HRP20020732A2 - Substituted 3-phenyl-5-alkoxi-1,3,4-oxdiazol-2-one and use thereof for inhibiting hormone-sensitive lipase - Google Patents
Substituted 3-phenyl-5-alkoxi-1,3,4-oxdiazol-2-one and use thereof for inhibiting hormone-sensitive lipase Download PDFInfo
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- HRP20020732A2 HRP20020732A2 HRP20020732A HRP20020732A2 HR P20020732 A2 HRP20020732 A2 HR P20020732A2 HR P20020732 A HRP20020732 A HR P20020732A HR P20020732 A2 HRP20020732 A2 HR P20020732A2
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- Prior art keywords
- alkyl
- substituted
- aryl
- halogen
- alkyloxy
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- 102000000019 Sterol Esterase Human genes 0.000 title claims description 15
- 108010055297 Sterol Esterase Proteins 0.000 title claims description 15
- 230000002401 inhibitory effect Effects 0.000 title claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 60
- 150000002367 halogens Chemical group 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 49
- -1 C1-C4-alkyloxy Chemical group 0.000 claims description 35
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 2
- 238000007385 chemical modification Methods 0.000 claims description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims 2
- 102100026020 Hormone-sensitive lipase Human genes 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 150000004651 carbonic acid esters Chemical class 0.000 claims 1
- 125000005059 halophenyl group Chemical group 0.000 claims 1
- 238000002844 melting Methods 0.000 description 89
- 230000008018 melting Effects 0.000 description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
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- WVEMHEUXDRVXJO-UHFFFAOYSA-N 3-(4-amino-3-methylphenyl)-5-methoxy-1,3,4-oxadiazol-2-one Chemical compound O=C1OC(OC)=NN1C1=CC=C(N)C(C)=C1 WVEMHEUXDRVXJO-UHFFFAOYSA-N 0.000 description 6
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 210000001789 adipocyte Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
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- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
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- SDNYTAYICBFYFH-TUFLPTIASA-N antipain Chemical compound NC(N)=NCCC[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SDNYTAYICBFYFH-TUFLPTIASA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
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- RERPRXPTVXLOFR-UHFFFAOYSA-N (2-methyl-4-nitrophenyl)hydrazine Chemical compound CC1=CC([N+]([O-])=O)=CC=C1NN RERPRXPTVXLOFR-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
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- KHICPASJCVEVBY-UHFFFAOYSA-N 3-[3-[(4-fluorophenyl)methoxy]-4-nitrophenyl]-5-methoxy-1,3,4-oxadiazol-2-one Chemical compound O=C1OC(OC)=NN1C1=CC=C([N+]([O-])=O)C(OCC=2C=CC(F)=CC=2)=C1 KHICPASJCVEVBY-UHFFFAOYSA-N 0.000 description 2
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- GFJGXSFOJGLCGD-UHFFFAOYSA-N 4-chloro-n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]butanamide Chemical compound O=C1OC(OC)=NN1C1=CC=C(NC(=O)CCCCl)C(C)=C1 GFJGXSFOJGLCGD-UHFFFAOYSA-N 0.000 description 2
- KFIXQXHBBYKXBJ-UHFFFAOYSA-N 5-methoxy-3-(4-nitrophenyl)-1,3,4-oxadiazol-2-one Chemical compound O=C1OC(OC)=NN1C1=CC=C([N+]([O-])=O)C=C1 KFIXQXHBBYKXBJ-UHFFFAOYSA-N 0.000 description 2
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- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PBNRFAMNCFKUJO-UHFFFAOYSA-N n-[2-fluoro-4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)phenyl]-4-(trifluoromethyl)benzamide Chemical compound O=C1OC(OC)=NN1C(C=C1F)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 PBNRFAMNCFKUJO-UHFFFAOYSA-N 0.000 description 1
- FMWALFXDYBSANK-UHFFFAOYSA-N n-[3-chloro-4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)phenyl]-4-heptylbenzamide Chemical compound C1=CC(CCCCCCC)=CC=C1C(=O)NC1=CC=C(N2C(OC(OC)=N2)=O)C(Cl)=C1 FMWALFXDYBSANK-UHFFFAOYSA-N 0.000 description 1
- JLSLIAMUMMHLHV-UHFFFAOYSA-N n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]-2-phenylethenesulfonamide Chemical compound O=C1OC(OC)=NN1C(C=C1C)=CC=C1NS(=O)(=O)C=CC1=CC=CC=C1 JLSLIAMUMMHLHV-UHFFFAOYSA-N 0.000 description 1
- KPMUKLJFNDTDSE-UHFFFAOYSA-N n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]naphthalene-1-sulfonamide Chemical compound O=C1OC(OC)=NN1C(C=C1C)=CC=C1NS(=O)(=O)C1=CC=CC2=CC=CC=C12 KPMUKLJFNDTDSE-UHFFFAOYSA-N 0.000 description 1
- ANSXSXRHYSZEFR-UHFFFAOYSA-N n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]piperidine-1-carboxamide Chemical compound O=C1OC(OC)=NN1C(C=C1C)=CC=C1NC(=O)N1CCCCC1 ANSXSXRHYSZEFR-UHFFFAOYSA-N 0.000 description 1
- OZKDLPCWKJNTAH-UHFFFAOYSA-N n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]pyridine-3-carboxamide Chemical compound O=C1OC(OC)=NN1C(C=C1C)=CC=C1NC(=O)C1=CC=CN=C1 OZKDLPCWKJNTAH-UHFFFAOYSA-N 0.000 description 1
- KEZYVRNCEKIFCI-UHFFFAOYSA-N n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-phenylmethoxyphenyl]-4-(trifluoromethyl)benzamide Chemical compound O=C1OC(OC)=NN1C(C=C1OCC=2C=CC=CC=2)=CC=C1NC(=O)C1=CC=C(C(F)(F)F)C=C1 KEZYVRNCEKIFCI-UHFFFAOYSA-N 0.000 description 1
- GVODTCVMWJMRSF-UHFFFAOYSA-N n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-3-methylphenyl]-4-(trifluoromethoxy)benzamide Chemical compound O=C1OC(OC)=NN1C(C(=C1)C)=CC=C1NC(=O)C1=CC=C(OC(F)(F)F)C=C1 GVODTCVMWJMRSF-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- KMPKTVKLWXJAPO-UHFFFAOYSA-N phenyl n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]carbamate Chemical compound O=C1OC(OC)=NN1C(C=C1C)=CC=C1NC(=O)OC1=CC=CC=C1 KMPKTVKLWXJAPO-UHFFFAOYSA-N 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ADMYBPBXNPUKTP-UHFFFAOYSA-N pyridin-3-ylmethyl n-[4-(5-methoxy-2-oxo-1,3,4-oxadiazol-3-yl)-2-methylphenyl]carbamate Chemical compound O=C1OC(OC)=NN1C(C=C1C)=CC=C1NC(=O)OCC1=CC=CN=C1 ADMYBPBXNPUKTP-UHFFFAOYSA-N 0.000 description 1
- 108700022737 rat Fat1 Proteins 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D413/10—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 carbon chain containing aromatic rings
-
- 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
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- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Enzymes And Modification Thereof (AREA)
Description
Ovaj izum se odnosi na supstituirane 3-fenil-5-alkoksi-1,3,4-oksadiazol-2-one koji pokazuju inhibitorske učinke na hormonski osjetljivu lipazu (HSL), i na njihove farmaceutski prihvatljive soli ili kiselinske adicijske soli.
Neki 5-alkoksi-1,3,4-oksadiazol-2-oni s orto-supstituiranim fenilnim prstenom kao supstituentom ili s dokondenziranim petero- ili šesteročlanim prstenovima imaju antelmintičke (DE-A 26 04 110) i insekticidne učinke (DE-A 26 03 877, EP-b 0 048 040, EP-b 0 067 471).
Neki 5-fenoksi-1,3,4-oksadiazol-2-oni s orto-supstituiranim fenilnim prstenom kao supstituentom pokazuju endoparaziticidno djelovanje (EP-A 0 419 918).
Cilj izuma je bio da se pronađu spojevi koji pokazuju inhibicijsko djelovanje prema hormonski osjetljivoj lipazi, HSL.
To je postignuto sa supstituiranim 3-fenil-5-alkoksi-1,3,4-oksadiazol-2-onima formule 1,
[image]
u kojoj
R1 predstavlja C1-C6-alkil, C3-C9-cikloalkil, gdje obje skupine mogu biti jednostruko ili višestruko supstituirane sa supstituentom iz niza koji čine fenil, C1-C4-alkiloksi, S-C1-C4-alkil, N(C1-C4-alkil) 2, i gdje fenil sa svoje strane može biti jednostruko ili višestruko supstituiran s halogenim, C1-C4-alkilom, C1-C4-alkiloksi, nitro, CF3; i
R2, R3, R4 i R5 međusobno neovisno predstavljaju vodik, halogen, nitro, C1-C4-alkil, C1-C9-alkiloksi;
C6-C10-aril-C1-C4-alkiloksi, C6-C10-ariloksi, C6-C10-aril, C3-C8-cikloalkil ili O-C3-C8-cikloalkil, od kojih svaki može biti jednostruko, dvostruko ili trostruko supstituiran s halogenim, CF3, C1-C4-alkiloksi ili C1-C4-alkilom;
2-okso-pirolidin-1-il, 2,5-dimetilpirol-1-il ili NR6-A-R7,
pod uvjetom da R2, R3, R4 i R5 nisu istovremeno vodik, i najmanje jedan od radikala R2, R3, R4 i R5 predstavlja radikal 2-okso-pirolidin-1-il, 2,5-dimetilpirol-1-il, ili NR6-A-R7, i gdje
R6 je vodik, C1-C4-alkil ili C6-C10-aril-C1-C4-alkil, pri čemu aril može biti supstituiran s halogenim, CF3, C1-C8-alkiloksi ili C1-C4-alkilom;
A je jednostruka veza, COn, SOn, ili CONH;
n je 1 ili 2;
R je vodik;
ili C1-C18-alkenil ili C2-C18-alkenil, koji mogu biti jednostruko do trostruko supstituirani sa supstituentom iz niza koji čine C1-C4-alkil, halogen, CF3, C1-C4-alkiloksi, N(C1-C4-alkil)2, -COOH, C1-C4-alkil-oksi-karbonil, C6-C12-aril, C6-C12-ariloksi, C6-C12-aril-karbonil, C6-C10-aril-C1-C4-alkiloksi ili okso, pri čemu aril sa svoje strane može biti supstituiran s halogenim, C1-C4-alkilom, amino-sulfonilom ili metil-merkapto;
C6-C10-aril-C1-C4-alkil, C5-C8-cikloalkil-C1-C4-alkil, C5-C8-cikloalkil, C6-C10-aril-C2-C6-alkenil, C6-C10-aril, difenilil, difenilil-C1-C4-alkil, indanil, od kojih svaki može biti jednostruko ili dvostruko supstituiran sa supstituentom iz niza koji čine C1-C18-alkil, C1-C18-alkil-oksi, C3-C18-cikloalkil, COOH, hidroksi, C1-C4-alkil-karbonil, C6-C10-aril-C1-C4-alkil, C6-C10-aril-C1-C4-alkil-oksi, C6-C10-ariloksi, nitro, cijano, C6-C10-aril, fluor-sulfonil, C1-C6-alkiloksikarbonil, C6-C10-arilsulfonil-oksi, piridil, NHSO2-C6-C10-aril, halogen, CF3 ili OCF3, pri čemu alkil sa svoje strane može biti još supstituiran sa C1-C4-alkiloksikarbonilom, CF3 ili s karboksi, i aril također može biti supstituiran s halogenim, CF3 ili sa C1-C4-alkiloksi;
ili skupina Het-(CH2)r-, gdje
r je 0, 1, 2 ili 3 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i prema potrebi supstituiran sa supstituentom iz niza koji čine C1-C4-alkil, C6-C10-aril, halogen, C1-C4-alkiloksi, C1-C4-alkil-oksikarbonil, C6-C10-aril-C1-C4-alkil, C6-C10-aril-C1-C4-alkilmerkapto ili nitro, pri čemu benzo-kondenzirani aril sa svoje strane može biti supstituiran s halogenim, C1-C4-alkiloksi ili sa CF3 i alkil u arilalkilu također može biti supstituiran s metoksi i sa CF3,
kao i s njihovim farmaceutski prihvatljivim solima i kiselinskim adicijskim solima.
Spomenuti arilni radikali mogu biti prema potrebi supstituirani jednom ili više puta sa C1-C9-alkilom, C1-C8-alkiloksi, halogenim, i trifluormetilom. Spomenuti ciklo-alkilni radikali mogu biti prema potrebi supstituirani jednom ili više puta sa C1-C4-alkilom, C6-C10-arilom, i spomenuti alkilni radikali mogu biti prema potrebi supstituirani s hidroksi, di-C1-C4-alkilamino i fluorom. Halogen je fluor, klor, brom, ponajprije fluor i klor. Alkil, alkenil, alkiloksi, itd. mogu biti razgranati ili nerazgranati.
Prednost se daje spojevima formule 1 u kojoj:
R1 predstavlja C1-C4-alkil, i/ili
R5 predstavlja vodik, i/ili
R2 predstavlja vodik, halogen, C1-C4-alkil, C1-C9-alkiloksi ili amino.
Prednost se, nadalje, daje spojevima formule 1 u kojoj:
R3 predstavlja vodik, C1-C4-alkil, C6-C10-aril-C1-C4-alkiloksi, koji može biti prema potrebi supstituiran u arilnom dijelu s halogenim, ili je NR6-A-R7 gdje
R6 je vodik ili benzil,
A je jednostruka veza i
R7 je C6-C10-aril-C1-C4-alkil, koji može biti supstituiran s halogenim, CF3, cijano, fenil-C1-C4-alkil-oksi, CF3-fenoksi, C5-C8-cikloalkilom ili f luor-sulfonil-oksi;
C1-C12-alkil, koji može biti supstituiran sa C1-C4-alkiloksi, fenilom, CF3 ili fenil-C1-C4-alkiloksi;
C2-C12-alkenil ili skupina Het-(CH2)r-/ u kojoj
r je 0 ili 1, i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i supstituiran sa C1-C4-alkilom ili halogenim.
Osim toga, prednost se daje spojevima formule 1 u kojoj:
R4 predstavlja vodik, 2-okso-pirolidin-1-il, 2,5-di-metilpirol-1-il, ili C1-C10-aril-C1-C4-alkil-oksi, koji može biti supstituiran s halogenim, i/ili spojevima formule 1 u kojoj:
R4 predstavlja NR6-A-R7 gdje
R6 je vodik ili metil,
A je jednostruka veza i
R7 je vodik;
C1-C12-alkil, koji može biti jednostruko ili dvostruko supstituiran s halogenim;
C2-C18-alkenil, koji može biti jednostruko ili dvostruko supstituiran sa C1-C4-alkilom ili sa C1-C4-alkil-oksikarbonilom;
C6-C10-aril-C1-C4-alkil, koji može biti supstituiran s halogenim, C1-C6-alkiloksi, CF3, cijano, C5-C6-cikloalkilom, C1-C4-alkiloksikarbonilom, C6-C10-aril-C1-C4 aril-C1-C4-alkiloksi, C6-C10-aril-C1-C4-alkiloksi,pri čemu aril može biti još jednom supstituiran s halogenim ili sa CF3;
C5-C8-cikloalkil-C1-C4-alkil;
ili skupina Het-(CH2)r-,
u kojoj r je 1, 2 ili 3 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti supstituiran s halogenim, C1-C4-alkiloksi ili sa C1-C4-alkiloksikarbonilom, i/ili spojevima formule 1 u kojoj:
R4 predstavlja NR6A-R7, gdje
R6 je vodik,
A je -CO- i
R7 je C1-C18-alkil, koji može biti supstituiran s halogenim, fenilom, fenoksi, fenilkarbonilom ili sa C1-C4-alkiloksikarbonilom, pri čemu fenoksi može biti još supstituiran s metilom, halogenim ili s metilmerkapto;
C2-C18-alkenil, koji može biti supstituiran sa C6-C10-arilom;
C6-C10-aril, koji može biti supstituiran s halogenim, C1-C8-alkilom, fenil-C1-C4-alkilom, CF3, OCF3, fluor-sulfonilom, C1-C4-alkiloksikarbonilom, fenoksi, pri čemu aril može biti još supstituiran sa C1-C4-alkiloksi;
C6-C10-aril-C1-C4-alkil, pri čemu alkil može biti supstituiran s metoksi ili sa CF3 i aril može biti supstituiran s halogenim; ili
skupina Het-(CH2)r-, u kojoj
r je 0 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i supstituiran sa C1-C4-alkilom, halogenim, C1-C4-alkiloksi, halogenfenilom ili halogen-benzilmerkapto, pri čemu benzo-kondenzirani aril može biti još supstituiran s halogenim ili s metoksi, i/ili spojevima formule 1 u kojoj:
R4 predstavlja NR6-A-R7, gdje
R6 je vodik,
A je -CO2- i
R7 je C1-C18-alkil, koji je supstituiran sa CF3 ili fenilom;
C6-C10-aril;
C6-C10-aril-C1-C4-alkil, koji je supstituiran sa C1-C4-alkilom, halogenim, CF3 ili OCF3, benziloksi ili fenilom; ili
skupina Het-(CH2)r-, u kojoj
r je 0 ili 1 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i supstituiran sa C1-C4-alkilom ili s benzilom, i/ili spojevima formule 1 u kojoj
R4 predstavlja NR6-A-R7, gdje
R je vodik,
A je -SO2- i
R je C1-C6-alkil, koji može biti supstituiran sa CF3;
C2-C4-alkenil, koji može biti supstituiran s fenilom;
C6-C10-aril, koji može biti supstituiran sa C1-C6-alkilom, halogenim, C1-C4-alkiloksi ili s benzilom;
difenilil-C1-C4-alkil supstituiran s halogenim; ili
skupina Het-(CH2)r-, u kojoj
r je 0 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, i/ili spojevima formule 1 u kojoj:
R4 predstavlja NR6-A-R7, gdje
R6 je vodik,
A je -CO-NH- i
R7 je C1-C10-alkil, koji može biti supstituiran sa C1-C4-alkiloksikarbonilom, N(C1-C4-alkil)2 ili s fenilom, koji sa svoje strane može biti supstituiran s halogenim ili s aminosulfonilom;
C6-C10-aril, koji može biti supstituiran sa C1-C6-alkilom, C1-C6-alkiloksi, C1-C6-alkiloksikarbonilom, fenoksi, OCF3, benzilom ili piridilom, pri čemu alkil može biti još jednom supstituiran sa C1-C4-alkiloksikarbonilom ili s karboksi;
C5-C8-Cikloalki, koji može biti supstituiran s hidroksi, ili s indanilom; ili
skupina Het-(CH2)r-, u kojoj
r je 0 ili 1 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti supstituiran s benzilom.
Posebnu prednost daje se spojevima formule 1 u kojoj R1 predstavlja metil.
Posve posebnu prednost daje se skupini spojeva formule 1 koji su navedeni u primjerima 21, 22, 27, 28, 30 do 34, 36 do 42, 53, 54, 58, 60, 62, 65, 69, 71, 74, 92, 97, 107, 116, 128, 130, 136, 139, 142, 152, 166 i 171.
Spojevi prema izumu opće formule 1 imaju iznenađujuće inhibitorsko djelovanje na hormonski osjetljivu lipazu, HSL, alosterički enzim u adipocitima, koji se inhibira s inzulinom i odgovoran je za razgradnju masti u masnim stanicama i time za prevođenje masnih sastojaka u krvotok. Inhibicija tog enzima odgovara stoga djelovanju spojeva prema izumu koje je slično inzulinu, a koja konačno dovodi do smanjenja slobodnih masnih kiselina u krvi i šećera u krvi. Zbog toga se oni također mogu upotrijebiti za liječenje poremećaja izmjene tvari kao na primjer, kod dijabetesa melitusa koji ne ovisi o inzulinu, diabetičkog sindroma, i kod neposrednih ozljeda pankreasa.
Spojevi prema izumu opće formule I mogu se proizvesti poznatim metodama na različite načine.
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Na primjer, supstituirani 3-fenil-5-alkoksi-1,3,4-oksadiazol-2-oni formule 1 mogu se proizvesti reakcijom hidrazina formule 2 s klormravljim esterima formule 3 ili s drugim reaktivnim derivatima ugljičnih kiselina, u kojima su R1, R2, R3, R4 i R5 definirani kao gore, čime se dobiju spojevi formule 4, koji se aciliraju s fozgenom, karbonil-diimidazolom, difozgenom ili trifozgenom, cikliziraju i prevedu, prema potrebi daljnjim kemijskim modifikacijama radikala R2 - R5, kao na primjer, redukcijom nitro skupine u amino radikale poznatim postupcima, i zatim aciliranjem ili alkiliranjem u spojeve formule 1. Budući da se u tim reakcijama obično oslobađaju kiseline, preporuča se za ubrzavanje reakcije dodati bazu kao što je piridin, trietilamin, otopinu natrijevog hidroksida ili karbonata alkalijskih metala. Reakcije se mogu provesti u širokom temperaturnom području. U pravilu, pokazalo se je povoljnim raditi u temperaturnom području od 0°C do vrelišta upotrijebijenog otapala. Primjeri otapala koja se mogu upotrijebiti jesu metilen klorid, THF, DMF, toluen, etil acetat, n-heptan, dioksan i dietil eter.
Hidrazini formule 2 mogu se proizvesti poznatim metodama, na primjer diazotizacijom odgovarajućeg anilina i
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zatim redukcijom poznatim metodama ili nukleofilnom supstitucijom prikladno supstituiranog fenilnog derivata formule 6 (X je F, Cl, Br, J, OSO2CF3) s hidrazin hidratom. Takovi prikladni fenilni derivati mogu biti s nitro supstituirani halogenbenzeni, kao što su fluor- i klornitrobenzeni, od kojih se spojevi izuma mogu proizvesti poznatim metodama redukcijom u odgovarajućem trenutku tijeka sinteze i reakcijom sa sredstvima za aciliranje ili alkiliranje, kao što su, na primjer, kiselinski kloridi, anhidridi, izocijanati, esteri klormravlje kiseline, sulfonil kloridi ili alkil i arilalkil halogenodidi, ili redukcijskim alkiliranjem s aldehidima.
Djelovanje spojeva prema izumu na HSL ispitano je primjenom slijedećeg sistema enzimskog ispitivanja:
Priprava enzima
Priprava djelomično očišćenog HSL-a:
Izolirane masne stanice štakora dobivene su iz epididimalnog adipoznog tkiva neobrađenih mužjaka štakora (Wistar, 220-250 g) obradom s kolagenazom u skladu s objavljenim metodama (npr. S. Nilsson et al., Anal. Biochem. 158:399-407 (1986); G. Fredrikson et al., J. Biol. Chem. 256:6311-6320 (1981); H. Tornguist et al. , J. Biol. Chem. 251:813-819 (1976)). Masne stanice iz 10 štakora su isprane tri puta flotacijom svaki puta sa po 50 ml pufera za homogenizaciju (25 ml tris/HCl, pH 7,4, 0,25 M saharoze, 1 mM EDTA, l mM DTT, 10 μg/ml leupeptina, 10 μg/ml antipaina, 20 μg/ml pepstatina) i na kraju su preuzete u 10 ml pufera za homogenizaciju. Masne stanice su homogenizirane u homogenizeru teflon-u-staklu (Braun-melsungen) s 10 podizaja pri 1500 okr/min i 15°C. Homogenizat je centrifugiran (epruvete Sorvall SM24, 5000 okr/min, 10 min, 4°C). Uzeta je tekućina između gornjeg masnog sloja i taloga i centrifugiranje je ponovljeno. Dobiveni supernatant je ponovno centrifugiran (epruvete Sorvall SM24, 20000 okr/min, 45 min, 4°C). Supenatant je uzet i pomiješan s 1 g heparin-Sepharose (Pharmacia-biotech, CL-6B, ispran 5 puta s 25 mM tris/HCl, pH 7,4, 150 mM NaCl). Nakon inkubacije 60 minuta pri 4°C (mućkanje u intervalima po 15 minuta), centrifugirano je (epruvete Sorvall SM24, 3000 okr/min, 10 min, 4°C). Supernatant je namješten na pH 5,2 dodatkom ledene octene kiselina i inkubiran 30 minuta pri 4°C. Talog je skupljen centrifugiranjem (Sorvall SS34, 12000 okr/min, 10 min, 4°C) i suspendiran je u 2,5 ml 20 mM tris/HCl, pH 7,0,1 mM EDTA, 65 mM NaCl, 13% saharoze, 1 mM DTT, 10 ng/ml leupeptin/pepstatin/antipaina. Suspenzija je dijalizirana preko noći prema 25 mM tris/HCl, pH 7,4, 50% glicerola, 1 mM DTT, 10 ug/ml leupeptina, pepstatin, antipain pri 4°C i zatim je stavljena na stupac hidroksi apatita (0,1 g po 1 ml suspenzije, ekvilibriranim s 10 mM kalijevim fosfatom, pH 7,0, 30% glicerola, 1 mM DTT). Stupac je ispran sa četiri volumena pufera za ekvilibraciju s brzinom protoka od 20 do 30 ml/h. HSL je ispran s jednim volumom pufera za ekvilibraciju koji je sadržavao 0,5 M kalijevog fosfata, i zatim je dijaliziran (vidi gore) i koncentriran 5- do 10-struko ultrafiltracijom (Amicon Diaflo PM 10 filter) pri 4°C. Djelomično očišćen HSL može se pohraniti pri -70°C na 4 do 6 tjedana.
Ispitivanje:
Za pripravu supstrata pomiješa se 25-50 μCi [H3]-trioleoil glicerola (u toluenu), 6,8 umola neobilježenog trioleoil glicerola i 0,6 mg fosfolipida (fosfatidilholin/ fosfatidilinozitol 3:1 masa/vol), osuši s N2 i zatim se preuzme u 2 ml 0,1 M KPi (pH 7,0) uz obradu ultrazvukom (Branson 250, mikrotip, namješten na 1-2, 2x1 min u intervalima od 1 minute). Nakon dodatka 1 ml KPi i ponovne obrade s ultrazvukom (4 x 30 sek na ledu u intervalima od 30 sek) doda se 1 ml 20% BSA (i KPi) (krajnja koncentracija trioleoil glicerola 1,7 mM). Za reakciju, 100 μl otopine supstrata se pipetira u 100 μl otopine HSL-a (HSL proizveden kao gore, razrijeđen u 20 mM KPi, pH 7,0,1 mM EDTA, 1 mM DTT, 0,02% BSA, 20 μg/ml pepstatina, 10 μg/ml leupeptina) i inkubira se 30 minuta pri 37°C. Doda se 3,25 ml metanol/klorform/heptana (10:9:7) i 1,05 ml 0,1 M K2CO3, 0,1 M borne kiseline (pH 10,5) uz miješanje i zatim se centrifugira (800 x g, 20 min). Nakon odvajanja faza uzme se jedan ekvivalent gornje faze (l ml) i radioaktivnost se utvrdi tekućinskim scintilacijskim mjerenjem.
Ocjenjivanje:
Tvari su normalno ispitane u četiri neovisne reakcijske smjese. Inhibicija HSL enzimskog djelovanja s ispitnim tvarima utvrđena je usporedbom s neinhibiranom kontrolnom reakcijom. Vrijednost IC50 je izračunata pomoću krivulje inhibicije s najmanje 10 koncentracija ispitne tvari. Podaci su analizirani upotrebom računalnog programa GRAPHIT, Elsevier-bIOSOFT.
U ovom ispitivanju spojevi izuma su pokazali slijedeći učinak:
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U slijedećim primjerima pobliže se objašnjavaju postupci priprave, bez namjere ograničenja izuma samo na njih.
PRIMJER 1
3-metil-4-nitrofenilhidrazin
5 g of hidrazin hidrata doda se polako kap po kap u otopinu od 15,9 g 2-metil-4-fluornitrobenzena u 10 ml N-metilpirolidona pri sobnoj temperaturi, i smjesu se grije uz miješanje 4 sata pri 65°C. Proizvod se istaloži dodatkom 70 ml vode i odfiltrira odsisavanjem i zatim se prekristalizira iz izopropanola. Iskorištenje: 13,3 g, tal.: 138°C.
Analognim postupkom su proizvedeni slijedeći primjeri:
PRIMJER 2
3-fluor-4-nitrofenilhidrazin
Tal.: 130°C.
PRIMJER 3
2-klor-4-nitrofenilhidrazin
Tal.: 144°C.
PRIMJER 4
2-metil-4-nitrofenilhidrazin
Tal.: 135°C.
PRIMJER 5
3-(4-fluorbenziloksi)-2-nitrofenilhidrazin
Tal.: 164°C.
Polazni spoj 2-fluor-4-(4-fluorbenziloksi)nitrobenzen (tal.: 99°C) je proizvedeb alkiliranjem 3-fluor-4-nitro-fenola sa 4-fluorbenzil kloridom u DMF-u u prisutnosti kalijevog karbonata.
PRIMJER 6
3-(4-fluorbenziloksi)-4-nitrofenilhidrazin (intermedijat)
Tal.: 145°C.
PRIMJER 7
4-(4-klorfenoksi)-3-nitroanilin
1,4 g kalijevog karbonata se doda u otopinu od 1,29 g 4-klorfenola u 8 ml DMF-a i nakon miješanja 30 minuta doda se 1,6 g 4-fluor-3-nitroanilina i smjesu se miješa 3 sata pri 100°C. Kad se ohladi doda se 80 ml vode i nakon kratkog miješanja talog se odsisa i osuši u vakuumu pri 40°C.
Iskorištenje: 2,0 g; tal.: 101°C.
PRIMJER 8
4-(4-klorfenoksi)-3-nitrofenilhidrazin
Otopinu od 0,52 g natrijevog nitrita u 5 ml vode doda se kap po kap u miješanu smjesu koja sadrži 1,9 g 4-(4-klorfenoksi)-3-nitroanilina, 25 ml koncentrirane solne kiseline i 25 ml etanola ohlađenu na 0CC, i smjesu se zatim miješa 60 minuta pri 0°C i zatim se doda kap po kap u suspenziju od 8,5 g kositrenog diklorid dihidrata u 8 ml koncentrirane HC1. Talog se odsisa, ispere s vodom, suspendira se u 200 ml vode pod dušikom i razgradi sa 100 ml 30%-tne otopine natrijevog hidroksida pri 10-15°C. Nastalo ulje se ekstrahira mućkanjem s etil acetatom i ispere s vodom, i organsku fazu se osuši s natrijevim sulfatom. Proizvod se zatim istaloži s izopropanolnom HCl, odsisa i osuši u vakuumu. Iskorištenje: 1,1 g; tal.: 221°C.
PRIMJER 9
Metil N'-(4-nitro-2-metilfenil)hidrazinoformat
0,43 ml metil klorformata doda se oprezno, uz hlađenje s ledom, kap po kap u smjesu koja sadrži 0,84 g 2-metil-4-nitrofenilhidrazina, 15 ml NMP i 2 ml piridina i smjesu se zatim miješa 2 sata pri čemu se polako zagrije na sobnu temperaturu. Razrijedi se s 50 ml vode, zatim se smjesu miješa preko noći i krutu tvar se osuši u vakuumu pri 40°C. Iskorištenje: 0,81 g; tal.: 153°C.
Analognim postupkom proizvedeni su slijedeći primjeri:
PRIMJER 10
Metil N'-(4-nitrofenil)hidrazinoformat (intermedijat)
Tal.: 179°C.
PRIMJER 11
Metil N'-(3-fluor-4-nitrofenil)hidrazinoformat
Tal.: 127,4°C.
PRIMJER 12
Metil N'-(3-metil-4-nitrofenil)hidrazinoformat
Tal.: 159°C.
PRIMJER 13
Metil N'-(2-klor-4-nitrofenil)hidrazinoformat
Tal.: 156°C.
PRIMJER 14
Metil N'-(3-(4-fluorbenziloksi)-4-nitrofenil)hidrazinoformat (intermedijat)
Tal.: 166°C.
PRIMJER 15
Metil N'-(3-(4-fluorbenziloksi)-2-nitrofenil)hidrazinoformat
Tal.: 193°C.
PRIMJER 16
Metil N'-(4-(4-klorfenoksi)-3-nitrofenil)hidrazinoformat
Tal.: 147°C.
PRIMJER 17
Metil N'-(3-piperidino-4-nitrofenil)hidrazinoformat (-)
Tal.: 131°C.
Ovaj spoj i spoj iz primjera 18 proizvedeni su reakcijom metil N'-(3-fluor-4-nitrofenil)hidrazinoformata s piperidinom, odnosno i N-benzil-piperazinom u NMP pri 80°C.
PRIMJER 18
Metil N'-(3-(N-benzilpiperazino)-4-nitrofenil)hidrazinoformat
Tal.: 156°C.
PRIMJER 19
5-metoksi-3-(4-nitrofenil)-3H-(1,3,4)oksadiazol-2-on
2,5 g metil N'-(4-nitrofenil)hidrazinoformata i 5 ml piridina stavi se u 15 ml metilen klorida i uz miješanje i hlađenje s ledom pomiješa se kap po kap s 3 ml 20%-tne otopine fozgena u toluenu. Tu smjesu se pusti stajati preko noći pri sobnoj temperaturi i razrijedi se s daljnjih 10 ml metilen klorida i zatim se ispere 3 puta s vodom. Nakon sušenja preko natrijevog sulfata, smjesu se koncentrira u vakuumu, i proizvod se očisti kromatografijom na stupcu (silika gel, otapala: metanol:metilen klorid = 2:98) i prekristalizira iz izopropanola. Iskorištenje: 1,5 g tal.: 151°C.
Analogno su proizvedena slijedeća 4 primjera:
PRIMJER 20
5-metoksi-3-(3-metil-4-nitrofenil)-3H-(1,3,4) oksadiazol-2-on
Tal.: 112°C.
PRIMJER 21
5-metoksi-3-(4-(4-klorfenoksi-3-nitrofenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: ulje
PRIMJER 22
5-metoksi-3-(3-(4-fluorbenziloksi)-2-nitrofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 99°C.
PRIMJER 23
5-metoksi-3-(2-metil-4-nitrofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 111°C.
PRIMJER 24
5-metoksi-3-(3-(4-fluorbenziloksi)-4-nitrofenil)-3H-(1,3,4)oksadiazol-2-on Tal.: 137°C.
PRIMJER 25
5-metoksi-3-(4-aminofenil)-3H-(1,3,4)oksadiazol-2-on
Smjesu koja sadrži 1,4 g 5-metoksi-3-(4-nitrofenil)-3H-(1,3,4)oksadiazol-2-ona, 0,5 g Pd/C i 20 ml metanola hidrira se pod atmosferskim tlakom i pri sobnoj temperaturi dok se potroši izračunatu količinu vodika. Katalizator se zatim odfiltrira i otopinu se koncentrira u vakuumu. Zaostalu polukrutu tvar se promiješa s izopropanolom i odsisa. Iskorištenje: 0,75 g; tal.: 85°C.
PRIMJER 26
5-metoksi-3-(2-amino-4-(4-fluorbenziloksi)fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
PRIMJER 27
5-metoksi-3-(3-amino-4-(4-klorfenoksi)fenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: 133°C.
PRIMJER 28
5-metoksi-3-(4-amino-3-metilf enil)-3H-(1,3,4) oksadiazol-2-on
Tal.: 114°C.
PRIMJER 29
5-metoksi-3-(4-amino-3-(4-fluorbenziloksi)fenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: 195°C.
PRIMJER 30
5-metoksi-3-(4-(4-klorfenilacetilamino)fenil)-3H-(1,3,4)-oksadiazol-2-on
201 mg 4-klorfenilacetil klorida doda se kap po kap u mješavinu koja sadrži 200 mg 5-metoksi-3-(4-aminofenil)-3H-(1,3,4)oksadiazol-2-ona, 20 ml metilen klorida i 0,1 ml piridina, ohlađenu na ledu, i smjesu se miješa 5 sati pri sobnoj temperaturi. Hlapijivo se odstrani u vakuumu. Ostatak se miješa s vodom i krutu tvar se odsisa i osuši pri 40°C u vakuumu. Iskorištenje: 318 mg; tal.: 161°C.
Analognim postupkom su proizvedeni slijedeći primjeri:
PRIMJER 31
5-metoksi-3-(4-(4-klorfenilacetilamino)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 190°C.
PRIMJER 32
5-metoksi-3-(4-oktanoilamino-3-metilfenil)-3H-(1,3,4)oksa-diazol-2-on
Tal.: 110°C.
PRIMJER 33
5-metoksi-3-(4-(4-heptilbenzoilamino) fenil)-3H-(l,3,4)oksa-diazol-2-on
Tal.: 155°C.
PRIMJER 34
5-metoksi-3-(4-(4-butilfenilsulfonilamino)fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 135°C.
PRIMJER 35
5-metoksi-3-(4-(4-klorbutanoilamino)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 137°C.
PRIMJER 36
5-metoksi-3-(4-pivaloilamino-3-metilfenil)-3H-(1,3,4)oksa-diazol-2-on
Tal.: 15°C.
PRIMJER 37
5-metoksi-3-(4-(4-klorfenilsulfonilamino)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on Tal.: 147°C.
PRIMJER 38
5-metoksi-3-(4-(1-naftilsulfonilamino)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 123°C.
PRIMJER 39
5-metoksi-3-(4-(2-feniletenilsulfonilamino)-3-metilf enil)-3H-(1,3,4) oksadiazol-2-on
Tal.: 129°C.
PRIMJER 40
5-metoksi-3-(4-(2,2,2-trifluoretilsulfonilamino)-3-metil-fenil)-3H-(1,3,4) oksadiazol-2-on
Tal.:151°C.
PRIMJER 41
5-metoksi-3-(4-(benziloksikarbonilamino)-3-metilfenil)-3H-(1,3,4) oksadiazol-2-on
Tal.: 115°C.
PRIMJER 42
5-metoksi-3-(4-(3, 4-diklorf enilaminokarbonilamino)-3-metilfenil)-3H-(1,3,4) oksadiazol-2-on
Tal.: 210°C.
Ovaj spoj je dobiven reakcijom 5-metoksi-3-(4-amino-3-metilfenil)-3H-(1,3,4) oksadiazol-2-ona s ekvimolarnom količinom 3,4-diklorfenil isocijanata u toluenu pri 50°C.
PRIMJER 43
5-metoksi-3-(4-(4-klorf enilsulfonilamino)fenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: 169°C.
PRIMJER 44
5-metoksi-3-(4-(2-klorf enilsulfonilamino) fenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: 171°C.
PRIMJER 45
5-metoksi-3-(4-(3-klorfenilsulfonilamino)fenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: 141°C.
PRIMJER 46
5-metoksi-3-(4-(4-klorfenilacetilamino)-3-(4-fluorbenzil-oksi)fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 167°C.
PRIMJER 47
5-metoksi-3-(4-benzilsulfonilaminofenil)-3H-(1,3,4)oksa-diazol-2-on
Tal.: 153°C.
PRIMJER 48
5-metoksi-3-(4-(-2-(4'-klorbifenil)etil)sulfonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 165°C.
PRIMJER 49
5-metoksi-3-(4-izopropilsulfonilaminofenil)-3H-(1,3,4)oksa-diazol-2-on
Tal.: 190°C.
PRIMJER 50
5-metoksi-3-(4-dimetilamino-3-metilfenil)-3H-(1,3,4)oksa-diazol-2-on
Tal.: 71°C.
Ovaj spoj je dobiven reakcijom 5-metoksi-3-(4-amino-3-metilfenil)-3H-(1,3,4)oksadiazol-2-ona s paraformaldehid/ mravljom kiselinom u DMF-u pri sobnoj temperaturi i očišćen je kromatografijom na stupcu (silika gel, etil acetatin-heptan = 1:1).
PRIMJER 51
5-metoksi-3-(4-(4-klorbenzilamino)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
Ovaj spoj je dobiven reakcijom 5-metoksi-3-(4-amino-3-metilfenil)-3H-(1,3,4)oksadiazol-2-ona sa 4-klorbenz-aldehid/natrijevim borohidridom u metanol/metilen kloridu pri sobnoj temperaturi i očišćen je kromatografijom na stupcu (silika gel, etil acetat:n-heptan = 1:1).
PRIMJER 52
5-metoksi-3-(4-(2-oksopirolidin-1-il)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
Ovaj spoj je proizveden reakcijom 5-metoksi-3-(4-(4-klorbutanoilamino)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-ona s natrijevim hidridom u dioksanu pri sobnoj temperature i sirov proizvod je očišćen kromatografijom na stupcu (silika gel, metilen klorid:metanol = 98:2).
PRIMJER 53
5-metoksi-3-(4-(4-oksopent-2-en-2-ilamino)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 143°C.
Ovaj spoj je dobiven reakcijom 5-metoksi-3-(4-amino-3-metilfenil)-3H-(1,3,4)oksadiazol-2-ona s ekvimolarnom količinom acetilacetona u ledenoj octenoj kiselini pri 80°C i izoliran je taloženjem s dodatkom vode i filtracijom.
PRIMJER 54
5-metoksi-3-(4-(2,5-dimetilpirol-1-il)-3-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
Ovaj spoj je dobiven reakcijom 5-metoksi-3-(4-amino-3-metilfenil)-3H-(1,3,4)oksadiazol-2-ona s ekvimolarnom količinom acetonilacetona u ledenoj octenoj kiselini pri 80°C. Obrada je provedena razredivanjem s vodom, ekstrakcijom uz mućkanje s etil acetatom i kromatografijom na stupcu (silika gel, metilen klorid) sirovog proizvoda dobivenog nakon koncentriranja osušene organske faze.
PRIMJER 55
5-metoksi-3-(3-(4-fluorbenziloksi)-4-metilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 98°C.
Ovaj spoj je dobiven kao sporedni proizvod hidriranja 5-metoksi-3-(3-(4-fluorbenziloksi)-4-nitrofenil)-3H-(1,3,4)-oksadiazol-2-ona s dioksidom platine kao katalizatorom, u metanolu, pri sobnoj temperaturi pod atmosferskim tlakom. Čišćenje je provedeno kromatografijom na stupcu (silika gel, metilen klorid) nakon odvajanja katalizatora filtracijom i koncentriranja reakcijske smjese.
Spojevi primjera 56-199 proizvedeni su analogno gornjim primjerima.
PRIMJER 56
5-metoksi-3-(3-aminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 95°C.
PRIMJER 57
5-metoksi-3-(3-dibenzilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 71°C.
PRIMJER 58
5-metoksi-3-(3-benzilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
PRIMJER 59
5-metoksi-3-(4-(pirid-2-il)aminokarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 81°C.
PRIMJER 60
5-metoksi-3-(3-(4-fluorbenziloksi)-4-benziloksikarbonil-aminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
PRIMJER 61
5-metoksi-3-(4-amino-2-metilfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
PRIMJER 62
5-metoksi-3-(3-metil-4-(2-klorbenziloksikarbonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 161°C.
PRIMJER 63
5-metoksi-3-(4-amino-2-klorfenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 126°C.
PRIMJER 64
5-metoksi-3-(2-klor-4-nitrofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 92°C.
PRIMJER 65
5-metoksi-3-(2-metil-4-benziloksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 112°C.
PRIMJER 66
5-metoksi-3-(2-metil-4-(4-trifluormetoksibenzoilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 150°C.
PRIMJER 67
5-metoksi-3-(2-klor-4-benziloksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 150°C.
PRIMJER 68
5-metoksi-3-(3-fluor-4-nitrofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 127°C.
PRIMJER 69
5-metoksi-3-(4-(4-t-butilbenzoilamino)fenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: 173°C.
PRIMJER 70
5-metoksi-3-(4-(4-klorbenziloksikarbonilamino)fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 177°C.
PRIMJER 71
5-metoksi-3-(2-klor-4-(4-heptilbenzoilamino)fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 135°C.
PRIMJER 72
5-metoksi-3-(4-(3,4-diklorbenzoilamino)fenil)-3H-(1,3,4)-oksadiazol-2-on
Tal.: 200°C.
PRIMJER 73
5-metoksi-3-(4-(2-(4-klorfenoksi)-2-metilpropionilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 153°C.
PRIMJER 74
5-etoksi-3-(3-metil-4-benziloksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 94°C.
PRIMJER 75
5-izopropoksi-3-(3-metil-4-benziloksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 119°C.
PRIMJER 76
5-izopropoksi-3-(3-metil-4-butiloksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 114°C.
PRIMJER 77
5-izopropoksi-3-(3-metil-4-(3-klorfenilaminokarbonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 201°C.
PRIMJER 78
5-terc-butoksi-3-(3-metil-4-benziloksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 113°C.
PRIMJER 79
5-metoksi-3-(3-metil-4-fenoksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 145°C.
PRIMJER 80
5-metoksi-3-(3-metil-4-(pirid-3-ilkarbonilamino) fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
PRIMJER 81
5-metoksi-3-(3-metil-4-(indan-2-ilaminokarbonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 206°C.
PRIMJER 82
5-metoksi-3-(3-metil-4-(pirid-3-ilmetilaminokarbonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 229°C.
PRIMJER 83
5-metoksi-3-(3-metil-4-(pirid-3-ilmetoksikarbonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 232°C.
PRIMJER 84
5-metoksi-3-(3-fluor-4-benziloksikarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on Tal.: ulje
PRIMJER 85
5-metoksi-3-(3-fluor-4-(4-trifluormetilbenzoilamino)fenil)3H-(1,3,4)oksadiazol-2-on
Tal.: ulje
PRIMJER 86
5-metoksi-3-(3-benziloksi-4-(4-trifluormetilbenzoilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 159°C.
PRIMJER 87
5-metoksi-3-(3-fluor-4-(4-tert-butilbenzoilamino)fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 144°C.
PRIMJER 88
5-metoksi-3-(3-metil-4-(2, 2, 2-trifluoretoksikarbonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 141°C.
PRIMJER 89
5-metoksi-3-(3-metil-4-piperidinokarbonilaminofenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 154°C.
PRIMJER 90
5-metoksi-3-(4-(6-metoksibenzofuran-2-il-karbonilamino)-fenil)-3H-(1,3,4)oksadiazol-2-on
Tal.: 191°C.
Daljnji primjeri koji su proizvedeni gore opisanim postupcima i karakterizirani su masenom spektroskopijom (M+1):
[image] [image] [image] [image] [image] [image]
Claims (16)
1. Spojevi formule 1
[image]
naznačeni time, da
u kojoj
R1 predstavlja C1-C6-alkil, C3-C9-cikloalkil, gdje obje skupine mogu biti jednostruko ili višestruko supstituirane sa supstituentom iz niza koji čine fenil, C1-C4-alkiloksi, S-C1-C4-alkil, N(C1-C4-alkil) 2, i gdje fenil sa svoje strane može biti jednostruko ili višestruko supstituiran s halogenim, C1-C4-alkilom, C1-C4-alkiloksi, nitro, CF3; i
R2, R3, R4 i R5 međusobno neovisno predstavljaju vodik, halogen, nitro, C1-C4-alkil, C1-C9-alkiloksi;
C6-C10-aril-C1-C4-alkiloksi, C6-C10-ariloksi, C6-C10-aril, C3-C8-cikloalkil ili O-C3-C8-cikloalkil, od kojih svaki može biti jednostruko, dvostruko ili trostruko supstituiran s halogenim, CF3, C1-C4-alkiloksi ili C1-C4-alkilom;
2-okso-pirolidin-1-il, 2, 5-dimetilpirol-1-il ili NR6-A-R7,
pod uvjetom da R2, R3, R4 i R5 nisu istovremeno vodik, i najmanje jedan od radikala R2, R3, R4 i R5 predstavlja radikal 2-okso-pirolidin-1-il, 2,5-dimetilpirol-1-il, ili NR6-A-R7, i gdje
R6 je vodik, C1-C4-alkil ili C6-C10-aril-C1-C4-alkil, pri čemu aril može biti supstituiran s halogenim, CF3, C1-C8-alkiloksi ili C1-C4-alkilom;
A je jednostruka veza, COn, SOn, ili CONH;
n je 1 ili 2;
R je vodik;
ili C1-C18-alkenil ili C2-C18-alkenil, koji mogu biti jednostruko do trostruko supstituirani sa supstituentom iz niza koji čine C1-C4-alkil, halogen, CF3, C1-C4-alkiloksi, N(C1-C4-alkil)2, -COOH, C1-C4-alkil-oksi-karbonil, C6-C12-aril, C6-C12-ariloksi, C6-C12-aril-karbonil, C6-C10-aril-C1-C4-alkiloksi ili okso, pri čemu aril sa svoje strane može biti supstituiran s halogenim, C1-C4-alkilom, amino-sulfonilom ili metil-merkapto;
C6-C10-aril-C1-C4-alkil, C5-C8-cikloalkil-C1-C4-alkil, C5-C8-cikloalkil, C6-C10-aril-C2-C6-alkenil, C6-C10-aril, difenilil, difenilil-C1-C4-alkil, indanil, od kojih svaki može biti jednostruko ili dvostruko supstituiran sa supstituentom iz niza koji čine C1-C18-alkil, C1-C18-alkil-oksi, C3-C18-cikloalkil, COOH, hidroksi, C1-C4-alkil-karbonil, C6-C10-aril-C1-C4-alkil, C6-C10-aril-C1-C4-alkil-oksi, C6-C10-ariloksi, nitro, cijano, C6-C10-aril, fluor-sulfonil, C1-C6-alkiloksikarbonil, C6-C10-arilsulfonil-oksi, piridil, NHSO2-C6-C10-aril, halogen, CF3 ili OCF3, pri čemu alkil sa svoje strane može biti još supstituiran sa C1-C4-alkiloksikarbonilom, CF3 ili s karboksi, i aril također može biti supstituiran s halogenim, CF3 ili sa C1-C4-alkiloksi;
ili skupina Het-(CH2)r-, gdje
r je 0, 1, 2 ili 3 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i prema potrebi supstituiran sa supstituentom iz niza koji čine C1-C4-alkil, C6-C10-aril, halogen, C1-C4-alkiloksi, C1-C4-alkil-oksikarbonil, C6-C10-aril-C1-C4-alkil, C6-C10-aril-C1-C4-alkilmerkapto ili nitro, pri čemu benzo-kondenzirani aril sa svoje strane može biti supstituiran s halogenim, C1-C4-alkiloksi ili sa CF3 i alkil u arilalkilu također može biti supstituiran s metoksi i sa CF3,
i njihove farmaceutski prihvatljive soli i kiselinske adicijske soli.
2. Spojevi formule 1 prema zahtjevu 1, naznačeni time, da R predstavlja C1-C4-alkil.
3. Spojevi formule 1 prema zahtjevu 1ili 2, naznačeni time, da R1 predstavlja metil.
4. Spojevi formule 1 prema zahtjevima 1 do 3, naznačeni time, da R5 predstavlja vodik.
5. Spojevi formule 1 prema zahtjevima 1 do 4, naznačeni time, da R2 predstavlja vodik, halogen, C1-C4-alkil, C1-C9-alkiloksi ili amino.
6. Spojevi formule 1 prema zahtjevima 1 do 5, naznačeni time, da R3 predstavlja vodik, C1-C4-alkil, C6-C10-aril-C1-C4-alkiloksi, koji može biti supstituiran u arilnom dijelu s halogenim, ili je NR6-A-R7 gdje
R6 je vodik ili benzil,
A je jednostruka veza i
R7 je C6-C10-aril-C1-C4-alkil, koji može biti supstituiran s halogenim, CF3, cijano, fenil-C1-C4-alkil-oksi, CF3-fenoksi, C5-C8-cikloalkilom ili fluorsulfonil-oksi;
C1-C12-alkil, koji može biti supstituiran sa C1-C4- alkiloksi, fenilom, CF3 ili fenil-C1-C4-alkiloksi;
C2-C12-alkenil ili skupina Het-(CH2)r-, u kojoj
r je 0 ili 1, i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i supstituiran sa C1-C4-alkilom ili halogenim.
7. Spojevi formule 1 prema zahtjevima 1 do 6, naznačeni time, da R4 predstavlja vodik, 2-okso-pirolidin-1-il, 2,5-dimetilpirol-1-il, ili C1-C10-aril-C1-C4-alkil-oksi, koji može biti supstituiran s halogenim.
8. Spojevi formule 1 prema zahtjevima 1 do 7, naznačeni time, da R4 predstavlja NR6-A-R7 gdje
R6 je vodik ili metil,
A je jednostruka veza i
R7 je vodik;
C1-C12-alki, koji može biti jednostruko ili dvostruko supstituiran s halogenim;
C2-C18-alkenil, koji može biti jednostruko ili dvostruko supstituiran sa C1-C4-alkilom ili sa C1-C4-alkil-oksikarbonilom;
C6-C10-aril-C1-C4-alkil, koji može biti supstituiran s halogenim, C1-C6-alkiloksi, CF3, cijano, C5-C6-cikloalkilom, C1-C4-alkiloksikarbonilom, C6-C10-aril-C1-C4-alkilom, C6-C10-aril-C1-C4-alkiloksi, pri čemu aril može biti još jednom supstituiran s halogenim ili sa CF3;
C5-C8-cikloalkil-C1-C4-alkil;
ili skupina Het-(CH2)r-, u kojoj
r je 1, 2 ili 3 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti supstituiran s halogenim, C1-C4-alkiloksi ili sa C1-C4-alkiloksikarbonilom.
9. Spojevi formule 1 prema zahtjevima 1 do 8, naznačeni time, da
R4 predstavlja NR6A-R7, gdje
R je vodik,
A je -CO- i
R7 je C1-C18-alkil, koji može biti supstituiran s halogenim, fenilom, fenoksi, fenilkarbonilom ili sa C1-C4-alkiloksikarbonilom, pri čemu fenoksi može biti još supstituiran s metilom, halogenim ili s metilmerkapto;
C2-C18-alkenil, koji može biti supstituiran sa C6-C10-arilom;
C6-C10-aril, koji može biti supstituiran s halogenim, C1-C8-alkilom, fenil-C1-C4-alkilom, CF3, OCF3, fluor-sulfonilom, C1-C4-alkiloksikarbonilom, fenoksi, pri čemu aril može biti još supstituiran sa C1-C4-alkiloksi;
C6-C10-aril-C1-C4-alkil, pri čemu alkil može biti supstituiran s metoksi ili sa CF3 i aril može biti supstituiran s halogenim; ili
skupina Het-(CH2)r-, u kojoj
r je 0 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i supstituiran sa C1-C4-alkilom, halogenim, C1-C4-alkiloksi, halogenf enilom ili halogen-benzilmerkapto, pri čemu benzo-kondenzirani aril može biti još supstituiran s halogenim ili s metoksi.
10. Spojevi formule 1 prema zahtjevima 1 do 10, naznačeni time, da
R4 predstavlja NR6-A-R7, gdje
R je vodik,
A je -CO2- i
R7 je C1-C18-alkil, koji je supstituiran sa CF3 ili s fenilom;
C6-C10-aril;
C6-C10-aril-C1-C4-alkil, koji je supstituiran sa C1-C4-alkilom, halogenim, CF3 ili OCF3, benziloksi ili fenilom; ili
skupina Het-(CH2)r-, u kojoj
r je 0 ili 1 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti benzo-kondenziran i supstituiran sa C1-C4-alkilom ili s benzilom.
11. Spojevi formule 1 prema zahtjevima 1 do 10, naznačeni time, da
R4 predstavlja NR6-A-R7, gdje
R6 je vodik, A je -SO2- i
R7 je C1-C6-alki, koji može biti supstituiran saCF3; C2-C4-alkenil, koji može biti supstituiran s fenilom; C6-C10-aril, koji može biti supstituiran sa C1-C6-alkilom, halogenim, C1-C4-alkiloksi ili s benzilom;
difenilil-C1-C4-alkil supstituiran s halogenim; ili
skupina Het-(CH2)r-, u kojoj
r je 0 i
Het je zasićen ili nezasićen 5-7-člani heterocikl.
12. Spojevi formule 1 prema zahtjevima 1 do 11, naznačeni time, da R predstavlja NR6-A-R7, gdje
R je vodik,
A je -CO-NH- i
R7 je C1-C10-alkil, koji može biti supstituiran sa C1-C4-alkiloksikarbonilom, N(C1-C4-alkil)2 ili s fenilom, koji sa svoje strane može biti supstituiran s halogenim ili s aminosulfonilom;
C6-C10-aril, koji može biti supstituiran sa C1-C6-alkilom, C1-C6-alkiloksi, C1-C6-alkiloksikarbonilom, fenoksi, OCF3, benzilom ili piridilom, pri čemu alkil može biti još jednom supstituiran sa C1-C4-alkiloksikarbonilom ili s karboksi;
C5-C8-cikloalki, koji može biti supstituiran s hidroksi, ili s indanilom; ili
skupina Het-(CH2)r-, u kojoj
r je 0 ili 1 i
Het je zasićen ili nezasićen 5-7-člani heterocikl, koji može biti supstituiran s benzilom.
13. Postupak za pripravu spojeva formule 1 prema zahtjevima 1 do 12, naznačen time, da uključuje reakciju hidrazina formule 2 s esterom klormravlje kiseline formule 3 ili s drugim reaktivnim derivatom estera ugljične kiseline,
[image]
u kojoj su R1, R2, R3, R4 i R5 definirani kao u zahtjevima 1 do 12, čime se dobiju spojevi formule 4, koji se aciliraju s fozgenom, karbonildiimidazolom, difozgenom ili s trifozgenom, čime se dobiju spojevi formule 5, i zatim se spojevi formule 5 cikliziraju i prema potrebi se daljnjom kemijskom modifikacijom radikala R2-R5, kao na primjer redukcijom nitro skupine u amino skupinu i zatim aciliranjem ili alkiliranjem, prevode u spojeve formule 1.
14. Spojevi formule 1 prema zahtjevima 1 do 12, naznačeni time, da se upotrebljavaju u lijekovima s inhibicijskim učinkom prema hormonski osjetljivoj lipazi, HSL.
15. Spojevi formule 1 prema zahtjevima 1 do 12, naznačeni time, da se upotrebljavaju u lijekovima za liječenje dijabetesa melitusa ili dijabetičkog sindroma koji ne ovisi o inzulinu.
16. Lijek za liječenje dijabetesa melitusa ili dijabetičkog sindroma koji ne ovisi o inzulinu, naznačen time, da sadrži najmanje jedan spoj formule 1 prema zahtjevima 1 do 12.
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US6087350A (en) * | 1997-08-29 | 2000-07-11 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Use of pretreatment chemicals to enhance efficacy of cytotoxic agents |
US6900233B2 (en) | 2002-02-28 | 2005-05-31 | Aventis Pharma Deutschland Gmbh | Substituted 3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-ones, pharmaceutical composition and method for treating obesity thereof |
DE10208987A1 (de) * | 2002-02-28 | 2003-09-11 | Aventis Pharma Gmbh | Substituierte 3-Phenyl-5-alkoxi-1,3,4-oxidiazol-2-one, ihre Herstellung und Verwendung in Arzneistoffen |
DE10208986A1 (de) * | 2002-02-28 | 2003-09-11 | Aventis Pharma Gmbh | Verwendung substituierter 3-Phenyl-5-alkoxi-1,3,4-oxdiazol-2-one zur Herstellung von Arzneimitteln mit hemmender Wirkung an der pankreatischen Lipase |
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FR2299328A1 (fr) | 1975-02-03 | 1976-08-27 | Rhone Poulenc Ind | Derives de l'alcoyloxy-5 phenyl-3 oxyde azo |
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