, FRG), oppløses 19 1 dobbeltdestillert vann og filtreres sterilt i flasker på 900 ml.
Vaskemedium
900 ml grunnmedium bufres med 9.5 ml 7. 5% natriumhydrogen-karbonatoppløsning og 5 ml EEPES (N-2-hydroksy-etyl-pipe-razin-N-2-etanolsulfonsyre) (Gibco, Eggenstein, FRG).
Bruksmedium
900 ml grunnmedium pluss 19 ml NaHCC^-oppløsning (7.556; 10 ml HEPES-oppløsning og 10 ml L-glutamin-oppløsning (200 mM)).
Medium for den mitogeninduserte lymfocyttproliferasjonen. Bruksmedium blandes med 1% varmeinaktivert (30 min., 56°C) føtalt kalveserum (FCS).
Tumorcellemedium
For opprettholdelsen av tumorcellene og hybridomcellene blandes bruksmediet med 5% FCS.
Kulturmedium for cellelinjer
For opprettholdelse av cellelinjer blandes 900 ml bruksmedium med 10% FCS, 10 ml NEA (ikke-essensielle aminosyrer ^oppløs-ning (Gibco), 10 ml natrium-pyruvat-oppløsning (100 mM, Gibco) og 5 ml 10_2M merkaptoetanol.
Utvinning og opparbeidelse av miltceller for den mitogeninduserte lymfocyttproliferasjonen
Musene avlives ved cervikal dislokasjon og miltene tas ut sterilt. På en steril sikt med en maskevidde på 80 mesh findeles miltene og føres med stempel av en plastsprøyte (10 ml) forsiktig inn i en petriskål med bruksmedium. For fjernelse av erytrocyttene fra miltcelle-suspensjonen inku-beres blandingen ca. 1 minutt, under periodisk oppristing i hypotonisk 0.17 M ammoniumkloridoppløsning ved romtemperatur. Erytrocyttene lyseres derved, mens vitaliteten og reaktivi-teten av lymfocyttene ikke påvirkes. Etter sentrifugering (7 min/340 g) kastes lysatet, cellene vaskes to ganger og opptas deretter i det aktuelle forsøksmediet.
Mitogenindusert lymfocyttproliferasjon
5 x 10^ opparbeidede miltceller fra NMRI-hunnmus ble sammen med forskjellige mitogener og preparat pipettert i 200 pl forsøksmedium pr. fordypning i en flatbunnet mikrotiterplate. Følgende mitogen- og preparatkonsentrasjoner ble anvendt:
Concanavalin A [Serva]: 0.5 - 0.25 pg/ml
Lipopolysakkarid [Calbiochem] : 1.0 - 0.5 - 0.1 jjg/ml Fytohemaglutinin [Gibco]: 0.5 - 0.25 - 0.1256 stamoppløsning Pokeweed (kermesbær) mitogen [Gibco] forbindelse 1 eller 2: 50, 25, 10, 7.5, 5, 2.5, 1, 0.5, 0.1 pmol.
Som positive kontroller defineres gruppen av mitogentilsatser uten preparat. Ved negative kontroller dreier det seg om celler i kulturmedium med preparat uten mitogentilsatser. Hver mitogenkonsentrasjon ble testet fire ganger med alle preparat-konsentrasjonene. Etter 48 timers inkubering ved 37°C/556 C02 tilsettes cellene 25 pl/fordypning Tritium-Thymidin (Amersham) med en aktivitet på 0.25 pCi/fordypning (9.25 x IO<3> Bq). Deretter følger en ytterligere inkubering, under de samme betingelsene, i et tidsrom på 16 timer. For bedømmelse av forsøksblandingen høstes cellene ved hjelp av et cellehøste-apparat (Flow Laboratories) på filterpapir, hvorved ikke-innbygget tymidin samles i en atskilt avfalls-flaske. Filterpapiret tørkes, utstanses og anbringes sammen med 2 ml scintillator ("Rotiszint 22", firma Roth) i flasker, som deretter avkjøles i 2 timer ved 4°C. Mengden av den av cellene innbygde radioaktiviteten måles i en Beta-teller (firma Packard, "Tricarb-460c" ).
Opparbeidelse av tumorcellene og cellelinjene for proliferasjonstesten
De i testen anvendte tumorcellene eller cellelinjene tas i den logaritmiske vekstfasen fra stamforrådet, vaskes to ganger med vaskemedium og suspenderes i tilsvarende medium.
Gjennomføring og bedømmelse av proliferasjonstesten
Proliferasjonstesten ble gjennomført i rundbunnede mikro-titer-plater. Forbindelse 1 og interleukiner ble oppløst i hver gang 50 pl/fordypning av det tilsvarende mediet og celletallet (5 x 10<5>) ble innstilt med 100 pl/fordypning, slik at det oppsto et sluttvolum på 200 pl/fordypning. I alle testene ble verdiene bestemt fire ganger. Celler uten preparat og uten vekstfaktor ble definert som negative kontroller og celler uten preparat med vekstfaktor ga verdiene for positivkontrollene. Verdien for negativkontrol-lene ble trukket av fra alle oppnådde verdier og differansen av positivkontroller minus negativkontroller ble satt til 10056.
Platene ble inkubert i 72 timer ved 37° C/556 C02 og prolife-rasjonsraten ble bestemt tilsvarende som ved den mitogeninduserte lymfocyttproliferasjonen.
Cellelinjene ble tatt fra stam-samlingen, American Type Culture Collection (ATCC).
Tabell 1 viser konsentrasjonene hvorved en 5056 hemning opptrådte:
Eksempel 2
Akutt toksisitet ved oral administrering
Forbindelse 1 ble for bestemmelse av den akutte toksisiteten for mus eller rotter administrert oralt.
LD5Q-verdiene ble bestemt ifølge Litchfield og Wilcoxon. Vekten av NMRI-musene (NMRI : Naval Medical Research Institute) utgjør 20 til 25 g og av SD-rottene (SD : Sprague-Dawley) utgjør vekten 120 til 165 g. Før forsøket fastet dyrene i ca. 18 timer. 5 timer etter administrering av stoffene som undersøkes f6res de igjen normalt. Etter tre uker ble dyrene avlivet med kloroform og oppsnittet. Pr. dosering ble det anvendt seks dyr. Resultatene er sammenfattet i Tabell 2.
Eksempel 3
Akutt toksisitet etter intraperitoneal administrering
Den akutte toksisiteten etter intraperitoneal administrering av forsøksstoffene ble gjennomført med NMRI-mus (20 til 25 g) og SD-rotter (120 til 195 g). Forsøksstoffet ble suspendert i en 1% natrium-karboksymetylcellulose-oppløsning. De forskjellige doseringene av forsøksstoffet ble administrert til musene i et volum på 10 ml/kg kroppsvekt og til rottene i et volum på 5 ml/kg kroppsvekt. Pr. dosering ble det anvendt 10 dyr. Etter 3 uker ble den akutte toksisiteten bestemt ved fremgangsmåten ifølge Litchfield og Wilcoxon. Resultatene er sammenfattet i Tabell 3.
Eksempel 4
A Fremstilling av 5-metylisoksazol-4-karboksylsyre-(4-tri-fluormetyl)-anilid
En oppløsning av 0.05 mol 5-metylisoksazol-4-karboksyl-syreklorid (7.3 g) i 20 ml acetonitril tilsettes dråpevis ved romtemperatur til en oppløsning av 0.1 mol 4-trifluormetylanilin (16.1 g) i 150 ml acetonitril. Etter 20 minutters omrøring frasuges det utfelte 4-trifluormetylanilin-hydrokloridet, vaskes to ganger med 20 ml acetonitril og de forenede filtratene inndampes under redusert trykk. Man oppnår på denne måten 12.8 g hvitt, krystal-lint 5-metylisoksazol-4-karboksylsyre (4-trifluormetyl)-anilid (Forbindelse 1).
B Fremstilling av N-(4-trifluormetylfenyl)-2-cyano-3-hydroksycrotonsyreamid
0.1 mol 5-metylisoksazol-4-karboksylsyre-(4-trifluor-metyl )-anilid oppløses i 100 ml metanol og blandes ved -10° C med en oppløsning av 0.11 mol (4.4 g) natronlut i 100 ml vann. Det omrøres i 30 minutter og det surgjøres etter fortynning med vann med konsentrert saltsyre. Den utfelte krystallgrøten frasuges, vaskes med vann og tørkes i luft. Utbyttet utgjør 24.4 g N-(4-trifluormetylfenyl)-2-cyano-3-hydroksycrotonsyreamid (Forbindelse 2). Smeltepunkt fra metanol 205 til 206°C.
Fremsti 11ingseksempler
Strukturen av alle de nedenfor omtalte forbindelsene ble fastslått ved elementæranalyse og IR- samt ^-H-NMR-spektere.
5. N-( 4 - klordi fluormetoksy ) fenyl- 5- etylisoksazol- 4- karboks-amld
0.1 mol (19.4 g) 4-klordifluormetoksyanilin, oppløst i 180 ml acetonitril, blandes ved romtemperatur dråpevis med en oppløsning av 0.05 mol (7.3 g) 5-metylisoksazolyl-4-karboksylsyreklorid i 30 ml acetonitril under omrøring. Det omrøres ytterligere i 20 minutter og væsken filtreres fra det utfelte saltet. Filtratet bringes til tørrhet under redusert trykk. Man oppnår på denne måten 28.5 g (94.256 av teoretisk) krystallinsk produkt.
Smeltepunkt [fra cykloheksan-aceton 20:1 (v/v)]: 112°-113° C.
Analogt det ovenfor omtalte eksemplet fremstilles følgende forbindelse med formel I. 6. N-( 4- fluorfenyl )- isoksazol- 4- karboksamid (av smeltepunkt 162° til 164°C) fra isoksazol-4-karboksylsyreklorid og 4—fluoranilin. 7. N-( 4- klorfenyl)- isoksazol- 4- karboksamid [av smeltepunkt 175° til 177°C (dekomp.)] fra isoksazol-4-karboksylsyre-klorid og 4-kloranilin. 8. N-( 4- bromfenyl)- isoksazol- 4- karboksamid [av smeltepunkt 184" til 186°C (dekomp.)] fra isoksazol-4-karboksylsyre-klorid og 4-bromanilin. 9. N-( 4-. 1odfenvl )- isoksazol- 4- karboksamid (av smeltepunkt 207° til 208°C) fra isoksazol-4-karboksylsyreklorid og 4-jodanilin. 10. N-( 4- nitrofen. vl )- isoksazol- 4- karboksamid [av smeltepunkt 208° til 210°C (dekomp.)] fra isoksazol-4-karboksylsyre-klorid og 4-nitroanilin. 11. N-( 3, 4- metylendioksyfenyl )- isoksazol- 4- karboksamid [av smeltepunkt 168° til 169°C) fra isoksazol-4-karboksyl-syreklorid og 3,4-metylendioksyanilin. 12. N-( 4- benzoylfenyl)- isoksazol- 4- karboksamid [av smeltepunkt 197° til 199°C (dekomp.)] fra isoksazol-4-karbok-sylsyreklorid og 4-aminobenzofenon. 13. N-( 4- fluorfenyl )- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 75° til 77° C) fra 5-etylisoksazol-4-karbok-sylsyreklorid og 4-fluoranilin. 14. N-( 4- klorfenyl)- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 103° til 105°C) fra 5-etylisoksazol-4-karboksyl-syreklorid og 4-kloranilin. 15. N-( 4- bromfenyl)- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 117° til 118°C) fra etylisoksazol-4-karboksylsyre-klorid og 4-bromanilin. 16. N-( 4- nitrofenyl )- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 139° til 141°C) fra etylisoksazol-4-karbok-sylsyreklorid og 4-nitroanilin. 17. N-( 3 , 4- metylendioksyfenyl)- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 105° til 106°C) fra 5-etylisoksazol-4-karboksylsyreklorid og 3,4-metylendioksyanilin. 18 . N- ( 4- tr i fluormetoksyfenyl)- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 52° til 54°C) fra 5-etylisoksazol-4-karboksamid og 4-trifluormetoksyanilin. 19. N-( 4- benzoylfenyl)- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 168° til 170°C) fra 5-etylisoksazol-4-karbok-sylsyreklorid og 4-aminobenzofenon. 20. N- f4-( 4- fluorbenzoyl) fenyli- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 153° til 155°C) fra 5-etylisoksazol-4-karboksylsyreklorid og 4-(4-fluorbenzoyl)anilin. 21. N- f4 -( 4- klorbenzoyl) fenyl1- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 159° til 161°C) fra 5-etylisoksazol-4-karboksylsyreklorid og 4-(4-klorbenzoyl)anilin. 22 . N - f4 - ( 4- brombenzoyl) f eny li - 5- etyl isoksazol - 4- karboksamid (av smeltepunkt 178° til 181°C) fra 5-etylisoksazol-4-karboksylsyreklorid og 4-(4-brombenzoyl)anilin. 23. N-( 4- benzoylfenyl)- 5- propylisoksazol- 4- karboksamid (av smeltepunkt 134° til 135°C) fra 5-propylisoksazol-4-karboksylsyreklorid og 4-aminobenzofenon. 24. N-( 4- klorfenyl)- 5- butylisoksazol- 4- karboksamid (av smeltepunkt 91° til 92°C) fra 5-butylisoksazol-4-karbok-sylsyreklorid og 4-kloranilin. 25. N-( 4- benzoylfenyl)- 5- butylisoksazol- 4- karboksamid (av smeltepunkt 108° til 110°C) fra 5-butylisoksazol-4-karboksylsyreklorid og 4-aminobenzofenon. 26 . N - ( 4- fluor f enyl )- 5- tr i f luormetyl isoksazol- 4- karboksamid (av smeltepunkt 97°C) fra 5-trifluormetylisoksazol-4-karboksylsyreklorid og 4-fluoranilin. 27 . N-( 4- klorfenyl ) - 5 - tr i f luormetyl i s ok sazol - 4- karboksamid (av smeltepunkt 90° til 92°C) fra 5-trifluormetylisoksazol-4-karboksylsyreklorid og 4-kloranilin. 28. N - ( 4- ni tr of enyl )- 5- trifluormetylisoksazol- 4- karboksamid (av smeltepunkt 136° til 138°C) fra 5-trifluormetylisoksazol-4-karboksylsyreklorid og 4-nitroanilin. 29 . N- ( 3 . 4 - me tylendloksyf enyl ) - 5 - tr i f luormetyl isoksazol- 4-karboksamid (av smeltepunkt 114° til 116°C) fra 5-trifluormetylisoksazol-4-karboksylsyreklorid og 3,4-metylendioksyanilin. 30 . N- ( 4- trif luormetylfenyl )- 5- klormetylisoksazol- 4- karboksamid (av smeltepunkt 136° til 137°C) fra 5-klormetylisoksazol-4-karboksylsyreklorid og 4-trifluormetylanilin. 31. N- ( 4- trif luormetylf enyl ) - 5- f enyl isoksazol- 4- karboksamid (av smeltepunkt 159° til 160°C) fra 5-fenylisoksazol-4-karboksylsyreklorid og 4-trifluormetylanilin. 32. N-( 4- fluorfenyl)- 5- fenylisoksazol- 4- karboksamid (av smeltepunkt 151° til 153°C) fra 5-fenylisoksazol-4-karboksylsyreklorid og 4-fluoranilin. 33. N- ( 4- metyl sul f onylf enyl 1 - 5- me tyl isoksazol- 4- karboksamid (av smeltepunkt 170° til 172°C) fra 5-metylisoksazol-4-karboksylsyreklorid og 4-metylsulfonylanilin. 34 . N- benzvl- N-( 4- tri fluormetylfeny1)- 5- metylisoksazol- 4-karboksamid (av smeltepunkt 87° til 89°C) fra 5-metylisoksazol-4-karboksylsyreklorid og N-benzyl-4-trifluormetylanilin. 36. N-( 5- klor- 2- pyridyl)- isoksazol- 4- karboksamid (av smeltepunkt 254° til 255°C) fra isoksazol-4-karboksylsyreklorid og 2-amino-5-klorpyridin. 37. N-( 5- klor- 2- pyridyl)- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 133° til 136°C) fra 5-etylisoksazol-4-karbok-sylsyreklorid og 2-amino-5-klorpyridin. 38. N-( 5- brom- 2- pyridyl)- 5- etylisoksazol- 4- karboksamid (av smeltepunkt 144° til 145°C) fra 5-etylisoksazol-4-karbok-sylsyreklorid og 2-amino-5-brompyridin. 39. N-( 5- nitro- 2- pyridyl)- 5- etylIsoksazol- 4- karboksamid (av smeltepunkt 236° til 237°C) fra 5-etylisoksazol-4-karbok-sylsyreklorid og 2-amino-5-nitropyridin. 40. N-( 5- klor- 2- pyridyl)- 5- fenylisoksazol- 4- karboksamid (av smeltepunkt 160° til 161°C) fra 5-fenylisoksazol-4-karboksylsyreklorid og 2-amino-5-klorpyridin. 41. N-( 5- indolyl)- 5- metyIisoksazol- 4- karboksamid (av smeltepunkt 155° til 157°C) fra 5-metylisoksazol-4-karboksyl-syreklorid og 5-aminoindol. 42. N-( 6- indazolyl)- 5- metyllsoksazol- 4- karboksamid (av smeltepunkt 198° til 202°C) fra 5-metylisoksazol-4-karboksylsyreklorid og 6-aminoindazol. 43. N-( 5- indazolyl)- 5- metvlisoksazol- 4- karboksamid (av smeltepunkt 218° til 220°C) fra 5-metylisoksazol-4-karboksylsyreklorid og 5-aminoindazol. 44. N- allyl- N- fenyl- 5- metylisoksazol- 4- karboksamid (av smeltepunkt 79° til 85°C) fra 5-metylisoksazol-4-karbok-sylsyreklorid og N-allylanilin. 45. N- f3-( 1. 1. 2. 2- tetrafluoretoksy) fenyII- 5- metylisoksazol- 4-karboksamid (av smeltepunkt 97°C) fra 5-metylisoksazol-4-karboksylsyreklorid og 3-(1,1,2,2-tetafluoretoksy)anilin. 46. N-( 4- cyanofenyl)- 5- metylisoksazol- 4- karboksamid (av smeltepunkt 197° til 200°C) fra 5-metylisoksazol-4-karboksylsyreklorid og 4-cyanoanilin. 47. N- ( 4 - metylmerkaptof enyl )- 5- metylisoksazol- 4- karboksamid (av smeltepunkt 134° til 136°C) fra 5-metylisoksazol-4-karboksylsyreklorid og 4-metylmerkaptoani1 in. 48. N-( 4 . 6- dimetyl- 2- pyridyl)- 5- metylisoksazol- 4- karboksamid (av smeltepunkt 210°C) fra 5-metylisoksazol-4-karboksyl-syreklorid og 2-amino-4,6-dimetylpyridin. 49 . N-( 4, 6- dimetyl- 2- pyrazinyl)- 5 - metyl isoksazol - 4- karboksamid (av smeltepunkt 222° til 226°C) fra 5-metylisoksazol-4-karboksylsyreklorid og 2-amino-4,6-dimetylpyrazin. 50. N-( 4- tri fluormetoksyfenyl)- 2- cyano- 3- hydroksycrotonsyreamid
0.1 mol (28.6 g) N-(4-trifluormetoksyfenyl)-5-metylisoksazol-4-karboksamid oppløses i 100 ml etanol og blandes ved 20°C med en oppløsning av 0.11 mol (4.4 g) natronlut i 100 ml vann. Det omrøres i 30 minutter og etter fortynning med vann surgjøres med konsentrert svovelsyre. Den utfelte krystallgrøten frasuges, vaskes med vann og tørkes i luft. Man oppnår på denne måten 27.7 g (97.156 av teoretisk) N-(4-trifluormetoksyfenyl)-2-cyano-3-hydroksycrotonsyreamid av smeltepunkt 171°-176°C (fra etanol).
Analogt ovenstående eksempel fremstilles følgende forbindelser med formel (Ia). 51. 2- cyano- 3- hydroksy- N- r4-( 1. 1. 2, 2- tetrafluoretoksy) fenyll-crotonsyreamid (av smeltepunkt 166° til 164°C) fra N—[4-(1,1,2,2-tetrafluoretoksy)fenyl]-5-metyli soksazol-4-karboksamid. 52. N-( 5- klor- 2- pyridyl )- 2- cyano- 3- hvdroksycrotonsvreamid [av smeltepunkt 213" til 215°C (dekomp.)] fra N-(5-klor-2-pyridyl)-5-metylisoksazol-4-karboksamid. 53. N-( 2- klor- 3- pyridyl)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 128" til 131°C) fra N-(2-klor-3-pyridyl)-5-metylisoksazol-4-karboksamid. 54. N-( 4- benzoylfenyl)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 186° til 188°C) fra N-(4-benzoylfenyl)-5-metyl-isoksazol-4-karboksamid. 55 . N- f 4 - ( 4- klorbenzoyl ) f eny li - 2- cyano- 3- hydroksy- 4- metyl-crotonsvreamid (av smeltepunkt 157° til 159°C) fra N-[4-(4-klorbenzoyl)fenyl]-5-etylisoksazol-4-karboksamid. 56. N- f 4- ( 4- brombenzoyl) fenyll- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 221° til 223°C) fra N-[4-(4-brombenzoyl )fenyl]-5-metylisoksazol-4-karboksamid. 57. N- r4-( 4- metoksybenzoyl) feny11- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 74° til 75°C) fra N-[4-(4-metoksybenzoyl)fenyl]-5-metylisoksazol-4-karboksamid. 58. N- f4-( 4- metylbenzoyl) fenyll- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 177° til 179°C) fra N-[4-(4-metylbenzoyl )fenyl]-5-metylisoksazol-4-karboksamid. 59 . N- ( 5- klor- 2- pyr idyl )- 2- cyano- 3- hydroksy- 4- metylcrotonsyreamid (av smeltepunkt 206° til 208°C) fra N-(5-klor-2-pyridyl)-5-etylisoksazol-4-karboksamid. 60 . N - ( 5 - brom- 2- pyr idyl ) - 2- cyano- 3- hydroksy- 4- metylcrotonsyreamid (av smeltepunkt 200° til 202°C (dekomp.)) fra N-(5-brom-2-pyridyl)-5-etyl isoksazol-4-karboksamid. 61. 2- cyano- 3- hydroksy- 4- metyl- N-( 4- nitrofenyl ) crotonsvreaniid (av smeltepunkt 202° til 203"C (dekomp.)) fra N-(4-nitrofenyl )-5-etylisoksazol-4-karboksamid. 62 . N - ( 3 . 4 - me ty lend i ok sy f enyl ) - 2- c vano- 3- hvdroksy- 4- metylcrotonsyreamid (av smeltepunkt 99" til 100°C) fra N-(3,4-metylendioksyfenyl )-5-etylisoksazol-4-karboksamid. 63. N-( 4- benzoylfenyl )- 2- cyano- 3- hydroksy- 4- propylcrotonsyre-amid fra N-(4-benzoylfenyl)-5-butylisoksazol-4-karboksamid. 64. N-( 5- brom- 2- pyridyl )- 2- cyano- 3- hydroksycrotonsyreamid [av smeltepunkt 220° til 223°C (dekomp.)] fra N-(5-brom-2-pyridyl)-5-metylisoksazol-4-karboksamid. 65. N- f4-( 4- klorbenzoyl) fenyll- 2- cyano- 3- hycroksycrotonsyre-amid [av smeltepunkt 219° til 223°C (dekomp.)] fra N-[4-(4-klorbenzoyl)fenyl]-5-metylisoksazol-4-karboksamid. 66. N- f4-( 4- fluorbenzoyl ) fenyll- 2- cvano- 3- hydroksycrotonsyreamid (av smeltepunkt 229° til 231°C (dekomp.)] fra N-[4-(4-fluorbenzoyl)fenyl]-5-metylisoksazol-4-karboksamid. 67 . N- f 4 - ( 4- f luorbenzoyl ) f enyll - 2- cyano- 4- metyl- 3- hydroksycrotonsyreamid (av smeltepunkt 147° til 148°C) fra N-[4-(4-fluorbenzoyl)fenyl]-5-etylisoksazol-4-karboksamid. 68. N- f 4 - ( 4- brombenzoyl ) f enyll - 2- cyano- 3- hydroksy- 4- metylcrotonsyreamid (av smeltepunkt 153° til 155°C) fra N-[4-(4-brombenzoyl)fenyl]-5-etylisoksazol-4-karboksamid. 69 . N- ( 4- tr if luormetoksy ) f enyl - 2- cvano- 3- hydr oksy- 4 - metyl - crotonsyreamid (av smeltepunkt 166° til 167°C) fra N-(4-trifluormetoksy)feny1-5-etyl isoksazol-4-karboksamid. 70 . N-( 4- fluorfenyl )- 2- cyano- 3- hydroksy- 4- metylcrotonsyreamid (av smeltepunkt 145°C) fra N-(4-fluorfenyl)-5-etylisoksazol -4 -karboksami d . 71. N-( 3 , 4- metylendioksvf enyl )- 2- cyano- 3- hydroksy- 4- metylcrotonsyreamid (av smeltepunkt 99" til 100°C) fra N-(3,4-metylendioksyfenyl)-5-etyl isoksazol-4-karboksamid. 72. N-( 4- metylsulfonyl) fenyl- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 196° til 198°C) fra N-(4-metylsulfonyl)-feny1-5-metylisoksazol-4-karboksamid. 73. N- allyl- N- fenyl- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 57° til 50°C) fra N-allyl-N-fenyl-5-metylisoksazol-4-karboksamid. 74. N-( 4- etoksykarbonylmetyl- 2- tiazolyl)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 147°C) fra N-(4-etoksykarbonylmetyl-2-tiazolyl)-5-metylisoksazol-4-karboksamid. 75. N-( 2- benzimidazolyl)- 2- cyano- 3- hydroksycrotonsyreamid (av dekomponeringspunkt >300°C) fra N-(2-benzimidazolyl)-5-metylisoksazol-4-karboksamid. 76 . N- ( 4- metyl - 2- t iazolyl )- 2- cyano- 3- hydroksycrotonsyreamid [av smeltepunkt 210° til 212°C (dekomp.)] fra N-(4-metyl-2-tiazolyl)-5-metylisoksazol-4-karboksamid. 77 . N- ( 4- klor- 2- benzotiazolyl )- 2- c, vano- 3- hvdroksycrotonsyreamid [av smeltepunkt 211° til 213°C (dekomp.)] fra N-(4-klor-2-benzotiazolyl)-5-metyl isoksazol-4-karboksamid. 78. N-( 3- pyridyl)- 2- cyano- 3- hydroksycrotonsyreamid [av smeltepunkt 240° til 250°C (dekomp.)] fra N-(3-pyridyl)-5-metylisoksazol-4-karboksamid. 79 . N-( 4 . 5- dimetyl- 2- pyridyl )- 2- cyano- 3- hvdroksycrotonsyreamid (av smeltepunkt 184" til 186°C) fra N-(4,6-dimetyl-2-pyridyl)-5-metyl isoksazol-4-karboksamid. 80. N-( 4 . 6- dimetyl- 2- pyrimidy1)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 221°C) fra N-(4,6-dimetyl-2-pyrimi-dyl)-5-metyl isoksazol-4-karboksamid. 81. N-( 6- indazolyl)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt >300°C) fra N-(6-indazolyl)-5-metylisoksazol-4-karboksamid. 82. N-( 5- indazolyl)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 220" til 223°C) fra N-(5-indazolyl)-5-metylisoksazol-4-karboksamid. 83. N-( 4- karboksy- 3- hydroksyfenyl)- 2- cyano- 3- hydroksycroton-svreamid (av smeltepunkt 242°C til 246°C (dekomp.)) fra N-(4-karboksy-3-hydroksyfenyl)-5-metylisoksazol-4-karboksamid. 84. N- ( 3- karboksy- 4- hydroksyfenvl)- 2- cyano- 3- hydroksycrotonsyreamid [av smeltepunkt 248° til 252°C (dekomp.)] fra N—(3-karboksy-4-hydroksyfenyl)-5-metylisoksazol-4-karboksamid. 85. N-( 4- karboksy- 3- klorfenyI)- 2- cyano- 3- hydroksycrotonsyreamid [av smeltepunkt 218° til 224°C (dekomp.)] fra N-(4-karboksy-3-klorfenyl)-5-metyl isoksazol-4-karboksamid. 86. N-( 4- hydroksyfenyl- 2- cyano- 3- hydroksvcrotonsyreamid [av smeltepunkt 184° til 186°C (dekomp.)] fra N-(4-hydroksyfenyl)-5-metylisoksazol-4-karboksamid. 87. N- f4-( 4- trifluormetylfenoksy) fenyll- 2- cyano- 3- hydroksy- 4-metylcrotonsyreamid (av smeltepunkt 147° til 149°C) fra
N - [4 - ( 4-trif luormetylf enoksy )f enyl ] - 5-etyl i soksazol - 4-karboksamid. 88. N- r 4 - ( 4 - tr if luormetylf enoksy ) f enyll - 2- cyano- 3- hydroksy-crotons<y>reamld (av smeltepunkt 171° til 173°C) fra N-[4-( 4-trifluormetylfenoksy)fenyl]-5-metylisoksazol-4-karboksamid. 89. N- metyl- N-( 4- trifluormetylfenyl)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 69° til 70°C) fra N-metyl-N-(4-trifluormetylfenyl)-5-metylisoksazol-4-karboksamid. 90. 2- hydroksyetyIidencyaneddiksyrepiperidid
fra N-(5-metyl-4-isoksazolylkarbonyl )piperidin. 91. 2- h<y>droksyetylidencyaneddiksyre- 4- metylpiperidid fra N-(5-metyl-4-isoksazolyl-karbonyl)-4-hydroksypiperi-din. 92. N-( 4- karboksybutyl)- 2- cyano- 3- hvdroksycrotonsyreamid (av smeltepunkt 92°C) fra N-(5-metyl-4-isoksazolylkarbonyl)-5-aminovaleriansyre. 93 . N- ( 4- etoksykarbonylbutyl )- 2- cyano- 3- hydroksycrotonsyreamid fra N-(4-etoksykarbonylbutyl)-5-metylisoksazol-4-karboksamid. 94. N-( 6- karboksyheksyl)- 2- cyano- 3- hydroksycrotonsyreamid (av smeltepunkt 93° til 94°C) fra N-(5-metyl-4-isoksa-zolylkarbonyl)-7-aminoheptansyre.
Claims (10)
1.
Analogifremgangsmåte for fremstilling av en terapeutisk aktiv forbindelse med formel (I) eller (Ia)
deres eventuelt stereoisomere former og/eller eventuelt minst ett av deres fysiologisk godtagbare salter, hvor
R<1> står for a) hydrogen, b) alkyl med 1 til 6 C-atomer, c) alkyl med 1 til 4 C-atomer, enkelt- eller flersubstituert med 1) halogen, som fluor, klor, brom eller jod, d) fenyl,
R2 står for a) hydrogen, b) alkyl med 1 til 4 C-atomer, c) fenyl-(C1-C2)-alkyl, spesielt benzyl, d) alkenyl med 2 til 3 C-atomer,
R<3> står for a) en pyridin—, indol-, indazol—, benzimidazol—, benz-tiazol-, pyrimidin- eller tiazolring,
usubstituert eller enkelt- eller flersubstituert med, 1) halogen, som fluor, klor, brom eller jod, 2) alkyl med 1 til 3 C-atomer, 3) nitro, 4) (Ci-Cs)-alkoksykarbonyl-(C1-C3)-alkylgruppe, b) en rest med formel (II),
hvori R<4>, R<5> og R<6> kan være like eller forskjellige og står for 1) hydrogen, 3) alkyl med 1 til 3 C-atomer, enkelt- eller flersubstituert med 3.1 halogen, som fluor, klor, brom eller jod, 4) hvori R<4> står for hydrogen og R<5> og R<6> danner en metylendioksyrest, 5) alkoksy med 1 til 3 C-atomer, enkelt- eller flersubstituert med 5.1 halogen, som fluor, klor, brom eller jod, 6) halogen, som fluor, klor, brom eller jod, 7) nitro, 8) hydroksy, 9) karboksy, 10) ( C1- C3)-alkylsulfonyl, 11) benzoyl, 12) benzoyl, enkelt- eller flersubstituert med 12.1 halogen, som fluor, klor, brom eller jod, 12.2 (C1-C3 )-alkyl, 13) fenoksy, 14) fenoksy, enkelt- eller flersubstituert med 14.1 (C1-C3 )-alkyl, enkelt- eller flersubstituert med halogen, som fluor, klor, brom eller jod, c) en rest med formel (III)
hvori R<10> står for 1) hydrogen, 2) alkyl med 1 til 4 C-atomer,
n står for et helt tall fra 1 til 12, d) R<2> og R<3> danner sammen med nitrogenatomet som de er bundet til en piperidinring, eventuelt substituert med Ci-Cs-alkyl
R<7> står for a) hydrogen, b) alkyl med 1 til 4 C-atomer,
R<8> står for a) hydrogen, b) metyl, c) alkenyl med 2 til 3 C-atomer,
karakterisert ved at den omfatter at man a) omsetter en forbindelse med formel (V),
hvori X står for et halogenatom, fortrinnsvis klor eller
brom og R<*> har den ved formel I angitte betydning, med aminet med formel (VI)
hvor R<2> og R<3> har betydningen angitt i formel (I), eller b) behandle en forbindelse med formel (VI)
hvor R<1> står for (C1-C4 )-alkyl og R4, R5 og R<6> har betydningen angitt ved formel I, med en hensiktsmessig ekvimolar mengde hydroksylamin i et organisk oppløsnings-middel, eller c) omsetter en forbindelse med formel (V), hvori X og R<1> har den ovenfor angitte betydningen, med et primært alifatisk amin med formel (VII)
hvor n og R<10> har betydningen angitt i formel (I), eller d) omsetter en forbindelse med formel V, hvori X og R<1> har den ovenfor nevnte betydningen, med et laktam med formel (VIII),
hvori m er et helt tall fra 1 til 6, eller e) omsetter forbindelsen med formel (I) i nærvær av et basisk
middel til den tilsvarende forbindelsen med formel (Ia),
og eventuelt omdanner en derved oppnådd forbindelse til et fysiologisk godtagbart salt.
2.
Analogifremgangsmåte ifølge krav 1, for fremstilling av en forbindelse med formel (I) eller (Ia), hvor
R<1> står for a) hydrogen, b) alkyl med 1 til 6 C-atomer, c) alkyl med 1 til 4 C-atomer, enkelt- eller flersubstituert med 1) halogen, som fluor, klor, brom eller jod, d) fenyl,
R<2> står for a) hydrogen, b) alkyl med 1 til 4 C-atomer, c) fenyl-(C^-C2)-alkyl, spesielt benzyl, d) alkenyl med 2 til 3 C-atomer,
R<3> står for a) pyridyl enkelt- eller flersubstituert med, 1) hydrogen, 2) halogen, som fluor, klor, brom eller jod, 3) nitro, 4) alkyl med 1 til 3 C-atomer, b) en rest med formel (II),
hvori R<4>, R<5>, R^ kan være like eller forskjellige og stå for 1) hydrogen, 3) alkyl med 1 til 3 C-atomer, enkelt- eller f lersubstituert med 3.1 halogen, som fluor, klor, brom eller jod, 4) hvori R<4> står for hydrogen og R<5> og R<6> danner en metylendioksyrest, 5) alkoksy med 1 til 3 C-atomer, enkelt- eller f lersubstituert med 5.1 halogen, som fluor, klor, brom eller jod, 6) halogen, som fluor, klor, brom eller jod, 7) nitro, 8) (C1-C3)-alkylsulfonyl, 9) benzoyl, 10) benzoyl, enkelt- eller flersubstituert med 10.1 halogen, som fluor, klor, brom eller jod, 10.2 (C1-C3)-alkyl, 11) fenoksy, 12) fenoksy, enkelt- eller flersubstituert med 12.1 (Cx-Cs )-alkyl, enkelt- eller flersubstituert med halogen, som fluor, klor, brom eller jod, c) en rest med formel (III),
hvori R<10> står for 1) hydrogen, 2) alkyl med 1 til 4 C-atomer,
n for et helt tall fra 1 til 12, d) R<2>Cg r<3> danner sammen med nitrogenatomet som de er
bundet til, en piperidinring,
R<7> står for a) hydrogen, b) alkyl med 1 til 4 C-atomer,
R<8> står for a) hydrogen, b) metyl, c) alkenyl med 2 til 3 C-atomer,
karakterisert ved at tilsvarende utgangs-materialer anvendes.
3.
Analogifremgangsmåte ifølge krav 1, for fremstilling av forbindelser, hvor
R<1> står for alkyl med 1 til 6 C-atomer,
R<2> står for hydrogen,
R<3> står for a) pyridyl, enkelt- eller flersubstituert med halogen, som fluor, klor, brom eller jod, b) en rest med formel (II)
hvori R<4>, R<5> og R" kan være like eller forskjellige og stå for 1) hydrogen, 3) alkyl med 1 til 3 C-atomer, enkelt- eller f lersubstituert med 3.1 halogen, som fluor, klor, brom eller jod, 4) hvori R<4> står for hydrogen og R<5> og R^ danner en metylendioksyrest, 5) alkoksy med 1 til 3 C-atomer, enkelt- eller flersubstituert med 5.1 halogen, som fluor, klor, brom eller jod, 6) halogen, som fluor, klor, brom eller jod, 7) nitro, 8) benzoyl, 9) benzoyl, enkelt- eller flersubstituert med 9.1 halogen, som fluor, klor, brom eller jod,9.2 (C-L-CsJ-alkyl , 10) fenoksy, 11) fenoksy, enkelt- eller flersubstituert med 11.1 (C1-C3)-alkyl, enkelt- eller flersubstituert med halogen, som fluor, klor, brom eller jod,
R<7> står for alkyl med 1 til 4 C-atomer,
R» står for hydrogen,
karakterisert ved at tilsvarende utgangs-materiale anvendes.
4 .
Analogifremgangsmåte ifølge krav 1, for fremstilling av metylisoksazol-4-karboksylsyre-(4-trifluormetyl)-anilid eller N-(4-trifluormetylfenyl)-2-cyano-3-hydroksy-crotonsyreamid, karakterisert ved at tilsvarende utgangs-materialer anvendes.
5.
Analogifremgangsmåte ifølge krav 1, for fremstilling av forbindelser med formel (I), hvor
R<1> står for a) hydrogen, b) alkyl med 2 til 6 C-atomer, c) alkyl med 1 til 4 C-atomer, enkelt- eller flersubstituert med 1) halogen, som fluor, klor, brom eller jod, d) fenyl,
R2 står for a) hydrogen, b) alkenyl med 2 til 3 C-atomer,
c ) benzyl,
R<3> står for a) pyridyl, enkelt- eller flersubstituert med 1) hydrogen, 2) halogen, som fluor, klor, brom eller jod, 3) nitro, 4) alkyl med 1 til 3 C-atomer,
hvori R4, R5, R<6> kan være like eller forskjellige og stå for 1) halogen, som fluor, klor, brom eller jod, 2) nitro, 3) hydrogen, 4) benzoyl, enkelt- eller flersubstituert med 4.1 halogen, som fluor, klor, brom eller jod, 4.2 metyl, 5) (C^-C3 )-alkoksy, enkelt- eller flersubstituert med 5.1 halogen, som fluor, klor, brom eller jod, 6) (C1-C3)-alkyl, enkelt- eller flersubstituert med 6.1 halogen, som fluor, klor, brom eller jod, 7) hydroksy, 8) alkylsulfonyl, med 1 til 3 C-atomer i alkylkjeden,9) R<4> står for hydrogen og R<5> og R^ danner sammen en metylendioksyrest, 10 ) benzoyl ,
karakterisert ved at tilsvarende utgangs-materialer anvendes.
6.
Analogifremgangsmåte ifølge krav 1, for fremstilling av en forbindelse med formel (I), hvor
R<1> står for a) hydrogen, b) alkyl med 2 til 6 C-atomer, c) alkyl med 1 til 4 C-atomer, enkelt- eller flersubstituert med 1) halogen, som fluor, klor, brom eller jod, d) fenyl,
R<2> står for a) hydrogen, b) alkenyl med 2 til 3 C-atomer, c) benzyl,
R<3> står for a) pyridyl, enkelt- eller flersubstituert med 1) hydrogen, 2) halogen, som fluor, klor, brom eller jod, 3) nitro, 4) alkyl med 1 til 3 C-atomer, b) en rest med formel (II),
hvori R<4>, R<5>, R^ kan være like eller forskjellige og stå for 1) halogen, som fluor, klor, brom eller jod, 2) nitro, 3 ) hydrogen, 4) benzoyl, enkelt- eller flersubstituert med 4.1 halogen, som fluor, klor, brom eller jod, 4.2 metyl, 5) ( C^- Cq )-alkoksy, enkelt- eller flersubstituert med 5.1 halogen, som fluor, klor, brom eller jod, 6) (C-L-C3 )-alkyl , enkelt- eller f lersubstituert med 6.1 halogen, som fluor, klor, brom eller jod, 7 ) hydroksy, 8) alkylsulfonyl, med 1 til 3 C-atomer i alkylkjeden, 9) hvori R<4> står for hydrogen og R<5> og R<6> sammen danner en metylendioksyrest, 10 ) benzoyl,
karakterisert ved at tilsvarende utgangs-materialer anvendes.
7.
Analogifremgangsmåte ifølge krav 1, for fremstilling av forbindelser med formel (I), hvor
R<1> står for alkyl med 2 til 6 C-atomer,
R<2> står for hydrogen,
R<3> står for a) pyridyl, enkelt- eller flersubstituert med, 1) hydrogen, 2) halogen, som fluor, klor, brom eller jod, b) en rest med formel (II),
hvori R<4>, R<5>, R^ kan være like eller forskjellige og står for 1) halogen, som fluor, klor, brom eller jod, 2) nitro, 3 ) benzoyl, 4) benzoyl, enkelt- eller flersubstituert med 4.1 halogen som fluor, klor, brom eller jod, 4.2 metyl, 5) (C1-C3)-alkoksy, enkelt- eller flersubstituert med 5.1 halogen, som fluor, klor, brom eller jod, 7) (C1-C3 )-alkyl, enkelt- eller flersubstituert med 7.1 halogen, som fluor, klor, brom eller jod, 8) hydrogen, 9) hvori R<4> står for hydrogen og R<5> og R^ sammen
danner en metylendioksyrest,
karakterisert ved at tilsvarende utgangs-materialer anvendes.
8.
Analogifremgangsmåte ifølge krav 1, for fremstilling av forbindesler med formel (Ia), hvor a) med R<7> står for 1) alkyl med 1 til 4 C-atomer, 2) hydrogen,
med R<8> står for 1) hydrogen, 2) metyl, 3) alkenyl med 2 til 3 C-atomer,
med R<3> står for 1) pyridyl, 2) pyridyl, enkelt- eller f lersubstituert med 2.1 halogen, som fluor, klor, brom eller jod, 2.2 alkyl med 1 til 3 C-atomer, 3) pyrimidinyl, substituert som ved 2) 4) tiazolyl, substituert som ved 2) og 4.1 alkoksykarbonyl , med 1 til 3 C-atomer i alkylkjeden, 5) benzotiazolyl, substituert som ved 2), 6) benzimidazolyl, substituert som ved 2), 7) indazolyl, substituert som ved 2), b) med R<7> står for
1) hydrogen,
2) alkyl med 1 til 4 C-atomer,
med R<8> står for
1) hydrogen,
2) metyl,
med R<3> står for
1) en rest med formel (III),
hvor R<10> står for 1.1 hydrogen, 1.2 alkyl med 1 til 4 C-atomer, c) med R<7> står for
1) hydrogen,
2) alkyl med 1 til 4 C-atomer,
R<8> og R<3> danner sammen med nitrogenet som de er bundet til en piperidinring,
eventuelt substituert med alkyl med 1 til 3 C-atomer,
karakterisert ved at tilsvarende utgangs-materialer anvendes.
9.
Analogifremgangsmåte ifølge krav 1, for fremstilling av forbindelser med formel (Ia), hvor
restene R<7>, R<8> og R3
med R<7> står for alkyl med 1 til 4 C-atomer,
med R<8> for hydrogen,
med R<3> for 1) pyridyl, 2) pyridyl, enkelt- eller flersubstituert med 2.1 halogen, som fluor, klor, brom eller jod, 2.2 alkyl med 1 til 3 C-atomer,
og de øvrige substituentene har den i krav 8 angitte betydningen,
karakterisert ved at tilsvarende utgangs-materialer anvendes.
10.
Analogifremgangsmåte ifølge krav 1, for fremstilling av forbindelser valgt fra gruppen N-(4-klordifluormetoksy)-fenyl-5-etylisoksazol-4-karboksamid, N-(4-metylsulfonylfenyl)-5-metylisoksazol-4-karboksamid, N-(5-indolyl)-5-metylisoksazol-4-karboksamid, N-(6-indazolyl)-5-metyl-isoksazol-4-karboksamid, N-(5-indazolyl)-5-metylisoksazol-4-karboksamid, N-allyl-N-fenyl-5-metyl-isoksazol-4-karboksamid, N-allyl-N-fenyl-5-metyl-isoksazol-4-karboksamid, N-(4,6-dimetyl-2-pyridyl)-5-metylisoksazol-4-karboksamid, N-( 4 ,6-dimetyl-2-pyrimidinyl )-5-metyl i soksazol-4-karboksamid, N-(4-trifluormetoksyfenyl)-2-cyano-3-hydroksy-crotonsyreamid, N-[4 - (1 ,1 ,2 ,2-tetrafluoretoksy )-f enyl] -2-cyano-3-hydroksycrotonsyreamid, N-[4-(4-fluorbenzoyl)-fenyl]-2-cyano-3-hydroksycrotonsyreamid eller N-(3,4-metylendioksyfenyl)-2-cyano-3-hydroksy-4-metyl-crotonsyreamid, karakterisert ved at tilsvarende utgangs-materialer anvendes.
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DE4016178 | 1990-05-18 | ||
DE4017020 | 1990-05-26 | ||
DE4017043 | 1990-05-26 | ||
PCT/EP1990/001800 WO1991017748A1 (de) | 1990-05-18 | 1990-10-24 | Isoxazol-4-carbonsäureamide und hydroxyalkyliden-cyanessigsäureamide, diese verbindungen enthaltende arzneimittel und deren verwendung |
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EP3600270B1 (en) | 2017-03-31 | 2023-06-14 | Aurigene Oncology Limited | Compounds and compositions for treating hematological disorders |
US20180369206A1 (en) | 2017-04-24 | 2018-12-27 | Aurigene Discovery Technologies Limited | Methods of Use for Trisubstituted Benzotriazole Derivatives as Dihydroorotate Oxygenase Inhibitors |
LT3615027T (lt) | 2017-04-24 | 2021-10-25 | Aurigene Discovery Technologies Limited | Tripakeistųjų benzotriazolo darinių kaip dihidroorotato oksigenazės inhibitorių naudojimo būdai |
CN117064897A (zh) | 2017-10-31 | 2023-11-17 | 库里斯公司 | 用于治疗血液病的化合物和组合物 |
TR202022336A2 (tr) | 2020-12-30 | 2022-07-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A film coated tablet comprising teriflunomide |
EP4162933A1 (en) | 2021-10-08 | 2023-04-12 | Algiax Pharmaceuticals GmbH | Compound for treating non-alcoholic fatty liver disease and related diseases |
EP4382097A1 (en) | 2022-11-25 | 2024-06-12 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A tablet comprising teriflunomide |
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DE2524959C2 (de) * | 1975-06-05 | 1983-02-10 | Hoechst Ag, 6000 Frankfurt | 5-Methyl-isoxazol-4-carbonsäureanilide, Verfahren zu ihrer Herstellung, diese Verbindungen enthaltende Mittel |
NL186239B (nl) * | 1975-06-05 | Hoechst Ag | Werkwijze voor de bereiding van een geneesmiddel met antiflogistische en/of analgetische werking, alsmede werkwijze voor de bereiding van een 2-hydroxyethylideencyaanazijnzuuranilide geschikt voor toepassing bij deze werkwijze. | |
NL178596C (nl) * | 1975-06-05 | 1986-04-16 | Hoechst Ag | Werkwijze voor het bereiden van een geneesmiddel met antiflogistische en/of analgetische werking, alsmede werkwijze voor het bereiden van daarin als geneeskrachtige verbindingen te gebruiken 5-methylisoxazool-4-carbonzuuraniliden. |
DE2557003A1 (de) * | 1975-12-18 | 1977-06-23 | Hoechst Ag | Neue cyanessigsaeureanilid-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende mittel |
DE2555789A1 (de) * | 1975-12-11 | 1977-07-07 | Hoechst Ag | Neue cyanessigsaeureanilid-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende mittel |
DE2655009A1 (de) * | 1976-12-04 | 1978-06-15 | Hoechst Ag | Isoxazolderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende mittel |
DE2854439A1 (de) * | 1978-12-16 | 1980-07-03 | Hoechst Ag | Ein isoxazolderivat, verfahren zu seiner herstellung, diese verbindung enthaltende mittel und verwendung |
DE3405727A1 (de) * | 1984-02-17 | 1985-08-22 | Hoechst Ag, 6230 Frankfurt | Isoxazol-derivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
DE3534440A1 (de) * | 1985-09-27 | 1987-04-02 | Hoechst Ag | Arzneimittel gegen chronische graft-versus-host-krankheiten sowie gegen autoimmunerkrankungen, insbesondere systemischen lupus erythematodes |
GB8619433D0 (en) * | 1986-08-08 | 1986-09-17 | Lilly Industries Ltd | Pharmaceutical compounds |
GB8619432D0 (en) * | 1986-08-08 | 1986-09-17 | Lilly Industries Ltd | Pharmaceutical compounds |
US4816467A (en) * | 1987-01-09 | 1989-03-28 | Farmitalia Carlo Erba S.R.L | Heteroaryl 3-oxo-propanenitrile derivatives, pharmaceutical compositions and use |
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