SE433352B - PROCEDURE FOR PREPARING SULPHONYL BENZIMIDAZOLES - Google Patents
PROCEDURE FOR PREPARING SULPHONYL BENZIMIDAZOLESInfo
- Publication number
- SE433352B SE433352B SE8008090A SE8008090A SE433352B SE 433352 B SE433352 B SE 433352B SE 8008090 A SE8008090 A SE 8008090A SE 8008090 A SE8008090 A SE 8008090A SE 433352 B SE433352 B SE 433352B
- Authority
- SE
- Sweden
- Prior art keywords
- amino
- benzimidazole
- dimethylaminosulfonyl
- isopropylsulfonyl
- toluenesulfonic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 25
- -1 SULPHONYL BENZIMIDAZOLES Chemical class 0.000 title claims description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 38
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 33
- IYUBCLHILARKQB-UHFFFAOYSA-N 2-sulfonylbenzimidazole Chemical class C1=CC=CC2=NC(=S(=O)=O)N=C21 IYUBCLHILARKQB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- BKYIGNVGWWWOOW-UHFFFAOYSA-N 2-amino-6-(1-hydroxy-1-phenylethyl)-n,n-dimethylbenzimidazole-1-sulfonamide Chemical compound C1=C2N(S(=O)(=O)N(C)C)C(N)=NC2=CC=C1C(C)(O)C1=CC=CC=C1 BKYIGNVGWWWOOW-UHFFFAOYSA-N 0.000 claims 1
- KPPANSOANILCFA-UHFFFAOYSA-N 2-amino-n,n-dimethyl-6-(1-phenylprop-1-enyl)benzimidazole-1-sulfonamide Chemical compound C=1C=C2N=C(N)N(S(=O)(=O)N(C)C)C2=CC=1C(=CC)C1=CC=CC=C1 KPPANSOANILCFA-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 241000700605 Viruses Species 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- KHPXETCHASHFOZ-UHFFFAOYSA-N 2-amino-6-benzoyl-n,n-dimethylbenzimidazole-1-sulfonamide Chemical compound C1=C2N(S(=O)(=O)N(C)C)C(N)=NC2=CC=C1C(=O)C1=CC=CC=C1 KHPXETCHASHFOZ-UHFFFAOYSA-N 0.000 description 4
- 241001466953 Echovirus Species 0.000 description 4
- 241000709661 Enterovirus Species 0.000 description 4
- 241000991587 Enterovirus C Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000000474 Poliomyelitis Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- SXUXQJLILGMLOR-UHFFFAOYSA-N (2-amino-3-propan-2-ylsulfonylbenzimidazol-5-yl)-phenylmethanone Chemical compound C1=C2N(S(=O)(=O)C(C)C)C(N)=NC2=CC=C1C(=O)C1=CC=CC=C1 SXUXQJLILGMLOR-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 241000709687 Coxsackievirus Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 241000710185 Mengo virus Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000007505 plaque formation Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- MQIRIQBIRNLOCD-UHFFFAOYSA-N 1-(2-amino-3-propan-2-ylsulfonylbenzimidazol-5-yl)-1-phenylethanol Chemical compound CC(C)S(=O)(=O)N1C(N)=NC2=CC=C(C=C12)C(C)(O)C1=CC=CC=C1 MQIRIQBIRNLOCD-UHFFFAOYSA-N 0.000 description 1
- JOHXFPFSFWIUGF-UHFFFAOYSA-N 1-(2-amino-3-propan-2-ylsulfonylbenzimidazol-5-yl)-1-phenylpropan-1-ol Chemical compound C=1C=C2N=C(N)N(S(=O)(=O)C(C)C)C2=CC=1C(O)(CC)C1=CC=CC=C1 JOHXFPFSFWIUGF-UHFFFAOYSA-N 0.000 description 1
- NKEHQRJWSZHEJH-UHFFFAOYSA-N 2-amino-6-(1-hydroxy-1-phenylpentyl)-N,N-dimethylbenzimidazole-1-sulfonamide Chemical compound CN(S(=O)(=O)N1C(=NC2=C1C=C(C=C2)C(C2=CC=CC=C2)(CCCC)O)N)C NKEHQRJWSZHEJH-UHFFFAOYSA-N 0.000 description 1
- HJOOHTAHIKWRGA-UHFFFAOYSA-N 2-amino-6-(1-hydroxy-2-methyl-1-phenylpropyl)-n,n-dimethylbenzimidazole-1-sulfonamide Chemical compound C=1C=C2N=C(N)N(S(=O)(=O)N(C)C)C2=CC=1C(O)(C(C)C)C1=CC=CC=C1 HJOOHTAHIKWRGA-UHFFFAOYSA-N 0.000 description 1
- ABWWJYZXFAULBK-UHFFFAOYSA-N 2-amino-6-(hydrazinecarbonyl)-n,n-dimethylbenzimidazole-1-sulfonamide Chemical compound C1=C(C(=O)NN)C=C2N(S(=O)(=O)N(C)C)C(N)=NC2=C1 ABWWJYZXFAULBK-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- GALFGPQPBLETEY-UHFFFAOYSA-N 6-(2-methyl-1-phenylprop-1-enyl)-1-propan-2-ylsulfonylbenzimidazol-2-amine Chemical compound C1=C2N(S(=O)(=O)C(C)C)C(N)=NC2=CC=C1C(=C(C)C)C1=CC=CC=C1 GALFGPQPBLETEY-UHFFFAOYSA-N 0.000 description 1
- OISQAJSGZSFUBQ-UHFFFAOYSA-N C1(CCCCC1)S(=O)(=O)N1C(=NC2=C1C=C(C=C2)C(C2=CC=CC=C2)(CC)O)N Chemical compound C1(CCCCC1)S(=O)(=O)N1C(=NC2=C1C=C(C=C2)C(C2=CC=CC=C2)(CC)O)N OISQAJSGZSFUBQ-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- LIMFPAAAIVQRRD-BCGVJQADSA-N N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine Chemical compound F[C@H]1CN(CC[C@H]1OC)C1=NC=CC(=N1)NC=1N=CC2=C(C=CC(=C2C=1)C(C)C)N1[C@@H]([C@H](C1)CS(=O)(=O)C)C LIMFPAAAIVQRRD-BCGVJQADSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 231100001228 moderately toxic Toxicity 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
Description
-8ÛG8U9Û-6 2 där R5 betecknar fenyl och R7 betecknar C1-C7-alkyliden, var- vid gruppen R2 är belägen i 5-ställning eller 6-ställning, och detta förfarande kännetecknas av att en tautomer bensimid- azol med den allmänna formeln: ï n N i RS -c \>- NHZ N l SO2R (II) där R och R5 har ovan angivna betydelser, omsättes med en C1-C7-alkylmagnesiumhalid eller med en C1-C7-alkyllitiumför- ening, varefter den resulterande föreningen hydrolyseras till en förening med formeln: OH N R '"_å ñš>*“' NH2 Ås I (III) SOgR där R och R5 har de ovan angivna betydelserna och Ra beteck- nar C1-C1-alkyl, varefter föreningen med formeln III dehydra- tiseras. Wherein R 5 is phenyl and R 7 is C 1 -C 7 alkylidene, wherein the group R 2 is in the 5-position or 6-position, and this process is characterized in that a tautomeric benzimidazole of the general formula: where N and R 5 have the meanings given above, are reacted with a C1-C7-alkylmagnesium halide or with a C1-C7-alkyllithium compound, after which the resulting compound is hydrolyzed to a compound of the formula: OH NR '"_å ñš> *“' NH2 Ås I (III) SOgR where R and R5 have the meanings given above and Ra represents C1-C1-alkyl, after which the compound of formula III dehydrates tiseras.
En föredragen grupp av de nya föreningarna är de É föreningar med formeln I, där R betecknar C1-Cu-alkyl eller -NRSRR, där R3 och Ra oberoende av varandra betecknar C1-C3- -alkyl.A preferred group of the novel compounds are those compounds of formula I, wherein R represents C 1 -C 6 alkyl or -NRSR R, where R 3 and R a independently represent C 1 -C 3 alkyl.
Med termen "tautomer bensimidazol" avses ett bens- imidazolreagens, som kan vara substituerat med en väteatom vid endera kväveatomen. Det bensimidazolreagens, som är osubsti- f tuerat på kvävet och har en substituentgrupp i 5-ställningen f av bensenkärnan, har en motsvarande tautomer form, där substi- f, tuenten befinner sig i 6-ställningen. Isomerblandningen kan an- ges genom att de alternativa ställningarna numreras "5(6)". 3 8008090-6 I föreliggande beskrivning har de olika symbolde- finitionerna följande betydelser.The term "tautomeric benzimidazole" refers to a benzimidazole reagent which may be substituted with a hydrogen atom at either nitrogen atom. The benzimidazole reagent, which is unsubstituted on the nitrogen and has a substituent group in the 5-position f of the benzene nucleus, has a corresponding tautomeric form, where the substituent is in the 6-position. The isomer mixture can be indicated by numbering the alternative positions "5 (6)". 3 8008090-6 In the present description, the various symbol definitions have the following meanings.
Med termen “Cl-C4-alkyl" avses raka och förgrena- de alifatiska grupper innehållande 1-4 kolatomer, såsom metyl, etyl, propyl, isopropyl, butyl, isobutyl, sek-butyl och tert- butyl. Termen "C1-Cr-alkyl" inkluderar i sin definition ter- men "C1-C3-alkyl". Med termen "Cl-C,-alkyl“ avses raka och förgrenade alifatiska grupper innehållande 1-7 kolatomer, så- som metyl, etyl, propyl, isopropyl, butyl, isobutyl, sek-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, 2,4-di- metyl-3-pentyl, t-butyl och neopentyl.The term "C 1 -C 4 alkyl" refers to straight and branched chain aliphatic groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. alkyl "includes in its definition the term" C 1 -C 3 alkyl ". The term" C 1 -C 3 alkyl "means straight and branched chain aliphatic groups containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, 2,4-dimethyl-3-pentyl, t-butyl and neopentyl.
Med termen "C5-C7-cykloalkyl" avses mättade ali- cykliska grupper innehållande 5-7 kolatomer, såsom cyklopentyl, cyklohexyl, 1-, 2-, 3- eller 4-metylcyklohexyl och cykloheptyl.The term "C 5 -C 7 cycloalkyl" means saturated alicyclic groups containing 5-7 carbon atoms, such as cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyl and cycloheptyl.
Med termen "Cl-C7-alkyliden“ avses raka och för- grenade grupper innehållande 1-7 kolatomer, såsom metylen, ety~ liden, propyliden, isopropyliden, butyliden, isobutyliden, 3- -metyl-2-butyliden, 2,4-dimetyl-3-pentyliden och n-hexyliden.By the term "C 1 -C 7 alkylidene" is meant straight and branched chain groups containing 1 to 7 carbon atoms, such as methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene, 2,4- dimethyl-3-pentylidene and n-hexylidene.
Lämpliga dehydratiseringsmedel vid förfarandet en- ligt uppfinningen är starka syror, såsom p-toluensulfonsyra, svavelsyra, trifluorättiksyra, metansulfonsyra och trifluor- metansulfonsyra. Såsom C1-C,-alkylmagnesiumhalid använder man ett lämpligt Grignard-reagens. Efter omsättningen med detta reagens hydrolyseras den erhållna föreningen. Ett C1-C7-alkyl- litiumreagens ger en produkt liknande den som erhålles med Grignard-reagenset. De föredragna lösningsmedlen för genomfö- rande av alkyleringssteget utgöres av inerta organiska lösnings- medel, såsom tetrahydrofuran, aromatiska lösningsmedel, såsom bensen eller toluen, och etrar, såsom dietyleter. De föredrag- na lösningsmedlen för dehydratiseringssteget utgöres av aroma- ter, såsom bensen eller toluen, alkaner, såsom hexan, och ha- logenerade kolväten, såsom metylenklorid och kloroform. Det vanligen använda temperaturområdet är mellan ca 25OC och lös- ningsmedlets återflödestemperatur.Suitable dehydrating agents in the process according to the invention are strong acids, such as p-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid. As the C1-C4-alkylmagnesium halide, a suitable Grignard reagent is used. After the reaction with this reagent, the resulting compound is hydrolyzed. A C1-C7 alkyl lithium reagent gives a product similar to that obtained with the Grignard reagent. The preferred solvents for carrying out the alkylation step are inert organic solvents, such as tetrahydrofuran, aromatic solvents, such as benzene or toluene, and ethers, such as diethyl ether. The preferred solvents for the dehydration step are aromatics such as benzene or toluene, alkanes such as hexane, and halogenated hydrocarbons such as methylene chloride and chloroform. The commonly used temperature range is between about 25 ° C and the reflux temperature of the solvent.
Utgångsföreningarna med formeln TI framställes på det sätt som beskrives i den svenska utläggningsskriften 415 477.The starting compounds of the formula TI are prepared in the manner described in Swedish Offenlegungsschrift 415 477.
Den framställda slutprodukten är en 1-sulfonylbens- imidazolförening. Produkten kan isoleras genom att reaktions- blandningen filtreras, varefter filtratet koncentreras för att pro- dukten skall kristallisera. Alternativt kan reaktionsblandningen aooaneu-6, 4 indunstas till torrhet, varefter återstoden behandlas med ett lämpligt lösningsmedel, såsom aceton eller metanol, för av- skiljande och avlägsnande av eventuellt olösligt material.The final product prepared is a 1-sulfonylbenzimidazole compound. The product can be isolated by filtering the reaction mixture, after which the filtrate is concentrated to crystallize the product. Alternatively, the reaction mixture aooaneu-6, 4 can be evaporated to dryness, after which the residue is treated with a suitable solvent, such as acetone or methanol, to separate and remove any insoluble material.
Lösningen innehållande sulfonylbensimidazolen koncentreras för kristallisering av produkten, eller den indunstas till bildning av en andra återstod, vilken löses i t.ex. metanol.The solution containing the sulfonylbenzimidazole is concentrated to crystallize the product, or it is evaporated to give a second residue, which is dissolved in e.g. methanol.
Sulfonylbensimidazolföreningen utvinnes därpå ur metanollös- ningen genom kristallisation. 5(6)-isomererna kan separeras från varandra genom fraktionerad kristallisation eller genom kolonnkromatografi. 6-isomeren kristalliserar vanligen först ur en lösning av iso- merblandningen.The sulfonylbenzimidazole compound is then recovered from the methanol solution by crystallization. The (6) isomers can be separated from each other by fractional crystallization or by column chromatography. The 6-isomer usually crystallizes first from a solution of the isomer mixture.
Uppfinningen illustreras genom följande exempel.The invention is illustrated by the following examples.
Med termen “m/e", som användes för att karaktärisera de fram- ställda produkterna, avses förhållandet massa/laddning hos joner, vilka uppträder i produkternas mass-spektra. Dessa vär- den motsvarar vanligen huvudtopparnas molekylvikter.The term "m / e", which is used to characterize the products produced, refers to the mass / charge ratio of ions which appear in the mass spectra of the products. These values usually correspond to the molecular weights of the major peaks.
Exempel 1 (a) Till en lösning av 600 ml tetrahydrofuran och 21,7 ml (60 mmol) metylmagnesiumbromid i dietyleter sattes droppvis under kvävgasatmosfär och under en tid av 1 timme en lösning av 4,1 g (12 mmol) 1-dimetylaminosulfonyl-2-amino-6- -bensoylbensimidazol i 180 ml tetrahydrofuran. Reaktionsbland- ningen kokades under återflöde i 5 timmar, varefter den häll- des i is och 1 N saltsyra, extraherades 2 gånger med dietyl- eter, tvättades med en mättad natriumkloridlösning, torkades och filtreraaes. Man erhöll härvid 2,9 g ífdimetylaminosulfo- nyl-2-amino-6-(u-hydroxi-a-metylbensyl)bensimidazol såsom ett amorft fast ämne. m/e 360. K_: Analys för C17H2°NqO3S (molekylvikt 360):'_ Beräknat: C 56,67 H 5,59 N 15,54 Funnet: C 56,77 H 5,46 N 15,27 (b) Två g (5,5 mmol) 1-dimetylaminosulfonyl-2- -amino-6-(m-hydroxi-a-metylbensyl)bensimidazol i 130 ml kloro- form omsattes med 1,3 g p-toluensulfonsyra. Reaktionsblandning- en kokades under återflöde och under omrörning i 6 timmar. Reak- tionsblandningen tvättades därpå med mättad natriumkarbonatlös- ning, torkades och filtrerades. Man erhöll 1,7 g 1-dimetylamí- nosulfonyl-2-amino-6-(a-metylenbensyßbensimidazol med en smält- punkt av 201 - 2o2°c. 5 8008090-6 Analys för C17H18NtO2S (molekylvikt 342): Beräknat: C 59,63 H 5,30 N 16,36 Funnet: C 59,67 H 5,35 N 16,07 Exempel 2 (a) Man arbetade på samma sätt som i exempel 1 (a) men använde 100 ml tetrahydrofuran, 22,2 ml (60 mmol) etylmag- nesiumbromid i dietyleter (2,7 mmol per ml) och 4,1 g 1~dime- tylaminosulfonyl-2-amino-6-bensoylbensimidazol. Man erhöll här- vid 3,2 g 1-dimetylaminosulfonyl-2~amino-6-(u-etyl-u-hydroxi- bensyl)bensimidazol i form av ett skum.Example 1 (a) To a solution of 600 ml of tetrahydrofuran and 21.7 ml (60 mmol) of methylmagnesium bromide in diethyl ether was added dropwise under a nitrogen atmosphere and over a period of 1 hour a solution of 4.1 g (12 mmol) of 1-dimethylaminosulfonyl- 2-amino-6-benzoylbenzimidazole in 180 ml of tetrahydrofuran. The reaction mixture was refluxed for 5 hours, then poured into ice and 1 N hydrochloric acid, extracted twice with diethyl ether, washed with saturated sodium chloride solution, dried and filtered. There was obtained 2.9 g of dimethylaminosulfonyl-2-amino-6- (u-hydroxy-α-methylbenzyl) benzimidazole as an amorphous solid. m / e 360. K_: Analysis for C 17 H 21 N 2 O 3 S (molecular weight 360): Calculated: C 56.67 H 5.59 N 15.54 Found: C 56.77 H 5.46 N 15.27 (b) Two g (5.5 mmol) of 1-dimethylaminosulfonyl-2-amino-6- (m-hydroxy-α-methylbenzyl) benzimidazole in 130 ml of chloroform were reacted with 1.3 g of p-toluenesulfonic acid. The reaction mixture was refluxed and stirred for 6 hours. The reaction mixture was then washed with saturated sodium carbonate solution, dried and filtered. 1.7 g of 1-dimethylaminosulfonyl-2-amino-6- (α-methylenebenzylbenzimidazole with a melting point of 201 DEG-202 DEG C. were obtained. Analysis for C17 H18 N2 O2 S (molecular weight 342): Calculated: C59 , 63 H 5.30 N 16.36 Found: C 59.67 H 5.35 N 16.07 Example 2 (a) The procedure was the same as in Example 1 (a) but using 100 ml of tetrahydrofuran, 22.2 ml (60 mmol) of ethylmagnesium bromide in diethyl ether (2.7 mmol per ml) and 4.1 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole to give 3.2 g of 1-dimethylaminosulfonyl- 2-amino-6- (u-ethyl-u-hydroxybenzyl) benzimidazole in the form of a foam.
Högupplösnings-masspektrum för C1flH,yN"O;S: Beräknat: 374,14123 Funnet: 374,141 (b) Man arbetade på samma sätt som i exempel 1 (b) men utgick från 1,2 g (3,21 mmol) 1-dimetylaminosulfonyl-2- -amino-6-(u-etyl-a-hydroxibensyl)bensimidazol, 750 mg p-toluen- sulfonsyra och 100 ml kloroform. Man erhöll härvid 388 mg 1-di- metylaminosulfonyl-2-amino-6-(a-etylidenbensyl)bensimídazol, som smälte vid 200 - 202OC under sönderdelning.High Resolution Mass Spectrum for C1 fl H, yN "O; S: Calculated: 374.14123 Found: 374.141 (b) The procedure was as in Example 1 (b) but starting from 1.2 g (3.21 mmol) 1- dimethylaminosulfonyl-2-amino-6- (u-ethyl-α-hydroxybenzyl) benzimidazole, 750 mg of p-toluenesulfonic acid and 100 ml of chloroform to give 388 mg of 1-dimethylaminosulfonyl-2-amino-6- ( α-ethylidenebenzyl) benzimidazole, melting at 200 DEG-202 DEG C. with decomposition.
Högupplösnings-masspektrum för C1BH2qN4O2S: Beräknat: 356,13107 Funnet: 356,131 Exemgel 3 (a) Man arbetade på samma sätt som i exempel 1 (a) men utgick från 4,1 g (12 mmol) 1-dimetylaminosulfonyl-2-amino- -6-bensoylbensimidazol i 180 ml tetrahydrofuran och 28,6 ml (60 mmol) isopropylmagnesiumklorid i 100 ml tetrahydrofuran.High Resolution Mass Spectrum for C1BH2qN4O2S: Calculated: 356.13107 Found: 356.131 Example Gel 3 (a) The procedure was as in Example 1 (a) but starting from 4.1 g (12 mmol) of 1-dimethylaminosulfonyl-2-amino- -6-benzoylbenzimidazole in 180 ml of tetrahydrofuran and 28.6 ml (60 mmol) of isopropylmagnesium chloride in 100 ml of tetrahydrofuran.
Man erhöll härvid 4,0 g (utbyte 65%) 1-dimetylaminosulfonyl- -2-amino-6~(u-isopropyl~u-hydroxibensyl)bensimidazol såsom ett gult skum. m/e 388.4.0 g (yield 65%) of 1-dimethylaminosulfonyl-2-amino-6- (u-isopropyl-u-hydroxybenzyl) benzimidazole were obtained as a yellow foam. m / e 388.
Analys för C19H¿qN~O3S: Beräknat: C 58,74 H 6,23 N 14,12 Funnet: C 59,00 H 6,20 N 14,52 (b) Man arbetade på samma sätt som i exempel 1 (b) men utgick från 1,2 g (3,2 mmol) 1-dimetylaminosulfonyl-2-ami- no-6-(a-isopropyl-a-hydroxibensyl)bensimidazol, 750 mg p-toluen- sulfonsyra och 100 ml kloroform. Man erhöll härvid 82 mg 1-di~ metylaminosulfonyl-2-amino-6-(u-isopropylidenbensyl)bensimidazol såsom ett beigefärgat fast ämne. 8008090-6 Analys för C1gH22NqO2S: Beräknat: C 61,60 H 5,99 N 15,12 Funnet: C 61,38 H 5,81 N 14,85 Exempel 4 (a) Till en lösning av 150 ml tetrahydrofuran och 31 ml (84 mmol) metylmagnesiumbromid i dietyleter sattes dropp- vis under kvävgasatmosfär en lösning av 5,0 g (15 mmol) 1-iso- propylsulfonyl-2-amino-6-bensoylbensimidazol i 200 ml tetrahyd- rofuran. Reaktionsblandníngen omrördes vid 250C under en timme, varefter den kokades under återflöde i två timmar. Reaktions- blandningen kyldes därefter, hälldes i en blandning av is och 1 N saltsyra och extraherades med dietyleter. 1500 ml lösning koncentrerades till 800 ml, torkades och koncentrerades under vakuum. Den bildade produkten omkristalliserades i en bland- ning av dietyleter och hexan, varvid man löste produkten i di- etyleter, tillsatte en blandning av dietyleter och hexan och kokade lösningen till dess att den blev grumlig. Lösningen kyldes sedan till 2500, varpå den hölls i ett kylskåp vid 10oC.Analysis for C 19 H 20 N 3 O 3 S: Calculated: C 58.74 H 6.23 N 14.12 Found: C 59.00 H 6.20 N 14.52 (b) The procedure was as in Example 1 (b ) but was based on 1.2 g (3.2 mmol) of 1-dimethylaminosulfonyl-2-amino-6- (α-isopropyl-α-hydroxybenzyl) benzimidazole, 750 mg of p-toluenesulfonic acid and 100 ml of chloroform. This gave 82 mg of 1-dimethylaminosulfonyl-2-amino-6- (u-isopropylidenebenzyl) benzimidazole as a beige solid. 8008090-6 Analysis for C 18 H 22 N 2 O 2 S: Calculated: C 61.60 H 5.99 N 15.12 Found: C 61.38 H 5.81 N 14.85 Example 4 (a) To a solution of 150 ml of tetrahydrofuran and 31 ml (84 mmol) of methylmagnesium bromide in diethyl ether was added dropwise under a nitrogen atmosphere a solution of 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 200 ml of tetrahydrofuran. The reaction mixture was stirred at 25 DEG C. for one hour, after which it was refluxed for two hours. The reaction mixture was then cooled, poured into a mixture of ice and 1 N hydrochloric acid and extracted with diethyl ether. 1500 ml of solution was concentrated to 800 ml, dried and concentrated in vacuo. The resulting product was recrystallized from a mixture of diethyl ether and hexane, dissolving the product in diethyl ether, adding a mixture of diethyl ether and hexane and boiling the solution until cloudy. The solution was then cooled to 2500, after which it was kept in a refrigerator at 10oC.
Genom filtrering utvanns 2 g produkt. Ytterligare 2 g produkt utvanns genom att det erhållna filtratet koncentrerades under vakuum. Produkten utgjordes av 1-isopropylsulfonyl-2-amino-6- -(a-hydroxi-a-metylbensyl)bensimidazol. m/e 360, 344 bas.By filtration, 2 g of product were recovered. An additional 2 g of product was recovered by concentrating the resulting filtrate in vacuo. The product was 1-isopropylsulfonyl-2-amino-6- - (α-hydroxy-α-methylbenzyl) benzimidazole. m / e 360, 344 bas.
Analys för C1QH21N3O3S (molekylvikt 359): Beräknat: C 60,15 H 5,89 N 11,69 Funnet: (sats ett) C 60,37 H 5,73 N 11,46 (sats två) C 61,30 H 6,26 N 10,69 _ (b) Två g (5,6 mmol) 1-isopropylsulfonyl-2-amino- -6-(u-hydroxi-d-metylbensyl)bensimidazol i 100 ml kloroform omsattes med 1,3 g p-toluensulfonsyra. Reaktionsblandningen kokades under återflöde och under omrörning i fyra timmar. Reak- tionslösningen kyldes därpå till 25°C, tvättades två gånger med mättad kaliumkarbonatlösning och två gånger med vatten, torkades över natriumsulfat och koncentrerades under vakuum.Analysis for C 10 H 21 N 3 O 3 S (molecular weight 359): Calculated: C 60.15 H 5.89 N 11.69 Found: (batch one) C 60.37 H 5.73 N 11.46 (batch two) C 61.30 H 6 26 N 10.69 (b) Two g (5.6 mmol) of 1-isopropylsulfonyl-2-amino-6- (u-hydroxy-d-methylbenzyl) benzimidazole in 100 ml of chloroform were reacted with 1.3 g of p -toluenesulfonic acid. The reaction mixture was refluxed and stirred for four hours. The reaction solution was then cooled to 25 ° C, washed twice with saturated potassium carbonate solution and twice with water, dried over sodium sulfate and concentrated in vacuo.
Den erhållna återstoden omkristalliserades i en blandning av dietyleter och hexan. Man erhöll härvid 1,1 g 1-isopropylsul- fonyl-2-amino-6-(u-metylmüænsylbensimidazol i form av svagt orangefärgade kristaller med en smältpunkt av 147 - 148°C. m/e 341. v 80008090-6 Analys för C18H1gN3O2S (molekylvikt 341): Beräknat: C 63,32 H 5,61 N 12,31 Funnet: C 63,58 H 5,53 N 12,15 Exempel 5 (a) Man arbetade på samma sätt som i exempel 4 (a) men utgick från 150 ml tetrahydrofuran, 31 ml dietyleterlösning av n- -butylmagnesiumbromid (84 mmol) och 5,0 g (15 mmol) 1-isopropylsul~ fonyl-2-aminc-6-bensoylbensimidazol, och man kokade reaktionsbland- ningen under återflöde i 20 timmar. Man erhöll 5,0 g 1-isopropyl- sulfony1-2-amino-6-(d-hydroxi-d-n-butylbensyl)bensimidazol i form av ett gulbrunt skum. m/e 401.The resulting residue was recrystallized from a mixture of diethyl ether and hexane. 1.1 g of 1-isopropylsulfonyl-2-amino-6- (u-methylmuenesylbenzimidazole were obtained in the form of pale orange crystals with a melting point of 147 DEG-148 DEG C., m / e 341). C18 H18 N3 O2 S (molecular weight 341): Calculated: C 63.32 H 5.61 N 12.31 Found: C 63.58 H 5.53 N 12.15 Example 5 (a) The procedure was as in Example 4 (a ) but was based on 150 ml of tetrahydrofuran, 31 ml of diethyl ether solution of n-butylmagnesium bromide (84 mmol) and 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amine-6-benzoylbenzimidazole, and the reaction mixture was boiled under reflux for 20 hours to give 5.0 g of 1-isopropylsulfonyl-2-amino-6- (d-hydroxy-dn-butylbenzyl) benzimidazole as a tan foam, m / e 401.
Analys för C21H27N3O3S (molekylvikt 401): Beräknat: C 62,80 H 6,78 N 10,47 Funnet: C 63,14 H 6,57 N 10,17 (b) Man arbetade på samma sätt som i exempel 4 (b) men utgick från 1 g (2,5 mmol) 1-isopropylsulfonyl-2-amino-6-(d-hydroxi- -u-n-butylbensyl)bensimidazol, 75 ml kloroform och 600 mg p-toluen- sulfonsyra, och man kokade reaktionsblandningen under återflöde i90 minuter. Man erhöll härvid 790 mg 1-isopropylsulfonyl-2~amino-6-(u- -n-butylidenbensyl)bensimidazol. m/e 383(modertopp),276(-SO2CH(CH@k).Analysis for C 21 H 27 N 3 O 3 S (molecular weight 401): Calculated: C 62.80 H 6.78 N 10.47 Found: C 63.14 H 6.57 N 10.17 (b) The procedure was as in Example 4 (b ) but was based on 1 g (2.5 mmol) of 1-isopropylsulfonyl-2-amino-6- (d-hydroxy-one-butylbenzyl) benzimidazole, 75 ml of chloroform and 600 mg of p-toluenesulfonic acid, and the reaction mixture was boiled. under reflux for 90 minutes. 790 mg of 1-isopropylsulfonyl-2-amino-6- (u- -n-butylidenebenzyl) benzimidazole were obtained. m / e 383 (parent peak), 276 (-SO 2 CH (CH @ k).
UV (CHaOH): A212 (2 35,166); A279 (c 17,200).UV (CH 2 OH): A 212 (2 35.166); A279 (c 17,200).
Analys för C21H25N30¿S (molekylvikt 383): Beräknat: C 65,77 H 6,57 N 10,96 Funnet: C 65,49 H 6,31 N 10,78 Exempel 6 (a) Man arbetade på samma sätt som i exempel 4(a) men utgick från 31 ml av en lösning av etylmagnesiumbromid i dietyleter, (2,7 mmol per ml), 5 g (15 mmol) 1-isopropylsulfo- nyl-2-amino-6-bensoylbensimidazol och 150 ml tetrahydrofuran.Analysis for C 21 H 25 N 3 O 5 S (molecular weight 383): Calculated: C 65.77 H 6.57 N 10.96 Found: C 65.49 H 6.31 N 10.78 Example 6 (a) The procedure was as in Example 4 (a) but starting from 31 ml of a solution of ethylmagnesium bromide in diethyl ether, (2.7 mmol per ml), 5 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole and 150 ml of tetrahydrofuran .
Man erhöll därvid 4,6 g 1-isopropylsulfonyl-2-amino-6-(u-hyd- roxi-d-etylbensyl)bensimidazol i form av ett beigefärgat skum. m/e 373, 343. UV (CH3OH): Ä213 (e 33,528); A256 (e 14,000). (b) Man arbetade på samma sätt som i exempel 4 (b) men utgick från 890 mg (2,4 mmol) 1-isopropylsulfonyl-2-amino- -6-(a-hydroxi-a-etylbensyl)bensimidazol, 50 ml kloroform och 600 mg p-toluensulfonsyra. Man erhöll härvid 630 mg 1-isopro- pylsulfonyl-2-amino-6-(d-etylidenbensyl)bensimidazol).4.6 g of 1-isopropylsulfonyl-2-amino-6- (u-hydroxy-d-ethylbenzyl) benzimidazole were obtained in the form of a beige foam. m / e 373, 343. UV (CH 3 OH): δ 213 (e 33.528); A256 (e 14,000). (b) The procedure was as in Example 4 (b) but starting from 890 mg (2.4 mmol) of 1-isopropylsulfonyl-2-amino- -6- (α-hydroxy-α-ethylbenzyl) benzimidazole, 50 ml chloroform and 600 mg of p-toluenesulfonic acid. 630 mg of 1-isopropylsulfonyl-2-amino-6- (d-ethylidenebenzyl) benzimidazole) were obtained.
Analys för C19H21N3O2S (molekylvikt 355): Beräknat: C 64,20 H 5,96 H 11,82 nunnan: c 63,93 H 6,04 N 11,64 m/e 355 (modertopp), 248 (-SO2CH)CHa)2). UV (CH3OH): A212 ~.-V _.__._......__.. _. _ i... _... . _ 8008090-6 (s35,000); A270 (s 17,000).Analysis for C 19 H 21 N 3 O 2 S (molecular weight 355): Calculated: C 64.20 H 5.96 H 11.82 nun: c 63.93 H 6.04 N 11.64 m / e 355 (parent peak), 248 (-SO 2 CH) CH 2 ) 2). UV (CH3OH): A212 ~.-V _.__._......__ .. _. _ i ... _.... _ 8008090-6 (s35,000); A270 (s 17,000).
Exempel 7 (a) Man arbetade på samma sätt som i exempel 1 (a) men utgick från 11,1 ml n-butylmagnesiumbromid i 80 ml tetra- hydrofuran och 2,05 g 1-dimetylaminosulfonyl-2-amino-6-benso- ylbensimidazol i 90 ml tetrahydrofuran. Man erhöll härvid 1,7 g 1-dimetylaminosulfonyl-2-amino-6-(a-hydroxi-a-n-butylbensyl)- bensimidazol i form av ett vitt skum. m/e 402. (b) Man arbetade på samma sätt som i exempel 1 (b) men utgick från 402mg1-dimetylaminosulfonyl-2-amino-6-(d-hyd- roxi-a-n-butylbensyl)bensimidazol i 20 ml kloroform och 234 mg p-toluensulfonsyra i 100 ml kloroform. Man erhöll härvid 302 mg 1-dimetylaminosulfonyl-2-amino-6-(u-n-butylidenbensyl)bens- imidazol. m/e 384.Example 7 (a) The procedure was the same as in Example 1 (a) but starting from 11.1 ml of n-butylmagnesium bromide in 80 ml of tetrahydrofuran and 2.05 g of 1-dimethylaminosulfonyl-2-amino-6-benzo ylbenzimidazole in 90 ml of tetrahydrofuran. 1.7 g of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-α-n-butylbenzyl) benzimidazole were obtained in the form of a white foam. m / e 402. (b) The procedure was as in Example 1 (b) but starting from 402 mg of 1-dimethylaminosulfonyl-2-amino-6- (d-hydroxy-an-butylbenzyl) benzimidazole in 20 ml of chloroform and 234 mg of p-toluenesulfonic acid in 100 ml of chloroform. 302 mg of 1-dimethylaminosulfonyl-2-amino-6- (u-n-butylidenebenzyl) benzimidazole were obtained. m / e 384.
Exempel 8 Man arbetade på samma sätt som i exempel 4 (b) men utgick från 1,0 g 1-isopropylsulfonyl-2-amino-6-(u-hydroxi-a- -isopropylbensyl)bensimidazol, 75 ml kloroform och 600 mg p- -toluensulfonsyra. Man erhöll härvid 850 mg 1-isopropylsulfo- nyl-2-amino-6-(a-isopropylidenbensyl)bensimidazol. m/e 369.Example 8 The procedure was as in Example 4 (b) but starting from 1.0 g of 1-isopropylsulfonyl-2-amino-6- (u-hydroxy-α-isopropylbenzyl) benzimidazole, 75 ml of chloroform and 600 mg of p - -toluenesulfonic acid. 850 mg of 1-isopropylsulfonyl-2-amino-6- (α-isopropylidenebenzyl) benzimidazole were obtained. m / e 369.
UV (CH3OH): A213 (e 34,700); A258 (a 14,800); Å280 (a 4,400).UV (CH 3 OH): A 213 (ε 34,700); A258 (a 14,800); Å280 (a 4,400).
Exempel 9 Man arbetade på samma sätt som i exempel 4 (b) men utgick från 602 mg 1-dimetylaminosulfonyl-2-amino-6-(a-hydroxi- -u-n-propylbensyl)bensimidazol, 20 ml kloroform och 362 mg p-toluensulfonsyra. Härvid erhölls 93 mg 1-dimetylaminosulfo- nyl-2-amino-6-(u-n-propylidenbensyl)bensimidazol.Example 9 The procedure was as in Example 4 (b) but starting from 602 mg of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-one-propylbenzyl) benzimidazole, 20 ml of chloroform and 362 mg of p-toluenesulfonic acid . This gave 93 mg of 1-dimethylaminosulfonyl-2-amino-6- (u-n-propylidenebenzyl) benzimidazole.
Analys för C19H24NyO¿S: Beräknat: C 61,60 H 5,99 N 15,12 Funnet: C 61,53 H 6,14 N 15,01 Exempel 10 Till en lösning av 3,6 g (8,74 mmol) 1-cyklohexyl- sulfonyl-2-amino-6-(a-hydroxi-a-etylbensyl)bensimidazol i 125 ml kloroform sattes 2 g p-toluensulfonsyra. Reaktionsbland- ningen kokades under återflöde i 6 timmar, varpå den kyldes och fick stå vid rumstemperatur under 12 timmar. Den bildade produkten tvättades med en mättad natriumkarbonatlösning, tor- kades över natriumsulfat, filtrerades och torkades. Härvid er- hölls 5,25 g 1-cyklohexylsulfonyl-2-amino-6-(u-etylidenbensyl)- bensimidazol i form av ett skum. 9 8008090-6 Analys för C22H2nN3O2S: Beräknat: C 66,81 H 6,37 N 10,62 Funnet: C 66,58 H 6,46 N 10,38 Exempel 11: Man arbetade på samma sätt som i exempel H(b) men utgick från 1-cyklohexylsulfonyl-2-amino-6-@¿~hydroxi~1fmetyl- bensyl) bensimidazol [framställd utgående från 15 E 1'0YK10h@Xyl" sulfonyl-2-amíno-6-bensoylbensimidazol], 250 ml kloroform och 7,5 g p-toluensulfonsyra. Reaktionsblandingen kokades under åter- flöde i två timmar. Härvid erhölls 15,1 G ï“°Yk10h@XY1Su1f°nyl"2' .. __ to» amino-6-(i-metylenbensyl)bens1m1dazdl,med en smaltpunkt av 187 189 G. m/e 381, 255 (bas), 220, 165, 103- Analys för C21 H25 NB 02 S (molekylvikt 381): Beräknat: C 66,12 H 5,08 N 11,01 Funnet: C 66,08 H 6,25 N 10,89 Föreningarna med formeln I uppvisar ett brett spektrum för antivirusaktivitet. De är icke blott synnerli- gen effektiva som medel för inhibering av tillväxten av echo- virus och Mengo-, Coxsackie- (A9,A21, B5), polio- (typerna I, II, III), eller rhinovirus (25 stammar), utan de har också förmåga att inhibera olika typer av influensavirus, bl.a. så- dana stammar som Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a och Taylor C (typerna A, B). Att föreningarna inom ramen för formeln I ovan har förmåga att undertrycka tillväxt av olika slags virus in vitro kan lätt påvisas medelst ett test med undertryckt plaque-bildning, vilket liknar det test, som beskrivits av Siminoff, Applied Microöiology, 9(1), 66-72 (1961). De specifika testförfarandena beskrives nedan i detalj. Föreningarna med formeln I testades sålunda enligt ne- dan stâende förfaranden.Analysis for C 19 H 24 NyO 2 S: Calculated: C 61.60 H 5.99 N 15.12 Found: C 61.53 H 6.14 N 15.01 Example 10 To a solution of 3.6 g (8.74 mmol) 1-Cyclohexylsulfonyl-2-amino-6- (α-hydroxy-α-ethylbenzyl) benzimidazole In 125 ml of chloroform was added 2 g of p-toluenesulfonic acid. The reaction mixture was refluxed for 6 hours, then cooled and allowed to stand at room temperature for 12 hours. The resulting product was washed with a saturated sodium carbonate solution, dried over sodium sulfate, filtered and dried. This gave 5.25 g of 1-cyclohexylsulfonyl-2-amino-6- (u-ethylidenobenzyl) -benzimidazole as a foam. Analysis for C 22 H 21 N 3 O 2 S: Calculated: C 66.81 H 6.37 N 10.62 Found: C 66.58 H 6.46 N 10.38 Example 11: The procedure was as in Example H (b ) but was based on 1-cyclohexylsulfonyl-2-amino-6- (β-hydroxy-1-methyl-benzyl) benzimidazole [prepared from 15 E 1'OYK10 and 7.5 g of p-toluenesulfonic acid. The reaction mixture was refluxed for two hours to give 15.1 g of .beta.-Yk10h @ XY1Sulfonyl "2 '.. to 2 amino-6- (1-methylenebenzyl) benz1m1dazdl, with a melting point of 187 189 G. m / e 381, 255 (base), 220, 165, 103- Analysis for C .01 Found: C 66.08 H 6.25 N 10.89 The compounds of formula I show a broad spectrum of antiviral activity. They are not only particularly effective as agents for inhibiting the growth of echoviruses and Mengo, Coxsackie (A9, A21, B5), polio (types I, II, III), or rhinoviruses (strains), but they also have the ability to inhibit various types of influenza viruses, e.g. such strains as Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (types A, B). That the compounds within the framework of formula I above have the ability to suppress the growth of different kinds of virus in vitro can be easily demonstrated by means of a test with suppressed plaque formation, which is similar to the test described by Siminoff, Applied Microöiology, 9 (1), 66. -72 (1961). The specific test procedures are described in detail below. The compounds of formula I were thus tested according to the procedures below.
Testningsförfaranden Njurceller från afrikansk grön markatta (BSC-1) eller Hela-celler (5-3) fick tillväxa vid 37°C inuti 25 ml Falcon-kolvar i medium 199 med 5% inaktiverat nötkreatursfosterserum (FBS), pe- nicillin (150 enheter/ml) och streptomycin (150 ug/ml). När samman- vuxna cellskikt (skikttjocklek 1 cell) bildats, avlägsnades över- sLåundo tillvüxlmodium, ooh till varje kolv sattes 0,3 ml vätska med virus i lämplig utspädning (echo-virus, Mengo-virus, Coxsac- kie-virus, poliovirus eller rhinovirus). Efter en timmes absorp- tion vid rumstemperatur övertäcktes det med virus infekterade cellskiktet med ett medium, omfattande 1 del 1%-ig Ionagar nr 2 och 1 del dubbelstarkt medium 192 med EBS, penicillin och streptomycin, 8008090-'6 10 som innehöll den provade föreningen i koncentrationer av 100, 50, 25, 12, 6, 3 eller 0 ng/ml. Kolven utan provförening tjänstgjorde som kontrollprov. (Förrådslösningarna av sulfonylbensimidazolför- eningarna framställdes genom utspädning av en dimetylsulfoxid- lösning med koncentrationen 10" ug/ml). Kolvarna inkuberades under 72 timmar vid 37°C när det gällde polio, Coxsackie-, echo- och Mengo-virus, och under 120 timmar vid 32OC när det gällde rhinovirus. Plaques visade sig i de områden, där vi- ruset infekterade cellerna och förökade sig i cellerna. En lös- ning av 10% formalin och 2% natriumacetat sattes till varje kolv för inaktivering av viruset och fixering av cellskiktet vid kolvytan. Antalet plaques, som framkallats av viruset, räkna- des utan hänsyn till deras storlek efter det att omgivande cellzoner färgats med kristallviolett. Resultaten av plaque- räkningen för varje koncentration av den provade föreningen jämfördes med resultatet av plaque-räkningen hos kontrollpro- vet; testföreningens aktivitet uttrycktes som % plaque-minsk- ning eller % inhibering. Alternativt kan den koncentration av den provade föreningen 150, som inhiberar plaque-bildningen med 50%, användas som mått på aktiviteten.Test Procedures Kidney cells from African Green Market (BSC-1) or Hela cells (5-3) were grown at 37 ° C inside 25 ml Falcon flasks in medium 199 with 5% inactivated fetal bovine serum (FBS), penicillin (150 units). / ml) and streptomycin (150 ug / ml). When coagulated cell layers (layer thickness 1 cell) were formed, the supernatant growth medium was removed, and to each flask was added 0.3 ml of liquid with virus in appropriate dilution (echo virus, Mengo virus, Coxsackie virus, poliovirus or rhinovirus). After one hour of absorption at room temperature, the virus-infected cell layer was covered with a medium comprising 1 part of 1% Ionagar No. 2 and 1 part of double-strength medium 192 with EBS, penicillin and streptomycin, 8008090-'6 containing the tested the compound in concentrations of 100, 50, 25, 12, 6, 3 or 0 ng / ml. The flask without test compound served as a control sample. (The stock solutions of the sulfonylbenzimidazole compounds were prepared by diluting a dimethyl sulfoxide solution at a concentration of 10 "ug / ml). The flasks were incubated for 72 hours at 37 ° C for polio, Coxsackie, echo and Mengo viruses, and for 120 hours at 32 DEG C. for rhinovirus Plaques appeared in the areas where the virus infected the cells and multiplied in the cells A solution of 10% formalin and 2% sodium acetate was added to each flask to inactivate the virus and fix The number of plaques induced by the virus was counted regardless of their size after the surrounding cell zones were stained with crystal violet.The results of the plaque count for each concentration of the test compound were compared with the result of the plaque count of the control pro. The activity of the test compound was expressed as% plaque decrease or% inhibition, Alternatively, the concentration of the tested compound 150, which inhibits plaque formation by 50%, used as a measure of activity.
Testresultaten uttryckes som inhibering av polio- virus typ I, eftersom detta poliovirus lätt kan odlas och re- sultaten vid testningen alltid blir likformiga. Aktiviteten av föreningarna med formeln I har emellertid bestyrkts genom testning mot andra viruskulturer, t.ex. Coxsackie (A9, A21, B5), echo-virus (stammarna 1-4), Mengo, rhinovirus (25 stammar), po- lio (typerna I, II, III). De för olika sulfonyl-bensimidazol- föreningar erhållna resultaten är sammanställda i nedanstående tabell I, där den första spalten anger det exempel, vari prov- föreningen har framställts, den andra spalten anger ifrågava- rande bensimidazolprodukts 5(6)-ställning, och de därefter föl- jande spalterna (spalterna 3-10) anger den procentuella minsk- ningen av virusframkallade plaques vid provföreningskoncentra- tioner från 0,75 till 100 pg per ml. Med "tox.“ avses “toxisk", medan "mod.tox." betyder “måttligt toxisk" och “sl.tox.“ bety- der "något litet toxisk". u-. 8008090-6 11 Tabell I Koncentration av den provade föreningen, ng/ml Förening enl. exempel Iímeí 100 _30 LS _13 _6_ ___3_ ___1_,_5 O ,75 1 (b) 6 tox mod Sl 100 100 100 100 51 tox tox 2 (b) 6 100 100 100 100 100 100 100 100 4 (b) 6 tox tox tox tox 100 100 100 88 5 (b) 6 tox tox tox tox 100 100 100 100 5 (b) 6 tox tox tox tox 100 100 100 73 3 (b) 6 65 60 61 53 58 56 31 0 11 b tox tox tox tox 100 96 hß 0 I den svenska utläggningsskriften 7507482-3 beskri- ves närbesläktade sulfonylbensimidazoler med samma terapeutiska egenskaper. De nya föreningarna med formeln I uppvisar emeller- tid bättre egenskaper än dessa kända föreningar, vilket fram- går av jämförande försök genomförda enligt den ovan beskrivna försöksmetoden. De använda provföreningarna var dels förening- en enligt exempel 1 (b) ovan och dels tvâ jämförelseförening- ar beskrivna i utläggningsskriften 7507482-3, nämligen 1-dime- tylaminosulfonyl-2-amino-6-(hydrazinokarbonyl)bensimidazol (förening A) och 1-dimetylaminosulfonyl-2-amino-6-(N-etylkarb- oxamido)bensimidazol (förening B). De erhållna resultaten är sammanställda i nedanstående tabell II.The test results are expressed as inhibition of poliovirus type I, as this poliovirus can be easily cultured and the results of the testing will always be uniform. However, the activity of the compounds of formula I has been confirmed by testing against other virus cultures, e.g. Coxsackie (A9, A21, B5), echo virus (strains 1-4), Mengo, rhinovirus (25 strains), polio (types I, II, III). The results obtained for various sulfonyl-benzimidazole compounds are summarized in Table I below, where the first column indicates the example in which the test compound has been prepared, the second column indicates the position of the 5 (6) benzimidazole product in question, and the subsequent the following columns (columns 3-10) indicate the percentage reduction of virus-induced plaques at test compound concentrations from 0.75 to 100 pg per ml. By "tox." Is meant "toxic", while "mod.tox." means "moderately toxic" and "sl.tox." means "slightly toxic". u-. 8008090-6 11 Table I Concentration of the tested compound, ng / ml Compound according to Example Iímeí 100 _30 LS _13 _6_ ___3_ ___ 1 _, _ 5 0, 75 1 (b) 6 tox mod Sl 100 100 100 100 51 tox tox 2 (b) 6 100 100 100 100 100 100 100 100 4 4 (b) 6 tox tox tox tox 100 100 100 88 5 (b) ) 6 tox tox tox tox 100 100 100 100 5 (b) 6 tox tox tox tox 100 100 100 73 3 (b) 6 65 60 61 53 58 56 31 0 11 b tox tox tox tox 100 96 hß 0 In the Swedish explanatory memorandum 7507482-3 describes closely related sulfonylbenzimidazoles with the same therapeutic properties, however, the new compounds of formula I show better properties than these known compounds, as can be seen from comparative experiments carried out according to the experimental method described above. one according to Example 1 (b) above and two comparative compounds described in Offenlegungsschrift 7507482-3, namely 1-dimethylaminosulfonyl-2-amino-6- (hydrazinocarbonyl) benzimidazole (Compound A) and 1-dimethylaminosulfonyl-2-amino-6- (N-ethylcarboxamido) benzimidazole (Compound B). The results obtained are summarized in Table II below.
Tabell II Provförening Koncentration av den provade föreningen, ug/ml l99._5_f2__2å_lå__6._å__1_fí 0175 Exempel 1 (b) 100 100 100 100 100 100 100 93 Exempel A 77 39 25 0 O 0 0 -- Exempel B 100 100 100 92 50 15 0 0 Sulfonylbensimidazolföreningarna testades både som rena föreningar och som isomerblandningar. Båda isomererna in- hiberar virustillväxt, men i regel är 6-isomeren aktivare än 5- -isomeren.Table II Test compound Concentration of the test compound, ug / ml l99._5_f2__2å_lå__6._å__1_fí 0175 Example 1 (b) 100 100 100 100 100 100 100 93 Example A 77 39 25 0 0 0 - Example B 100 100 100 92 50 The sulfonylbenzimidazole compounds were tested both as pure compounds and as isomer mixtures. Both isomers inhibit virus growth, but as a rule the 6-isomer is more active than the 5-isomer.
Föreningarna kan administreras oralt till varmblo- diga däggdjur, inklusive människor, i doser om 1 - 300 mg/kg kroppsvikt. Administreringen kan alltefter behov upprepas pe- riodiskt. I enlighet med vanlig praxis kan den som antivirus- medel aktiva föreningen administreras var fjärde till var sjät- te timme.The compounds can be administered orally to warm-blooded mammals, including humans, in doses of 1 to 300 mg / kg body weight. The administration can be repeated periodically as needed. In accordance with standard practice, the antiviral active compound can be administered every four to six hours.
Claims (8)
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| US05/750,991 US4118742A (en) | 1975-08-28 | 1976-12-15 | Carbonyl-substituted 1-sulfonylbenzimidazoles |
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| FR2593177B1 (en) * | 1986-01-20 | 1988-04-01 | Novapharme | NEW BENZIMIDAZO |
| US5693661A (en) * | 1995-06-07 | 1997-12-02 | Eli Lilly And Company | Anti-viral compounds |
| JP7226480B2 (en) | 2020-07-30 | 2023-02-21 | 大日本印刷株式会社 | Antiviral article and antiviral resin composition |
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