HRP20040916A2 - Compounds that modulate ppar activity and methods for their preparation - Google Patents
Compounds that modulate ppar activity and methods for their preparationInfo
- Publication number
- HRP20040916A2 HRP20040916A2 HRP20040916A HRP20040916A2 HR P20040916 A2 HRP20040916 A2 HR P20040916A2 HR P20040916 A HRP20040916 A HR P20040916A HR P20040916 A2 HRP20040916 A2 HR P20040916A2
- Authority
- HR
- Croatia
- Prior art keywords
- acetic acid
- compound
- image
- methyl
- trifluoromethyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 685
- 238000002360 preparation method Methods 0.000 title claims description 318
- 238000000034 method Methods 0.000 title claims description 36
- 230000000694 effects Effects 0.000 title description 9
- 101150014691 PPARA gene Proteins 0.000 title 1
- COOMMSHFMOKEKM-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[(4-phenylphenyl)methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=C(C=2C=CC=CC=2)C=C1 COOMMSHFMOKEKM-UHFFFAOYSA-N 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 87
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 50
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 125000004429 atom Chemical group 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- 125000001188 haloalkyl group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 241000124008 Mammalia Species 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 150000002430 hydrocarbons Chemical class 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 150000003573 thiols Chemical class 0.000 claims description 14
- YBYRUZQLTYRCRF-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 YBYRUZQLTYRCRF-UHFFFAOYSA-N 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 12
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 12
- 208000008589 Obesity Diseases 0.000 claims description 12
- 235000020824 obesity Nutrition 0.000 claims description 12
- 102000016267 Leptin Human genes 0.000 claims description 11
- 108010092277 Leptin Proteins 0.000 claims description 11
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 claims description 11
- 229940039781 leptin Drugs 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 9
- QZCOZWYSOAUBJR-UHFFFAOYSA-N 2-[4-[[4-(2,4-dichlorophenyl)phenyl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=C(C=2C(=CC(Cl)=CC=2)Cl)C=C1 QZCOZWYSOAUBJR-UHFFFAOYSA-N 0.000 claims description 8
- WPLMYOVJSNXPMK-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[4-[3-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=C(C=2C=C(C=CC=2)C(F)(F)F)C=C1 WPLMYOVJSNXPMK-UHFFFAOYSA-N 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 7
- 230000029936 alkylation Effects 0.000 claims description 7
- 238000005804 alkylation reaction Methods 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 7
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 7
- MANTXHYUNLPBHE-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[3-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=CC(C=2C=CC(=CC=2)C(F)(F)F)=C1 MANTXHYUNLPBHE-UHFFFAOYSA-N 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- VFQRJNOXLNYYTE-UHFFFAOYSA-N 2-[3-methoxy-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=CC=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 VFQRJNOXLNYYTE-UHFFFAOYSA-N 0.000 claims description 5
- UXBLXTMVLIEOGI-UHFFFAOYSA-N 2-[4-[[4-(4-fluorophenyl)phenyl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=C(C=2C=CC(F)=CC=2)C=C1 UXBLXTMVLIEOGI-UHFFFAOYSA-N 0.000 claims description 5
- QPQVDUHBPMLTTD-UHFFFAOYSA-N 2-[4-[[4-[2-(3-fluorophenyl)ethenyl]phenyl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC(C=C1)=CC=C1C=CC1=CC=CC(F)=C1 QPQVDUHBPMLTTD-UHFFFAOYSA-N 0.000 claims description 5
- JLQGDIDQGNXZJJ-UHFFFAOYSA-N 2-[4-[[5-(4-chlorophenyl)-1,2-oxazol-3-yl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=NOC(C=2C=CC(Cl)=CC=2)=C1 JLQGDIDQGNXZJJ-UHFFFAOYSA-N 0.000 claims description 5
- AJQNSRYZFLLBOI-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[2-[4-[4-(trifluoromethyl)phenyl]phenyl]ethylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 AJQNSRYZFLLBOI-UHFFFAOYSA-N 0.000 claims description 5
- HXCKESKWJSVFAR-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[2-methyl-4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1C HXCKESKWJSVFAR-UHFFFAOYSA-N 0.000 claims description 5
- VVUWGDAIOYKXPE-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[3-[3-(trifluoromethoxy)phenyl]phenyl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=CC(C=2C=C(OC(F)(F)F)C=CC=2)=C1 VVUWGDAIOYKXPE-UHFFFAOYSA-N 0.000 claims description 5
- GSPKTIOMMLSIHT-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[3-[4-(trifluoromethyl)phenyl]-1,2-oxazol-5-yl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC(C=2C=CC(=CC=2)C(F)(F)F)=NO1 GSPKTIOMMLSIHT-UHFFFAOYSA-N 0.000 claims description 5
- ONKOHQZZVMTPOM-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 ONKOHQZZVMTPOM-UHFFFAOYSA-N 0.000 claims description 5
- WIOTZGHDAYUCBC-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=NOC(C=2C=CC(=CC=2)C(F)(F)F)=C1 WIOTZGHDAYUCBC-UHFFFAOYSA-N 0.000 claims description 5
- HEMOEZGWSUFMTR-UHFFFAOYSA-N 2-[5-methoxy-2-methyl-4-[[6-[4-(trifluoromethyl)phenyl]pyridin-3-yl]methylsulfanyl]phenoxy]acetic acid Chemical compound COC1=CC(OCC(O)=O)=C(C)C=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)N=C1 HEMOEZGWSUFMTR-UHFFFAOYSA-N 0.000 claims description 5
- DMZAKAJFNOKFPW-UHFFFAOYSA-N 2-[[5-methyl-7-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]-2,3-dihydro-1-benzofuran-4-yl]oxy]acetic acid Chemical compound C=12OCCC2=C(OCC(O)=O)C(C)=CC=1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=N1 DMZAKAJFNOKFPW-UHFFFAOYSA-N 0.000 claims description 5
- UUBMLUGVHDOXPD-UHFFFAOYSA-N 2-[[7-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetic acid Chemical compound C1=2CCCC=2C(OCC(=O)O)=CC=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 UUBMLUGVHDOXPD-UHFFFAOYSA-N 0.000 claims description 5
- IVINVXPMKZERSK-UHFFFAOYSA-N 2-[[7-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetic acid Chemical compound C1=2CCCC=2C(OCC(=O)O)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 IVINVXPMKZERSK-UHFFFAOYSA-N 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 238000007127 saponification reaction Methods 0.000 claims description 5
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 274
- 238000005160 1H NMR spectroscopy Methods 0.000 description 137
- -1 - OCF3 Chemical group 0.000 description 126
- 238000003786 synthesis reaction Methods 0.000 description 106
- 230000015572 biosynthetic process Effects 0.000 description 103
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 91
- 239000000047 product Substances 0.000 description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 46
- 239000000203 mixture Substances 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 235000019439 ethyl acetate Nutrition 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 35
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 description 35
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- URYHYZRICUTYIL-UHFFFAOYSA-N [4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methanol Chemical compound C1=CC(CO)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 URYHYZRICUTYIL-UHFFFAOYSA-N 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- 239000012267 brine Substances 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 229960000583 acetic acid Drugs 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 102000004877 Insulin Human genes 0.000 description 14
- 108090001061 Insulin Proteins 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 14
- 229940125396 insulin Drugs 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 125000001309 chloro group Chemical group Cl* 0.000 description 13
- 206010012601 diabetes mellitus Diseases 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- YRXGIYXRCPNLQO-UHFFFAOYSA-N (4-hydroxy-2-methoxy-5-methylphenyl) thiocyanate Chemical compound COC1=CC(O)=C(C)C=C1SC#N YRXGIYXRCPNLQO-UHFFFAOYSA-N 0.000 description 11
- YCVFDTRUBSFXSA-UHFFFAOYSA-N [4-[4-(trifluoromethyl)phenyl]phenyl]methanol Chemical compound C1=CC(CO)=CC=C1C1=CC=C(C(F)(F)F)C=C1 YCVFDTRUBSFXSA-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- IYQKPXHVUDFXKX-UHFFFAOYSA-N methyl 2-(5-methoxy-2-methyl-4-sulfanylphenoxy)acetate Chemical compound COC(=O)COC1=CC(OC)=C(S)C=C1C IYQKPXHVUDFXKX-UHFFFAOYSA-N 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000004001 thioalkyl group Chemical group 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- VKRULNTYXHYAAH-UHFFFAOYSA-N methyl 2-(2,3-dihydro-1h-inden-4-yloxy)acetate Chemical compound COC(=O)COC1=CC=CC2=C1CCC2 VKRULNTYXHYAAH-UHFFFAOYSA-N 0.000 description 3
- LVIWZUAGRHUNED-UHFFFAOYSA-N methyl 2-(2,5-dimethyl-4-sulfanylphenoxy)acetate Chemical compound COC(=O)COC1=CC(C)=C(S)C=C1C LVIWZUAGRHUNED-UHFFFAOYSA-N 0.000 description 3
- XHEWAVUQCYLXJT-UHFFFAOYSA-N methyl 2-(2,6-dimethyl-4-thiocyanatophenoxy)acetate Chemical compound COC(=O)COC1=C(C)C=C(SC#N)C=C1C XHEWAVUQCYLXJT-UHFFFAOYSA-N 0.000 description 3
- NBAUXWIBKMUMJV-UHFFFAOYSA-N methyl 2-(2-butyl-4-cyanophenyl)sulfanylacetate Chemical compound C(CCC)C1=C(SCC(=O)OC)C=CC(=C1)C#N NBAUXWIBKMUMJV-UHFFFAOYSA-N 0.000 description 3
- MSXJXHJYKWDCQD-UHFFFAOYSA-N methyl 2-(2-methyl-4-thiocyanatophenoxy)acetate Chemical compound COC(=O)COC1=CC=C(SC#N)C=C1C MSXJXHJYKWDCQD-UHFFFAOYSA-N 0.000 description 3
- WAPRRKJFRACMEK-UHFFFAOYSA-N methyl 2-(3-methoxy-4-thiocyanatophenoxy)acetate Chemical compound COC(=O)COC1=CC=C(SC#N)C(OC)=C1 WAPRRKJFRACMEK-UHFFFAOYSA-N 0.000 description 3
- FWHNDYVYVYLGPZ-UHFFFAOYSA-N methyl 2-(4-bromo-2-methylphenoxy)acetate Chemical compound COC(=O)COC1=CC=C(Br)C=C1C FWHNDYVYVYLGPZ-UHFFFAOYSA-N 0.000 description 3
- OLWMUEMPOVOVLB-UHFFFAOYSA-N methyl 2-(4-sulfanylphenoxy)acetate Chemical compound COC(=O)COC1=CC=C(S)C=C1 OLWMUEMPOVOVLB-UHFFFAOYSA-N 0.000 description 3
- DJKYKADHIYBHCV-UHFFFAOYSA-N methyl 2-(5-chloro-2-methyl-4-thiocyanatophenoxy)acetate Chemical compound COC(=O)COC1=CC(Cl)=C(SC#N)C=C1C DJKYKADHIYBHCV-UHFFFAOYSA-N 0.000 description 3
- NJVPEWHCLMBJGT-UHFFFAOYSA-N methyl 2-[(5-methyl-7-sulfanyl-2,3-dihydro-1h-inden-4-yl)oxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=C2CCCC2=C1S NJVPEWHCLMBJGT-UHFFFAOYSA-N 0.000 description 3
- SYQAXUAVRVDBBM-UHFFFAOYSA-N methyl 2-[(7-sulfanyl-2,3-dihydro-1h-inden-4-yl)oxy]acetate Chemical compound COC(=O)COC1=CC=C(S)C2=C1CCC2 SYQAXUAVRVDBBM-UHFFFAOYSA-N 0.000 description 3
- RQXULGGDLSMXHZ-UHFFFAOYSA-N methyl 2-[2-methyl-4-[(4-phenylphenyl)methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=CC=C(C=2C=CC=CC=2)C=C1 RQXULGGDLSMXHZ-UHFFFAOYSA-N 0.000 description 3
- UEEACGHNHRRKJP-UHFFFAOYSA-N methyl 2-[4-[(4-acetyloxyphenyl)methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=CC=C(OC(C)=O)C=C1 UEEACGHNHRRKJP-UHFFFAOYSA-N 0.000 description 3
- IVFRWIRSTLZDTE-UHFFFAOYSA-N methyl 2-[4-[(4-hydroxyphenyl)methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=CC=C(O)C=C1 IVFRWIRSTLZDTE-UHFFFAOYSA-N 0.000 description 3
- QTRYEZHSTLMULI-UHFFFAOYSA-N methyl 2-[4-[2-(1h-indol-3-yl)ethylsulfanyl]-5-methoxy-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCCC1=CNC2=CC=CC=C12 QTRYEZHSTLMULI-UHFFFAOYSA-N 0.000 description 3
- GNKBDWJKONZPLJ-UHFFFAOYSA-N methyl 2-[4-[[4-[(2,4-difluorophenyl)methoxy]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(F)C=C1F GNKBDWJKONZPLJ-UHFFFAOYSA-N 0.000 description 3
- HDZBVDINICUNPE-UHFFFAOYSA-N methyl 2-[5-chloro-2-methyl-4-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(Cl)=C1SCC1=CC=C(C=2N=CC(=CC=2)C(F)(F)F)C=C1 HDZBVDINICUNPE-UHFFFAOYSA-N 0.000 description 3
- ZIHCUSUALKPHDW-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[2-[4-[4-(trifluoromethyl)phenyl]phenyl]ethylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 ZIHCUSUALKPHDW-UHFFFAOYSA-N 0.000 description 3
- XQUNYNAQUGNOCA-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[6-[4-(trifluoromethyl)phenyl]pyridin-3-yl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)N=C1 XQUNYNAQUGNOCA-UHFFFAOYSA-N 0.000 description 3
- PLOOJVWUILFSQJ-UHFFFAOYSA-N methyl 2-[[6-methyl-8-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=C(C)C=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=N1 PLOOJVWUILFSQJ-UHFFFAOYSA-N 0.000 description 3
- SVCVLGXPQXRIBA-UHFFFAOYSA-N methyl 2-[[7-[(4-hydroxyphenyl)methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC1=CC=C(O)C=C1 SVCVLGXPQXRIBA-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- CQRYARSYNCAZFO-UHFFFAOYSA-N o-hydroxybenzyl alcohol Natural products OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
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- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- PJKNIMLOIPTHNE-UHFFFAOYSA-N methyl 2-(2-butyl-4-sulfanylphenoxy)acetate Chemical compound CCCCC1=CC(S)=CC=C1OCC(=O)OC PJKNIMLOIPTHNE-UHFFFAOYSA-N 0.000 description 2
- UOCOKTZWSBVJPY-UHFFFAOYSA-N methyl 2-(3-methoxy-4-sulfanylphenoxy)acetate Chemical compound COC(=O)COC1=CC=C(S)C(OC)=C1 UOCOKTZWSBVJPY-UHFFFAOYSA-N 0.000 description 2
- NOKYLJSWVAASOJ-UHFFFAOYSA-N methyl 2-(5-chloro-2-methyl-4-sulfanylphenoxy)acetate Chemical compound COC(=O)COC1=CC(Cl)=C(S)C=C1C NOKYLJSWVAASOJ-UHFFFAOYSA-N 0.000 description 2
- SJLPBWORMPHABI-UHFFFAOYSA-N methyl 2-[(6-methyl-8-sulfanyl-3,4-dihydro-2h-chromen-5-yl)oxy]acetate Chemical compound O1CCCC2=C1C(S)=CC(C)=C2OCC(=O)OC SJLPBWORMPHABI-UHFFFAOYSA-N 0.000 description 2
- GVZABZVGRKACTH-UHFFFAOYSA-N methyl 2-[2-butyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(OCC(=O)OC)C(CCCC)=CC(SCC=2C=CC(=CC=2)C=2C=CC(=CC=2)C(F)(F)F)=C1 GVZABZVGRKACTH-UHFFFAOYSA-N 0.000 description 2
- MMILWMPCFWFEOQ-UHFFFAOYSA-N methyl 2-[2-methyl-4-[(4-phenoxyphenyl)methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OC1=CC=CC=C1 MMILWMPCFWFEOQ-UHFFFAOYSA-N 0.000 description 2
- HFUIZAUOZMMGLA-UHFFFAOYSA-N methyl 2-[2-methyl-4-[(4-phenylmethoxyphenyl)methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=CC=C1 HFUIZAUOZMMGLA-UHFFFAOYSA-N 0.000 description 2
- RIAXMSOMYLFZAR-UHFFFAOYSA-N methyl 2-[2-methyl-4-[2-[4-[4-(trifluoromethyl)phenyl]phenyl]ethenyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1C=CC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 RIAXMSOMYLFZAR-UHFFFAOYSA-N 0.000 description 2
- OTXMGZLEOJVEDX-UHFFFAOYSA-N methyl 2-[2-methyl-4-[[3-[4-(trifluoromethyl)phenyl]-1,2-oxazol-5-yl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=CC(C=2C=CC(=CC=2)C(F)(F)F)=NO1 OTXMGZLEOJVEDX-UHFFFAOYSA-N 0.000 description 2
- INYFSJMDFOYYBP-UHFFFAOYSA-N methyl 2-[2-methyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 INYFSJMDFOYYBP-UHFFFAOYSA-N 0.000 description 2
- VJYCCLULANANMA-UHFFFAOYSA-N methyl 2-[2-methyl-4-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=CC=C(C=2N=CC(=CC=2)C(F)(F)F)C=C1 VJYCCLULANANMA-UHFFFAOYSA-N 0.000 description 2
- UKXLEPRUIDBFGI-UHFFFAOYSA-N methyl 2-[2-methyl-4-[[4-[[4-(trifluoromethoxy)phenyl]methoxy]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(OC(F)(F)F)C=C1 UKXLEPRUIDBFGI-UHFFFAOYSA-N 0.000 description 2
- AWVBVZCJSBAUBY-UHFFFAOYSA-N methyl 2-[2-methyl-4-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 AWVBVZCJSBAUBY-UHFFFAOYSA-N 0.000 description 2
- LIGJXDWHWYEGGR-UHFFFAOYSA-N methyl 2-[2-methyl-4-[[5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=NOC(C=2C=CC(=CC=2)C(F)(F)F)=C1 LIGJXDWHWYEGGR-UHFFFAOYSA-N 0.000 description 2
- OEFTZLHSZDWCLC-UHFFFAOYSA-N methyl 2-[2-propyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(OCC(=O)OC)C(CCC)=CC(SCC=2C=CC(=CC=2)C=2C=CC(=CC=2)C(F)(F)F)=C1 OEFTZLHSZDWCLC-UHFFFAOYSA-N 0.000 description 2
- SRCZIGQVHPCJAU-UHFFFAOYSA-N methyl 2-[3-methoxy-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound COC1=CC(OCC(=O)OC)=CC=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 SRCZIGQVHPCJAU-UHFFFAOYSA-N 0.000 description 2
- YGWBGEGHCUNZNY-UHFFFAOYSA-N methyl 2-[4-[(6-chloropyridin-3-yl)methylsulfanyl]-5-methoxy-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(Cl)N=C1 YGWBGEGHCUNZNY-UHFFFAOYSA-N 0.000 description 2
- NPXDQXBGHRTWPK-UHFFFAOYSA-N methyl 2-[4-[[4-(2,4-dichlorophenyl)phenyl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C(=CC(Cl)=CC=2)Cl)C=C1 NPXDQXBGHRTWPK-UHFFFAOYSA-N 0.000 description 2
- XQQDCVULUIAUNQ-UHFFFAOYSA-N methyl 2-[4-[[4-(3,4-dichlorophenyl)phenyl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C=C(Cl)C(Cl)=CC=2)C=C1 XQQDCVULUIAUNQ-UHFFFAOYSA-N 0.000 description 2
- JDEXWJPKJAGNGW-UHFFFAOYSA-N methyl 2-[4-[[4-(4-fluorophenyl)phenyl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C=CC(F)=CC=2)C=C1 JDEXWJPKJAGNGW-UHFFFAOYSA-N 0.000 description 2
- FXNYKNSKPKCPOP-UHFFFAOYSA-N methyl 2-[4-[[4-[(2,4-dichlorophenyl)methoxy]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(Cl)C=C1Cl FXNYKNSKPKCPOP-UHFFFAOYSA-N 0.000 description 2
- UCFCYRZSYKTCNK-UHFFFAOYSA-N methyl 2-[4-[[4-[(2,5-dichlorophenyl)methoxy]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC(Cl)=CC=C1Cl UCFCYRZSYKTCNK-UHFFFAOYSA-N 0.000 description 2
- KXSXAUPIYAHESS-UHFFFAOYSA-N methyl 2-[4-[[4-[(4-chlorophenyl)methoxy]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(Cl)C=C1 KXSXAUPIYAHESS-UHFFFAOYSA-N 0.000 description 2
- HYUMBMNSTNHLPH-UHFFFAOYSA-N methyl 2-[4-[[4-[(4-fluorophenyl)methoxy]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(F)C=C1 HYUMBMNSTNHLPH-UHFFFAOYSA-N 0.000 description 2
- WLESGZDLZOTIES-UHFFFAOYSA-N methyl 2-[4-[[4-[(4-methoxyphenyl)methoxy]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(OC)C=C1 WLESGZDLZOTIES-UHFFFAOYSA-N 0.000 description 2
- TZNXQDFUXBGMBS-UHFFFAOYSA-N methyl 2-[4-[[4-[(4-tert-butylphenyl)methoxy]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(C)(C)C)C=C1 TZNXQDFUXBGMBS-UHFFFAOYSA-N 0.000 description 2
- AFDHECXZDCGDCN-UHFFFAOYSA-N methyl 2-[4-[[4-[2-(3-fluorophenyl)ethenyl]phenyl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC(C=C1)=CC=C1C=CC1=CC=CC(F)=C1 AFDHECXZDCGDCN-UHFFFAOYSA-N 0.000 description 2
- IWMMVMMNIDBXES-UHFFFAOYSA-N methyl 2-[4-[[4-[4-chloro-3-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=CC=C(C=2C=C(C(Cl)=CC=2)C(F)(F)F)C=C1 IWMMVMMNIDBXES-UHFFFAOYSA-N 0.000 description 2
- XRFXLGQDXWWQQP-UHFFFAOYSA-N methyl 2-[4-[[5-(4-chlorophenyl)-1,2-oxazol-3-yl]methylsulfanyl]-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC=C1SCC1=NOC(C=2C=CC(Cl)=CC=2)=C1 XRFXLGQDXWWQQP-UHFFFAOYSA-N 0.000 description 2
- LVGYQBQGWWSGMM-UHFFFAOYSA-N methyl 2-[4-[[5-(4-chlorophenyl)-1,2-oxazol-3-yl]methylsulfanyl]-5-methoxy-2-methylphenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=NOC(C=2C=CC(Cl)=CC=2)=C1 LVGYQBQGWWSGMM-UHFFFAOYSA-N 0.000 description 2
- ISNUIUZHBRJQKF-UHFFFAOYSA-N methyl 2-[5-chloro-2-methyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(Cl)=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 ISNUIUZHBRJQKF-UHFFFAOYSA-N 0.000 description 2
- VMWJGTIBWLCEOC-UHFFFAOYSA-N methyl 2-[5-chloro-2-methyl-4-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(Cl)=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 VMWJGTIBWLCEOC-UHFFFAOYSA-N 0.000 description 2
- OVEHNMBXESCZOA-UHFFFAOYSA-N methyl 2-[5-chloro-2-methyl-4-[[5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(Cl)=C1SCC1=NOC(C=2C=CC(=CC=2)C(F)(F)F)=C1 OVEHNMBXESCZOA-UHFFFAOYSA-N 0.000 description 2
- DANQLTDPRWASKS-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[2-[1-[[4-(trifluoromethyl)phenyl]methyl]indol-3-yl]ethylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCCC(C1=CC=CC=C11)=CN1CC1=CC=C(C(F)(F)F)C=C1 DANQLTDPRWASKS-UHFFFAOYSA-N 0.000 description 2
- QKEKSHDGTKEXDJ-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[2-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 QKEKSHDGTKEXDJ-UHFFFAOYSA-N 0.000 description 2
- PRPQLYOWUTXFBZ-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[2-methyl-4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1C PRPQLYOWUTXFBZ-UHFFFAOYSA-N 0.000 description 2
- XEZKFLNHJSXRQB-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[3-[3-(trifluoromethoxy)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=CC(C=2C=C(OC(F)(F)F)C=CC=2)=C1 XEZKFLNHJSXRQB-UHFFFAOYSA-N 0.000 description 2
- HWKNOVZBKYEOHE-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[3-[4-(trifluoromethyl)phenyl]-1,2-oxazol-5-yl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC(C=2C=CC(=CC=2)C(F)(F)F)=NO1 HWKNOVZBKYEOHE-UHFFFAOYSA-N 0.000 description 2
- VWUWVLCOBKXIMS-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[4-[3-(trifluoromethoxy)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C=C(OC(F)(F)F)C=CC=2)C=C1 VWUWVLCOBKXIMS-UHFFFAOYSA-N 0.000 description 2
- PTVHGDJMKHFXQF-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[4-[3-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C=C(C=CC=2)C(F)(F)F)C=C1 PTVHGDJMKHFXQF-UHFFFAOYSA-N 0.000 description 2
- UQPLNGGMMNNHLV-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 UQPLNGGMMNNHLV-UHFFFAOYSA-N 0.000 description 2
- HLBPHSXQGYRDST-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfinyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1S(=O)CC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 HLBPHSXQGYRDST-UHFFFAOYSA-N 0.000 description 2
- HHDJDISYASLJPU-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfonyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1S(=O)(=O)CC1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 HHDJDISYASLJPU-UHFFFAOYSA-N 0.000 description 2
- KWRBTVOUVZWXSI-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=CC=C(C=2N=CC(=CC=2)C(F)(F)F)C=C1 KWRBTVOUVZWXSI-UHFFFAOYSA-N 0.000 description 2
- RTBSBIGLBCOBGP-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 RTBSBIGLBCOBGP-UHFFFAOYSA-N 0.000 description 2
- PPYLECZZTUJEIG-UHFFFAOYSA-N methyl 2-[5-methoxy-2-methyl-4-[[5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methylsulfanyl]phenoxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=CC(OC)=C1SCC1=NOC(C=2C=CC(=CC=2)C(F)(F)F)=C1 PPYLECZZTUJEIG-UHFFFAOYSA-N 0.000 description 2
- MPCZTZIZHRLHPO-UHFFFAOYSA-N methyl 2-[[5-methyl-7-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=C2CCCC2=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 MPCZTZIZHRLHPO-UHFFFAOYSA-N 0.000 description 2
- UTZXQILJDZRVOI-UHFFFAOYSA-N methyl 2-[[5-methyl-7-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]-2,3-dihydro-1-benzofuran-4-yl]oxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=C2CCOC2=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=N1 UTZXQILJDZRVOI-UHFFFAOYSA-N 0.000 description 2
- KAYODKXXCBUOKZ-UHFFFAOYSA-N methyl 2-[[5-methyl-7-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=C2CCCC2=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=N1 KAYODKXXCBUOKZ-UHFFFAOYSA-N 0.000 description 2
- VQGMAQIRTOSILA-UHFFFAOYSA-N methyl 2-[[5-methyl-7-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=C(C)C(OCC(=O)OC)=C2CCCC2=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 VQGMAQIRTOSILA-UHFFFAOYSA-N 0.000 description 2
- JLUVMQDJKRUNDG-UHFFFAOYSA-N methyl 2-[[7-[(4-acetyloxyphenyl)methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC1=CC=C(OC(C)=O)C=C1 JLUVMQDJKRUNDG-UHFFFAOYSA-N 0.000 description 2
- HNHOEVVLIVZRHS-UHFFFAOYSA-N methyl 2-[[7-[2-[4-[4-(trifluoromethyl)phenyl]phenyl]acetyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1C(=O)CC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 HNHOEVVLIVZRHS-UHFFFAOYSA-N 0.000 description 2
- FUMPMIXMNOCGPH-UHFFFAOYSA-N methyl 2-[[7-[2-[4-[4-(trifluoromethyl)phenyl]phenyl]ethyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1CCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 FUMPMIXMNOCGPH-UHFFFAOYSA-N 0.000 description 2
- DNASJQNRLJMRPG-UHFFFAOYSA-N methyl 2-[[7-[2-[4-[4-(trifluoromethyl)phenyl]phenyl]ethylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 DNASJQNRLJMRPG-UHFFFAOYSA-N 0.000 description 2
- DNOJIGAIZBODMQ-UHFFFAOYSA-N methyl 2-[[7-[[2-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 DNOJIGAIZBODMQ-UHFFFAOYSA-N 0.000 description 2
- NGRZOPVOIQFFGR-UHFFFAOYSA-N methyl 2-[[7-[[2-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC1=CC=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 NGRZOPVOIQFFGR-UHFFFAOYSA-N 0.000 description 2
- PJKJZTATBLCBEC-UHFFFAOYSA-N methyl 2-[[7-[[3,5-dichloro-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1Cl)=CC(Cl)=C1OCC1=CC=C(C(F)(F)F)C=C1 PJKJZTATBLCBEC-UHFFFAOYSA-N 0.000 description 2
- BBUSUGUJHBPBNK-UHFFFAOYSA-N methyl 2-[[7-[[3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazol-4-yl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl BBUSUGUJHBPBNK-UHFFFAOYSA-N 0.000 description 2
- ZZHNTGQQEHGREL-UHFFFAOYSA-N methyl 2-[[7-[[3-(4-chlorophenyl)-1,2-oxazol-5-yl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(ON=1)=CC=1C1=CC=C(Cl)C=C1 ZZHNTGQQEHGREL-UHFFFAOYSA-N 0.000 description 2
- BRWLOXSQQPEEPO-UHFFFAOYSA-N methyl 2-[[7-[[3-[4-(trifluoromethyl)phenyl]-1,2-oxazol-5-yl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(ON=1)=CC=1C1=CC=C(C(F)(F)F)C=C1 BRWLOXSQQPEEPO-UHFFFAOYSA-N 0.000 description 2
- XJIZAXJBHXOMHB-UHFFFAOYSA-N methyl 2-[[7-[[3-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=1)=CC=CC=1C1=CC=C(C(F)(F)F)C=C1 XJIZAXJBHXOMHB-UHFFFAOYSA-N 0.000 description 2
- SKEGBMRMIKRRDO-UHFFFAOYSA-N methyl 2-[[7-[[3-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=1)=CC=CC=1C1=CC=C(C(F)(F)F)C=N1 SKEGBMRMIKRRDO-UHFFFAOYSA-N 0.000 description 2
- COEWJBSTGGPQJI-UHFFFAOYSA-N methyl 2-[[7-[[3-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=1)=CC=CC=1OCC1=CC=C(C(F)(F)F)C=C1 COEWJBSTGGPQJI-UHFFFAOYSA-N 0.000 description 2
- LFWIIISCRGRPDA-UHFFFAOYSA-N methyl 2-[[7-[[3-[[4-chloro-3-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=1)=CC=CC=1OCC1=CC=C(Cl)C(C(F)(F)F)=C1 LFWIIISCRGRPDA-UHFFFAOYSA-N 0.000 description 2
- ORUBONIIIKZNQK-UHFFFAOYSA-N methyl 2-[[7-[[4-[(2,4-dichlorophenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(Cl)C=C1Cl ORUBONIIIKZNQK-UHFFFAOYSA-N 0.000 description 2
- GXEKVNIVTCGQFZ-UHFFFAOYSA-N methyl 2-[[7-[[4-[(2,4-difluorophenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(F)C=C1F GXEKVNIVTCGQFZ-UHFFFAOYSA-N 0.000 description 2
- HYWJIAOVLDSXNR-UHFFFAOYSA-N methyl 2-[[7-[[4-[(2,5-dichlorophenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC(Cl)=CC=C1Cl HYWJIAOVLDSXNR-UHFFFAOYSA-N 0.000 description 2
- IIWBMVAJJPPCMZ-UHFFFAOYSA-N methyl 2-[[7-[[4-[(3,4-dichlorophenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 IIWBMVAJJPPCMZ-UHFFFAOYSA-N 0.000 description 2
- FGCNVUAPCWOSGZ-UHFFFAOYSA-N methyl 2-[[7-[[4-[(3,5-dichlorophenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC(Cl)=CC(Cl)=C1 FGCNVUAPCWOSGZ-UHFFFAOYSA-N 0.000 description 2
- YDIDJPRYASPNAN-UHFFFAOYSA-N methyl 2-[[7-[[4-[(4-chlorophenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(Cl)C=C1 YDIDJPRYASPNAN-UHFFFAOYSA-N 0.000 description 2
- JVENZGGBNNSTAM-UHFFFAOYSA-N methyl 2-[[7-[[4-[(4-methoxyphenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(OC)C=C1 JVENZGGBNNSTAM-UHFFFAOYSA-N 0.000 description 2
- ARFSCPDOWCFLHU-UHFFFAOYSA-N methyl 2-[[7-[[4-[(4-tert-butylphenyl)methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(C)(C)C)C=C1 ARFSCPDOWCFLHU-UHFFFAOYSA-N 0.000 description 2
- YRUUNPXRZDNSAS-UHFFFAOYSA-N methyl 2-[[7-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 YRUUNPXRZDNSAS-UHFFFAOYSA-N 0.000 description 2
- HVNIATGKLQZTAU-UHFFFAOYSA-N methyl 2-[[7-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=N1 HVNIATGKLQZTAU-UHFFFAOYSA-N 0.000 description 2
- FWZSZZJHMDQUIB-UHFFFAOYSA-N methyl 2-[[7-[[4-[[4-(fluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(CF)C=C1 FWZSZZJHMDQUIB-UHFFFAOYSA-N 0.000 description 2
- KNCGJRVQNSIMPI-UHFFFAOYSA-N methyl 2-[[7-[[4-[[4-(trifluoromethoxy)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(OC(F)(F)F)C=C1 KNCGJRVQNSIMPI-UHFFFAOYSA-N 0.000 description 2
- UHMYEWBPNFWLDK-UHFFFAOYSA-N methyl 2-[[7-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 UHMYEWBPNFWLDK-UHFFFAOYSA-N 0.000 description 2
- XWVIVUKZDZOHNE-UHFFFAOYSA-N methyl 2-[[7-[[4-[[4-(trifluoromethyl)phenyl]methyl]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1CC1=CC=C(C(F)(F)F)C=C1 XWVIVUKZDZOHNE-UHFFFAOYSA-N 0.000 description 2
- QRBXBUJTMWEYCP-UHFFFAOYSA-N methyl 2-[[7-[[4-[[4-chloro-3-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(Cl)C(C(F)(F)F)=C1 QRBXBUJTMWEYCP-UHFFFAOYSA-N 0.000 description 2
- SVZWWXBNHLFXPT-UHFFFAOYSA-N methyl 2-[[7-[[4-[[4-fluoro-2-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(F)C=C1C(F)(F)F SVZWWXBNHLFXPT-UHFFFAOYSA-N 0.000 description 2
- LMLVKIGGDHRBMF-UHFFFAOYSA-N methyl 2-[[7-[[4-[[4-fluoro-3-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(F)C(C(F)(F)F)=C1 LMLVKIGGDHRBMF-UHFFFAOYSA-N 0.000 description 2
- NLLDMRFDRAVZQL-UHFFFAOYSA-N methyl 2-[[7-[[4-methoxy-3-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(C=1)=CC=C(OC)C=1OCC1=CC=C(C(F)(F)F)C=C1 NLLDMRFDRAVZQL-UHFFFAOYSA-N 0.000 description 2
- IVKQMXASIHXTAA-UHFFFAOYSA-N methyl 2-[[7-[[5-(2-chlorophenyl)-1,2-oxazol-3-yl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(=NO1)C=C1C1=CC=CC=C1Cl IVKQMXASIHXTAA-UHFFFAOYSA-N 0.000 description 2
- PBDIKPJXZUFSTJ-UHFFFAOYSA-N methyl 2-[[7-[[5-(4-chlorophenyl)-1,2-oxazol-3-yl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(=NO1)C=C1C1=CC=C(Cl)C=C1 PBDIKPJXZUFSTJ-UHFFFAOYSA-N 0.000 description 2
- JNWHOOBDULSEOL-UHFFFAOYSA-N methyl 2-[[7-[[5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methylsulfanyl]-2,3-dihydro-1h-inden-4-yl]oxy]acetate Chemical compound C1=2CCCC=2C(OCC(=O)OC)=CC=C1SCC(=NO1)C=C1C1=CC=C(C(F)(F)F)C=C1 JNWHOOBDULSEOL-UHFFFAOYSA-N 0.000 description 2
- YPWVYYSFKLYBSW-UHFFFAOYSA-N methyl 2-[[8-[[3-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=CC=C1SCC(C=1)=CC=CC=1OCC1=CC=C(C(F)(F)F)C=C1 YPWVYYSFKLYBSW-UHFFFAOYSA-N 0.000 description 2
- SZIJBWDMKZLXJI-UHFFFAOYSA-N methyl 2-[[8-[[4-[(2,5-dichlorophenyl)methoxy]phenyl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC(Cl)=CC=C1Cl SZIJBWDMKZLXJI-UHFFFAOYSA-N 0.000 description 2
- MLNANIYHSUYOGU-UHFFFAOYSA-N methyl 2-[[8-[[4-[4-(trifluoromethyl)phenyl]phenyl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=C1 MLNANIYHSUYOGU-UHFFFAOYSA-N 0.000 description 2
- GSLLEYGJXMSGHZ-UHFFFAOYSA-N methyl 2-[[8-[[4-[5-(trifluoromethyl)pyridin-2-yl]phenyl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1C1=CC=C(C(F)(F)F)C=N1 GSLLEYGJXMSGHZ-UHFFFAOYSA-N 0.000 description 2
- VPLSUCWRJIYNEW-UHFFFAOYSA-N methyl 2-[[8-[[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=CC=C1SCC(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 VPLSUCWRJIYNEW-UHFFFAOYSA-N 0.000 description 2
- JDTILJJBRCBDAB-UHFFFAOYSA-N methyl 2-[[8-[[5-(4-chlorophenyl)-1,2-oxazol-3-yl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=CC=C1SCC(=NO1)C=C1C1=CC=C(Cl)C=C1 JDTILJJBRCBDAB-UHFFFAOYSA-N 0.000 description 2
- DQYSYWYICGJUHP-UHFFFAOYSA-N methyl 2-[[8-[[5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methylsulfanyl]-3,4-dihydro-2h-chromen-5-yl]oxy]acetate Chemical compound C1=2OCCCC=2C(OCC(=O)OC)=CC=C1SCC(=NO1)C=C1C1=CC=C(C(F)(F)F)C=C1 DQYSYWYICGJUHP-UHFFFAOYSA-N 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
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- C07C59/40—Unsaturated compounds
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- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
- C07C59/70—Ethers of hydroxy-acetic acid, e.g. substitutes on the ring
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- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D233/68—Halogen atoms
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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Description
Ova Patentna prijava zahtjeva prioritet prema US. privremenoj patentnoj prijavi broja. 60/370,508, podnesenoj 5. travnja, 2002. i prijavi 60/386,026, podnesenoj 5. lipnja, 2002.
Područje izuma
Ovaj izum se odnosi na spojeve i farmaceutske pripravke koji se mogu rabiti u liječenju stanja u kojima posreduju nuklearni hormonski receptori, odnosno konkretnije, na spojeve i farmaceutske pripravke koji mijenjaju aktivnost Peroksisom Receptora Aktivacije Proliferacije (PPAR).
Pozadina izuma
Hiperkolesterolemija, dislipidemija, dijabetes i gojaznost su dobro-poznati faktori rizika u nastanku ateroskleroze i koronarnih srčanih oboljenja. Bolesti su karakterizirane visokom razinom kolesterola i lipida u krvi. Količina kolesterola u krvi općenito ovisi o unosu kolesterola iz hrane preko probavila, i o biosintezi kolesterola u tijelu, posebno u jetri. Većina kolesterola u plazmi je vezana na apolipoprotein B- koji sadrži lipoproteine, kao što su lipoproteini male gustoće (LDL) i lipoproteini vrlo male gustoće (VLDL). Rizik nastanka koronarnih arterijskih oboljenja u čovjeka raste s porastom razine LDL i VLDL. Suprotno, visoke razine kolesterola vezane na lipoproteine velike gustoće (HDL) štite od koronarnih arterijskih oboljenja (Am. J. Med., 1977.;62:707-714).
Statini vjerojatno predstavljaju najvažniju skupinu lijekova koji snižavaju razinu lipida. Ovi spojevi inhibiraju HMG-CoA reduktazu koja je uključena u postupak kontrole razine u staničnoj biosintezi kolesterola. Tipični statini uključuju atorvastatin, lovastatin, pravastatin, i simvastatin. Učinkovitost ovih spojeva ovisi o regulaciji LDL receptora. Ostali važni antilipidemijski lijekovi uključuju fibrate kao što su gemfibril i klofibrat, spojeve za odvajanje žučne kiseline kao što su kolestiramin i kolestipol, probukol, i analoge nikotinske kiseline.
Do danas su razvijena mnogobrojna oralna antidijabetička sredstva. Hipoglikemijski lijek koji se najčešće rabi je sulfonilureja. Sulfonilureja se općenito rabi za pobuđivanje inzulina. Biguanid metformin se općenito rabi za povećanje osjetljivosti inzulina i smanjenje otpuštanja glukoze iz jetre. Akarboza se rabi za ograničenje hiperglikemije nakon obroka. Tiazolidin 2,4 dioni se rabe za poboljšanje djelovanja inzulina bez povećanja njegovog lučenja.
Gojaznost je kronična bolest koja je visoko učestala u modernom društvu i nije samo vezana uz društvenu sramotu, već također uz smanjenje životnog vijeka i mnogobrojne medicinske probleme, uključujući šećernu bolest, otpornost na inzulin, hipertenziju, hiperkolesterolemiju, tromboembolijske bolesti, i koronarna srčana oboljenja. Rissanen i sur., British Medical Journal, 301:835-837 (1990.). Liječenje gojaznosti predstavlja problem i još je nejasno da li pravilna prehrana pridonosi smanjenju dugotrajnog rizika rane smrti. Sljedeća važna stavka za gojaznost je fizička aktivnost. Općenito, vježbanje se ipak pokazalo samo kao djelomično uspješno u smanjenju tjelesne težine. Program koji uključuje i pravilnu prehranu i vježbanje kao i promjene navika je prihvaćen kao optimalan pristup u postupku gubitka tjelesne težine. Istraživanja su pokazala da kombinacija kontrolirane prehrane uz vježbanje dovodi do stvarnog gubitka masti dok prehranjuje nemasno tkivo.
Peroksisom Receptori Aktivacije Proliferacije (PPAR) su uključeni u mnogobrojne biološke procese i stadije bolesti uključujuću hiperkolesterolemiju, dislipidemiju, i dijabetes. PPAR su pripadnici nuklearnih receptora nadobitelji transkripcijskih faktora koji uključuju steroidne, tiroidne, i receptore vitamina D. Njiihova uloga je u kontroli ekspresije proteina koji reguliraju metabolizam lipida. Osim toga, PPAR aktiviraju masne kiseline i metaboliti masnih kiselina. Postoje tri PPAR podvrste PPAR α, PPAR β (također poznat kao PPAR δ), i PPAR γ. Svaki receptor pokazuje različit način tkivne ekspresije, i različito ih aktiviraju strukturno različiti spojevi. PPAR γ je, na primjer, najčešće pobuđen u adipoznom tkivu i u manjim razinama u skeletnim mišićima, srcu, jetri, probavilu, bubrezima, vaskularnom endotelu i glatkim mišićnim stanicama kao i u makrofagima. PPAR receptori su povezani i s regulacijom inzulinske osjetljivosti i razinom glukoze u krvi, diferencijacijom makrofaga, upalnim stanjima, i staničnom diferencijacijom. Prema tome, PPAR se povezuju uz gojaznost, dijabetes, karcinogenezu, hiperplaziju, aterosklerozu, dislipidemiju, i hiperkolesterolemiju.
Osim toga, PPARα agonisti snizuju plazma trigliceride i LDL kolesterol i zbog toga su korisni u liječenju hipertrigliceridemije, dislipidemije i gojaznosti. PPAR γ je vezan uz razvoj inzulin-neovisne šećerne bolesti (NIDDM), hipertenzije, koronarnih arterijskih bolesti, dislipidemije i određenih malignosti. Konačno, dokazano je da aktivacija PPAR β povisuje HDL razinu. (Leibowitz, WO97/28149, kolovoz 1997.). U zadnje vrijeme se potvrđuje da PPAR β izabrani agonisti pokazuju povećanje ovisno o dozi u serumu HDL-C i sniženje i LDL-C i VLDL-TG u insulin-otpornim rezus majmunima srednjih godina. (W. R. Oliver i sur., PNAS, v. 98, pp. 5306-5311, 2001.).
Još se uvijek smatra da antilipidemijska, antidijabetička i sredstva protiv gojaznosti imaju ne-jednoliku učinkovitost. Učinkovitost antidijabetičke i antilipidemijske terapije je ograničena, djelomično zbog slabe prihvatljivosti pacijenta zbog neočekivanih popratnih djelovanja. Ovi popratni učinci uključuju dijareju i gastrointestinalne poremećaje, i u slučaju antidijabetika, edem, hipoglikemiju i hepatoksičnost. Osim toga, svaka vrsta lijeka ne djeluje jednako u svih pacijenata.
S obzirom na gore navedene razloge, postoji potreba za novim antilipidemijskim, antidijabetičkim i sredstvima protiv gojaznosti koji će se moći rabiti pojedinačno ili u kombinaciji. Osim toga, aktivacija višestrukih PPAR, na primjer, PPARβ samog ili u kombinaciji s istovremenom aktivacijom PPAR α i/ili PPAR γ, može biti poželjna u oblikovanju liječenja dislipidemije u kojoj je HDL povišen i LDL snižen.
Sažetak izuma
Ovaj izum prikazuje spojeve koji imaju sposobnost promjene PPAR aktivnosti. Spojevi iz ovog izuma su opisani Formulom I:
[image]
kao i farmaceutski prihvatljive soli, gdje:
X0 i Xl su neovisno odsutni, O, S, -CH2-, -CH2-CH2-, -CH=CH-, -CH≡CH-, -S(O)2-, ili -S(O)-;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani aril ili heteroaril, uz uvjete da Arl nije tiazolil ili oksazolil;
[image] je odsutan; ili ako je prisutan, [image] je zasićeni ili nezasićeni ugljikovodikov lanac koji je supstituiran ili nesupstituiran, a spomenuti lanac ima od 1 do 4 atoma tako da [image] , Ar1, X1, (CH2)r i Ar2, zajedno tvore lanac od pet do osam članova;
R1 i R2 su izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2R5, ili -NR6R7, ili zajedno s atomima na koje su vezani tvore lanac od pet do osam članova;
R3 i R4 izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
uz mogućnost da bar jedan od R1-R4 predstavlja H, niži alkil, niži alkoksi, haloalkil, -O-(CH2)mCF3, halogen, nitro, cijano, -OH, -SH, -CF3, -S(O)palkil, S(O)paril, -(CH2)mOR5, -(CH2)mNR6R7, ili -NR6R7;
R5 je vodik, alkil, alkenil, alkinil, ili aril;
R6 i R7 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, ili R6 i R7 zajedno s atomima na koje su vezani tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
m je 0 do 5;
p je 0, l, ili 2;
q je 0 do 6; i
r je 0 do 6.
Izum se također odnosi na spojeve formule (II):
[image]
i na farmaceutski prihvatljive soli, gdje:
X0 i Xl su neovisno odsutni, O, S, -CH2-, -CH2-CH2-, -CH=CH-, -CH≡CH-, -S(O)2-, ili -S(O)-;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani aril ili heteroaril, uz uvjete da Arl nije tiazolil ili oksazolil;
[image] je odsutan; ili ako je prisutan, [image] je zasićeni ili nezasićeni ugljikovodikov lanac koji je supstituiran ili nesupstituiran, a spomenuti lanac ima od 1 do 4 atoma tako da [image] , Ar1, X1, (CH2)r, i Ar2, zajedno tvore lanac od pet do osam članova;
R3 i R4 izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
R5 je vodik, alkil, alkenil, alkinil, ili aril;
R6 i R7 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, SO2alkil, -SO2aril, ili R6 i R7 zajedno s atomima na koje su vezani tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
[image] zasićeni ili nezasićeni, supstituirani ili nesupstituirani ugljikovodikov lanac ili ugljikovodikov-heteroatomski lanac koji ima od 3 do 6 atoma i u kojem je ugljikov atom na poziciji 2 povezan s ugljikovim atomom na poziciji 3 i tvore lanac od pet do osam članova;
m je 0 do 5;
p je 0 do 2;
q je 0 do 6; i
r je 0 do 6.
Ostala ostvarenja ovog izuma se odnose na postupke liječenja, prevencije ili kontrole hiperkolesterolemije i dislipidemije u sisavaca. Postupak uključuje primjenu terapijski djelotvorne količine spojeva iz ovog izuma na sisavce kojima su potrebni. Osim toga, spojevi iz ovog izuma su također korisni u postupcima koji se rabe u izumu za liječenje, prevenciju ili kontrolu gojaznosti, poremećaja prehrane, hiperglikemije, ateroskleroze, hipertrigliceridemije, hiperinzulinemije i dijabetesa. Također, spojevi iz ovog izuma su korisni u postupcima smanjenja apetita u sisavaca, mijenjanju razina leptina u sisavaca i liječenju pacijenata s poremećajima razine glukoze vezanim uz cirkulirajuće glukokortikoide, hormone rasta, katekolamine, glukagon, ili paratiroidne hormone.
Za svako stanje bolesti koje se može liječiti, spriječiti, ili kontrolirati postupcima iz ovog izuma, primjenjuje se terapijski djelotvorna količina spojeva iz ovog izuma na sisavce kojima su potrebni.
Još jedno dostignuće izuma je prikazivanje postupka za pripremu spojeva s Formulom I-II, ili farmaceutski prihvatljivih soli. Takav postupak uključuje reakciju
[image]
u otapalu uz prisustvo baze kao što je cezijev karbonat s
[image]
gdje
X0 predstavlja OH ili SH;
n, q, r, R1, R2, R3, R4, X1, [image] , Ar1, Ar2 su kao što je gore navedeno za Formulu I;
R11 je niži alkil; i
X je vodik.
U dostignuće ovog izuma se ubraja i alternativni postupak za pripremu spojeva Formule I-II, ili farmaceutski prihvatljivih soli. Takav postupak uključuje reakciju
[image]
gdje je X halid, R1-R4 imaju bilo koje prije navedeno značenje i R11 je niži alkil s:
[image]
gdje --- predstavlja vezu ili je odsutan i gdje su n, q, r, X0, X1, [image] , Ar1, Ar2 kao što je gore navedeno za Formulu I;
u prisutnosti katalizatora kao što je paladij katalizator kako bi se dobio
[image]
gdje --- predstavlja vezu ili je odsutan.
Dvostruka veza se može prema potrebi ukloniti, na primjer, hidrogenacijom i rezultirajući ester je najbolje hidrolizirati kako bi se dobili spojevi Formule I ili II.
Kao ostvarenje ovog izuma smatra se i postupak za pripremu spojeva formule I-4 koja je:
[image]
ili farmaceutski prihvatljivih soli, što uključuje:
a) pretvorbu fenola 1A u tiocijanat 1B;
[image]
(b) alkilaciju fenol skupine tiocijanata 1B u acetoksiester 1C;
[image]
(c) redukciju tiocijanatne skupine iz 1C kako bi se dobio tiol 1D;
[image]
(d) alkilaciju tiola 1D s kloridom 3C kako bi se dobio 4a;
[image]
(e) saponifikaciju skupine estera iz 4a kako bi se dobio I-4;
gdje
R1 je vodik ili zajedno s R2 tvori karbociklički prsten od 5 članova;
R2 je metoksi ili zajedno s R1 tvori karbociklički prsten od 5 članova;
R3 je vodik ili metil;
R4 je vodik;
X1 je odsutan ili O; i
r je 0 ili 1.
Detaljan opis izuma
U tekstu se rabe sljedeće definicije, osim ako nije drugačije navedeno: halo je fluoro, kloro, bromo, ili jodo. Alkil, alkoksi, alkenil, alkinil, itd. označavaju i ravne i razgranate skupine; ali referenca koja se odnosi na pojedinačni radikal kao što je "propil" se odnosi samo na ravnolančani radikal, izomer razgranatog lanca poput "izopropila" je posebno naznačen.
Pojam "alkil" koji se ovdje primjenjuje se odnosi na ravne ili razgranate ugljikovodike od 1 do 11 ugljikovih atoma i uključuje, na primjer, metil, etil, n-propil, izopropil, n-butil, sec-butil, izobutil, tert-butil, n-pentil, n-heksil, i slično. Alkilna skupina također može biti supstituirana s jednim ili više supstituenata izabranih između nižih alkoksila, nižih tioalkoksila, -O(CH2)1-5CF3, halogena, nitro, cijano, =O, =S, -OH, -SH, -CF3, -OCF3, -CO2H, -CO2C1-C6 alkila, -NH2, -NHC1-C6 alkila, -CONR'R", ili -N(C1-C6alkil)2 gdje su R' i R" neovisno alkil, alkenil, alkinil, aril, ili skupa povezani i tvore prsten od 4 do 7 članova. Alkilne skupine koje se preferiraju imaju od 1 do 6 ugljikovih atoma (C1-C6alkil).
Pojam "niži alkil" koji se ovdje primjenjuje se odnosi na podskupinu alkila i uključuje ravne ili razgranate radikale ugljikovodika koji imaju od 1 do 6 ugljikovih atoma i uključuje, na primjer, metil, etil, n-propil, izopropil, n-butil, sec-butil, izobutil, tert-butil, n-pentil, n-heksil, i slično. Opcijski se niži alkil odnosi i na "C1-C6alkil."
Pojam "haloalkil" koji se ovdje primjenjuje se odnosi na radikale nižih alkila, koji su gore definirani, stvarajući bar jedan halogeni supstituent, na primjer, klorometil, fluoroetil, trifluorometil, ili 1,1,1-trifluoroetil i slično. Haloalkil može također uključivati perfluoroalkil gdje su svi vodici nižih alkilnih skupina zamjenjeni s atomima fluorina.
Pojam "alkenil" označava ravne ili razgranate nezasićene radikale ugljikovodika koji sadrže od 2 do 12 ugljikovih atoma i uključuje, na primjer, etenil, 1-propenil, 2-propenil, 1-butenil, 2-butenil, 1-pentenil, 2-pentenil, 3-metil-3-butenil, 1-heksenil, 2-heksenil, 3-heksenil, 3-heptenil, 1-oktenil, 1-nonenil, 1-decenil, 1-undecenil, 1-dodecenil, i slično.
Pojam "alkinil" označava ravne ili razgranate radikale ugljikovodika koji sadrže od 2 do 12 ugljikovih atoma koji imaju bar jednu trostruku i uključuje, na primjer, 1-propinil, 1-butinil, 3-butinil, 1-pentinil, 3-pentinil, 3-metil-3-butinil, 1-heksinil, 3-heksinil, 3-heptinil, 1-oktinil, 1-noninil, 1-decinil, 1-undecinil, 1-dodecinil, i slično.
Pojam "alkilen" koji se ovdje primjenjuje se odnosi na bivalentnu skupinu nastalu uklanjanjem dva atoma vodika iz ravnog ili razgranatog lanca zasićenih ugljikovodika koji sadrže od 1 do 10 ugljikovih atoma, na primjer metilen, 1,2-etilen, 1,1-etilen, 1,3-propilen, 2,2-dimetilpropilen, i slično. Skupine alkilena iz ovog izuma mogu biti prema potrebi supstituirane. Skupine alkilena također mogu biti supstituirane s jednim ili više supstituenata izabranih između nižih alkila, nižih alkoksila, nižih tioalkoksila, -O(CH2)1-5CF3, halogena, nitro, cijano, =O, =S,-OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkila, -NH2, -NHC1-C6 alkila, -CONR'R", ili -N(C1-C6alkil)2 gdje su R' i R" neovisno alkil, alkenil, alkinil, aril, ili skupa povezani i tvore prsten od 4 do 7 članova. Alkilne skupine koje se preferiraju imaju od 1 do 6 ugljikovih atoma (C1-C6alkil).
Pojam "cikloalkil" označava prsten ugljikovodika koji sadrži od 3 do 12 ugljikovih atoma, na primjer, ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, cikloktil, dekalinil, norpinanil, i adamantil. Tamo gdje je moguće, skupina cikloalkila može sadržavati dvostruku vezu, na primjer, 3-cikloheksen-1-il. Cikloalkilni prsten može biti nesupstituiran ili supstituiran s 1 do 3 supstituenta izabrana između alkila, alkoksi, tioalkoksi, hidroksi, nitro, halogena, amino, alkila i dialkilamino, formila, karboksila, CN, -NH-CO-R', -CO-NHR'-, -CO2R', -COR', arila, ili heteroarila, gdje su alkil, aril, i heteroaril kao što je ovdje definirano. Primjeri supstituiranih cikloalkilnih skupina uključuju fluorociklopropil, 2-jodociklobutil, 2,3-dimetilciklopentil, 2,2-dimetoksicikloheksil, i 3-fenilciklopentil.
Pojam "heteroatom" koji se ovdje rabi predstavlja kisik, dušik, ili sumpor (O, N, ili S) kao i sulfoksil ili sulfonil (SO ili SO2) osim ako nije drugačije navedeno.
Pojam "heterocikloalkil" označava monocikličke, spojene, povezane, ili spiro bicikličke sustave heterocikličkog prstena. Monociklički heterociklički prsten sadrži od oko 3 do 12 atoma u prstenu, gdje je od 1 do 5 heteroatoma izabranih između N,O, i S, i preferira se od 3 do 7 atoma članova prstena. Biciklički heterociklički prsten sadrži od 7 do 17 atoma, preferira se 7 do12 atoma članova prstena. Biciklički heterociklički prsten sadrži od oko 7 do oko 17 atoma, preferira se 7 do12 atoma u prstenu. Biciklički heterociklički prstenovi mogu biti spojeni, spiro, ili povezani prstenasti sustavi. Primjeri heterocikličkih skupina uključuju cikličke etere (oksirane) kao što su etilenoksidi, tetrahidrofurani, dioksani, i supstituirane cikličke etere, gdje su supstituenti isti kao što je prije navedeno za alkilne i cikloalkilne skupine. Tipični supstituirani ciklički eter uključuje propilenoksid, feniloksiran (oksid stirena), cis-2-buten-oksid (2,3-dimetiloksiran), 3-klorotetrahidrofuran; 2,6-dimetil-1,4-dioksan, i slično. Heterociklički spojevi koji sadrže dušik su skupine poput pirolidina, piperidina, piperazina, tetrahidrotriazina, tetrahidropirazola, i supstituirane skupine poput 3-aminopirolidina, 4-metilpiperazin-1-il, i slično. Tipični heterociklički spojevi koji sadrže sumpor uključuju tetrahidrotiofen, dihidro-1,3-ditiol-2-il, i heksahidrotiepin-4-il. Ostali heterociklički spojevi koji se obično primjenjuju uključuju dihidro-oksatiol-4-il, tetrahidro-oksazolil, tetrahidro-oksadiazolil, tetrahidro-dioksazolil, tetrahidro-oksatiazolil, heksahidrotriazinil, tetrahidro-oksazinil, morfolinil, tiomorfolinil, tetrahidropirimidinil, dioksolinil, oktahidrobenzofuranil, oktahidrobenzimidazolil, i oktahidrobenzotiazolil. U heterocikličke spojeve koji sadrže sumpor spadaju i oksidirani sumporni heterociklički spojevi koji sadrže SO ili SO2 skupine. Primjeri uključuju sulfoksidne i sulfonske oblike tetrahidrotiofena.
Pojam "ugljikovodični lanac" koji se ovdje rabi se odnosi na ravni ugljikovodik koji ima od 2 do 6 ugljikovih atoma. Ugljikovodični lanac se opcijski može supstituirati s jednim ili više supstituenata izabranih između nižih alkila, nižih alkoksila, nižih tioalkoksila, -O(CH2)0-2CF3, halogena, nitro, cijano, =O, =S,-OH, -SH, -CF3, -CO2H, -CO2(C1-C6 alkila), -NH2, -NHC1-C6 alkila, -CONR'R", ili -N(C1-C6alkil)2 gdje su R' i R" neovisno alkil, alkenil, alkinil, aril, ili skupa povezani i tvore prsten od 4 do 7 članova.
Pojam "aril" označava ciklički ili policiklički aromatski prsten koji ima od 5 do 12 ugljikovih atoma, i nesupstituiran je ili supstituiran s do 4 skupine izabrane između C1-C6 alkila, cikloalkila, heteroarila, dialkilaminoalkoksi, ili onih koje su prije navedene kao supstituenti za alkil. Pojam aril uključuje i jednovalentne oblike, na primjer gdje je Ar2 aril, i bivalentne oblike, na primjer gdje je Ar1 aril. Primjeri arilnih skupina uključuju, ali bez ograničenja, fenil, bifenil, naftil, 2-klorofenil, 3-klorofenil, 4-klorofenil, 2-metilfenil, 3-metilfenil, 4-metilfenil, 2-metoksifenil, 3-metoksifenil, 4-metoksifenil, 2-kloro-3-metilfenil, 2-kloro-4-metilfenil, 2-kloro-5-metilfenil, 3-kloro-2-metilfenil, 3-kloro-4-metilfenil, 4-kloro-2-metilfenil, 4-kloro-3-metilfenil, 5-kloro-2-metilfenil, 2,3-diklorofenil, 2,5-diklorofenil, 3,4-diklorofenil, 2,3-dimetilfenil, 3,4-dimetilfenil, 4-trifluorometil i slično.
Pojam "heteroaril" označava aromatski mono-, bi-, ili, policiklički prsten koji uključuje jedan ili više (tj. 1-4) heteroatoma izabranih između N, O, i S. Pojam heteroaril uključuje i monovalentne oblike, na primjer gdje je Ar2 heteroaril, i bivalentne oblike, na primjer gdje je Ar1 heteroaril. Podrazumijeva se da je heterociklički spoj opcijski supstituiran s do 4 skupine izabrane između C1-C6 alkila, cikloalkila, heteroarila, dialkilaminoalkoksi, ili onih koje su prije navedene kao supstituenti za alkil. Primjeri prikladnih monocikličkih heteroarila uključuju, ali bez ograničenja, supstituirani ili nesupstituirani tienil, furanil, pirolil, imidazolil, pirazolil, izotiazolil, izoksazolil, triazoil, tetrazolil, piridinil, pirazinil, pirimidinil, piperidinil, pirolidinil, piperazinil, azetidinil, aziridinil, morfolinil, tietanil, oksetaril. Monociklički diheterociklički spojevi koji se preferiraju uključuju, ali bez ograničenja, 1-, 2-, 4-, ili 5-imidazolil, 1-, 3-, 4-, ili 5-pirazolil, 3-, 4-, ili 5-izotiazolil, 3-, 4-, ili 5- izoksazolil, 1, 3-, ili 5-triazolil, 1-, 2-, ili 3-tetrazolil, 2-pirazinil, 2-,4-, ili 5- pirimidinil, 1-ili 2-piperazinil, 2-, 3-, ili 4-morfolinil. Primjeri prikladnih bicikličkih i policikličkih heteroarilnih skupina uključuju, ali bez ograničenja, 1-, 2-, 3-, 5-, 6-, 7-, ili 8-indolizinil, 1-, 3-, 4-, 5-, 6-, ili 7-izoindolil, 2-, 3-, 4-, 5-, 6-, ili 7-indolil, 2-, 3-, 4-, 5-, 6-, ili 7-indazolil, 2-, 4-, 5-, 6-, 7-, ili 8-purinil, 1-, 2-, 3-, 4-, 6-, 7-, 8-, ili 9-kinolizinil, 2-, 3-, 4-, 5-, 6-, 7-, ili 8-kinolil, 1-, 3-, 4-, 5-, 6-, 7-, ili 8-izokinolil, 1-, 4-, 5-, 6-, 7-, ili 8-ftalazinil, 2-, 3-, 4-, 5-, ili 6-naftiridinil, 2-, 3-, 5-, 6-, 7-, ili 8-kinazolinil, 3-, 4-, 5-, 6-, 7-, ili 8- kinolinil, 2-, 4-, 6-, ili 7-pteridinil, 1-, 2-, 3-, 4-, 5-, 6-, 7-, ili 8-4aH karbazolil, 1-, 2-, 3-, 4-, 5-, 6-, 7-, ili 8-karbzaolil, 1-, 3-, 4-, 5-, 6-, 7-, 8-, ili 9-karbolinil, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, ili 10-fenantridinil, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, ili 9-akridinil, 1-, 2-, 4-, 5-, 6-, 7-, 8-, ili 9-perimidinil, 2-, 3-, 4-, 5-, 6-, 8-, 9-, ili 10-fenatrolinil, 1-, 2-, 3-, 4-, 6-, 7-, 8-, ili 9-fenazinil, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, ili 10-fenotiazinil, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, ili 10-fenoksazinil, 2-, 3-, 4-, 5-, 6-, ili 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, ili 10-benzisoknolinil, 2-, 3-, 4-, ili tieno[2,3-b]furanil, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, ili 11-7H-pirazino[2,3-c]karbazolil, 2-, 3-, 5-, 6-, ili 7-2H-furo[3,2-b]-piranil, 2-, 3-, 4-, 5-, 7-, ili 8-5H-pirido[2,3-d]-o-oksazinil, 1-, 3-, ili 5-1H-pirazolo[4,3-d]-oksazolil, 2-, 4-, ili 5-4H-imidazo[4,5-d]tiazolil, 3-, 5-, ili 8-pirazino[2,3-d]piridazinil, 2-, 3-, 5-, ili 6-imidazo(2,1-b]tiazolil, 1-, 3-, 6-, 7-, 8-, ili 9-furo[3,4-c]cinolinil, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, ili 11-4H-pirido[2,3-c]karbazolil, 2-, 3-, 6-, ili 7-imidazo[1,2-b][1,2,4]triazinil, 7-benzo[b]tienil, 2-, 4-, 5-, 6-, ili 7-benzoksazolil, 2-, 4-, 5-, 6-, ili 7-benzimidazolil, 2-, 4-, 5-, 6-, ili 7-benzotiazolil, 1-, 2-, 4-, 5-, 6-, 7-, 8-, ili 9-benzoksapinil, 2-, 4-, 5-, 6-, 7-, ili 8-benzoksazinil, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, ili 11-1H-pirolo[1,2-b][2]benzazapinil. Tipične povezane heteroarilne skupine uključuju, ali bez ograničenja 2-, 3-, 4-, 5-, 6-, 7-, ili 8-kinolinil, 1-, 3-, 4-, 5-, 6-, 7-, ili 8-izokinolinil, 2-, 3-, 4-, 5-, 6-, ili 7-indolil, 2-, 3-, 4-, 5-, 6-, ili 7-benzo[b]tienil, 2-, 4-, 5-, 6-, ili 7-benzoksazolil, 2-, 4-, 5-, 6-, ili 7-benzimidazolil, 2-, 4-, 5-, 6-, ili 7-benzotiazolil.
Pojam "ugljikovodikov-heteroatomski lanac" koji se ovdje rabi se odnosi na ugljikovodikov lanac u kojem je jedan ili više ugljikovih atoma zamjenjeno s heteroatomom. Ugljikovodikov-heteroatomski lanac se može prema potrebi supstituirati s jednim ili više supstituenata izabranih između nižih alkila, nižih alkoksila, nižih tioalkoksila, -O(CH2)0-2CF3, halogena, nitro, cijano, =O, =S, -OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkila, -NH2, -NHC1-C6 alkila, -CONR'R", ili -N(C1-C6alkil)2 gdje su R' i R" neovisno alkil, alkenil, alkinil, aril, ili skupa povezani i tvore prsten od 4 do 7 članova.
Pojam "heteroalkilen" koji se ovdje rabi se odnosi na prije definirane radikale alkilena koji uključuju jedan ili više heteroatoma kao što su kisik, sumpor, ili dušik (valencija je podešena s vodikom ili kisikom) u ugljikovom lancu ili na kraju ugljikovog lanca.
Pojmovi "niži alkoksi" i "niži tioalkoksi" koji se ovdje primjenjuju se odnose na O-alkil ili S-alkil s 1 do 6 ugljikovih atoma kao što je prije navedeno za "niže alkile."
Pojam "cikloalkenil" označava cikloalkilnu skupinu koja ima jedan ili više ugljik-ugljik duplikata. Primjeri uključuju ciklobuten, ciklopenten, cikloheksen, ciklohepten, ciklobutadien, ciklopentadien, i slično.
Simbol "[image] " označava vezu prema skupini gdje je oblikovan prsten od 4 do 8 članova. Uglavnom će se ovaj simbol pojavljivati u parovima.
Kada je veza predstavljena linijom kao što je "---" tada znači da veza može biti odsutna ili prisutna omogućujući da je krajnji spoj stabilan i zadovoljavajuće valencije.
Pojam "pacijent" označava sve sisavce uključujući čovjeka. Primjeri za pacijenta uključuju ljude, krave, pse, mačke, koze, ovce, svinje i zečeve.
"Terapijski djelotvorna količina" je količina spoja iz ovog izuma koja kada se primjeni na pacijenta poboljšava simptome dislipidemije, inzulin neovisne šećerne bolesti, gojaznosti, hiperglikemije, hiperkolesterolemije, hiperlipidemije, ateroskleroze, hipertrigliceridemije, hiperinzulinemije, poremećaja razine glukoze povezanih s cirkulirajućim glukokortikoidima, hormonima rasta, katekolaminima, glukagonom, ili paratiroidnim hormonom. Osim toga, "terapijski djelotvorna količina" količina spoja iz ovog izuma koja kada se primjeni na pacijenta poboljšava simptome poremećene ishrane, smanjenog apetita, ili mijenja razinu leptina.
Pojam "farmaceutski prihvatljiva sol" se odnosi na relativno ne-toksične, anorganske i organske soli spojeva iz ovog izuma nastale dodatkom baze ili kiseline. Ove soli se mogu prirediti in situ za vrijeme finalizacije i pročišćavanja spojeva ili odvojenom reakcijom pročišćenih spojeva u njihovom slobodnom obliku s prikladnom organskom ili anorganskom bazom ili kiselinom i izolacijom tako oblikovane soli. Tipične soli uključuju hidrobromidne, hidrokloridne, sulfatne, bisulfatne, nitratne, acetatne, oksalatne, valeratne, oleatne, palmitatne, stearatne, lauratne, boratne, benzoatne, laktatne, fosfatne, tozilatne, citratne, maleatne, fumaratne, sukcinatne, tartratne, naftilat mezilatne, glukoheptonatne, laktobionatne, i laurilsulfonatne soli, i slično. Ovdje također spadaju kationi koji se baziraju na alkalijskim i zemnoalkalijskim metalima, kao što su natrij, litij, kalij, kalcij, magnezij, i slično, kao i ne-toksični amonijak, kvartarni amonijak i amino kationi uključujući, ali bez ograničenja amonijak, tetrametilamonijak, tetraetilamonijak, metilamin, dimetilamin, trimetilamin, trietilamine, ethylamin, i slično. (Vidi, na primjer, Berge S. M., i sur., "Pharmaceutical Salts," J. Pharm. Sci., 1977.; 66:1-19, koji je ovdje uključen referencom.) Oblik slobodne baze se može obnoviti reakcijom oblika soli s bazom. Dok se slobodna baza može razlikovati od oblika soli s obzirom na fizikalna svojstva, kao što je topivost, soli su jednake njihovoj odgovarajućoj slobodnoj bazi zbog svrhe ovog izuma.
Spojevi iz ovog izuma su opisani Formulom I:
[image]
i farmaceutski prihvatljive soli, gdje:
X0 i Xl su neovisno odsutni, O, S, -CH2-, -CH2-CH2-, -CH=CH-, -CH≡CH-, -S(O)2-, ili -S(O)-;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani aril ili heteroaril, uz uvjete da Arl nije tiazolil ili oksazolil;
[image] je odsutan; ili ako je prisutan, [image] je zasićeni ili nezasićeni ugljikovodikov lanac koji je supstituiran ili nesupstituiran, a spomenuti lanac ima od 1 do 4 atoma tako da [image] , Ar1, X1, (CH2)r i Ar2, zajedno tvore lanac od pet do osam članova;
R1 i R2 su izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2R5, ili -NR6R7, ili zajedno s atomima na koje su vezani tvore lanac od pet do osam članova;
R3 i R4 izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
uz mogućnost da bar jedan od R1-R4 predstavlja H, niži alkil, niži alkoksi, haloalkil, -O-(CH2)mCF3, halogen, nitro, cijano, -OH, -SH, -CF3, -S(O)palkil, S(O)paril, -(CH2)mOR5, -(CH2)mNR6R7, ili -NR6R7;
R5 je vodik, alkil, alkenil, alkinil, ili aril;
R6 i R7 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, ili R6 i R7 zajedno s atomima na koje su vezani tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
m je 0 do 5;
p je 0, 1, ili 2;
q je 0 do 6; i
r je 0 do 6.
U spojeva Formule I se preferira da su R1, R2, R3, i R4 izabrani između vodika, alkila, ili alkoksila. Još je povoljnije da su R2 i R3 vodik; i da su R1 i R4 alkil ili alkoksi. U određenim ostvarenjima Formule I koja se preferiraju, R2 i R3 su vodik; R1 je alkil; i R4 je alkoksi. Alkoksi koji se preferira uključuje metoksi, etoksi, izopropoksi, n-propoksi, t-butoksi, n-butoksi, ili izobutoksi. Slično, Similarly, alkil koji se preferira uključuje metil, etil, izopropil, n-propil, t-butil, n-butil, ili izobutil. U najpovoljnijim ostvarenjima Formule I, q je 1, Ar1 je fenil, X1 je odsutan, r je 0, V1 je odsutan, i Ar2 je 4-trifluorometilfenil.
U spojeva Formule I, preferira se da je [image] (CH2)t pri čemu je t od 1 do 4.
Osim toga, [image] se po potrebi može supstituirati s bar jednim supstituentom, pri čemu supstituent uključuje ali bez ograničenja niže alkile, niže alkoksile, niže tioalkoksile, -O(CH2)0-2CF3, halogen, nitro, cijano, =O, =S, -OH, -SH, -CF3, -OCF3, -CO2H, -CO2C1-C6 alkil, -NH2, -NHC1-C6 alkil, -CONR'R", ili -N(C1-C6alkil)2 gdje su R' i R" neovisno alkil, akenil, alkinil, aril, ili zajedno tvore prsten od 4 do 7 članova.
Pri ostvarenju Formule I koje se preferira, R1 i R2 su povezani i čine prsten od pet do sedam članova koji sadrži Formulu II. Takav prsten uključuje, na primjer, cikloalkilni, arilni, heterocikloalkilni, ili heteroarilni prsten gdje svaki takav prsten može po potrebi biti supstituiran kao što je prije navedeno.
[image]
i farmaceutski prihvatljive soli, gdje:
X0 i Xl su neovisno odsutni, O, S, -CH2-, -CH2-CH2-, -CH=CH-, -CH≡CH-, -S(O)2-, ili -S(O)-;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani aril ili heteroaril, uz uvjete da Arl nije tiazolil ili oksazolil;
[image] je odsutan; ili ako je prisutan, [image] je zasićeni ili nezasićeni ugljikovodikov lanac koji je supstituiran ili nesupstituiran, a spomenuti lanac ima od 1 do 4 atoma tako da [image] , Ar1, X1, (CH2)r i Ar2, zajedno tvore lanac od pet do osam članova;
R3 i R4 izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
R5 je vodik, alkil, alkenil, alkinil, ili aril;
R6 i R7 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, SO2alkil, -SO2aril, ili R6 i R7 zajedno s atomima na koje su vezani tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
[image] zasićeni ili nezasićeni, supstituirani ili nesupstituirani ugljikovodikov lanac ili ugljikovodikov-heteroatomski lanac koji ima od 3 do 6 atoma i u kojem je ugljikov atom na poziciji 2 povezan s ugljikovim atomom na poziciji 3 i tvore lanac od pet do osam članova;
m je 0 do 5;
p je 0 do 2;
q je 0 do 6; i
r je 0 do 6.
Preferira se da je, [image] -CH2CH2CO-O-, -CH2-CH2-O-CO-, -CH2-CH2-CH2-CH2-, -HC=CH-HC=CH-, -N=CH-HC=CH-, -HC=N-HC=CH-, -HC=CH-N=CH-, -HC=CH-HC=N-, -CH2-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-O-CH2-CH2-, -CH2-HC=CH-CH2-, -CH2-HC=CH-, -CH2CH2-NR4-CH2-, -COCH=CH-O-, -O-CH=CH-CO-, -CH=CH-NR4-, -NR4-CH=CH-, -CH=CH-CH2-, -CH2-CH2-NR4-, -NR4-CH2-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, -CH2-CH2-CO-, -CH2-CO-CH2-, -CO-CH2-CH2-, -CH2-CH2-CH2-CO-, -CO-CH2-CH2-CH2-, -CH2-CO-CH2-CH2-, -CH2-CH2-CO-CH2, -CH2-CH2-CH2-NR4-, -NR4-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-, -CO-NR4-CH2-CH2-, NR4CO-CH2-CH2-, -CH2-CH2-NR4-CO-, ili -CH2-CH2-CO-NR4-. Podrazumijeva se da je atom koji je najviše lijevo iz ovih skupina vezan na atom označen kao "3" u Formuli I a atom koji je najviše desno iz ovih skupina vezan na atom označen kao "2" u Formuli I.
U prikazanom dostignuću je [image] opcijski supstituiran s 1 ili više supstituenata izabranih iz skupine koju čine niži alkili, niži alkoksili, niži tioalkoksili, -O(CH2)1-5CF3, halogen, nitro, cijano, =O, =S, -OH, -SH, -CF3, -CO2H, -CO2C1-C6 alkil, -NH2, -NHC1-C6 alkil, -OCH2O-, i -N(C1-C6alkil)2.
U spojeva Formule II se preferira da su R3 i R4 izabrani između vodika, alkila, ili alkoksila. Još je povoljnije da su R3 i R4 vodik; a [image] je zasićeni ili nezasićeni, nesupstituirani ugljikovodikov lanac koji ima od 3 do 6 atoma i u kojem je ugljikov atom na poziciji 2 povezan s ugljikovim atomom na poziciji 3 i tvore lanac od pet do osam članova kao što je ciklopentilni ili cikloheksilni prsten. U ostvarenju Formule II koje se najviše preferira, q je 1, Ar1 je fenil, X1 je O, r je 1, V1 je odsutan, i Ar2 je 4-trifluorometilfenil.
Također se u ovom dostignuću preferira da je [image] (CH2)t pri čemu je t od 1 do 4.
Osim toga, [image] se po potrebi može supstituirati s bar jednim supstituentom, pri čemu supstituent uključuje ali bez ograničenja niže alkile, niže alkoksile, niže tioalkoksile, -O(CH2)0-2CF3, halogen, nitro, cijano, =O, =S, -OH, -SH, -CF3, -OCF3, -CO2H, -CO2C1-C6 alkil, -NH2, -NHC1-C6 alkil, -CONR'R", ili -N(C1-C6alkil)2 gdje su R' i R" neovisno alkil, akenil, alkinil, aril, ili zajedno tvore prsten od 4 do 7 članova.
Primjeri spojeva Formule I i Formule II uključuju
[4-(Bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[4-(Bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octena kiselina;
[2-Metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(2',4',6'-trimetil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[4-(4'-Kloro-3'-trifluorometil-bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octena kiselina;
[4-(2',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[4-(3',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(3'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[4-(4'-Fluoro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[7-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octena kiselina;
[4-(4-Benziloksi-benzilsulfanil)-2-metil-fenoksi]-octena kiselina;
{5-Metoksi-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octena kiselina;
{2-Metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octena kiselina;
[5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-3-ilmetilsulfanil)-fenoksi]-octena kiselina;
[4-(9H-Fluoren-2-ilmetilsulfanil-2-metil-fenoksi]-octena kiselina;
{[5-Metoksi-2-metil-4-(4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octena kiselina;
{5-Metoksi-2-metil-4-[6-(4-trifluorometil-fenil)-piridin-3-ilmetilsulfanil]-fenoksi}-octena kiselina;
[5-Kloro-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[3-Metoksi-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
{2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octena kiselina;
{5-Metoksi-2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octena kiselina;
{2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octena kiselina;
{2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octena kiselina;
{7-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
[5-Metil-7-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octena kiselina;
(4-{4-[2-(3-Fluoro-fenil)-vinil]-benzilsulfanil}-5-metoksi-2-metil-fenoksi)-octena kiselina;
{2-Metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octena kiselina;
{4-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octena kiselina;
{4-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octena kiselina;
{4-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octena kiselina;
{4-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octena kiselina;
{2-Metil-4-[4-(4-trifluorometoksi-benziloksi)-benzilsulfanil]-fenoksi}-octena kiselina;
{6-Metil-8-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octena kiselina;
{5-Kloro-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octena kiselina;
[5-hidroksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(3-metil-4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
{7-[4-(4-trifluorometil-benzil)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-5-metoksi-2-metil-fenoksi}-octena kiselina;
{2-Metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octena kiselina;
{5-Metoksi-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octena kiselina;
{7-[5-(4-Trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octena kiselina;
{2-Metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octena kiselina;
{5-Metoksi-2-metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octena kiselina;
[2-Metil-4-(4-fenoksi-benzilsulfanil)-fenoksi]-octena kiselina;
[7-(4'-Trifluorometil-bifenil-3-ilmetilsulfanil)-indan-4-iloksi]-octena kiselina;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-3-ilmetilsulfanil)-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4i-ilmetanesulfonil)-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetanesulfinil)-fenoksi]-octena kiselina;
[2-Propil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
{7-[3-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
(5-Metoksi-2-metil-4-{2-[1-(4-trifluorometil-benzil)-1H-indol-3-il]-etilsulfanil}-fenoksi)-octena kiselina;
[7-(4'-Trifluorometil-bifenil-2-ilmetilsulfanil)-indan-4-iloksi]-octena kiselina;
{5-Metoksi-2-metil-4-[2-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octena kiselina;
{4-[4-(4-Fluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octena kiselina;
{4-[4-(4-Kloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octena kiselina;
4-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octena kiselina;
{2-Metil-4-[4-(piridin-2-ilmetoksi)-benzilsulfanil]-fenoksi}-octena kiselina;
{5-Kloro-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octena kiselina;
{7-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{5-Metil-7-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-Fluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
[7-(4-Benziloksi-benzilsulfanil)-indan-4-iloksi]-octena kiselina;
{7-[4-(4-Kloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(3,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-Fluoro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-Trifluorometoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(4-Fluoro-2-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-(3,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[4-Metoksi-3-(4-trifluoroemtil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[3-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[2-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[3,5-Dikloro-4-(4-trifluorometil-benziloksi)-benzilsulfonil]-indan-4-iloksi}-octena kiselina;
{8-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octena kiselina;
{8-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octena kiselina;
{8-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octena kiselina;
{8-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octena kiselina;
{7-[5-(2-Kloro-fenil)-izoksazol-3-ilmetilsulfaniI]-indan-4-iloksi}-octena kiselina;
{7-[3-(2,6-Dikloro-fenil)-5-metil-izoksazol-4-ilmetilsulfanil]-indan-4-iloksi)-octena kiselina;
{7-[3-(4-Trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[2-(4'-Trifluorometil-bifenil-4-il)-etilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[2-(4'-Trifluorometil-bifenil-4-il)-etil]-indan-4-iloksi}-octena kiselina;
{5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-2,3-dihidro-benzofuran-4-iloksi}-octena kiselina;
[8-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-kroman-5-iloksi]-octena kiselina;
{8-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-kroman-5-iloksi}-octena kiselina;
{4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-2-metil-fenoksi}-octena kiselina;
{7-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octena kiselina;
{7-[3-(4-Kloro-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octena kiselina;
{5-Kloro-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octena kiselina;
2-[2-butil-4-({4-[4-(trifluorometil)fenil]fenil}metiltio)fenoksi]octena kiselina;
{6-metil-8-[4-(4-trifluorometil-benziloksi)-benzil-sulfanil]-kroman-5-iloksi}-octena kiselina;
{4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-5,6,7,8-tetrahidro-naftalen-1-iloksi}-octena kiselina;
(4-{2-Butil-5-kloro-1-[4-(1-cijano-ciklopentil)-benzil]-1H-imidazol-4-ilmetilsulfanil}-2-metil-fenoksi)-octena kiselina;
[4-(5-Bifenil-4-il-2-tiofen-2-il-4,5-dihidro-oksazol-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
{4-[2-(4-Bromo-fenoksi)-etilsulfanil]-2,6-dimetil-fenoksi}-octena kiselina;
[4-(3-{2-[4-(2-Dietilamino-etoksi)-fenil]-benzimidazol-1-il}-propilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[4-(5-Bifenil-4-il-2-tiofen-2-il-4,5-dihidro-oksazol-4-ilmetilsulfanil)-2-metil-fenoksi]-octena kiselina;
(4-{2-[3-(4-Fluoro-fenil)-benzo[b]tiofen-7-il]-etilsulfanil}-2-metil-fenoksi)-octena kiselina;
{2-Metil-4-[2-(5-fenil-naftalen-1-iloksi)-etilsulfanil]-fenoksi}-octena kiselina;
[2-Metil-4-(3-fenoksi-benzilsulfanil)-fenoksi]-octena kiselina;
[2,5-Dimetil-4-(5-p-tolil-1,3,4-oksadiazol-2-ilmetilsulfanil)-fenoksi]-octena kiselina;
[2-Metil-4-(4-pirazol-1-il-benzilsulfanil)-fenoksi]-octena kiselina;
[2-Metil-4-(5-metil-3-fenil-izoksazol-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[4-(Bifenil-2-ilmetilsulfanil)-2-metil-fenoksi]-octena kiselina;
{4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-2-metil-fenoksi}-octena kiselina;
[2-Metil-4-(5-p-tolil-1,3,4-oksadiazol-2-ilmetilsulfanil)-fenoksi]-octena kiselina;
{4-[3-(4-Kloro-fenil)-1,2,4-oksadiazol-5-ilmetilsulfanil]-2-metil-fenoksi}-octena kiselina;
[2,5-Dimetil-4-(4-pirazol-1-il-benzilsulfanil)-fenoksi]-octena kiselina;
[4-(Bifenil-2-ilmetilsulfanil)-2,5-dimetil-fenoksi]-octena kiselina;
[4-(4-Benziloksi-benzilsulfanil)-5,6,7,8-tetrahidro-naftalen-1-iloksi]-octena kiselina;
[4-(4-Benziloksi-benzilsulfanil)-2,6-dimetil-fenoksi]-octena kiselina;
[4-(4-Benziloksi-benzilsulfanil)-2,5-dimetil-fenoksi]-octena kiselina;
[4-(4-Benziloksi-benzilsulfanil)-2-metil-fenoksi]-octena kiselina;
[4-(4-Benziloksi-benzilsulfanil)-fenoksi]-octena kiselina;
[4-(Bifenil-4-ilmetilsulfanil)-5,6,7,8-tetrahidro-naftalen-1-iloksi]-octena kiselina;
[4-(Bifenil-4-ilmetilsulfanil)-2,6-dimetil-fenoksi]-octena kiselina;
[4-(Bifenil-4-ilmetilsulfanil)-2,5-dimetil-fenoksi]-octena kiselina;
[4-(Bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
{4-[3-(2-Fluoro-fenoksi]-benzilsulfanil]-2,6-dimetil-fenoksi}-octena kiselina;
[4-(2-{4-[2-(3-Kloro-4-cikloheksil-fenil)-etil]-piperazin-1-il}-etilsulfanil)-2-metil-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(2-{4-[2-(3-fenil-benzofuran-7-il)-etil]-piperazin-1-il}-etilsulfanil)-fenoksi]-octena kiselina;
{4-[2-(2,6-Difenil-piperidin-1-il)-etilsulfanil]-5-metoksi-2-metil-fenoksi}-octena kiselina;
[2-Metil-4-(2-{4-[2-(3-fenil-benzofuran-7-il)-etil]-piperazin-1-il}-etilsulfanil)-fenoksi]-octena kiselina;
{4-[2-(2,6-Difenil-piperidin-1-il)-etilsulfanil]-2-metil-fenoksi}-octena kiselina;
i farmaceutski prihvatljive soli.
Podskupina primjera spojeva Formule I i Formule II uključuje
[4-(Bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[4-(2',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[5-Metoksi-2-metil-4-(3'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
[4-(4'-Fluoro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octena kiselina;
[7-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octena kiselina;
{5-Metoksi-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octena kiselina;
[5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-3-ilmetilsulfanil)-fenoksi]-octena kiselina;
{{5-Metoksi-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octena kiselina;
{5-Metoksi-2-metil-4-[6-(4-trifluorometil-fenil)-piridin-3-ilmetilsulfanil]-fenoksi}-octena kiselina;
[3-Metoksi-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
{5-Metoksi-2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octena kiselina
(4-{4-[2-(3-Fluoro-fenil)-vinil]-benzilsulfanil}-5-metoksi-2-metil-fenoksi)-octena kiselina;
[5-Metoksi-2-metil-4-(3-metil-4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octena kiselina;
{4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-5-metoksi-2-metil-fenoksi}-octena kiselina;
{5-Metoksi-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octena kiselina;
{5-Metoksi-2-metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octena kiselina;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-3-ilmetilsulfanil)-fenoksi]-octena kiselina;
{7-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octena kiselina;
{5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-2,3-dihidro-benzofuran-4-iloksi}-octena kiselina;
i farmaceutski prihvatljive soli.
Određeni spojevi iz ovog izuma imaju jedan ili više kiralni centar i svaki centar može postojati u R ili S konfiguraciji. Ovaj izum uključuje sve dijastereomerne, enantiomerne, i epimerne oblike kao i njihove prikladne smjese. Stereoizomeri se mogu dobiti, ako je potrebno, uobičajenim postupcima poznatim iskusnim stručnjacima, na primjer, odvajanjem stereoizomera kiralnim kromatografskim kolonama. Osim toga, spojevi iz ovog izuma mogu biti prisutni kao geometrijski izomeri. Ovaj izum uključuje sve cis, trans, sin, anti, odvojene (E), i povezane (Z) izomere kao i njihove prikladne smjese.
U nekim slučajevima, spojevi mogu biti prisutni kao tautomeri. Svi tautomeri su obuhvaćeni Formulama I i II i dobiveni su u ovom izumu.
Osim toga, spojevi iz ovog izuma mogu biti prisutni u netopivom kao i u topivom obliku s farmaceutski prihvatljivim otapalima kao što su voda, etanol, i slično. Općenito se topivi oblici smatraju jednakim netopivim oblicima za svrhe ovog izuma.
Ovaj izum uključuje sve farmaceutski prihvatljive, ne-toksične estere spojeva Formule I i II. Takvi esteri uključuju C1-C6 alkil estere u kojima je alkilna skupina ravni ili razgranati lanac. Prihvatljivi esteri također uključuju C5-C7 cikloalkil estere kao i arilalkil estere kao što je, ali bez ograničenja, benzil. C1-C4 esteri se preferiraju. Esteri spojeva iz ovog izuma se mogu prirediti prema uobičajenim postupcima.
Spojevi iz ovog izuma su prikladni za primjenu na pacijente za liječenje, kontrolu ili prevenciju hiperkolesterolemije, dislipidemije, gojaznosti, hiperglikemije, hiperkolesterolemije, ateroskleroze, hipertrigliceridemije, i hiperinzulinemije. Spojevi iz ovog izuma su također prikladni za primjenu na pacijente u svrhu smanjenja apetita i promjene razine leptina. Prema tome, spojevi se mogu primijeniti na pacijente sami ili kao dio pripravka koji sadrži i druge sastojke kao što su ekscipijenti, sredstva za razrjeđivanje, i nosači, koji su već dobro poznati iskusnim stručnjacima. Pripravci se mogu primijeniti na ljude i/ili životinje bilo oralno, rektalno, parenteralno (intravenozno, intramuskularno, ili subkutano), intracisternalno, intravaginalno, intraperitonealno, intravezikalno, lokalno (puderi, masti, ili kapljice), ili kao oralni ili nazalni sprej.
Spojevi prikladni za parenteralno ubrizgavanje mogu sadržavati fiziološki prihvatljive sterilne vodene ili bezvodne otopine, disperzije, suspenzije ili emulzije, i sterilne pudere za postavljanje u sterilne ubrizgavajuće otopine ili disperzije. Primjeri prikladnih vodenih ili bezvodnih nosača, sredstava za razrjeđivanje, otapala ili sredstava za prijenos uključuju vodu, etanol, poliole (propilenglikol, polietilenglikol, glicerol, i slično), i njihove prikladne smjese, biljna ulja (poput maslinovog ulja), i organske estere za ubrizgavanje poput etil oleata. Odgovarajuća gustoća se može postići, na primjer, uporabom premaza kao što je lecitin, uporabom čestica odgovarajuće veličine u slučaju disperzija i uporabom sredstava za smanjenje površinske napetosti.
Ovi spojevi mogu također sadržavati dodatna sredstva kao što su sredstva za konzerviranje, sušenje, emulgiranje i sredstva za disperziju. Sprječavanje djelovanja mikroorganizama se može postići različitim antibakterijskim i antigljivičnim sredstvima, na primjer, parabensom, klorobutanolom, fenolom, sorbinska kiselinom, i slično. Također može biti poželjno da se uvrste i izotonična sredstva, na primjer šećeri, natrijev klorid, i slično. Produžena apsorpcija farmaceutskih oblika koji se ubrizgavaju se može postići uporabom sredstava za odgađanje apsorpcije, na primjer, aluminijevog stearata i želatine.
Kruti oblici za doziranje uključuju kapsule, tablete, pilule, pudere, i granule. U ovakvim krutim oblicima za doziranje je aktivni sastojak pomiješan s bar jednim uobičajenim inertnim ekscipijentom (ili nosačem) kao što je natrijev citrat ili dikalcijev fosfat ili (a) sredstvom za punjenje ili proširenje, kao što je na primjer, škrob, laktoza, sukroza, glukoza, manitol, i silikatna kiselina; (b) sredstvom za povezivanje, kao što je na primjer, karboksimetilceluloza, alignati, želatina, polivinilpirolidon, sukroza, i akacija; (c) sredstvom za povećanje vlažnosti, kao što je na primjer, glicerol; (d) sredstvom za razgradnju, kao što je na primjer, agar, kalcijev karbonat, krumpirov ili škrob tapioke, alginska kiselina, određeni kompleksni silikati, i natrijev karbonat; (e) sredstvom za odgađanje otapanja, kao što je na primjer, parafin; (f) sredstvom za ubrzavanje apsorpcije, kao što su na primjer, četveročlani amonijevi spojevi; (g) sredstvom za isušivanje, kao što je na primjer, cetilni alkohol i glicerol monostearat; (h) sredstvom za adsorpciju, kao što je na primjer, kaolin i bentonit; i (i) sredstvom za podmazivanje, kao što je na primjer, talk, kalcijev stearat, magnezijev stearat, kruti polietilenski glikoli, natrijev lauril sulfat, ili njihove smjese. U slučaju kapsula, tableta, i pilula, oblici za doziranje mogu također sadržavati pufere.
Slični kruti pripravci se također mogu primjeniti kao sredstva za punjenje u mekano i kruto-punjenim kapsulama uporabom ekscipijenata kao što je as laktoza ili mliječni šećer, kao i polietilenglikoli visoke molekulske mase, i slično.
Kruti oblici za doziranje kao što su tablete, dražeje, kapsule, pilule, i granule se mogu prirediti sa sredstvima za premazivanje i ovojnicama, kao što su enteričke ovojnice i druge već dobro poznate iskusnim stručnjacima. Oni mogu sadržavati neprozirna sredstva, i također mogu biti takvog sastava da otpuštaju aktivni sastojak ili sastojke u određeni dio probavnog trakta uz odgođeno djelovenje. Primjeri umetnutih sastojaka koji se mogu rabiti su polimerne tvari i vosak. Aktivni spojevi mogu također biti u mikro-kapsularnom obliku, ako je prikladno, s jednim ili više prije-spomenutih ekscipijenata.
Tekući oblici za doziranje za oralnu primjenu uključuju farmaceutski prihvatljive emulzije, otopine, suspenzije, sirupe, i eliksire. Uz aktivne sastojke, tekući oblici za doziranje mogu sadržavati inertna sredstva za razrjeđivanje koja se obično rabe u struci, kao što je voda ili druga otapala, sredstva za otapanje i emulgiranje, kao što su na primjer, etilni alkohol, izopropilni alkohol, etil karbonat, etil acetat, benzilni alkohol, benzil benzoat, propilenglikol, 1,3-butilenglikol, dimetilformamid, ulja, posebno, ulje sjemena pamuka, ulje kikirikija, ulje kukuruznog sjemena, maslinovo ulje, ricinusovo ulje, i sezamovo ulje, glicerol, tetrahidrofurfurilni alkohol, polietilenglikoli i esteri masnih kiselina sorbitana ili smjese ovih spojeva, i slično.
Osim ovakvih inertnih sredstava za razrjeđivanje, pripravci mogu također sadržavati dodatne sastojke, kao što su sredstva za sušenje, sredstva za emulgiranje i suspendiranje, zaslađivače, sredstva za okus i miris.
Suspenzije, uz aktivne sastojke, mogu sadržavati sredstva za suspendiranje, kao što su naprijmer, etokslirani izostearilni alkoholi, polioksietilen sorbitol i sorbitan esteri, microkristalna celuloza, aluminijev metahidroksid, bentonit, agar-agar i tragakant, ili smjese ovih spojeva, i slično.
Preferira se da su pripravci za rektalnu primjenu u obliku čepića koji se mogu prirediti miješanjem spojeva iz ovog izuma s prikladnim ne-iritirajućim ekscipijentima ili nosačima kao što su kakao maslac, polietilenglikol, ili voštani čepić, koji su krutine na određenim temperaturama ali tekući na tjelesnoj temperaturi te se stoga otapaju u rektumu ili vaginalnoj šupljini i oslobađaju aktivne sastojke.
Oblici za doziranje spojeva iz ovog izuma za lokalnu primjenu uključuju masti, pudere, sprejeve, i sredstva za inhaliranje. Aktivni sastojak se pomiješa u sterilnim uvjetima s fiziološki prihvatljivim nosačem uz uporabu bilo kojeg konzervansa, pufera, ili sredstva za ubrzanje. Oblici za očne bolesti, masti za oči, puderi, i otopine se također razmatraju kao svrha ovog izuma.
Spojevi iz ovog izuma se mogu primijeniti na pacijenta u razinama doza od oko 0,1 do oko 2,000 mg dnevno. Za normalnu odraslu osobu mase oko 70 kilograma, preferirana doza je u razini od oko 0,01 do oko 10 mg po kilogramu tjelesne mase dnevno. Ipak, određene doze koje se rabe mogu varirati. Na primjer, doza može ovisiti o mnogobrojnim faktorima uključujući pacijentove potrebe, ozbiljnost stanja koje se liječi, i farmakološkoj aktivnosti spojeva koji se rabe. Određivanje optimalne doze za određenog pacijenta je dobro poznato iskusnim stručnjacima.
PRIPREMA SPOJEVA IZ IZUMA
Ovaj izum sadržava spojeve koji se mogu sintetizirati na mnogobrojne načine poznate iskusnim stručnjacima u organskim sintezama. Ovdje izdvojeni spojevi se mogu sintetizirati prema ispod opisanim postupcima, kao i postupcima koji se obično rabe u sintetičkoj kemiji, i kombinacijom ili varijacijom ovih postupaka, koji su općenito poznati iskusnim stručnjacima u sintetičkoj kemiji. Način sinteze spojeva iz ovog izuma nije ograničen na ispod istaknute postupke. Pretpostavlja se da će iskusni stručnjak biti sposoban rabiti dolje navedene sheme u svrhu sinteze spojeva zahtijevanih u ovom izumu. Pojedini spojevi mogu zahtijevati promjenu uvjeta u svrhu prilagodbe različitih funkcionalnih skupina. Može biti zahtijevano mnoštvo zaštitnih skupina koje su općenito poznate iskusnim stručnjacima. Pročišćavanje se može, ako je neophodno, provesti na koloni silika gela koja se ispire s prikladnim organskim otapalom. Također se može primijeniti HPLC na reverznoj fazi ili rekristalizacija.
Preferira se da se mnogi od spojeva Formule I i II prirede reakcijom:
[image]
u otapalu uz prisustvo baze kao što je cezijev karbonat, s aril halidom:
[image]
gdje su:
n, R1, R2, R3, R4, X0, X1, V1, Ar1 i Ar2 isti kao što je gore navedeno za Formulu I;
R11 je niži alkil; i
X je vodik.
Preferira se da se rezultirajući ester zatim hidrolizira kako bi nastali spojevi Formula I i II. Osim toga, spojevi Formula I i II se mogu prirediti uporabom sintetičkog puta prikazanog na Shemama 1-6.
Shema 1 obuhvaća pripremu spojeva Formula I i II u kojima X0 predstavlja S, q je 0-3, [image] je odsutan, X1 je odsutan i r je 0. Spojevima opće formule A se dodaje tiocijanatna skupina kao smjesa bromina i natrijevog tiocijanata kako bi se dobili spojevi opće formule B. Spojevi opće formule B se zatim alkiliraju s alkil haloakarboksilatom kako bi se dobili spojevi opće formule C. Haloakarboksilat koji se preferira je metil bromoacetat. Alternativni načini dobivanja spojeva formule C će biti brzo očigledni iskusnim stručnjacima u organskoj sintezi. Spojevi opće formule D se zatim priređuju redukcijom C s ditiotreitolom u metanolu. Spojevi opće formule D se zatim alkiliraju sa spojevima opće formule Y, na isti način kao kod B, da bi se dobili E. Spojevi opće formule Y se priređuju prema opisu na Shemi 7 (ispod) ili su odmah raspoloživi iz komercijalnih izvora. Spojevi opće formule E se zatim saponificiraju s LiOH u THF da bi se dobio konačni spoj F.
[image]
Shema 2 obuhvaća pripremu spojeva Formula I-II u kojima X0 predstavlja O, q je 0-3, X1 je odsutan, [image] je odsutan, i r je 0. Spojevi opće formule A se alkiliraju s alkil haloakarboksilatom kako bi se dobili spojevi opće formule G. Haloakarboksilat koji se preferira je metil bromoacetat. Alternativni načini dobivanja spojeva formule G kada Y predstavlja O će biti brzo očigledni iskusnim stručnjacima u organskoj sintezi. Spojevi opće formule G se zatim aciliraju u Friedel-Crafts uvjetima kako bi se dobili spojevi opće formule H koji se onda oksidiraju s m-kloroperoksibenzojevom kiselinom i zatim hidroliziraju u svrhu dobivanja fenolnih spojeva opće formule I. Spojevi opće formule I reagiraju na sličan način kao kod D, da bi se nakon saponifikacije s LiOH u THF dobili spojevi opće formule K.
[image]
Shema 3 obuhvaća pripremu spojeva Formula I-II u kojima X0 predstavlja -CH2-CH2-, -C=C-, q je 0-3, X1 je odsutan, [image] je odsutan, i r je 0. Spojevi opće formule A se bromiraju s brominom, uporabom octene kiseline kao otapala kako bi se dobio L. Alternativno se može rabiti N-bromosukcinimid umjesto bromina i diklorometan umjesto octene kiseline kao otapalo. Spojevi opće formule L se zatim alkiliraju s alkil haloakarboksilatom kako bi se dobili spojevi opće formule M. Haloakarboksilat koji se preferira je metil bromoacetat. Alternativni načini dobivanja spojeva formule M će biti brzo očigledni iskusnim stručnjacima u organskoj sintezi. Spojevi opće formule M zatim reagiraju, u prisustvu tetrakisa (trifenilfosfin)paladij(0) i bifenilnih spojeva opće formule EE kako bi se dobili spojevi opće formule N. Spojevi opće formule EE se priređuju kao što je opisano u Shemi 9 ili su odmah raspoloživi iz komercijalnih izvora. Spojevi opće formule N se zatim saponificiraju s LiOH u THF da bi se dobio konačni spoj O.
[image]
Shema 4 obuhvaća pripremu spojeva formula I-II u kojima X0 predstavlja -CH2-CH2-, q je 0-3, X1 je odsutan, [image] je odsutan, i r je 0. Prema tome, spojevi koji su općenito N se mogu reducirati s vodikom i paladijem kao katalizatorom kako bi se dobili spojevi opće formule P koji se zatim saponificiraju s LiOH u THF da bi se dobio konačni spoj Q.
[image]
Shema 5 obuhvaća pripremu spojeva formula I-II u kojima je X0 odsutan, q je 0, X1 je odsutan, [image] je odsutan, i r je 0. Spojevi opće formule M zatim reagiraju s tetrakis (trifenilfosfin)paladij(0) i bifenilnim spojevima opće formule HH kako bi se dobili spojevi opće formule R. Spojevi opće formule HH se priređuju kao što je opisano u Shemi 10 ili su odmah raspoloživi iz komercijalnih izvora. Spojevi opće formule R se zatim saponificiraju s LiOH u THF da bi se dobio konačni spoj S.
[image]
Spojevi formula I-II, u kojima X0 predstavlja S ili O, q je 1-3, X1 je O, i r je 1-3, su priređeni prema Shemi 6 uporabom istih uvjeta koji se rabe za pripremu K.
[image]
Spojevi opće formule X su priređeni prema Shemi 7 reakcijom aril borne kiseline W s aril bromidom V uz prisustvo Pd(0) i cezijevog karbonata. Spojevi opće formule X zatim reagiraju s metansulfonil kloridom kako bi se dobili kloridi opće formule Y.
[image]
Spojevi opće formule CC su priređeni prema Shemi 8 tako da se prikladni hidroksi benzilni alkohol AA alkilira s prikladnim bromidom Z. Rezultirajući spoj BB zatim reagira s metansulfonil kloridom kako bi se dobili kloridi opće formule CC.
[image]
Spojevi opće formule EE su priređeni prema Shemi 9 reakcijom aril borne kiseline V s aril bromidom DD uz prisustvo Pd(0) i cezijevog karbonata.
[image]
Spojevi opće formule HH su priređeni prema Shemi 10 reakcijom aril bromida V s bornom kiselinom FF kako bi se dobio GG. Spojevi opće formule GG zatim reagiraju s alkil litijevim reagensom i zatim se preliju s boratom koji se hidrolizira kako bi se dobio spoj opće formule HH.
[image]
Spojevi formula I-II, u kojima X0 predstavlja S ili O, q je 1-3, X1 je odsutan, r je 0, i V1 je zasićeni ili nezasićeni ugljikovodikov lanac koji je supstituiran ili nesupstituiran, su priređeni prema Shemi 11 uporabom istih uvjeta koji se rabe za pripremu K. Spojevi opće formule NN se priređuju kao što je opisano u Shemi 12 ili su odmah raspoloživi iz komercijalnih izvora.
[image]
Spojevi opće formule NN su priređeni prema Shemi 12 reakcijom prikladnog supstituiranog aril amina LL u Sandmeyer uvjetima te zatim grijanjem kako bi se dobio intermedijer MM. Rezultirajući intermedijer MM zatim reagira s metansulfonil kloridom kako bi se dobili kloridi opće formule NN.
[image]
Svi spojevi Formula I-II koji odgovaraju prikazanim oblicima nisu prikladni za određene opisane reakcijske uvjete. Takva ograničenja su odmah očigledna iskusnim stručnjacima u organskoj sintezi, i tada se rabe alternativni postupci.
Sljedeći opisi, koji nisu ograničavajući, također prikazuju postupke za sintezu spojeva Formula I-II.
Primjer 1
Sinteza [4-(Bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 1)
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Korak 1. Priprema 5-Metoksi-2-metil-fenola (spoj 1A)
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2-Hidroksi-4-metoksi-benzaldehid (3 g, 19,7 mmol), amonijev format (6,2 g, 99 mmol) i palladij/ugljik (900 mg @ 10%) se dodaju u 26 ml ledene octene kiseline i zagrijavaju 1 h na 110°C. Reakcijska smjesa se ohladi, filtrira i razrijedi s vodom (100 ml). Nepročišćeni produkt se ekstrahira s kloroformom (3x50 ml), ispere s vodom, slanom vodom i isuši preko bezvodnog natrijevog sulfata. Rezultirajuća otopina se koncentrira i rabi u sljedećem koraku bez daljenjeg pročišćavanja. MS m/z 139 (M+1).
Korak 2. Priprema 5-Metoksi-2-metil-4-tiocijanato-fenola (spoj 1B)
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Produkt iz Primjera 1A (3,5 g, 25 mmol), natrijev tiocijanat (6,48 g, 80 mmol), i natrijev bromid (2,6 g, 25 mmol) se otope u 30 ml bezvodnog metanola. Bromin (4,4 g, 28 mmol) se dodaje kap po kap više od 15 minuta i miješa na sobnoj temperaturi 1 h. Zatim se doda slana voda (50 ml) i nepročišćeni produkt se ekstrahira u etil acetatu (3 x 100 ml). Kombinirani organski ekstrakti se isperu sa slanom vodom i isuše preko bezvodnog natrijevog sulfata, odliju, i koncentriraju da se dobije dobra čistoća produkta. 400 MHz 1H NMR (DMSO-d6) δ 10,13 (s, 1H), 7,25 (s, 1H), 6,54 (s, 1H), 3,77 (s, 3H), 2,0 (s, 3H); MS m/z 196 (M+1).
Korak 3. Priprema metil estera (5-Metoksi-2-metil-4-tiocijanato-fenoksi)-octene kiseline (spoj 1C)
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Produkt iz Primjera 1B (620 mg, 3,2mmol), metil bromoacetat (854 mg, 3,5mmol), i cezijev karbonat (3,1 g, 9,6 mmol) se miješaju u 10 ml bezvodnog acetonitrila 1 h na sobnoj temperaturi. Reakcijska smjesa se filtrira preko Celite®, koncentrira, i pročisti uporabom kromatografije na normalnoj fazi. 400 MHz 1H NMR (DMSO-d6) δ 7,33 (s, 1H), 6,72 (s, 1H), 4.93 (s, 2H), 3,84 (s, 3H), 3.66 (s, 3H), 2.09 (s, 3H); MS m/z 268 (M+1).
Korak 4. Priprema metil estera (4-Merkapto-5-metoksi-2-metil-fenoksi)-octene kiseline (spoj 1D)
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Produkt iz Primjera 1C (1,1 g, 4,1 mmol) i ditiotreitol (824 mg, 5,4 mmol) se otope u 20 ml metanola s 2,5ml vode. Otopina se zagrijava na temperaturi refluksa 4 h, ohladi, koncentrira, i pročisti kromatografijom na normalnoj fazi. 400 MHz 1H NMR (DMSO-d6) δ 7,02 (s, 1H), 6,54 (s, 1H), 4,79 (s, 2H), 4,41 (s, 1H), 3,72 (s, 3H), 3,64 (s, 3H), 2,02 (s, 3H); MS m/z 243 (M+1).
Korak 5. Priprema 4-Bromometil-bifenila (spoj 1E)
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Bifenil-4-il-metanol (500 mg, 2,72 mmol), fosfor tribromid (809 mg, 2,99 mmol), i litijev bromid (260 mg, 2,99 mmol) se otope u 10 ml DMF i miješaju na sobnoj temperaturi 1 h. Doda se voda (10 ml) i kruti produkt se ekstrahira u diklorometanu, isuši preko bezvodnog natrijevog sulfata, filtrira preko silika gela, i koncentrira. MS m/z 167 (M+1-Br).
Korak 6. Priprema [4-(Bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 1F)
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Produkt iz Primjera 1D (100 mg, 0,38 mmol), produkt iz Primjera 1E (92 mg, 0,38 mmol) i cezijev karbonat (250 mg, 0,76 mmol) se dodaju u 5 ml acetonitrila i miješaju na sobnoj temperaturi 4 h. Reakcijska smjesa se filtrira preko Celite®, koncentrira, i pročisti preko kromatografije na normalnoj fazi. MS m/z 409 (M+1).
Korak 7. Priprema [4-(Bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 1)
Produkt iz Primjera 1F (101 mg) se otopi u 10ml THF /vodena otopina (10:1). Zatim se doda litij hidroksid monohidrat (300 mg) i miješa 30 minuta. 2 N vodena otopina HCI se dodaje do pH<5 i zatim ispire s etilnim acetatom. Organski ekstrakt se ispere preko bezvodenog natrijevog sulfata, odlije, i koncentrira. Produkt iz naslova se rekristalizira iz kloroform/heksana. mp 60-62°C; 400 MHz 1H NMR (DMSO-d6) δ 12,94 (br(s), 1H), 7,58 (d, 2H, J = 8 Hz), 7,52 (d, 2H, J = 8 Hz), 7,39 (t, 2H, J = 7,2 Hz), 7,30 (m, 3H), 7,02 (s, 1H), 6,52 (s, 1H), 4,69 (s, 2H), 4,01 (s, 2H), 3,73 (s, 3H), 2,01 (s, 3H). MS m/z 393 (M-1), Anal. Izrač. za C32H22O4S·3H2O C, 69,05; H, 5,07; nađeno: C, 69,04; H, 5,35.
Primjer 2
Sinteza [4-(Bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 2)
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Korak 1. Priprema 2-Metil-4-tiocijanato-fenola (spoj 2A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1B iz 2-metilfenola. 400 MHz 1H NMR (DMSO-d6) δ 10,09 (s, 1H), 7,36 (s, 1H), 7,30 (d, 1H, J= 8,1 Hz), 6,83 (d, 1H, J = 8,1 Hz), 2,08 (s, 3H); MS m/z 166 (M+1).
Korak 2. Priprema metil estera (2-Metil-4-tiocijanato-fenoksi)-octene kiseline (spoj 2B)
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Spoj iz naslova je priređen iz 2 Primjera 2A na isti način kao Primjer 1C. 400 MHz 1H NMR (DMSO-d6) δ 7,46 (s, 1H), 6,95 (d, 1H, J = 8,5 Hz), 6,80 (d, 1H, J = 8,5 Hz), 4,86 (s, 2H), 3,65 (s, 3H), 2,17 (s, 3H); MS m/z 238 (M+l).
Korak 3. Priprema metil estera (4-Merkapto-2-metil-fenoksi)-octene kiseline (spoj 2C)
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Spoj iz naslova je priređen iz metil estera (2-metil-4-tiocijanato-fenoksi)-octene kiseline na isti način kao Primjer 1D. 400 MHz 1H NMR (DMSO-d6) δ 7,05 (s, 1H), 7,00 (d, 1H, J = 10,3 Hz), 6,70 (d, 1H, J = 10,3 Hz), 5,00 (s, 1H), 4,73 (s, 1H), 3,63 (s, 3H), 2,09 (s, 3H); MS m/z 213 (M+1).
Korak 4. Priprema metil estera [4-(Bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 2D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 2C i 1E. MS m/z 379 (M+1).
Korak 5. Priprema metil estera [4-(Bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 2)
Spoj iz naslova je priređen na isti način kao i Primjer 1. mp 138 °C; 400 MHz 1H NMR (DMSO-d6) δ 7,59 (d, 2H, J = 9,5 Hz); 7,53 (d, 2H, J = 9,5 Hz), 7,40 (m, 2H), 7,31 (m, 3H), 7,14 (d, 1H, J = 1,7 Hz), 7,09 (d, 1H, J =10,7 Hz), 6,70 (d, 1H, J =10,7 Hz), 4,62 (s, 2H), 4,11 (s, 2H), 2,09 (s, 3H); MS m/z 363 (M-l).
Primjer 3
Sinteza [2-Metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 3)
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Korak 1. Priprema (4'-Trifluorometil-bifenil-4-il)-metanola (spoj 3A)
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1-Bromo-4-trifluorometil-benzen (814 mg, 3,62 mmol), 4-hidroksimetilfenilborna kiselina (600 mg, 3,98 mmol), cezijev karbonat (2,36 g, 7,24 mmol), i PdCl2(dppf) (132 mg, 0,181 mmol) se dodaju u 10 ml 1:1 otopinu DMF/THF. Reakcijska smjesa se isplahne s dušikom i i zagrijava do 90°C 1 h. Reakcijska smjesa se ohladi, prelije u dietil eter i ispere s vodom (2x50 ml), slanom vodom (1x50ml) i isuši preko bezvodnog natrijevog sulfata. Nepročišćeni produkt se filtrira preko silika gela, ispere s dietil eterom, i koncentrira kako bi se dobio spoj iz naslova. MS m/z 251 (M-1).
Korak 2. Priprema 4-Klorometil-4'-trifluorometil-bifenila (spoj 3B)
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Produkt iz Primjera 3A se otopi u 10 ml metilen klorida. Zatim se dodaju trietilamin (468 mg, 4,62 mol) i metansulfonil klorid (422 mg, 3,68 mmol) i miješaju 18 h. Reakcijska smjesa se prelije u vodu i ekstrahira s metilen kloridom. Organska smjesa se isuši preko bezvodnog natrijevog sulfata, prelije i koncentrira kako bi se dobio spoj iz naslova koji se rabi bez daljnjeg pročišćavanja. MS m/z 235 (M-Cl+1).
Korak 3. Priprema metil estera [2-Metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 3C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 3B i 2C. MS m/z 447 (M+1).
Korak 4. Priprema [2-Metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 3)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 3C. mp 140-141 °C; 400 MHz 1H NMR (DMSO-d6) δ 12,95 (br(s),1H), 7,82 (d, 2H, J = 8,4 Hz), 7,74 (d, 2H, J = 8,4 Hz), 7,61 (d, 2H, J = 8,4 Hz), 7,35 (d, 2H, J =8,4 Hz), 7,10 (m, 2H), 6,70 (d, 1H, J = 8,4 Hz), 4,62 (s, 2H), 4,13 (s, 2H), 2,08 (s, 3H); MS m/z 431 (M-1). Anal. Izrač. za C23H19F3O3S·0,7 H2O C, 62,07; H, 4,62; nađeno: C, 61,98; H, 4,22.
Primjer 4
Sinteza [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 4)
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Korak 1. Priprema metil estera [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 4A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1D i 3B. MS m/z 477 (M+1).
Korak 2. Priprema [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 4)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 4A. mp 170-171 °C; 400 MHz 1H NMR (DMSO-d6) δ 7,81 (d, 2H, J =8 Hz), 7,60 (d, 2H, J = 8,4 Hz), 7,32 (d, 2H, J = 8,4 Hz), 7,02 (s, 1H), 6,52 (s, 1H), 4,70 (s, 2H), 4,03 (s, 2H), 3,73 (s, 3H), 2,00 (s, 3H), MS m/z 463 (M+l). Anal. Izrač. za C24H21F3NO4S·0,1 H2O C, 62, 09; H, 4,60; nađeno: C, 62,00; H, 4,36.
Primjer 5
Sinteza [5-Metoksi-2-metil-4-(2',4',6'-trimetil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 5)
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Korak 1. Priprema metil estera [5-Metoksi-2-metil-4-(2',4',6'-trimetil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 5A)
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2-Bromo-1,3,5-trimetil-benzen (396 mg, 2mmol), 4-hidroksimetilfenilborna kiselina (334 mg, 2,2 mmol), cezijev karbonat (1,3 g, 4 mmol), i PdCl2(dppf) (82 mg, 0,1 mmol) se dodaju u 5 ml 1:1 otopine DMF/THF. Reakcijska smjesa se isplahne s dušikom i i zagrijava do 90°C 1 h. Reakcijska smjesa se ohladi, prelije u dietil eter i ispere s vodom (2x10 ml), slanom vodom (1x10ml) i isuši preko bezvodnog natrijevog sulfata. Nepročišćeni produkt se filtrira preko silika gela, ispere s dietil eterom, i koncentrira. Nepročišćeni produkt se otopi u 10 ml diklorometana. U ovu otopinu se dodaje trietilamin (202 mg, 2 mmol), zatim metansulfonil klorid (184 mg, 1,6 mmol) i miješa na sobnoj temperaturi 18 h. Reakcijska smjesa se izlije u vodu i ekstrahira s metilen kloridom. Organska smjesa se isuši preko bezvodnog natrijevog sulfata, prelije i koncentrira kako bi se dobio nepročišćeni alkil klorid. Produkt iz Primjera 1D (387 mg, 1,6 mmol), nepročišćeni 4'-klorometil-2,4,6-trimetil-bifenil, i cezijev karbonat (1 g, 3,06 mmol) se miješaju u 10 ml acetonitrila 3h, filtriraju, koncentriraju, i pročiste kromatografijom na normalnoj fazi kako bi se dobio produkt iz naslova. MS m/z 451 (M+1).
Korak 2. Priprema [5-Metoksi-2-metil-4-(2',4',6'-trimetil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 5A. mp 141 °C; 400 MHz 1H NMR (DMSO-d6) δ 12,81 (br(s),1H), 7,04 (d, 2H, J = 8,4 Hz), 6,77 (m, 3H), 6,69 (s, 2H), 6,36 (s, 1H), 4,43 (s, 2H), 3,82 (s, 2H), 3,58 (s, 3H), 2,03 (s, 3H), 1,82 (s, 3H), 1,67 (s, 6H). MS m/z 437 (M+1).
Primjer 6
Sinteza [4-(4'-Kloro-3'-trifluorometil-bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 6)
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Korak 1. Priprema (4'-Kloro-3'-trifluorometil-bifenil-4-il)-metanola (spoj 6A)
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Spoj iz naslova je priređen na isti način kao i Primjer 3A uporabom 4-bromo-1-kloro-2-trifluorometil-benzena. MS m/z 288 (M+1).
Korak 2. Priprema 4-Kloro-4'-klorometil-3'-trifluorometil-bifenila (spoj 6B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 6A. MS m/z 305 (M).
Korak 3. Priprema metil estera [4-(4'-Kloro-3'-trifluorometil-bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 6C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 2C i 6B. MS m/z 481 (M+1).
Korak 4. Priprema [4-(4'-Kloro-3'-trifluorometil-bifenil-4-ilmetilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 6)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 6C. 400 MHz 1H NMR (DMSO-d6) δ 7,97 (s, 1H), 7,92 (d, 1H, J = 10,5 Hz), 7,74 (d, 1H, J = 10,5 Hz), 7,64 (d, 2H, J = 8,9 Hz), 7,34 (d, 2H, J = 8,9 Hz), 7,14 (s, 1H), 7,08 (d, 1H, J = 11,0 Hz), 6,70 (d, 1H, J = 11,0 Hz), 4,62 (s, 2H), 4,12 (s, 2H), 2,08 (s, 3H); MS m/z 465 (M-1).
Primjer 7
Sinteza [4-(2',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 7)
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Korak 1. Priprema metil estera [4-(2',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 7A)
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Spoj iz naslova je priređen na isti način kao i Primjer 5A uporabom 1D i 1-bromo-2,4-dikloro-benzena. MS m/z 479 (M+2).
Korak 2. Priprema [4-(2',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 7)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 7A. 400 MHz 1H NMR (DMSO-d6) δ 12,95 (br(s),1H), 7,67 (dd, 1H, J = 2 Hz, J'=8,4 Hz), 7,43 (d, 1H, J = 2,4 Hz), 7,37 (s, 1H), 7,28 (s, 4H), 7,02 (s, 1H), 6,52 (s, 1H), 4,70 (s, 2H), 4,02 (s, 2H), 3,72 (s, 3H), 2,01 (s, 3H); MS m/z 465 (M+2).
Primjer 8
Sinteza [4-(3',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 8)
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Korak 1. Priprema metil estera [4-(3',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 8A)
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Spoj iz naslova je priređen na isti način kao i Primjer 5A uporabom 1D i 4-bromo-1,2-dikloro-benzena MS m/z 479 (M+2).
Korak 2. Priprema [4-(3',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 8)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 8A. mp 161-162 °C; 400 MHz 1H NMR (DMSO-d6) δ 7,87 (d, 1H, J = 2 Hz), 7,57-7,66 (m, 4H), 7,29 (d, 2H, J = 8,4 Hz), 7,01 (s, 1H), 6,52 (s, 1H), 4,69 (s, 2H), 4,02 (s, 2H), 3,72 (s, 3H), 2,03 (s, 3H); MS m/z 494 (M+1).
Primjer 9
Sinteza [5-Metoksi-2-metil-4-(3'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 9)
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Korak 1. Priprema metil estera [5-Metoksi-2-metil-4-(3'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 9A)
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Spoj iz naslova je priređen na isti način kao i Primjer 5A uporabom 1D i 1-bromo-3-trifluorometil-benzena. MS m/z 477(M+1).
Korak 2. Priprema [5-Metoksi-2-metil-4-(3'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 9)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 9A. mp 138-139 °C; 400 MHz 1H NMR (DMSO-d6) δ 12,95 (br(s), 1H), 7,91 (m, 2H), 7,63 (m, 4H), 7,32 (d, 2H, J = 8,4 Hz), 7,02 (s, 1H), 6,52 (s, 1H), 4,69 (s, 2H), 4,03 (s, 2H), 3,73 (s, 3H), 2,06 (s, 3H); MS m/z 463 (M+1).
Primjer 10
Sinteza [4-(4'-Fluoro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 10)
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Korak 1. Priprema (4'-Fluoro-bifenil-4-il)-metanola (spoj 10A)
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Spoj iz naslova je priređen na isti način kao i Primjer 3A uporabom 1-bromo-4-fluorobenzena. MS m/z 185 (M-H2O).
Korak 2. Priprema 4-Klorometil-4'-fluoro-bifenila (spoj 10B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 10A. MS m/z 222 (M+2).
Korak 3. Priprema metil estera [4-(4'-Fluoro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 10C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 10B. MS m/z 427 (M+1).
Korak 3. Priprema [4-(4'-Fluoro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 10C. 400 MHz 1H NMR (DMSO-d6) δ 12,93 (br(s), 1H), 7,62 (m, 2H), 7,49 (d, 2H, J = 8,4 Hz), 7,27 (d, 2H, J = 8,4 Hz), 7,22 (m, 2H), 7,02 (s, 1H), 6,52 (s, 1H), 4,69 (s, 2H), 4,01 (s, 2H), 3,73 (s, 3H), 2,01 (s, 3H). MS m/z 411 (M-1).
Primjer 11
Sinteza [5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 11)
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Korak 1. Priprema metil estera [5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 11A)
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Spoj iz naslova je priređen na isti način kao i Primjer 5A uporabom 1D i 1-bromo-3-trifluorometoksi-benzena. MS m/z 493(M+ 1).
Korak 2. Priprema [5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 11)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 11A. mp 137 °C; 400 MHz 1H NMR (DMSO-d6) δ 12,95 (br(s), 1H), 7,66 (d, 1H, J = 8,8 Hz), 7,56 (m, 4H), 7,30 (m, 3H), 7,02 (s, 1H), 6,52 (s, 1H), 4,69 (s, 2H), 4,02 (s, 2H), 3,73 (s, 3H), 2,01 (s, 3H). MS m/z 493 (M+1).
Primjer 12
Sinteza [7-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 12)
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Korak 1. Priprema Indan-4-ol (spoj 12A)
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Smjesa 4-hidroksi-indan-1-one (5,0 g, 33,7 mmol), natrijevog cijanoborohidrida (6,4 g, 101,1 mmol), i cinkovog jodida (32,3 g, 101,1 mmol) u dikloroetanu, se grije na temperaturi refluksa dva sata. Reakcijska smjesa se zatim filtrira kroz 50 g SiO2 dok je još topla, i dalje ispere s dikloroetanom. Filtrat se skuplja i koncentrira pod vakumom. Ostatku se doda dietil eter i rezultirajući bijeli talog se profiltrira. Filtrat se skuplja i koncentrira pod vakumom kako bi se dobilo 4,2 g spoja iz naslova dovoljno visoke čistoće za kasniju uporabu. 400 MHz 1H NMR (DMSO-d6) δ 9,06 (s, 1H), 6,86 (t, 1H, J = 7,8 Hz), 6,59 (d, 1H, J = 7,8 Hz), 6,48 (d, 1H, J = 7,8 Hz), 2,75 (t, 2H, J = 7,3 Hz), 2,67 (t, 2H, J = 7,3Hz), 1,92 (m, 2H).
Korak 2. Priprema 7-Tiocijanato-indan-4-ol (spoj 12B)
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Spoj iz naslova je priređen na isti način kao i Primjer 1B uporabom 12A.MS m/z 192 (M+1).
Korak 3. Priprema metil estera (7-Merkapto-indan-4-iloksi)-octene kiseline (spoj 12C)
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7-Tiocijanato-indan-4-ol (Primjer 12B) (1,47g, 7,7mmol), cezijev karbonat (3,77g, 11,6 mmol) i metil bromoacetat (1,24g, 8,08 mmol) se miješaju u 20 ml acetonitrila na sobnoj temperaturi 4 h. Reakcijska smjesa se zatim filtrira i koncentrira. Nepročišćeni produkt se tretira u istim uvjetima kao Primjer 1D kako bi se dobio produkt iz naslova. MS m/z 239(M+1).
Korak 4. Priprema metil estera [7-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 12D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 3B. MS m/z 473 (M+ 1).
Korak 5. Priprema [7-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 12)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 12D. mp 158-159 °C; 400 MHz 1H NMR (DMSO-d6) δ 12,94 (br(s), 1H), 7,82 (d, 2H, J = 8 Hz), 7,74 (d, 2H, J = 8,8 Hz), 7,60 (d, 2H, J = 6,4 Hz), 7,31 (d, 2H, J =8 Hz), 7,08 (d, 1H, J =8,8 Hz), 6,58 (d, 1H, J =8,4 Hz), 4,61 (s, 2H), 4,06 (s, 2H), 2,72 (m, 4H), 1,90 (q, 2H); MS m/z 457 (M-1).
Primjer 13
Sinteza [4-(4-Benziloksi-benzilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 13)
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Korak 1. Priprema metil estera [4-(4-Benziloksi-benzilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 13A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1-klorometil-4-benziloksi-benzena i 2C. MS m/z 409 (M+1).
Korak 2. Priprema [4-(4-Benziloksi-benzilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 13)
Spoj iz naslova je priređen na isti način kao Primjer 1 i 13A. mp 120-121 °C; 400 MHz 1H NMR (DMSO-d6) δ 7,39-7,25 (m, 5H), 7,15-7,03 (m, 4H), 6,85 (d, 2H, J = 8,5 Hz), 6,68 (d, 1H, J = 8,4 Hz), 5,00 (s, 2H), 4,62 (s, 2H), 4,00 (s, 2H), 2,08 (s, 3H); MS m/z 395 (M+1).
Primjer 14
Sinteza {5-Metoksi-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 14)
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Korak 1. Priprema [4-(4-Trifluorometil-benziloksi)-fenil]-metanola (spoj 14A)
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4-Hidroksimetil-fenol (1g, 8,06 mmol), 1-Klorometil-4-trifluorometil-benzen (1,57g, 8,06 mmol), i cezijev karbonat (5,26g, 16,12 mmol) se zagrijavaju na temperaturi refluksa u acetonitrilu 20h, ohlade, filtriraju, i koncentriraju da bi se dobio spoj iz naslova. MS m/z 265 (M-H2O+1).
Korak 2. Priprema 4-Klorometil-(4-trifluorometil-benziloksi-benzena) (spoj 14B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 14A. MS m/z 265 (M-Cl+1).
Korak 3. Priprema metil estera {5-Metoksi-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 14C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 14B i 1D. MS m/z 507 (M+1).
Korak 4. Priprema {5-Metoksi-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 14)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 14C. mp 145°C; 400 MHz 1H NMR (DMSO-d6) δ 12,94 (br(s), 1H), 7,70 (d, 2H, J = 8 Hz), 7,76 (d, 2H, J = 8 Hz), 7,14 (d, 2H, J = 8,8 Hz), 6,97 (s, 1H), 6,87 (m, 2H), 6,50 (s, 1H), 5,14 (s, 2H), 4,68 (s, 2H), 3,91 (s, 2H), 3,71 (s, 3H), 2,00 (s, 3H); MS m/z 491 (M-1).
Primjer 15
Sinteza {2-Metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 15)
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Korak 1. Priprema metil estera {2-Metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 15A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 2C i 14B. MS m/z 477 (M+1).
Korak 2. Priprema {2-Metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 15)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 15A. mp 133°C; 400 MHz 1H NMR (DMSO-d6) δ 7,70 (d, 2H, J = 8 Hz), 7,76 (d, 2H, J = 8 Hz), 7,14 (d, 2H, J = 8,8 Hz), 7,09 (m, 1H), 7,04 (dd, 1H, J=2,4 Hz, J'=8,4 Hz), 6,87 (m, 2H), 6,68 (d, 1H, J=8,4Hz), 5,14 (s, 2H), 4,61 (s, 2H), 3,99 (s, 2H), 2,08 (s, 3H); MS m/z 461 (M-1).
Primjer 16
Sinteza [5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-3-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 16)
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Korak 1. Priprema (3'-Trifluorometoksi-bifenil-3-il)-metanola (spoj 16A)
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Spoj iz naslova je priređen na isti način kao i Primjer 3A uporabom 3-hidroksimetilfenilborne kiseline i 1-bromo-3-trifluorometoksi-benzena. MS m/z 251 (M-1).
Korak 2. Priprema 3-Klorometil-3'-trifluorometoksi-bifenila (spoj 16B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 16A. MS m/z 251 (M-1).
Korak 3. Priprema metil estera [5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-3-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 16C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 16B. MS m/z 491 (M-1).
Korak 4. Priprema [5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-3-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 16)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 16C. mp 92-94°C; 400 MHz 1H NMR (DMSO-d6) δ 12,96 (br(s), 1H), 7,55-7,24 (m, 8H), 7,01 (s, 1H), 6,52 (s, 1H), 4,68 (s, 2H), 4,03 (s, 2H), 3,72 (s, 3H), 1,99 (s, 3H); MS m/z 479 (M+1).
Primjer 17
Sinteza [4-(9H-Fluoren-2-ilmetilsulfanil-2-metil-fenoksi]-octene kiseline (spoj 17)
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Korak 1. Priprema (9H-Fluoren-2-il)-metanola (spoj 17A)
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9H-Fluoren-2-karbaldehid (500 mg, 2,6 mmol) se otopi u 10 ml metanola. Doda se natrijev borohidrid (200 mg, 5,2 mmol) i miješa na sobnoj temperaturi 1 h. Zatim se doda voda (10 ml) i nepročišćeni produkt se ekstrahira u etil acetatu (50 ml), ispere sa slanom vodom (50 ml), isuši preko bezvodnog natrijevog sulfata, odijeli i koncentrira kako bi se dobio produkt iz naslova zadovoljavajuće čistoće. MS m/z 195 (M+1).
Korak 2. Priprema 2-Klorometil-9H-fluorena (spoj 17B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 17A. MS m/z 179 (M-Cl+1).
Korak 3. Priprema metil estera [4-(9H-Fluoren-2-ilmetilsulfanil-2-metil-fenoksi]-octene kiseline (spoj 17C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 17B. MS m/z 422 (M+1).
Korak 4. Priprema [4-(9H-Fluoren-2-ilmetilsulfanil-2-metil-fenoksi]-octene kiseline (spoj 17)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 17C. 400 MHz 1H NMR (DMSO-d6) δ 12,93 (br(s), 1H), 7,80 (d, 1H, J = 7,6 Hz), 7,23 (d, 1H, J = 8 Hz), 7,5 (d, 1H, J = 7,6 Hz), 7,43 (s, 1H), 7,31 (t, 1H, J=6,4 Hz), 7,24 (m, 2H), 7,15 (m, 1H), 7,08 (dd, 1H, J=2,4 Hz, J'=8,4 Hz), 6,7 (d, 1H, J=8,8 Hz), 4,62 (s, 2H), 4,13 (s, 2H), 3,82 (s, 2H), 2,09 (s, 3H). MS m/z 375 (M-l). Anal. Izrač. za C23H20O3S·0,3 H2O C, 72,34; H, 5,44; nađeno: C, 72,46; H, 5,20.
Primjer 18
Sinteza {5-Metoksi-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 18)
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Priprema [4-(5-Trifluorometil-piridin-2-il)-fenil]-metanola (spoj 18A)
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Spoj iz naslova je priređen iz 2-Kloro-5-trifluorometil-piridina i 4-(hidroksimetil)borne kiseline, PdCl2(dppb) katalizator, na isti način kao i Primjer 3A. 400 MHz 1H NMR (DMSO-d6) δ 8,98 (s, 1H), 8,2 (dd, 1H, J = 2,4 Hz, J' = 8,4 Hz), 8,09 (m, 3H), 7,42 (d, 2H, J = 8,54 Hz), 5,23 (t, 1H), 4,54 (d, 2H, J = 6 Hz); MS m/z 254 (M+l).
Priprema 2-(4-Klorometil-fenil)-5-trifluorometil-piridina (spoj 18B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 18A. MS m/z 272 (M+1).
Priprema metil estera {5-Metoksi-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 18C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1D i 18B. MS m/z 478 (M+1).
Priprema {5-Metoksi-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 18)
Spoj iz naslova je priređen iz produkta Primjera 18C na isti način kao u Primjeru 1. mp 225°C (dec.); 400 MHz 1H NMR (DMSO-d6) δ 8,97 (s, 1H), 8,2 (dd, 1H, J = 2,4 Hz, J' = 8,4 Hz), 8,13 (m, 1H), 8,01 (d, 2H, J = 8,4 Hz), 7,34 (s, 2H, J = 8,4 Hz), 6,95 (s, 1H), 6,42 (s, 1H), 4,23 (s, 2H), 4,01 (s, 2H), 3,69 (s, 3H), 1,96 (s, 3H) MS m/z 464(M+1).
Primjer 19
Sinteza {5-Metoksi-2-metil-4-[6-(4-trifluorometil-fenil)-piridin-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 19)
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Korak 1. Priprema metil estera [4-(6-Kloro-piridin-3-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 19A)
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Spoj iz naslova je priređen iz 2-Kloro-5-klorometil-piridina i 1D na isti način kao u Primjeru 1F. MS m/z 370 (M+2).
Korak 2. Priprema metil estera {5-Metoksi-2-metil-4-[6-(4-trifluorometil-fenil)-piridin-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 19B)
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Spoj iz naslova je priređen iz produkta Primjera 19B i 1-bromo-4-trifluorometil-benzen na isti način kao u Primjeru 3A. MS m/z 478 (M+1).
Korak 2. Priprema {5-Metoksi-2-metil-4-[6-(4-trifluorometil-fenil)-piridin-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 19)
Spoj iz naslova je priređen iz produkta Primjera 19B na isti način kao u Primjeru 1. mp 203°C (dec.); 400 MHz 1H NMR (DMSO-d6) δ 8,34 (d, 1H, J = 1,6 Hz), 8,21 (d, 2H, J = 8 Hz), 7,92 (d, 1H, J = 8,4 Hz), 7,77 (d, 2H, J = 8,4 Hz), 7,65 (dd 1H, J = 2,4 Hz, J' = 8,4 Hz), 6,93 (s, 1H), 6,39 (s, 1H), 4,15 (s, 2H), 4,00 (s, 2H), 3, 66 (s, 3H), 1,95 (s, 3H). MS m/z 464 (M+1).
Primjer 20
Sinteza [5-Kloro-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 20)
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Korak 1. Priprema 5-Kloro-2-metil-4-tiocijanato-fenola (spoj 20A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1B iz 5-kloro-2-metil-fenola. 400 MHz 1H NMR (DMSO-d6) δ 10,60 (s, 1H), 7,54 (s, 1H), 6,98 (s, 1H), 2,07 (s, 3H).
Korak 2. Priprema metil estera (5-Kloro-2-metil-4-tiocijanato-fenoksi)-octene kiseline (spoj 20B)
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Spoj iz naslova je priređen iz produkta Primjera 20A na isti način kao u Primjeru 1C. 400 MHz 1H NMR (DMSO-d6) δ 7,62 (s, 1H), 7,40 (s, 1H), 4,94 (s, 2H), 3,65 (s, 3H),2,15 (s, 3H).
Korak 3. Priprema metil estera (5-Kloro-4-merkapto-2-metil-fenoksi)-octene kiseline (spoj 20C)
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Spoj iz naslova je priređen iz metil estera (5-kloro-2-metil-4-tiocijanato-fenoksi)-octene kiseline na isti način kao i Primjer 1D. 400 MHz 1H NMR (DMSO-d6) δ 7,27 (s, 1H), 6,97 (s, 1H), 5,31 (s, 1H), 4,79 (s, 2H), 3,64 (s, 3H), 2,07 (s, 3H).
Korak 4. Priprema metil estera [5-Kloro-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 20D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 3B i 20C. 400 MHz 1H NMR (DMSO-d6) δ 7,82 (d, 2H, J = 8,3 Hz), 7,74 (d, 2H, J = 8,3 Hz), 7,62 (d, 2H, J = 8,3 Hz), 7,39 (d, 2H, J = 8,3 Hz), 7,27 (s, 1H), 7,00 (s, 1H), 4,82 (s, 2H), 4,20 (s, 2H), 3,64 (s, 3H), 2,09 (s, 3H); MS m/z 480 (M+).
Korak 5. Priprema [5-Kloro-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 20)
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Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 20D. mp 161-162 °C; 400 MHz 1H NMR (DMSO-d6) δ 7,83 (d, 2H, J = 8,3 Hz), 7,74 (d, 2H, J = 8,3 Hz), 7,62 (d, 2H, J = 8,3 Hz), 7,51 (d, 2H, J =8,3 Hz), 7,26 (s, 1H), 6,95 (s, 1H), 4,69 (s, 2H), 4,20 (s, 2H), 2,08 (s, 3H); MS m/z 467 (M+1).
Primjer 21
Sinteza [3-Metoksi-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 21)
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Korak 1. Priprema 3-Metoksi-4-tiocijanato-fenola (spoj 21A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1B iz 3-metoksi-fenola. 400 MHz 1H NMR (DMSO-d6) δ 10,21 (s, 1H), 7,34 (d, 1H, J = 8,3 Hz), 6,53 (s, 1H), 6,43 (d, 1H, J = 8,3 Hz), 3,81 (s, 3H).
Korak 2. Priprema metil estera (3-Metoksi-4-tiocijanato-fenoksi)-octene kiseline (spoj 21B)
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Spoj iz naslova je priređen iz produkta Primjera 21A na isti način kao u Primjeru 1C. MS m/z 227 (M-CN).
Korak 4. Priprema metil estera (4-Merkapto-3-metoksi-fenoksi)-octene kiseline (spoj 21C)
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Spoj iz naslova je priređen iz metil estera (3-Metoksi-4-tiocijanato-fenoksi)-octene kiseline na isti način kao u Primjeru 1D. 400 MHz 1H NMR (DMSO-d6) δ 7,13 (d, 1H, J = 8,5 Hz), 6,56 (s, 1H), 6,39 (d, 1H, J = 8,5 Hz), 4,72 (s, 2H), 4,51 (s, 1H), 3,75 (s, 3H), 3,64 (s, 3H).
Korak 5. Priprema metil estera [3-Metoksi-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 21D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 3B i 21C. 400 MHz 1H NMR (DMSO-d6) δ 7,81 (d, 2H, J = 8,3 Hz), 7,53 (d, 2H, J = 8,3 Hz), 7,59 (d, 2H, J =8,3 Hz), 7,32 (d, 2H, J =8,3 Hz), 7,11 (d, 1H, J = 8,5 Hz), 6,56 (s, 1H), 6,37 (d, 1H, J = 8,5 Hz), 4,73 (s, 2H), 4,04 (s, 2H), 3,76 (s, 3H), 3,63 (s, 3H); MS m/z 463 (M+1).
Korak 6. Priprema [3-Metoksi-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 21)
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Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 21D. 400 MHz 1H NMR (DMSO-d6) δ 7,83 (d, 2H, J = 8,3 Hz), 7,76 (d, 2H, J = 8,3 Hz), 7,61 (d, 2H, J =8,3 Hz), 7,34 (d, 2H, J =8,3 Hz), 7,13 (d, 1H, J =8,5 Hz), 6,56 (s, 1H), 6,39 (d, 1H, J = 8,5 Hz), 4,63 (s, 2H), 4,06 (s, 2H), 3,77 (s 3H); MS m/z 449 (M+I). Anal. Izrač. za C23H19F3O4S, C, 61,60; H, 4,27; nađeno: C, 61,35; H, 4,25.
Primjer 22
Sinteza {2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline (spoj 22)
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Korak 1. Priprema 2-(4'-Trifluorometil-bifenil-4-il)-etanola (spoj 22A)
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Smjesa 2-(4-bromo-fenil)-etanola (2,3 ml, 3,3 g, 16,4 mmol), 4-trifluorometilfenilborne kiseline (5,0 g, 26,3 mmol), 1,0 M vodene otopine natrijevog karbonata (44,0 ml), i tetrakis(trifenilfosfin)paladija (0,98 g, 0,85 mmol) u 180 ml etanola i 180 ml toluena se zagrijava na temperaturi refluksa 4 h. Ohlađena reakcijska smjesa se razrijedi s 500 ml etil acetata i filtrira kroz podlogu Celite filtera. Filtrat se ispere s 5% vodenom otopinom natrijevog karbonata (2x750 ml) i slanom vodom (3x750 ml), zatim isuši preko bezvodnog natrijevog sulfata i koncentrira. Nepročišćeni produkt se pročisti kromatografijom na normalnoj fazi. MS m/z 266 (M).
Korak 2. Priprema 4-(2-Bromo-etil)-4'-trifluorometil-bifenila (spoj 22B)
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Otopina 2-(4'-trifluorometil-bifenil-4-il)-etanola (2,8 g, 10,3 mmol) i ugljikovog tetrabromida (3,8 g, 11,5 mmol) u 50 ml diklorometana se ohladi na ledu, i dodaje se trifenilfosfin (2,9 g, 11,1 mmol) po porcijama preko 10 minuta. Smjesa se miješa na sobnoj temperaturi 18 h, i otapalo ispari. Ostatak se promiješa u 75 ml etera, i smjesa se filtrira. Netopivi dio se ispere preko lijevka sa svježim eterom (3x75 ml). Sjedinjeni filtrati etera se koncentriraju, i nepročišćeni produkt se pročisti kromatografijom na normalnoj fazi. MS m/z 328 (M-1).
Korak 3. Priprema metil estera {2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline (spoj 22C)
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Otopina 4-(2-bromo-etil)-4'-trifluorometil-bifenila (0,66 g, 2,0 mmol) i metil estera (4-merkapto-2-metil-fenoksi)-octene kiseline (0,42 g, 2,0 mmol) u 10 ml acetonitrila se tretira s cezijevim karbonatom (1,3 g, 4,0 mmol), i smjesa se miješa na sobnoj temperaturi 18 h. Reakcijska smjesa se doda u 200 ml slane vode i ekstrahira s etil acetatom (4x75 ml). Sjedinjeni ekstrakti se isperu sa slanom vodom (2x200 ml), zatim isuše preko bezvodnog natrijevog sulfata i koncentriraju. Nepročišćeni produkt se pročisti kromatografijom na normalnoj fazi. MS m/z 461 (M+l).
Korak 4. Priprema {2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline (spoj 22)
Otopina metil estera {2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline (0,78 g, 1,7 mmol) u 10 ml tetrahidrofurana i 2,0 ml vode se tretira s litij hidroksid monohidratom (0,21 g, 5,0 mmol), i smjesa se miješa na sobnoj temperaturi 2 h. Reakcijska smjesa se razrijedi s 5,0 ml vode i jako zakiseli dodatkom 4,0 N klorovodične kiseline. Smjesa se ekstrahira s etil acetatom (4x30 ml), i sjedinjeni ekstrakti se isperu sa slanom vodom (2x50 ml), zatim isuše preko bezvodnog natrijevog sulfata i koncentriraju. Nepročišćeni produkt se rekristalizira iz etil acetat/heksana. mp 132-134°C; IR (tanki sloj) cm-1 1741, 1709, 1490, 1326, 1239, 1110; 400 MHz 1H NMR (DMSO-d6) δ 7,82 (d, 2H, J = 8,0 Hz), 7,74 (d, 2H, J = 8,0 Hz), 7,61 (d, 2H, J = 8,3 Hz), 7,31 (d, 2H, J = 8,3 Hz), 7,15 (m, 2H), 6,75 (d, 1H, J = 8,3 Hz), 4,64 (s, 2H), 3,11 (t, 2H, J = 7,6 Hz), 2,82 (t, 2H, J = 7,6 Hz), 2,12 (s, 3H); MS m/z 447 (M+1). Anal. Izrač. za C24H21F3O3S: C, 64,56; H, 4,74; nađeno: C, 64,45; H, 4,58.
Primjer 23
Sinteza {5-Metoksi-2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline (spoj 23)
[image]
Korak 1. Priprema metil estera {5-Metoksi-2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline (spoj 23A)
[image]
Spoj iz naslova je priređen na isti način kao i Primjer 22C uporabom 4-(2-bromo-etil)-4'-trifluorometil-bifenila i 1D. MS m/z 491 (M+1).
Korak 2. Priprema {5-Metoksi-2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline (spoj 23)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom metil estera {5-metoksi-2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline. mp 169-171 °C; IR (tanki sloj) cm-1: 1718, 1500, 1330, 1162, 1109, 1052; 400 MHz 1H NMR (DMSO-d6) δ 7,82 (d, 2H, J = 8,3 Hz), 7,74 (d, 2H, J = 8,6Hz), 7,61 (d, 2H, J = 8,3 Hz), 7,31 (d, 2H, J = 8,3 Hz), 7,06 (s, 1H), 6,53 (s, 1H), 4,69 (s, 2H), 3,73 (s, 3H), 3,02 (t, 2H, J = 7,5 Hz), 2,78 (t, 2H, J = 7,5 Hz), 2,06 (s, 3H); MS m/z 477 (M+1). Anal. Izrač. za C25H23F3O4S: C, 63,02; H, 4,87; nađeno: C, 62,77; H, 4,62.
Primjer 24
Sinteza {2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octene kiseline (spoj 24)
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Korak 1. Priprema metil estera (4-Bromo-2-metil-fenoksi)-octene kiseline (spoj 24A)
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Otopina metil estera o-toliloksi-octene kiseline (Belleney J., i sur., J. Heterocyclic Chem., 1984.; 21:1431; 3,7 g, 20,5 mmol) u 70 ml acetonitrila se tretira s N-bromosukcinimidom (3,8 g, 21,3 mmol) u porcijama preko 10 minuta. Smjesa se miješa na sobnoj temperaturi 18 h, i otapalo ispari. Ostatak se miješa u 75 ml ugljikovog tetraklorida, i smjesa se filtrira. Netopivi dio se ispere preko lijevka sa svježim ugljikovim tetrakloridom (2x50 ml). Sjedinjeni filtrati se koncentriraju i nepročišćeni produkt se pročisti kromatografijom na normalnoj fazi. MS m/z 258 (M-l).
Korak 2. Priprema 4-Trifluorometil-4'-vinil-bifenila (spoj 24B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3A uporabom 1-bromo-4-vinil-benzena i 4-trifluorometilfenilborne kiseline. MS m/z 248 (M).
Korak 3. Priprema metil estera {2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octene kiseline i {2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octene kiseline (spoj 24)
Smjesa 4-trifluorometil-4'-vinil-bifenila (1,9 g, 7,7 mmol), metil estera (4-Bromo-2-metil-fenoksi)-octene kiseline (2,0 g, 7,7 mmol), bezvodnog natrijevog acetata (1,2 g, 14,6 mmol), N,N-dimetilglicina (0,23 g, 2,2 mmol), i paladij acetata (0,025 g, 0,11 mmol) u 10 ml 1-metil-pirolidin-2-one se zagrijava 10 h na 130 °C. Reakcijska smjesa se razdijeli između 250 ml slane vode i 300 ml etil acetata. Sva smjesa se filtrira kroz podlogu Celite filtera. Organski sloj se ispere s 5% vodenom otopinom natrijevog karbonata (3x250ml) i slanom vodom (2x250 ml), zatim isuši preko bezvodnog natrijevog sulfata i koncentrira. Ostatak se pročisti kromatografijom na normalnoj fazi kako bi se dobio metil ester {2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octene kiseline; MS m/z 427 (M+1).
Za vrijeme gore opisanih ispiranja s natrijevim karbonatom nastaje talog koji se ukloni filtracijom. Krutina se miješa 18 h u otopini od 150 ml vode, 50 ml metanola, i 50 ml 4,0 N klorovodične kiseline. Zakiseljeni produkt se filtrira i rekristalizira iz vodene otopine acetonitrila kako bi se dobila {2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octena kiselina. mp 243-245°C; IR (tanki sloj) cm-1: 1746, 1717, 1502, 1323, 1125, 1069; 400 MHz 1H NMR (DMSO-d6) δ 7,88 (d, 2H, J = 8,0 Hz), 7,76 (d, 2H, J = 8,3 Hz), 7,71 (d, 2H, J =8,5 Hz), 7,64 (d, 2H, J = 8,5 Hz), 7,43 (d, 1H, J = 1,7 Hz), 7,32 (dd, 1H, J = 2,1, 8,5 Hz), 7,21 (d, 1H, J = 16,5 Hz), 7,10 (d, 1H, J = 16,4 Hz), 6,79 (d, 1H, J = 8,5 Hz), 4,68 (s, 2H), 2,18 (s, 3H); MS m/z 413 (M+l). Anal. Izrač. za C24H19F3O3: C, 69,90; H, 4,64; nađeno: C, 69,77; H, 4,57.
Primjer 25
Sinteza {2-Metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etil]-fenoksi}-octene kiseline (spoj 25)
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Otopina {2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-vinil]-fenoksi}-octene kiseline (0,98 g, 2,4 mmol) u 100 ml tetrahidrofurana se hidrogenira preko 0,16 g 20% paladij uz ugljik kao katalizator. Katalizator se ukloni filtracijom, i filtrat ispari. Nepročišćeni produkt rekristalizira iz vodene otopine acetonitrila. mp 174-176°C; IR (tanki sloj) cm-1: 1747, 1711, 1500, 1318, 1160, 1123; 400 MHz 1H NMR (DMSO-d6) δ 7,83 (d, 2H, J = 8,1 Hz), 7,74 (d, 2H, J = 8,3 Hz), 7,60 (d, 2H, J = 6,5 Hz), 7,32 (d, 2H, J = 8,3 Hz), 7,01 (d, 1H, J = 2,0 Hz), 6,94 (dd, 1H, J = 2,0, 8,3 Hz), 6,66 (d, 1H, J = 8,3 Hz), 4,59 (s, 2H), 2,83 (m, 2H), 2,76 (m, 2H), 2,11 (s, 3H); MS m/z 413 (M-1). Anal. Izrač. za C24H21F3O3: C, 69,56; H, 5,11; nađeno: C, 69,28; H, 4,96.
Primjer 26
Sinteza {7-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 26)
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Korak 1. Priprema metil estera {7-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 26A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 18B i 12C. MS m/z 474 (M+1).
Korak 2. Priprema {7-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 26)
[image]
Spoj iz naslova je priređen iz produkta Primjera 26A na isti način kao u Primjeru 1. mp 220°C (dec.); 400 MHz 1H NMR (DMSO-d6) δ 12,94 (s, 1H), 8,97 (s, 1H), 8,2 (dd, 1H, J = 2 Hz, J'= 8,8 Hz), 8,13 (d, 1H, J = 8,4 Hz), 8,01 (d, 2H, J = 8,4 Hz), 7,34 (d, 2H, J = 8,8 Hz), 7,07 (d, 1H, J = 8,4 Hz), 6,57 (d, 1H, J = 8 Hz), 4,61 (s, 2H), 4,07 (s, 2H), 2,72 (m, 4H), 1,89 (m, 2H). MS m/z 460(M+l).
Primjer 27
Sinteza {5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 27)
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Korak 1. Priprema metil estera {5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 27A)
[image]
Spoj iz naslova je priređen iz produkta Primjera 18B i metil estera (7-merkapto-5-metil-indan-4-iloksi)-octene kiseline (priređen na sličan način kao što je opisano u Primjeru 12C) na isti način kao i Primjer 1F. MS m/z 488 (M+1).
Korak 2. Priprema {5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 27)
[image]
Spoj iz naslova je priređen iz produkta Primjera 27A na isti način kao u Primjeru 1. mp 186 °C; 400 MHz 1H NMR (DMSO-d6) δ 12,94 (s, 1H), 8,97 (s, 1H), 8,24 (dd, 1H, J = 2Hz, J' = 8,8Hz), 8,14 (d, 1H, J = 8,4 Hz), 8,01 (d, 2H, J = 8,4 Hz), 7,34 (d, 2H, J = 8,8 Hz), 6,99 (s, 1H), 4,41 (s, 2H), 4,13 (s, 2H), 2,83 (t, 2H, J = 7,2 Hz), 2,62 (t, 2H, J = 7,2Hz), 2,13 (s, 3H), 1,87 (m, 2H). MS m/z 474 (M+1).
Primjer 28
Sinteza [5-Metil-7-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 28)
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Korak 1. Priprema metil estera [5-Metil-7-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 28A)
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Spoj iz naslova je priređen iz produkta Primjera 3B i metil estera (7-Merkapto-5-metil-indan-4-iloksi)-octene kiseline na isti način kao i Primjer 1F. MS m/z 487 (M+1).
Korak 2. Priprema [5-Metil-7-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 28)
[image]
Spoj iz naslova je priređen iz produkta Primjera 28A na isti način kao u Primjeru 1. mp 177°C; 400 MHz 1H NMR (DMSO-d6) δ 12,82 (s, 1H), 7,82 (d, 2H, J = 8 Hz), 7,75 (d, J = 8 Hz), 7,61 (d, 2H, J = 8 Hz), 7,35 (d, 2H, J = 8 Hz), 6,99 (s, 1H), 4,41 (s, 2H), 4,12 (s, 2H), 2,83 (t, 2H, J = 7,2 Hz), 2,62 (t, 2H, J = 7,2 Hz), 2,13 (s, 3H), 1,89 (m, 2H). MS m/z 473 (M+1).
Primjer 29
Sinteza (4-{4-[2-(3-Fluoro-fenil)-vinil]-benzilsulfanil}-5-metoksi-2-metil-fenoksi)-octene kiseline (spoj 29)
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Korak 1. Priprema {4-[2-(3-Fluoro-fenil)-vinil]-fenil}-metanola (spoj 29A)
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(4-Bromo-fenil)-metanol (1 g, 5,35 mmol), 3-fluorostiren (718 mg, 5,89 mmol), paladij acetat (60 mg, 0,3 mmol), i trifenilfosfin (140 mg, 0,6 mmol) se zagrijavaju u trietilaminu na 90°C zapečaćenoj cijevi 18h. Reakcijska smjesa se koncentrira i pročisti kromatografijom na normalnoj fazi kako bi se dobio spoj iz naslova. MS m/z 227 (M-1).
Korak 2. Priprema {4-[2-(3-Fluoro-fenil)-vinil]-fenil}-klorometana (spoj 29B)
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Spoj iz naslova je priređen iz produkta Primjera 29A na isti način kao u Primjeru 3B. MS m/z 245 (M-1).
Korak 3. Priprema metil estera (4-{4-[2-(3-Fluoro-fenil)-vinil]-benzilsulfanil}-5-metoksi-2-metil-fenoksi)-octene kiseline (spoj 29C)
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Spoj iz naslova je priređen iz produkta Primjera 29B i produkta Primjera 1D na isti način kao u Primjeru 1F. MS m/z 453 (M+1).
Korak 4. Priprema (4-{4-[2-(3-Fluoro-fenil)-vinil]-benzilsulfanil}-5-metoksi-2-metil-fenoksi)-octene kiseline (spoj 29)
[image]
Spoj iz naslova je priređen iz produkta Primjera 29C na isti način kao u Primjeru 1. mp 154°C (dec.); 400 MHz 1H NMR (DMSO-d6) δ 12,94 (s, 1H), 7,46-7,34 (m, 5H), 7,27-7,15 (m, 4H), 7,06-6,99 (m, 2H), 6,52 (s, 1H), 4,69 (s, 2H), 3,98 (s, 2H), 3,73 (s, 3H), 2,00 (s, 3H), MS m/z 439(M+1).
Primjer 30
Sinteza {2-Metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 30)
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Korak 1. Priprema metil estera {2-Metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 30A)
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Spoj iz naslova je priređen iz produkta Primjera 2C i produkta Primjera 18B na isti način kao u Primjeru 1F. MS m/z 448 (M+1).
Priprema {2-Metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline
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Spoj iz naslova je priređen iz produkta Primjera 30A na isti način kao u Primjeru 1. 400 MHz 1H NMR (DMSO-d6) δ 8,97 (s, 1H), 8,2 (dd, 1H, J =2 Hz, J' = 8,8 Hz), 8,13 (d, 1H, J = 8,4 Hz), 8,01 (d, 2H, J = 8,4 Hz), 7,36 (d, 2H, J = 8,4 Hz), 7,07 (s, 1H), 7,01 (dd, 1H, J = 8,4 Hz, J' = 2,4 Hz), 6,57 (d, 1H, J = 8,8 Hz), 4,09 (s, 2H), 4,06 (s, 2H), 2,04 (s, 3H). MS m/z 434 (M+1).
Primjer 31
Sinteza {4-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 31)
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Korak 1. Priprema [4-(2,4-Difluoro-benziloksi)-fenil]-metanola (spoj 31A)
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Spoj iz naslova je priređen na isti način kao u Primjeru 14A uporabom 1-bromometil-2,4-difluoro-benzena i 4-hidroksimetil-fenola. MS m/z 233 (M-OH).
Korak 2. Priprema 1-(4-Klorometil-fenoksimetil)-2,4-difluoro-benzena (spoj 31B)
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Spoj iz naslova je priređen na isti način kao u Primjeru 3B uporabom 31A. MS m/z 233 (M-CI).
Korak 3. Priprema metil estera {4-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 31C)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1F uporabom 31B i 2C. MS m/z 445 (M+1).
Priprema {4-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline
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U otopinu produkta iz Primjera 31C (1,5 g, 3,3 mmol) u smjesi 20 mL tetrahidrofurana i 4 mL vode se doda litij hidroksid monohidrat (0,42 g, 9,9mmol). Reakcijska smjesa se miješa na sobnoj temperaturi 18 h i zatim isparava da se dobije ostatak, koji se suspendira u 50 mL vode. Smjesa se zakiseli s 1N klorovodičnom kiselinom do pH 2. Istaložena krutina koja se skupi se filtrira, ispere s vodom, i zatim isuši kako bi se dobio spoj iz naslova koji se ne treba dalje pročišćavati. mp 139-141°C; IR (KBr) cm-1: 3081, 2917, 1735, 1604, 1508, 1233; 400 MHz 1H NMR (DMSO-d6) δ 7,51-7,59 (m, 1H), 7,02-7,31 (m, 6H), 6,85-6,92 (m, 2H), 6,68 (d, 1H, J = 8,6 Hz), 5,01 (s, 2H), 4,60 (s, 2H), 4,00 (s, 2H), 2,08 (s, 3H); MS m/z 429 (M-1). Anal. Izrač. za C23H20F2O4S: C, 64,17; H, 4,68; nađeno: C, 64,11; H, 4,59.
Primjer 32
Sinteza {4-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 32)
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Korak 1. Priprema [4-(2,4-Dikloro-benziloksi)-fenil]-metanola (spoj 32A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 2,4-dikloro-1-klorometil-benzena i 4-hidroksimetil-fenola. MS m/z 265 (M-OH).
Korak 2. Priprema 2,4-Dikloro-1-(4-klorometil-fenoksimetil)-benzena (spoj 32B)
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Spoj iz naslova je priređen na isti način kao u Primjeru 3B uporabom 32A. MS m/z 265 (M-Cl).
Korak 3. Priprema metil estera {4-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 32C)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1F uporabom 32B i 2C. MS m/z 477 (M+1).
Korak 4. Priprema {4-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 32)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1 uporabom 32C. mp 143-145 °C; IR (KBr) cm-1: 3062, 2936, 1724, 1492, 1227, 1192; 400 MHz 1H NMR (DMSO-d6) δ 12,97 (br(s), 1H), 7,64 (d, 1H, J = 2,0 Hz), 7,54 (d, 1H, J = 8,3 Hz), 7,42 (dd, 1H, J = 8,3, 2,0 Hz), 7,01-7,20 (m, 4H), 6,84-6,92 (m, 2H), 6,69 (d, 1H, J = 8,5 Hz), 5,05 (s, 2H), 4,62 (s, 2H), 4,01 (s, 2H), 2,08 (s, 3H); MS m/z 461 (M-1). Anal. Izrač. za C23H20C12O4S: C, 59,62; H, 4,35; nađeno: C, 59,33; H, 4,28.
Primjer 33
Sinteza {4-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 33)
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Korak 1. Priprema [4-(4-Metoksi-benziloksi)-fenil]-metanola (spoj 33A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 1-klorometil-4-metoksi-benzena i 4-hidroksimetil-fenola. MS m/z 227 (M-OH).
Korak 2. Priprema 4-Metoksi-1-(4-klorometil-fenoksimetil)-benzena (spoj 33B)
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Spoj iz naslova je priređen na isti način kao u Primjeru 3B uporabom 33A. MS m/z 227 (M-CI).
Korak 3. Priprema metil estera {4-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 33C)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1F uporabom 33B i 2C. MS m/z 439 (M+1).
Korak 4. Priprema {4-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 33)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1 uporabom 33C. mp 150-152°C; HPLC: područje % = 96,69, r.t. = 2,93 min., γ = 214 nm, mobilna faza = acetonitril/voda s 0,10% TFA; IR (KBr) cm-1: 2929, 1728, 1707, 1513, 1491, 1225; 400 MHz 1H NMR (DMSO-d6) δ 12,98 (br(s), 1H), 7,27-7,34 (m, 2H), 7,02-7,16 (m, 4H), 6,81-6,91 (m, 4H), 6,69 (d, 1H, J = 8,6 Hz), 4,91 (s, 2H), 4,61 (s, 2H), 3,99 (s, 2H), 3,69 (s, 3H), 2,08 (s, 3H); MS m/z 423 (M-l). Anal. Izrač. za C24H24O5S: C, 67,90; H, 5,70; nađeno: C, 67,48; H, 5,59.
Primjer 34
Sinteza {4-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 34)
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Korak 1. Priprema [4-(4-tert-Butil-benziloksi)-fenil]-metanola (spoj 34A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 1-bromometil-4-tert-butil-benzena i 4-hidroksimetil-fenola. MS m/z 253 (M-OH).
Korak 2. Priprema 4-tert-Butil-1-(4-klorometil-fenoksimetil)-benzena (spoj 34B)
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Spoj iz naslova je priređen na isti način kao u Primjeru 3B uporabom 34A. MS m/z 253 (M-Cl).
Korak 3. Priprema metil estera {4-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 34C)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1F uporabom 34B i 2C. MS m/z 465 (M+1).
Korak 4. Priprema {4-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 34)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1 uporabom 34C. mp 135-137°C; IR (KBr) cm-1: 2961, 2908, 1751, 1495, 1233, 1194; 400 MHz 1H NMR (DMSO-d6): δ 13,00 (br(s), 1H), 7,27-7,38 (m, 4H), 7,02-7,17 (m, 4H), 6,82-6,88 (m, 2H), 6,69 (d, 1H, J = 8,5 Hz), 4,96 (s, 2H), 4,61 (s, 2H), 3,99 (s, 2H), 2,08 (s, 3H), 1,22 (s, 9H); MS m/z 451 (M+l). Anal. Izrač. za C27H30O4S: C, 71,97; H, 6,71; nađeno: C, 71,66; H, 6,52.
Primjer 35
Sinteza {2-Metil-4-[4-(4-trifluorometoksi-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 35)
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Korak 1. Priprema metil estera [4-(4-Acetoksi-benzilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 35A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom octena kiselina 4-klorometil-fenil estera i 2C. MS m/z 361 (M+1).
Korak 2. Priprema [4-(4-Hidroksi-benzilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 35B)
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Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 35A. MS m/z 303 (M-1).
Korak 3. Priprema metil estera [4-(4-Hidroksi-benzilsulfanil)-2-metil-fenoksi]-octene kiseline (spoj 35C)
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U otopinu produkta iz Primjera 35B (0,43 g, 1,4 mmol) u 14 mL 2,2-dimetoksi propana se doda 1,4 mL koncentrirane klorovodične kiseline. Reakcijska smjesa se miješa na sobnoj temperaturi 18 sati. Smjesa se koncentrira i pročisti flash kromatografijom kako bi se dobio spoj iz naslova. MS m/z 317 (M-1).
Korak 4. Priprema metil estera {2-Metil-4-[4-(4-trifluorometoksi-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 35D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1-bromometil-4-trifluorometoksi-benzena i 35C. MS m/z 493 (M+1).
Korak 5. Priprema {2-Metil-4-[4-(4-trifluorometoksi-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 35)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1 uporabom 35D. mp 141-142°C; 400 MHz 1H NMR (DMSO-d6): δ 12,96 (br(s), 1H), 7,46-7,57 (m, 2H), 7,28-7,38 (m, 2H), 7,00-7,20 (m, 4H), 6,82-6,91 (m, 2H), 6,69 (d, 1H, J = 8,6 Hz), 5,05 (s, 2H), 4,62 (s, 2H), 4,00 (s, 2H), 2,08 (s, 3H); MS m/z 477 (M-1). Anal. Izrač. za C24H21F3O5S: C, 60,25; H, 4,42; neđeno: C, 59,92; H, 4,07.
Primjer 36
Sinteza {6-Metil-8-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 36)
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Korak 1. Metil ester {6-Metil-8-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 36A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom metil estera (8-merkapto-6-metil-kroman-5-iloksi)-octene kiseline i 18B. MS m/z 504 (M+1).
Korak 2. Metil ester {6-Metil-8-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 36)
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Spoj iz naslova je priređen na isti način kao u Primjeru 1 uporabom 36A. mp 156-157°C; IR (KBr) cm-1: 2928, 1731, 1710, 1603, 1329, 1113, 1082; 400 MHz 1H NMR (DMSO-d6): δ 12,84 (br(s), 1H), 8,97 (s, 1H), 8,22 (dd, 1H, J = 8,4, 2,0 Hz), 8,12 (d, 1H, J = 8,4 Hz), 8,04 (d, 2H, J = 8,2 Hz), 7,42 (d, 2H, J = 8,2 Hz), 6,88 (s, 1H), 4,29 (s, 2H), 4,05-4,14 (m, 4H), 2,64 (t, 2H, J = 6,3 Hz), 2,04 (s, 3H), 1,81 (pentet, 2H); MS m/z 490 (M+1). Anal. Izrač. za C25H22F3NO4S: C, 61,34; H, 4,53; N, 2,86; nađeno: C, 60,96; H, 4,48; N, 2,79.
Primjer 37
Sinteza {5-Kloro-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 37)
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Korak 1. Priprema metil estera {5-Kloro-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 37A)
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Spoj 37A je priređen na isti način kao i Primjer 1F uporabom produkata iz Primjera 18B i Primjera 20C. MS m/z 482 (M+).
Korak 2. Priprema {5-kloro-2-metil-4-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 37)
Spoj iz naslova je priređen na isti način kao u Primjeru 1 uporabom 37A. IR cm-1: 1708, 1122; 400 MHz 1H NMR (DMSO-d6) δ 8,97 (s, 1H), 8,22 (d, 1H, J = 8,3 Hz), 8,12 (d, 1H, J = 8,3 Hz), 8,04 (d, 2H, J = 8,3 Hz), 7,43 (d, 2H, J = 8,3 Hz), 7,25 (s, 1H), 6,94 (s, 1H), 4,70 (s, 2H), 4,21 (s, 2H), 2,06 (s, 3H). Anal. Izrač. za C22H17ClF3NO3S: C, 56,47, H, 3,66, N 2,99; nađeno: C, 56,48, H, 3,28, N 3,04.
Primjer 38
Sinteza [5-hidroksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 38)
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Otopina [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline, priređena prema Primjeru 4, (1,0 g, 2,2 mmol) u 75 mL DCM na 0°C, se tretira s BBr3 koji se dodaje kap po kap (5,5 mL 1,0 M otopina u DCM). Nakon 30 minuta, reakcijska smjesa se pažljivo polije s 50% NH4OH. Reakcijska smjesa se zatim zakiseli s konc. HCl do pH 1, i ekstrahira s EtOAC. Organski sloj se osuši (Na2SO4) i koncentrira u vakumu. Nepročišćena reakcijska smjesa se zatim stavi u MeOH, te se doda 50 µL H2SO4, i onda zagrijava na temperaturi refluksa 3 sata. Reakcijska smjesa se dalje razrijedi s EtOAc, ispere s 1 x 50 mL vode, osuši (Na2SO4), i onda koncentrira u vakumu. Rezultirajući ester se pročisti rekristalizacijom iz EtOAC/Heksana. Ester se zatim saponificira na isti način kao što je opisano u Primjeru 1, kako bi se dobio spoj iz naslova ukupnog iskorištenja 37%. IR cm-1: 3408, 1752, 1323; 400 MHz 1H NMR (DMSO-d6) δ 9,56 (s, 1H), 7,82 (d, 2H, J = 8,4 Hz), 7,74 (d, 2H, J = 8,4 Hz), 7,31 (d, 2H, J = 8,4 Hz), 6,92 (s, 1H), 6,30 (s, 1H), 4,55 (s, 2H), 4,00 (s, 2H), 1,95 (s, 3H). Anal. Izrač. za C23H19F3NO4S·0,1 H2O C, 61,35; H, 4,30; nađeno: C, 61,08; H, 3,92.
Primjer 39
Sinteza [5-Metoksi-2-metil-4-(3-metil-4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 39)
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Korak 1. Priprema (3-Metil-4'-trifluorometil-bifenil-4-il)-metanola (spoj 39A)
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Spoj iz naslova je priređen na isti način kao i Primjer 3A uporabom (4-bromo-2-metil-fenil)-metanola i 4-(trifluorometil)benzenborne kiseline. MS m/z 249 (M-OH).
Korak 2. Priprema 4-klorometil-3-metil-4'-trifluorometil-bifenila (spoj 39B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 39A. 400 MHz 1H NMR (DMSO-d6) δ 7,84 (d, 2H, J = 8,3 Hz), 7,76 (d, 2H, J = 8,3 Hz), 7,57 (s, 1H), 7,48 (m, 2H), 4,80 (s, 2H), 2,41 (s, 3H).
Korak 3. Priprema metil estera [5-Metoksi-2-metil-4-(3-metil-4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 39C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1D i 39B. MS m/z 491 (M+1).
Korak 4. Priprema [5-Metoksi-2-metil-4-(3-metil-4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 39)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 39C. IR cm-1: 1740, 1322; 400 MHz 1H NMR (DMSO-d6) δ 7,81 (d, 2H, J = 8,1 Hz), 7,73 (d, 2H, J = 8,1 Hz), 7,51 (s, 1H), 7,39 (d, 1H, J = 7,8 Hz), 7,16 (d, 1H, J = 7,8 Hz), 7,04 (s, 1H), 6,53 (s, 1H), 4,71 (s, 2H), 4,00 (s, 2H), 3,73 (s, 3H), 2,39 (s, 3H), 2,02 (s, 3H); MS m/z 477 (M+1). Anal. Izrač. za C25H23F3O4S·0,1 H2O; C, 62,78; H, 4,89; nađeno: C, 62,57; H, 4,82.
Primjer 40
Sinteza {7-[4-(4-trifluorometil-benzil)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 40)
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Korak 1. Priprema metil estera 4-(4-trifluorometil-benzil)-benzojeve kiseline (spoj 40A)
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U otopinu 1-bromo-4-trifluorometil-benzena (10,0 g, 44,4 mmol) u THF na -78°C se dodaje kap po kap n-butil litij (33,3 mL 1,6 M otopine u heksanu). Nakon 20 minuta se doda metil ester 4-formil-benzojeve kiseline u 50 mL THF. Reakcijska smjesa se može zagrijati na sobnu temperaturu i nakon 1 H, se prelije sa zasićenim NH4Cl. Reakcijska smjesa se zatim koncentrira u vakumu, stavi u EtOAc, i ispere s 2 M HCl (1 x 100 mL), slanom vodom (1 x 100 mL), osuši (Na2S04) i otapalo se ukloni u vakumu da se dobije alkohol kao intermedijer. Pročišćavanjem flash kolonskom kromatografijom (gradijent ispiranja: 5% EtOAc/heksan do 40% EtOAc/heksan) se dobije 6,2 g alkohol kao intermedijera. 4,0 g (12,9 mmol) intermedijera se zatim hidrogenira u EtOAc uporabom 0,5g 10 % Pd(OH)2/C kao katalizatora. Filtracijom kroz Celite®, i koncentiranjem u vakumu se dobije spoj iz naslova (3,60 g, 95%). MS m/z 295 (M+l).
Korak 2. Priprema [4-(4-trifluorometil-benzil)-fenil]-metanola (spoj 40B)
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Otopina 40A (3,6 g, 12,2 mmol) u 75 mL THF se tretira po porcijama na sobnoj temperaturi s litij aluminij hidridom (0,97 g, 25,6 mmol). Nakon 1 sata se rekacijska smjesa pažljivo prelije sa zasićenim NH4Cl. Rekacijska smjesa se zatim ekstrahira s EtOAc, i organski sloj se ispere s 2 M HCl (1 x 50 mL), slanom vodom (1 x 50 mL), osuši (Na2S04) i otapalo se ukloni u vakumu. Pročišćavanjem flash kolonskom kromatografijom (gradijent ispiranja: 5% EtOAc/heksan do 40% EtOAc/heksan) se dobije spoj iz naslova (2,8 g, 86%). MS m/z 265 (M-1).
Korak 3. Priprema Kloro-[4-(4-trifluorometil-benzil)-fenil]-metana (spoj 40C)
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Spoj iz naslova je priređen na isti način kao što je opisano za 3B uporabom 40B i tionil klorida. 400 MHz 1H NMR (DMSO-d6) 7,59 (d, 2H, J = 8,4 Hz), 7,40 (d, 2H, J = 8,4 Hz), 7,31 (d, 2H, J = 8,4 Hz), 7,20 (d, 2H, J =8,4 Hz), 4,67 (s, 2H), 3,99 (s, 2H).
Korak 4. Priprema metil estera {7-[4-(4-Trifluorometil-benzil)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 40D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom produkata iz Primjera 12C i Primjera 40C. MS m/z 487 (M+1).
Korak 5. Priprema {7-[4-(4-trifluorometil-benzil)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 40)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 40D. IR cm-1: 1745, 1704, 1325; 400 MHz 1H NMR (DMSO-d6) δ 7,58 (d, 2H, J = 8,1 Hz), 7,37 (d, 2H, J = 8,1 Hz), 7,09 (s, 2H), 7,05 (d, 2H, J =8,3 Hz), 6,55 (d, 1H, J = 8,3 Hz), 4,60 (s, 2H), 3,94 (s, 4H), 2,71 (t, 2H, J = 8,3 Hz), 2,58 (t, 2H, J = 8,3 Hz), 1,81 (m, 2H); MS m/z 473 (M+1). Anal. Izrač. za C26H23F3O3S·0,1 H2O, C, 65,84; H, 4,93; nađeno: C, 65,58; H, 4,96.
Primjer 41
Sinteza {4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-5-metoksi-2-metil-fenoksi}-octene kiseline (spoj 41)
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Korak 1. Priprema metil estera {4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-5-metoksi-2-metil-fenoksi}-octene kiseline (spoj 41A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1D i 3-klorometil-5-(4-kloro-fenil)-izoksazola. MS m/z 434 (M+1).
Korak 2. Priprema {4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-5-metoksi-2-metil-fenoksi}-octene kiseline (spoj 41)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 41A. IR cm-1: 1747, 1432; 400 MHz 1H NMR (DMSO-d6) δ 7,81 (d, 2H, J = 8,8 Hz), 7,53 (d, 2H, J = 8,8 Hz), 7,05 (s, 1H), 6,92 (s, 1H), 6,52 (s, 1H), 4,69 (s, 2H), 4,01 (s, 2H), 3,71 (s, 3H), 2,00 (s, 3H); MS m/z 420 (M+1). Anal. Izrač. za C20H18ClNO5S, C 57,21; H, 4,32 N, 3,34; nađeno: C, 56,84; H, 4,62, N, 2,96.
Primjer 42
Sinteza {2-Metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 42)
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Korak 1. Priprema etil estera 5-(4-Trifluorometil-fenil)-izoksazol-3-karboksilne kiseline (spoj 42A)
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Natrijev hidrid (1,6 g, 63,7 mmol, 95%) se doda u otopinu 1-(4-trifluorometil-fenil)-etanona (10,0 g, 53,1 mmol) i dietil estera oksalne kiseline (8,7 mL, 63,7 mmol) u 75 mL suhog DMF na 0°C. Reakcijska smjesa se zagrije na sobnu temperaturu i zatim grije do 45°C 45 minuta. Reakcijska smjesa se zatim ohladi, koncentrira u vakumu, i ostatak se stavi u EtOAc. Organski sloj se zatim ispere s 2 M HCl (1 x 100 mL), osuši (Na2SO4) i otapalo se ukloni u vakumu. Pročišćavanjem flash kolonskom kromatografijom (gradijent ispiranja: 5% EtOAc/heksan do 55% EtOAc/heksan) se dobije intermedijer etil ester 2,4-diokso-4-(4-trifluorometil-fenil)-maslačne kiseline (12,2 g, 80%) koja se zatim stavi u EtOH i zagrijava na temperaturi refluksa u prisustvu hidroksil amin klorovodika (10,2 g, 132,3 mmol) 3H. Reakcijska smjesa se zatim ohladi, razrijedi s EtOAc, ispere s razrijeđenim NaHCO3, slanom vodom, osuši (Na2SO4), i koncentrira u vakumu. Rekristalizacijom iz EtOAc/heksana se dobije 5,2 g spoja iz naslova. MS m/z 286 (M+1).
Korak 2. Priprema [5-(4-Trifluorometil-fenil)-izoksazol-3-il]-metanola (spoj 42B)
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Spoj iz naslova je priređen na isti način kao i Primjer 40B uporabom 42A. MS m/z 244 (M+1).
Korak 3. Priprema 3-klorometil-5-(4-trifluorometil-fenil)-izoksazola (spoj 42C)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 42B. MS m/z 262 (M+1).
Korak 4. Priprema metil estera {2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 42D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 42C i 2C. MS m/z 438 (M+1).
Korak 5. Priprema {2-Metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 42)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 42D. IR cm-1: 1746, 1326; 400 MHz 1H NMR (DMSO-d6) δ 12,97 (br(s), 1H), 8,02 (d, 2H, J = 8,0 Hz), 7,83 (d, 2H, J = 8,0 Hz), 7,20 (s, 1H), 7,15 (s, 2H), 6,71 (d, 1H, J = 8,5 Hz), 4,63 (s, 2H), 4,14 (s, 2H), 2,08 (s, 3H); MS m/z 424 (M+1). Anal. Izrač. za C20H16F3NO4S C, 56,73; H, 3,81; N, 3,31 nađeno: C, 56,59; H, 3,58; N, 3,22.
Primjer 43
Sinteza {5-Metoksi-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 43)
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Korak 1. Priprema metil estera {5-Metoksi-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 43A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 42C i 1D. MS m/z 468 (M+1).
Korak 2. Priprema {5-Metoksi-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 43)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 43A. IR cm-1: 1745, 1322; 400 MHz 1H NMR (DMSO-d6) δ 12,96 (br(s), 1H), 8,01 (d, 2H, J = 8,3 Hz), 7,83 (d, 2H, J = 8,3 Hz), 7,07 (s, 2H), 6,52 (s, 1H), 4,70 (s, 2H), 4,03 (s, 2H), 3,71 (s, 3H), 1,99 (s, 3H); MS m/z 454 (M+1). Anal. Izrač. za C21H18F3NO5S·0,1 H2O C, 54,46; H, 3,92; N, 3,01 nađeno: C, 54,54; H, 3,74; N, 2,93.
Primjer 44
Sinteza {7-[5-(4-Trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 44)
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Korak 1. Priprema metil estera {7-[5-(4-Trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 44A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 42C i 12C. MS m/z 464 (M+1).
Korak 2. Priprema {7-[5-(4-Trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 44)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 44A. 400 MHz 1H NMR (DMSO-d6) δ 12,94 (br(s), 1H), 8,01 (d, 2H, J = 8,4 Hz), 7,83 (d, 2H, J = 8,4 Hz), 7,09 (s, 2H), 6,58 (d, 1H, J = 8,6 Hz), 4,62 (s, 2H), 4,08 (s, 2H), 2,77 (m, 4H), 1,89 (m, 2H); MS m/z 450 (M+1). Anal. Izrač. za C22H18F3NO4S C, 58,79; H, 4,04; N, 3,12 nađeno: C, 58,59; H, 3,80; N, 3,01.
Primjer 45
Sinteza {2-Metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 45)
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Korak 1. Priprema 5-klorometil-3-(4-trifluorometil-fenil)-izoksazola (spoj 45A)
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Otopina 4-trifluorometil-benzaldehid oksima (8,9 g, 47,1 mmol) u 100 mL DCM se doda u otopinu, koja se brzo miješa, propargil klorida (47,1 mmol), trietil amina (4,71 mmol) i 91 mL komercijalnog sredstva za izbjeljivanje (6,5% po masi), sve u 50 mL DCM na 0°C. Nakon 1 sata se odvoje slojevi i organski sloj se osuši (Na2SO4), i koncentrira u vakumu. Pročišćavanjem flash kolonskom kromatografijom (gradijent ispiranja: 5% EtOAc/heksan do 25% EtOAc/heksan) se dobije spoj iz naslova (2,9 g, 23%) MS m/z 262 (M+1).
Korak 2. Priprema metil estera {2-Metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 45B)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 45A i 2C. MS m/z 438 (M+1).
Korak 3. Priprema {2-Metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 45)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 45B. IR cm-1: 1747; 400 MHz 1H NMR (DMSO-d6) δ 12,97 (br(s), 1H), 7,99 (d, 2H, J = 8,0 Hz), 7,81 (d, 2H, J = 8,0 Hz), 7,21 (s, 1H), 7,16 (d, 1H, J = 8,5 Hz), 6,86 (s, 1H), 6,74 (d, 1H, J = 8,5 Hz), 4,63 (s, 2H), 4,30 (s, 2H), 2,09 (s, 3H); MS m/z 424 (M+1).
Primjer 46
Sinteza {5-Metoksi-2-metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 46)
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Korak 1. Priprema metil estera {5-Metoksi-2-metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 46A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 45A i 1D. MS m/z 468 (M+1).
Korak 2. Priprema {5-Metoksi-2-metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 46)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 46A. IR cm-1: 1752, 1711; 400 MHz 1H NMR (DMSO-d6) δ 12,96 (br(s), 1H), 7,98 (d, 2H, J = 8,1 Hz), 7,81 (d, 2H, J = 8,1 Hz), 7,09 (s, 1H), 6,80 (s, 1H), 6,54 (s, 1H), 4,71 (s, 2H), 4,18 (s, 2H), 3,79 (s, 3H), 2,00 (s, 3H); MS m/z 454 (M+1).
Primjer 47
Sinteza [2-Metil-4-(4-fenoksi-benzilsulfanil)-fenoksi]-octene kiseline (spoj 47)
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Korak 1. Priprema metil estera [2-Metil-4-(4-fenoksi-benzilsulfanil)-fenoksi]-octene kiseline (spoj 47A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F s 1-klorometil-4-fenoksi-benzenom i 2C. MS m/z 321 (M-metilacetat).
Korak 2. Priprema [2-Metil-4-(4-fenoksi-benzilsulfanil)-fenoksi]-octene kiseline (spoj 47)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 47A. 400 MHz 1H NMR (DMSO-d6) δ 12,95 (br(s), 1H), 7,33 (m, 2H), 7,22 (m, 2H), 7,07 (m, 3H), 6,93 (m, 2H), 6,87 (m, 2H), 6,71 (d, 1H, J =8,3 Hz), 4,62 (s, 2H), 4,04 (s, 2H), 2,09 (s, 3H). MS m/z 379 (M-1).
Primjer 48
Sinteza [7-(4'-Trifluorometil-bifenil-3-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 48)
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Korak 1. Priprema (4'-Trifluorometil-bifenil-3-il)-metanola (spoj 48A)
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Spoj iz naslova je priređen na isti način kao i Primjer 3A s 1-bromo-4-trifluorometil-benzenom i 3-(hidroksimetil)fenil bornom kiselinom. MS m/z 251 (M-1).
Korak 2. Priprema 3-Klorometil-4'-trifluorometil-bifenila (spoj 48B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 48A. MS m/z 236 (M+1-Cl).
Korak 3. Priprema metil estera [7-(4'-Trifluorometil-bifenil-3-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 48C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 48B. MS m/z 473 (M+1).
Korak 4. Priprema [7-(4'-Trifluorometil-bifenil-3-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 48)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 48C. 400 MHz 1H NMR (DMSO-d6) δ 12,96 (br(s), 1H), 7,75 (d, 2H, J = 8,3 Hz), 7,67 (d, 2H, J = 8,1 Hz), 7,52 (m, 1H), 7,37 (t, 1H, J =7,6 Hz), 7,29 (m, 2H), 7,13 (d, 1H, J =8,5 Hz), 6,61 (d, 1H, J =8,5 Hz), 4,63 (s, 2H), 4,05 (s, 2H), 2,71 (t, 2H), 2,58 (t, 2H), 1,81 (m, 2H). MS m/z 459 (m+1).
Primjer 49
Sinteza [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-3-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 49)
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Korak 1. Priprema metil estera [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-3-ilmetilsulfanil)-fenoksi}-octene kiseline (spoj 49A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 48B i 1D. MS m/z 477 (M+1).
Korak 2. Priprema [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-3-ilmetilsulfanil)-fenoksi}-octene kiseline (spoj 49)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 49A. 400 MHz 1H NMR (DMSO-d6) δ 12,96 (br(s), 1H), 7,73 (d, 2H, J = 9 Hz), 7,71 (d, 2H, J =9 Hz), 7,50 (m, 1H), 7,42 (m, 1H), 7,36 (t, 1H, J =7,8 Hz), 7,28 (m, 1H), 6,99 (s, 1H), 6,53 (s, 1H), 4,70 (s, 2H), 4,03 (s, 2H), 3,73 (s, 3H), 1,99 (s, 3H). MS m/z 463 (M+1).
Primjer 50
Sinteza [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetansulfonil)-fenoksi]-octene kiseline (spoj 50)
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Korak 1. Priprema metil estera [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetansulfonil)-fenoksi]-octene kiseline (spoj 50A)
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Primjer 4 (200 mg) se otopi u 5 ml diklorometana. Zatim se doda u suvišku m-kloroperbenzojeva kiselina (300 mg) i reakcijska smjesa se miješa 3h. Otapalo se ukloni pod vakumom i nepročišćeni produkt se pročisti s MPLC. MS m/z 509 (M+1).
Korak 2. Priprema [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetansulfonil)-fenoksi]-octene kiseline (spoj 50)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 50A. 400 MHz 1H NMR (DMSO-d6) δ 13,13 (br(s), 1H), 7,85 (d, 2H, J =8,1 Hz), 7,77 (d, 2H, J =8,3 Hz), 7,66 (d, 2H, J =8,6 Hz), 7,3 (m, 3H), 6,76 (s, 1H), 4,89 (s, 2H), 4,67 (s, 2H), 3,96 (s, 3H), 2,04 (s, 3H). MS m/z 495 (M+1).
Primjer 51
Sinteza [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetansulfinil)-fenoksi]-octene kiseline (spoj 51)
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Korak 1. Priprema metil estera [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetansulfinil)-fenoksi]-octene kiseline (spoj 51A)
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Primjer 4 (0,5g, 1,0 mmol) se otopi u 25 ml diklorometana, nakon čega se doda 2-benzensulfonil-3-fenil-oksaziridin (0,274, 1,04 mmol). Reakcijska smjesa se miješa 1h. Doda se 10 ml vode, slojevi se odvoje, te se otopina diklorometana osuši iznad bezvodnog natrijevog sulfata, prelije, i koncentrira. Produkt se rekristalizira iz etil acetata kako bi se dobio produkt iz naslova. MS m/z 493 (M+1).
Korak 2. Priprema [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetansulfinil)-fenoksi]-octene kiseline (spoj 51)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 51A. 400 MHz 1H NMR (DMSO-d6) δ 7,83 (d, 2H, J =8,78 Hz), 7,76 (d, 2H, J =8,30 Hz), 7,59 (d, 2H, J =8,30 Hz), 7,11 (d, 2H, J =8,30 Hz), 7,02 (s, 1H), 6,64 (s, 1H), 4,79 (s, 2H), 4,20 (d, 1H, J =12,7 Hz), 3,91 (d, 1H, J =12,4 Hz), 3,76 (s, 3H), 2,03 (s, 3H). MS m/z 479 (M+1).
Primjer 52
Sinteza [2-Propil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 52)
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Korak 1. Priprema metil estera [2-Propil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 52A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 48B i metil estera (4-Merkapto-2-propil-fenoksi)-octene kiseline, priređenog iz 2-propilfenola na isti način kao u Primjeru 2. MS m/z 475 (M+1).
Korak 2. Priprema [2-Propil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline (spoj 52)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 52A. 400 MHz 1H NMR (DMSO-d6) δ 7,81 (d, 2H, J=8,5 Hz), 7,74 (d, 2H, J=8,5 Hz), 7,60 (d, 2H, J=8,1 Hz), 7,33 (d, 2H, J=8, 3 Hz), 7,10 (m, 1H), 7,02 (m, 1H), 6,71 (d, 1H, J=8,5 Hz), 4,60 (s, 2H), 4,11 (s, 2H), 1,43 (m, 2H), 0,77 (m, 3H). MS m/z 459 (M-l).
Primjer 53
Sinteza {7-[3-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 53)
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Korak 1. Priprema [3-(5-Trifluorometil-piridin-2-il)-fenil]-metanola (spoj 53A)
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Spoj iz naslova je priređen na isti način kao i Primjer 3A uporabom 3-(hidroksimetil)fenil borne kiseline i 2-kloro-5-trifluorometil-pyridina. MS m/z 253 (M+1).
Korak 2. Priprema 2-(3-Klorometil-fenil)-5-trifluorometil-piridina (spoj 53B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 53A. MS m/z 237 (M+1-Cl).
Korak 3. Priprema metil estera {7-[3-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 53C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 53B. MS m/z 474 (M+1).
Korak 4. Priprema {7-[3-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 53)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 53C. 400 MHz 1H NMR (DMSO-d6) δ 8,98 (m, 1H), 8,23 (dd, 1H, J=1,7 Hz, J'=8,5 Hz), 7,99 (m, 2H), 7,87 (s, 1H), 7,39 (t, 1H, J=7, 6 Hz), 7,33 (m, 1H), 7,11 (d, 1H, J=8,5 Hz), 6,58 (d, 1H, J=8,5 Hz), 4,61 (s, 2H), 4,08 (s, 2H), 2,70 (t, 2H, J=7,3 Hz), 2,63 (t, 2H, J=7,6 Hz), 1,84 (m, 2H). MS m/z 460 (M+1).
Primjer 54
Sinteza (5-Metoksi-2-metil-4-{2-[1-(4-trifluorometil-benzil)-1H-indol-3-il]-etilsulfanil}-fenoksi)-octene kiseline (spoj 54)
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Korak 1. Priprema metil estera {4-[2-(1H-Indol-3-il)-etilsulfanil]-5-metoksi-2-metil-fenoksi]-octene kiseline (spoj 54A)
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Spoj 1D (1,622 g, 6,7 mmol) i 3-(2-bromo-etil)-1H-indol (1,50g, 6,69 mmol) se otope u 5ml DMF. Zatim se doda kalijev karbonat (1,11g, 8,03 mmol) i miješa na sobnoj temperaturi 3h. Rekacijska smjesa se filtrira, koncentrira i pročisti s MPLC da se dobije spoj iz naslova. MS m/z 225 (M+1).
Korak 2. Priprema metil estera (5-Metoksi-2-metil-4-{2-[1-(4-trifluorometil-benzil)-1H-indol-3-il]-etilsulfanil}-fenoksi)-octene kiseline (spoj 54B)
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Spoj 54A (0,300g, 0,778 mmol) se otopi u 5 ml DMF. Zatim se doda NaH i miješa 1/2 h. 4-trifluorometilbenzil bromid (0,223 g, 0,934 mmol) se doda i rekacijska smjesa se miješa 1,5h. 10 ml 2N HCI se doda do pH<4. Otopina DMF se razdijeli između 30ml vode i 30 ml etil acetata. Organska otopina se ispere s 2x30ml vode, 1x30ml slane vode, osuši preko natrijevog sulfata, odlije, koncentrira i pročisti s MPLC da se dobije spoj iz naslova. MS m/z 544 (M+1).
Korak 3. Priprema (5-Metoksi-2-metil-4-{2-[1-(4-trifluorometil-benzil)-1H-indol-3-il]-etilsulfanil}-fenoksi)-octene kiseline (spoj 54)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 54B. 400 MHz 1H NMR (DMSO-d6) δ 13,0 (br(s), 1H) 7,60 (d, 1H, J=8,1 Hz), 7,42 (d, 1H, J=7,96Hz), 7,31 (m, 4H), 7,04 (m, 2H), 6,96 (m, 1H), 6,53 (s, 1H), 5,43 (s, 2H), 4,70 (s, 2H), 3,72 (s, 3H), 3,03 (t, 2H, J=8,8 Hz), 2,86 (t, 2H, J=7,6 Hz), 2,04 (s, 3H). MS m/z 530 (M+1).
Primjer 55
Sinteza [7-(4'-Trifluorometil-bifenil-2-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 55)
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Korak 1. Priprema metil estera [7-(4'-Trifluorometil-bifenil-2-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 55A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 2-klorometil-4'-trifluorometil-bifenil, koji je priređen na isti način kao i Primjeri 3A i 3B. MS m/z 473 (M+1).
Korak 2. Priprema [7-(4'-Trifluorometil-bifenil-2-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 55)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 55A. 400 MHz 1H NMR (DMSO-d6) δ 12,97 (br(s), 1H), 7,68 (d, 2H, J=8,5 Hz), 7,32 (m, 5H), 7,11 (m, 1H), 6,77 (d, 1H, J=8,5 Hz), 6,47 (d, 1H, J=8,3 Hz), 4,62 (s, 2H), 3,87 (s, 2H), 2,70 (m, 2H), 1,76 (m, 2H). MS m/z 459 (M+1).
Primjer 56
Sinteza {5-Metoksi-2-metil-4-[2-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 56)
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Korak 1. Priprema metil estera {5-Metoksi-2-metil-4-[2-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 56A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 81A i 1D. MS m/z 507 (M+1).
Korak 2. Priprema {5-Metoksi-2-metil-4-[2-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 56)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 56A. 400 MHz 1H NMR (DMSO-d6) δ 12,95 (br(s), 1H), 7,67 (m, 4H), 7,12 (m, 2H), 6,96 (m, 2H), 6,80 (m, 1H), 6,49 (s, 1H), 5,19 (s, 2H), 4,68 (s, 2H), 3,99 (s, 2H), 3,67 (s, 3H), 1,96 (s, 3H). MS m/z 493 (M+1).
Primjer 57
Sinteza {4-[4-(4-Fluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 57)
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Korak 1. Priprema [4-(4-Fluoro-benziloksi)-fenil]-metanola (spoj 57A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 1-bromometil-4-fluoro-benzena i 4-hidroksimetil-fenola. MS m/z 215 (M-OH).
Korak 2. Priprema 1-(4-Klorometil-fenoksimetil)-4-difluoro-benzena (spoj 57B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 57A. MS m/z 215 (M-Cl).
Korak 3. Priprema metil estera {4-[4-(4-Fluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 57C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 57B i 2C. MS m/z 427 (M+1).
Korak 4. Priprema {4-[4-(4-Fluoro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 57)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom produkta iz Primjera 57C. mp 154-155°C; IR (KBr) cm-1: 3050, 2925, 1727, 1495, 1228, 1156; 400 MHz 1H NMR (DMSO-d6): δ 13,00 (br(s), 1H), 7,37-7,48 (m, 2H) 6,99-7,22 (m, 6H), 6,80-6,90 (m, 2H), 6,69 (d, 1H, J = 8,5 Hz), 4,98 (s, 2H), 4,61 (s, 2H), 4,00 (s, 2H), 2,08 (s, 3H); MS m/z 411 (M-1). Anal. Izrač. za C23H21FO4S: C, 66,97; H, 5,13; nađeno: C, 66,64; H, 4,88.
Primjer 58
Sinteza {4-[4-(4-Kloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 58)
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Korak 1. Priprema metil estera {4-[4-(4-Kloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 58A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1-bromometil-4-kloro-benzena i produkta iz Primjera 35C. MS m/z 443 (M+1).
Korak 2. Priprema {4-[4-(4-Kloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 58)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 58A. mp 164 °C; IR (KBr) cm-1: 3062, 1727, 1612, 1493, 1226, 1193: 400 MHz 1H NMR (DMSO-d6): δ 12,99 (br(s), 1H), 7,36-7,44 (m, 4H), 7,01-7,17 (m, 4H), 6,81-6,89 (m, 2H), 6,69 (d, 1H, J = 8,5 Hz), 5,01 (s, 2H), 4,61 (s, 2H), 4,00 (s, 2H), 2,08 (s, 3H); MS m/z 427 (M-1). Anal. Izrač. za C23H21ClO4S: C, 64,40; H, 4,93; nađeno: C, 64,43; H, 4,81.
Primjer 59
Sinteza {4-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 59)
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Korak 1. Priprema metil estera {4-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 59A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 2-bromometil-1,4-dikloro-benzena i produkta priređenog prema Primjeru 35C. m/z 265 (M-211).
Korak 2. Priprema {4-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 59)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 59A. mp 101-103°C; IR (KBr) cm-1: 3077, 1715, 1608, 1496, 1437, 1234; 400 MHz 1H NMR (DMSO-d6): δ 7,37-7,63 (m, 3H), 6,99-7,20 (m, 4H), 6,85-6,94 (m, 2H), 6,63 (d, 1H, J =8,5 Hz), 5,05 (s, 2H), 4,45 (s, 2H), 3,99 (s, 2H), 2,07 (s, 3H); HPLC: područje % = 97,61, r.t. = 5,56 min., λ = 214 nm, mobilna faza = acetonitril/voda s 0,10% TFA; MS m/z 461 (M-l). Anal. Izrač. za C23H20Cl2O4S: C, 59,62; H, 4,35; nađeno: C, 58,04; H, 4,26.
Primjer 60
Sinteza {2-Metil-4-[4-piridin-2-ilmetoksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 60)
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Korak 1. Priprema metil estera {2-Metil-4-[4-piridin-2-ilmetoksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 60A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 2-bromometil-piridin klorovodika i produkta priređenog prema Primjeru 35C. MS m/z 410 (M+1).
Korak 2. Priprema {2-Metil-4-[4-piridin-2-ilmetoksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 60)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 60A. mp 150°C; IR (KBr) cm-1: 2917, 1723, 1605, 1511, 1490, 1217; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (brs, 1H), 8,49-8,55 (s, 1H), 7,73-7,81 (m, 1H), 7,40-7,48 (m, 1H), 7,24-7,33 (m, 1H), 7,00-7,19 (m, 4H), 6,83-6,93 (m, 2H), 6,69 (d, 1H, J =8,5 Hz), 5,08 (s, 2H), 4,62 (s, 2H), 4,00 (s, 2H), 2,08 (s, 3H); HPLC: područje % = 96,24, r.t. = 1,95 min., y = 214 nm, mobilna faza = acetonitril/voda s 0,10% TFA; MS m/z 396 (M+1). Anal. Izrač. za C22H21NO4S: C, 66,82; H, 5,35; N, 3,54; nađeno: C, 66,12; H, 5,09; N, 3,44.
Primjer 61
Sinteza {5-Kloro-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 61)
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Korak 1. Priprema metil estera {5-Kloro-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 61A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 14B i 20C. MS m/z 265 (M-245).
Korak 2. Priprema {5-Kloro-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline (spoj 61)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 61A. mp 142-143°C; IR (KBr) cm-1: 3074, 1747, 1321, 1234, 1175, 1124; 400 MHz 1H NMR (DMSO-d6): δ 13,01 (br(s), 1H), 7,67-7,73 (m, 2H), 7,57-7,64 (m, 2H), 7,16-7,25 (m, 4H), 6,87-6,95 (m, 4H), 5,15 (s, 2H), 4,69 (s, 2H), 4,07 (s, 2H), 2,07 (s, 3H); MS m/z 495 (M-1). Anal. Izrač. za C24H20ClF3O4S: C, 58,01; H, 4,06; nađeno: C, 57,73; H, 4,06.
Primjer 62
Sinteza {7-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 62)
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Korak 1. Priprema metil estera {7-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 62A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 4-klorometil-(2,4-dikloro-benziloksi-benzena) priređenog iz 4-hidroksimetil-fenola i 1-klorometil-2,4-dikloro-benzena na isti način kao i Primjeri 14A i 14B. MS m/z 503 (M+l).
Korak 2. Priprema {7-[4-(2,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 62)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 62A. mp 149-150°C; IR (KBr) cm-1: 3089, 1734, 1512, 1473, 1295, 1234; 400 MHz 1H NMR (DMSO-d6): δ 13,11 (br(s), 1H), 7,40-7,71 (m, 3H), 6,88-7,19 (m, 5H), 6,58 (d, 1H, J = 8,5 Hz), 5,07 (s, 2H), 4,61 (s, 2H), 3,96 (s, 2H), 2,77 (t, 2H, t, J = 7,4 Hz), 2,69 (t, 2H, J = 7,4 Hz), 1,91 (pentet, 2H); MS m/z 487 (M-1). Anal. Izrač. za C25H22Cl2O4S: C, 61,35; H, 4,53; nađeno: C, 60,95; H, 4,41.
Primjer 63
Sinteza {7-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 63)
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Korak 1. Priprema metil estera {7-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 63A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 14B i 12C. MS m/z 265 (M-237).
Korak 2. Priprema {7-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 63)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 63A. mp 145°C; IR (KBr) cm-1: 2968, 1740, 1510, 1325, 1248, 1110; 400 MHz 1H NMR (DMSO-d6): δ 12,99 (br(s), 1H), 7,66-7,75 (m, 2H), 7,55-7,65 (m, 2H); 7,01-7,15 (m, 3H) 6,83-6,90 (m, 2H), 6,56 (d, 1H, J = 8,5 Hz), 5,14 (s, 2H), 4,60 (s, 2H), 3,93 (s, 2H), 2,74 (t, 2H, t, J = 7,6 Hz), 2,65 (t, 2H, J = 7,4 Hz), 1,87 (pentet, 2H); MS m/z 487 (M-1). Anal. Izrač. za C26H23F3O4S: C, 63,92; H, 4,75; nađeno: C, 63,95; H, 4,65.
Primjer 64
Sinteza {5-Metil-7-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 64)
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Korak 1. Priprema metil estera {5-Metil-7-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 64A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 14B i metil estera (7-merkapto-5-metil-indan-4-iloksi)-octene kiseline, koji je priređen na isti način kao što je opisano za Primjer 12C. MS m/z 265 (M-251).
Korak 2. Priprema {5-Metil-7-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 64)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 64A. mp 165-167°C; IR (KBr) cm-1: 3039, 1707, 1510, 1329, 1163, 1112; 400 MHz 1H NMR (DMSO-d6): δ 12,81 (br(s), 1H), 7,66-7,74 (m, 2H), 7,56-7,64 (m, 2H); 7,11-7,19 (m, 2H), 6,94 (s, 1H), 6,85-6,91 (m, 2H), 5,15 (s, 2H), 4,40 (s, 2H), 3,99 (s, 2H), 2,81 (t, 2H, J = 7,4 Hz), 2,59 (t, 2H, J = 7,4 Hz), 2,13 (s, 3H), 1,86 (pentet, 2H); MS m/z 501 (M-l). Anal. Izrač. za C27H25F3O4S: C, 64,53; H, 5,01; nađeno: C, 64,33; H, 4,82.
Primjer 65
Sinteza {7-[4-(4-Fluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 65)
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Korak 1. Priprema metil estera {7-[4-(4-Fluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 65A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 4-klorometil-(4-fluoro-benziloksi-benzena), priređenog iz 4-hidroksimetil-fenola i 1-bromometil-4-fluoro-benzena na isti način kao i Primjeri 14A i 14B. MS m/z 453(M+1).
Korak 2. Priprema {7-[4-(4-Fluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 65)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 65A. mp 153-155°C; IR (KBr) cm-1: 3117, 3028, 1731, 1512, 1471, 1231; 400 MHz 1H NMR (DMSO-d6): δ 12,94 (br(s), 1H), 7,39-7,47 (m, 2H), 7,01-7,20 (m, 5H); 6,82-6,89 (m, 2H) 6,56 (d, 1H, J = 8,4 Hz), 4,99 (s, 2H), 4,61 (s, 2H), 3,94 (s, 2H), 2,75 (t, 2H, J = 7,5 Hz), 2,67 (t, 2H, J = 7,5 Hz), 1,89 (pentet, 2H); MS m/z 437 (M-1). Anal. Izrač. za C25H23FO4S: C, 68,48; H, 5,29; mađeno: C, 68,24; H, 5,15.
Primjer 66
Sinteza {7-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 66)
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Korak 1. Priprema metil estera {7-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 66A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 4-klorometil-(2,4-difluoro-benziloksi-benzena), priređenog iz 4-hidroksimetil-fenola i 1-bromometil-2,4-difluoro-benzena na isti način kao i Primjeri 14A i 14B. MS m/z 471 (M+l).
Korak 2. Priprema {7-[4-(2,4-Difluoro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 66)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 66A. mp 158-160°C; IR (KBr) cm-1: 3065, 3043, 1751, 1510, 1433, 1239; 400 MHz 1H NMR (DMSO-d6): δ 12,94 (br(s), 1H), 7,51-7,61 (m, 1H), 7,21-7,30 (m, 1H); 7,01-7,16 (m, 4H) 6,83-6,92 (m, 2H), 6,57 (d, 1H, J = 8,5 Hz), 5,01 (s, 2H), 4,61 (s, 2H), 3,94 (s, 2H), 2,76 (t, 2H, J = 7,4 Hz), 2,68 (t, 2H, J = 7,4Hz), 1,90 (pentet, 2H); MS m/z 455 (M-1). Anal. Izrač. za C25H22F2O4S: C, 65,78; H, 4,86; nađeno: C, 65,58; H, 4,83.
Primjer 67
Sinteza {7-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 67)
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Korak 1. Priprema metil estera {7-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 67A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 4-klorometil-(4-tert-butil-benziloksi-benzena), priređenog iz 4-hidroksimetil-fenola i 1-bromometil-4-tert-butil-benzena na isti način kao i Primjeri 14A i 14B. m/z 491 (M+1).
Korak 2. Priprema {7-[4-(4-tert-Butil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 67)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 67A. mp 152-153°C; IR (KBr) cm-1: 3134, 3032, 1745, 1708, 1473, 1228; 400 MHz 1H NMR (DMSO-d6): δ 12,94 (br(s), 1H), 7,25-7,39 (m, 4H), 7,01-7,14 (m, 3H) 6,80-6,89 (m, 2H), 6,57 (d, 1H, J = 8,5 Hz), 4,97 (s, 2H), 4,61 (s, 2H), 3,93 (s, 2H), 2,75 (t, 2H, J = 7,5 Hz), 2,67 (t, 2H, J = 7,5 Hz), 1,89 (pentet, 2H), 1,22 (s, 9H); MS m/z 475 (M-1). Anal. Izrač. za C29H32O4S: C, 73,08; H, 6,77; nađeno: C, 72,97; H, 6,84.
Primjer 68
Sinteza {7-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 68)
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Korak 1. Priprema metil estera {7-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 68A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 4-klorometil-(4-metoksi-benziloksi-benzena), priređenog iz 4-hidroksimetil-fenola i 1-bromometil-4-metoksi-benzena na isti način kao i Primjeri 14A i 14B. MS m/z 465 (M+l).
Korak 2. Priprema {7-[4-(4-Metoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 68)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 68A. mp 183-185°C; IR (KBr) cm-1: 3015, 2588, 1742, 1716, 1514, 11243; 400 MHz 1H NMR (DMSO-d6): δ 12,97 (br(s), 1H), 7,26-7,34 (m, 2H), 7,06-7,13 (m, 2H) 7,04 (d, 1H, J = 8,5 Hz), 6,80-6,92 (m, 4H), 6,56 (d, 1H, J = 8,5 Hz), 4,92 (s, 2H), 4,60 (s, 2H), 3,93 (s, 2H), 3,69 (s, 3H), 2,75 (t, 2H, J = 7,3 Hz), 2,67 (t, 2H, J = 7,3 Hz), 1,89 (pentet, 2H); MS m/z 449 (M-1), Anal. Izrač. za C26H26O5S: C, 69,31; H, 5,82; nađeno: C, 69,00; H, 5,74.
Primjer 69
Sinteza [7-(4-Benziloksi)-benzilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 69)
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Korak 1. Priprema metil estera [7-(4-Benziloksi)-benzilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 69A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 1-benziloksi-4-klorometil-benzena, priređenog iz 4-hidroksimetil-fenola i 4-bromometil-benzena na isti način kao i Primjeri 14A i 14B. MS m/z 435 (M+1).
Korak 2. Priprema [7-(4-Benziloksi)-benzilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 69)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 69A. mp 145-147°C; IR (KBr) cm-1: 3066, 2584, 1742, 1511, 1234; 400 MHz 1H NMR (DMSO-d6): δ 12,94 (br(s), 1H), 7,21-7,44 (m, 5H), 6,99-7,15 (m, 3H) 6,80-6,90 (m, 2H), 6,56 (d, 1H, J = 8,3 Hz), 5,01 (s, 2H), 4,61 (s, 2H), 3,93 (s, 2H), 2,75 (t, 2H, J = 7,3 Hz), 2,67 (t, 2H, J = 7,3 Hz), 1,89 (pentet, 2H); MS m/z 419 (M-1). Anal. Izrač. za C25H24O4S: C, 71,40; H, 5,75; nađeno: C, 71,46; H, 5,75.
Primjer 70
Sinteza {7-[4-(4-Kloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 70)
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Korak 1. Priprema metil estera {7-[4-(4-Kloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 70A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 1-(4-kloro-benziloksi)-4-klorometil-benzena, priređenog iz 1-bromometil-4-kloro-benzena i 4-hidroksimetil-fenola na isti način kao i Primjeri 14A i 14B. MS m/z 469 (M+1).
Korak 2. Priprema {7-[4-(4-Kloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 70)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 70A. mp 170-172°C; IR (KBr) cm-1: 3054, 25,77, 1731, 1710, 1471, 1234; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,39 (s, 4H), 6,99-7,25 (m, 3H), 6,79-6,97 (m, 2H), 6,56 (d, 1H, J = 8,4 Hz), 5,01 (s, 2H), 4,60 (s, 2H), 3,93 (s, 2H), 2,74 (t, 2H, J = 7,4 Hz), 2,66 (t, 2H, J = 7,4 Hz), 1,88 (pentet, 2H); MS m/z 453 (M-1). Anal. Izrač. za C25H23ClO4S: C, 66,00; H, 5,10; nađeno: C, 65,95; H,4,97.
Primjer 71
Sinteza {7-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 71)
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Korak 1. Priprema metil estera {7-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 71A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 1,4-Dikloro-2-(4-klorometil-fenoksimetil)-benzena, priređenog iz 1,4-dikloro-2-klorometil-benzena i 4-hidroksimetil-fenola na isti način kao i Primjeri 14A i 14B. MS m/z 265 (M-237).
Korak 2. Priprema {7-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 71)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 71A. mp 158-160°C; IR (KBr) cm-1: 3070, 2573, 1747, 1716, 1236, 1106; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,57-7,62 (m, 1H) 7,47-7,53 (m, 1H), 7,38-7,45 (m, 1H), 7,08-7,16 (m, 2H), 7,04 (d, 1H, J = 8,5 Hz), 6,85-6,92 (m, 2H), 6,56 (d, 1H, J = 8,5 Hz), 5,06 (s, 2H), 4,61 (s, 2H), 3,94 (s, 2H), 2,75 (t, 2H, J = 7,3 Hz), 2,67 (t, 2H, J = 7,3 Hz), 1,89 (pentet, 2H); MS m/z 487 (M-1). Anal. Izrač. za C25H22Cl2O4S: C, 61,35; H, 4,53; nađeno: C, 61,24; H, 4,43.
Primjer 72
Sinteza {7-[4-(3,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 72)
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Korak 1. Priprema metil estera {7-[4-(3,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 72A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 1,2-Dikloro-4-(4-klorometil-fenoksimetil)-benzena, priređenog iz 1-bromometil-3,4-dikloro-benzena i 4-hidroksimetil-fenola na isti način kao i Primjeri 14A i 14B. MS m/z 503 (M+1).
Korak 2. Priprema {7-[4-(3,4-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 72)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 72A. mp 168°C; IR (KBr) cm-1: 3084, 3039, 1744, 1708, 1244, 1226; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,57-7,67 (m, 2H) 7,37 (dd, 1H, J = 8,3, 2,0 Hz), 7,01-7,14 (m, 3H), 6,82-6,89 (m, 2H), 6,56 (d, 1H, J = 8,4 Hz), 5,04 (s, 2H), 4,61 (s, 2H), 3,93 (s, 2H), 2,75 (t, 2H, J = 7,4 Hz), 2,66 (t, 2H, J = 7,4 Hz), 1,88 (pentet, 2H); MS m/z 487 (M-1). Anal. Izrač. za C25H22Cl204S: C, 61,35; H, 4,53; nađeno: C, 61,13; H, 4,38.
Primjer 73
Sinteza {7-[4-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 73)
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Korak 1. Priprema metil estera {7-[4-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 73A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 1-Kloro-4-(4-klorometil-fenoksimetil)-2-trifluorometil-benzena, priređenog iz 1-bromometil-4-kloro-3-trifluorometil-benzena i 4-hidroksimetil-fenola na isti način kao i Primjeri 14A i 14B. MS m/z 299 (M-237).
Korak 2. Priprema {7-[4-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 73)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 73A. mp 151-152°C; IR (KBr) cm-1: 3076, 3050, 1748, 1426, 1244, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12,94 (br(s), 1H), 7,87 (s, 1H), 7,68-7,72 (m, 2H) 7,00-7,15 (m, 3H), 6,82-6,92 (m, 2H), 6,56 (d, 1H, J = 8,5 Hz), 5,12 (s, 2H), 4,61 (s, 2H), 3,94 (s, 2H), 2,74 (t, 2H, J = 7,5 Hz), 2,66 (t, 2H, J = 7,5 Hz), 1,87 (pentet, 2H); MS m/z 521 (M-1). Anal. Izrač. za C26H22ClF3O4S: C, 59,71; H, 4,24; nađeno: C, 59,54; H, 4,11.
Primjer 74
Sinteza {7-[4-(4-Fluoro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 74)
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Korak 1. Priprema metil estera {7-[4-(4-Fluoro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 74A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 4-(4-Klorometil-fenoksimetil)-1-fluoro-2-trifluorometil-benzena, priređenog iz 1-bromometil-4-fluoro-3-trifluorometil-benzena i 4-hidroksimetil-fenola na isti način kao i Primjeri 14A i 14B. MS m/z 283 (M-237).
Korak 2. Priprema {7-[4-(4-Fluoro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 74)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 74A. mp 116-117°C; IR (KBr) cm-1: 3028, 1741, 1704, 1511, 1235, 1110; 400 MHz 1H NMR (DMSO-d6): δ 12,96 (br(s), 1H), 7,74-7,85 (m, 2H) 7,45-7,54 (m, 1H), 7,08-7,15 (m, 2H), 7,04 (d, 1H, J = 8,5 Hz), 6,84-6,91 (m, 2H), 6,56 (d, 1H, J = 8,5 Hz), 5,09 (s, 2H), 4,61 (s, 2H), 3,94 (s, 2H), 2,75 (t, 2H, J = 7,5 Hz), 2,66 (t, 2H, J = 7,5 Hz), 1,88 (pentet, 2H); MS m/z 505 (M-l). Anal. Izrač. za C26H22F4O4S: C,61,65; H, 4,38; nađeno: C, 61,50; H, 4,07.
Primjer 75
Sinteza {7-[4-(4-Trifluorometoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 75)
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Korak 1. Priprema metil estera [7-(4-Acetoksi-benzilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 75A)
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Spoj iz naslova je priređen na isti način kao i Primjer 35A uporabom octena kiselina 4-klorometil-fenil estera i 12C. MS m/z 387 (M+1).
Korak 2. Priprema [7-(4-Hidroksi-benzilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 75B)
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Spoj iz naslova je priređen na isti način kao i Primjer 35B uporabom 75A. MS m/z 391 (M-1).
Korak 3. Priprema metil estera [7-(4-Hidroksi-benzilsulfanil)-indan-4-iloksi]-octene kiseline (spoj 75C)
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Spoj iz naslova je priređen na isti način kao i Primjer 35C uporabom produkta iz Primjera 75B. MS m/z 237 (M-107).
Korak 4. Priprema metil estera {7-[4-(4-Trifluorometoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 75D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1-bromometil-4-trifluorometoksi-benzena i 75C. MS m/z 519 (M+1).
Korak 5. Priprema {7-[4-(4-Trifluorometoksi-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 75)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 75D. mp 140-142°C; IR (KBr) cm-1: 3072, 3043, 1724, 1511, 1226, 1156; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,47-7,57 (m, 2H), 7,29-7,39 (m, 2H), 7,00-7,16 (m, 3H), 6,81-6,91 (m, 2H), 6,56 (d, 1H, J = 8,5 Hz), 5,05 (s, 2H), 4,61 (s, 2H), 3,94 (s, 2H), 2,75 (t, 2H, J = 7,4 Hz), 2,67 (t, 2H, J = 7,4 Hz), 1,88 (pentet, 2H) MS m/z 503 (M-1). Anal. Izrač. za C26H23F3O5S: C, 61,90; H, 4,60; nađeno: C, 61,53; H, 4,36.
Primjer 76
Sinteza {7-[4-(4-Fluoro-2-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 76)
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Korak 1. Priprema metil estera {7-[4-(4-Fluoro-2-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 76A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 1-bromometil-4-fluoro-2-trifluorometil-benzena i produkta priređenog iz Primjera 75C. MS m/z 283
Korak 2. Priprema {7-[4-(4-Fluoro-2-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 76)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 76A. mp 125-127°C IR (KBr) cm-1: 3132, 3032, 1742, 1708, 1244, 1110; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,71-7,81 (m, 1H), 7,65 (dd, 1H, J = 9,3, 2,6 Hz), 7,51-7,61 (m, 1H), 7,01-7,19 (m, 3H), 6,81-6,91 (m, 2H), 6,57 (d, 1H, J = 8,5 Hz), 5,11 (s, 2H), 4,61 (s, 2H), 3,95 (s, 2H), 2,75 (t, 2H, J = 7,4 Hz), 2,66 (t, 2H, J = 7,4 Hz), 1,89 (pentet, 2H); MS m/z 502 (M-l). Anal. Izrač. za C26H22F4O4S: C, 61,65; H, 4,38; nađeno: C, 61,28; H, 4,12.
Primjer 77
Sinteza {7-[4-(3,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 77)
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Korak 1. Priprema metil estera {7-[4-(3,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 77A)
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Produkt iz Primjera 75C (0,42 g, 1 mmola), (3,5-diklorofenil)-metanol (0,24 g, 1,3mmola), trifenil fosfin (0,38 g, 1,5 mmola), i 0,23 mL dietil azodikarboksilata (0,25 g, 1,5 mmola) se otope u 9 mL tetrahidrofurana. Reakcijska smjesa se miješa na sobnoj temperaturi u struji dušika 18 sati. Reakcijska smjesa isparava da se dobije ostatak, koji se podvrgne flash kromatografiji (silika gel, 20% etil acetat u heksanu) kako bi se dobio spoj iz naslova dobre čistoće. MS m/z 265
Korak 2. Priprema {7-[4-(3,5-Dikloro-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 77)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 77A. mp 134-135°C; IR (KBr) cm-1: 3070, 1747, 1708, 1572, 14321, 1244; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,51-7,53 (m, 1H), 7,42-7,45 (m, 2H), 7,07-7,13 (m, 2H), 7,04 (d, 1H, J = 8,6 Hz), 6,83-6,90 (m, 2H), 6,56 (d, 1H, J = 8,6 Hz), 5,05 (s, 2H), 4,61 (s, 2H), 3,93 (s, 2H), 2,75 (t, 2H, J = 7,5 Hz), 2,66 (t, 2H, 7,5 Hz), 1,88 (pentet, 2H); MS m/z 487 (M-1). Anal. Izrač. za C25H22Cl2O4S: C, 61,35; H, 4,53; nađeno: C, 61,01; H, 4,36.
Primjer 78
Sinteza {7-[4-Metoksi-3-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 78)
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Korak 1. Priprema [4-Metoksi-3-(4-trifluorometil-benziloksi)-fenil]-metanola (spoj 78A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 12C 1-bromometil-4-trifluorometil-benzena i 5-hidroksimetil-2-metoksi-fenola. MS m/z 295 (M-OH).
Korak 2. Priprema 4-Klorometil-1-metoksi-2-(4-trifluorometil-benziloksi)-benzena (spoj 78B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 78A. MS m/z 295 (M-Cl).
Korak 3. Priprema metil estera {7-[4-Metoksi-3-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 78C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 78B i 12C. MS m/z 373 (M-159).
Korak 4. Priprema {7-[4-Metoksi-3-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 78)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 78C. mp 150-151°C; IR (KBr) cm-1: 3046, 1722, 1515, 1328, 1232, 1106; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,71 (d, 2H, J = 8,1 Hz), 7,58 (d, 2H, J = 8,1 Hz), 7,03 (d, 1H, J = 8,5 Hz), 6,70-6,86 (m, 3H), 6,57 (d, 1H, J = 8,5 Hz), 5,01 (s, 2H), 4,61 (s, 2H), 3,89 (s, 2H), 3,69 (s, 3H), 2,75 (t, 2H, J = 7,3 Hz), 2,62 (t, 2H, J = 7,3 Hz), 1,87 (pentet, 2H); MS m/z 517 (M-1). Anal. Izrač. za C27H25F305S: C, 62,54; H, 4,86; nađeno: C, 62,54; H, 4,71.
Primjer 79
Sinteza {7-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 79)
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Korak 1. Priprema [3-(4-trifluorometil-benziloksi)-fenil]-metanola (spoj 79A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 1-bromometil-4-trifluorometil-benzena i 3-hidroksimetil-fenola. MS m/z 265 (M-OH).
Korak 2. Priprema 1-(4-trifluorometil-benziloksi)-3-klorometil-benzena (spoj 79B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 79A. MS m/z 265 (M-CI).
Korak 3. Priprema metil estera {7-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 79C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 79B i 12C. MS m/z 503 (M+1).
Korak 4. Priprema {7-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 79)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 79C. mp 145-146°C; IR (KBr) cm-1: 3076, 3028, 1705, 1318, 1232, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12,94 (br(s), 1H), 7,71 (d, 2H, J = 8,2 Hz), 7,59 (d, 2H, J = 8,0 Hz), 7,10-7,19 (m, 1H), 7,05 (d, 1H, J = 8,5 Hz), 6,75-6,86 (m, 4H), 6,58 (d, 1H, J = 8,5 Hz), 5,08 (s, 2H), 4,61 (s, 2H), 3,95 (s, 2H), 2,75 (t, 2H, J = 7,5 Hz), 2,64 (t, 2H, J = 7,5 Hz), 1,88 (pentet, 2H); MS m/z 487 (M-1). Anal. Izrač. za C26H23F3O4S: C, 63,92; 4,75; nađeno: C, 63,78; H, 4,53.
Primjer 80
Sinteza {7-[3-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 80)
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Korak 1. Priprema [3-(4-Kloro-3-trifluorometil-benziloksi)-fenil]-metanola (spoj 80A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 4-bromometil-1-kloro-2-trifluorometil-benzena i 3-hidroksimetil-fenola. MS m/z 299 (M-OH).
Korak 2. Priprema 1-Kloro-4-(3-klorometil-fenoksimetil)-2-trifluorometil-benzena (spoj 80B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 80A. MS m/z 299 (M-Cl).
Korak 3. Priprema metil estera {7-[3-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 80C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 80B i 12C. MS m/z 537 (M+1).
Korak 4. Priprema {7-[3-(4-Kloro-3-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 80)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 80C. mp 121-122°C; IR (KBr) cm-1: 3027, 2584, 1742, 1255, 1129, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,87 (s, 1H), 7,64-7,75 (m, 2H), 7,09-7,19 (m, 1H), 7,01-7,09 (m, 1H), 6,73-6,88 (m, 3H), 6,56 (d, 1H, J = 8,5 Hz), 5,06 (s, 2H), 4,60 (s, 2H), 3,95 (s, 2H), 2,74 (t, 2H, J = 7,4 Hz), 2,63 (t, 2H, J = 7,4 Hz), 1,87 (pentet, 2H); MS m/z 523 (M+1). Anal. Izrač. za C26H22ClF3O4S: C, 59,71; H, 4,24; nađeno: C, 59,45; H, 4,08.
Primjer 81
Sinteza {7-[2-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 81)
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Korak 1. Priprema [2-(4-Trifluorometil-benziloksi)-fenil]-metanola (spoj 81A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 1-bromometil-4-trifluorometil-benzena i 2-hidroksimetil-fenola. MS m/z 265 (M-OH).
Korak 2. Priprema 1-(4-trifluorometil-benziloksi)-2-klorometil-benzena (spoj 81B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 81A. MS m/z 265 (M-Cl).
Korak 3. Priprema metil estera {7-[2-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 81C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 81B i 12C. MS m/z 503 (M+l).
Korak 4. Priprema {7-[2-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 81)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 81C. mp 150-152°C; IR (KBr) cm-1: 3074, 3042, 1701, 1324, 1124, 1099; 400 MHz 1H NMR (DMSO-d6): δ 7,58-7,75 (m, 2H), 6,92-7,20 (m, 4H), 6,80 (t, 1H, J = 7,5 Hz), 6,51 (d, 1H, J = 8,5 Hz), 5,16 (s, 2H), 4,57 (s, 2H), 3,99 (s, 2H), 2,70 (t, 2H, J = 7,5 Hz), 2,62 (t, 2H, J = 7,5 Hz), 1,80 (pentet, 2H); MS m/z 487 (M-1). Anal. Izrač. za C26H23F3O4S: C, 63,92; H, 4,75; nađeno: C, 63,54; H, 4,52.
Primjer 82
Sinteza litijeve soli {7-[3,5-Dikloro-4-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 82)
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Korak 1. Priprema [3,5-Dikloro-(4-trifluorometil-benziloksi)-fenil]-metanola (spoj 82A)
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Spoj iz naslova je priređen na isti način kao i Primjer 14A uporabom 1-bromometil-4-trifluorometil-benzena i 2,6-dikloro-hidroksimetil-fenola. MS m/z 191 (M-159).
Korak 2. Priprema 1,3-Dikloro-5-klorometil-2-(4-trifluorometil-benziloksi)-benzena (spoj 82B)
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Spoj iz naslova je priređen na isti način kao i Primjer 3B uporabom 82A. MS m/z 333 (M-CI).
Korak 3. Priprema metil estera {7-[3,5-Dikloro-4-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 82C)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 82B i 12C. MS m/z 571 (M+1).
Korak 4. Priprema litijeve soli {7-[3,5-Dikloro-4-(4-trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 82)
Spoj iz naslova je, u neprotoniranom obliku, priređen na isti način kao i Primjer 1 uporabom 82C. mp 235°C dec; IR (KBr) cm-1: 3414, 1622, 1591, 1472, 1326, 1265; 400 MHz 1H NMR (DMSO-d6): δ 7,66-7,77 (m, 4H), 7,26 (s, 2H), 6,99 (d, 1H, J = 8,5 Hz), 6,45 (d, 1H, J = 8,5 Hz), 5,03 (s, 2H), 4,02 (s, 2H), 3,92 (s, 2H), 2,73 (t, 2H, J = 7,3 Hz), 2,65 (t, 2H, J = 7,3 Hz), 1,88 (pentet, 2H); MS m/z 555 (M-1). Anal. Izrač. za C26H20Cl2F3O4S: Li: 0,50 H2O: C, 54,56; H, 3,70; Li, 1,21; H2O, 1,57; nađeno: C, 54,63; H, 3,68; Li, 1,46; H2O, 1,61.
Primjer 83
Sinteza {8-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 83)
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Korak 1. Priprema metil estera {8-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 83A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom metil estera (8-merkapto-kroman-5-iloksi)-octene kiseline i 14B. MS m/z 519 (M+1).
Korak 2. Priprema {8-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 83)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 83A. mp 143-144°C; HPLC: područje % = 96,02, r. t. = 3,770 min, γ = 214 nm, mobilna faza = acetonitril / voda w/0,10% TFA; IR (KBr) cm-1: 3042, 2581, 1739, 1714, 1325, 1116; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,66-7,74 (m, 2H), 7,56-7,63 (m, 2H); 7,10-7,17 (m, 2H), 6,92 (d, 1H, J = 8,7 Hz), 6,83-6,89 (m, 2H), 6,26 (d, 1H, J = 8,5 Hz), 5,13 (s, 2H), 4,58 (s, 2H), 4,08 (t, 2H, J = 4,8 Hz), 3,90 (s, 2H), 2,55 (t, 2H, J = 6,5 Hz), 1,83 (pentet, 2H); MS m/z 503 (M-1). Anal. Izrač. za C26H23F3O5S: C, 61,90; H, 4,60; nađeno: C, 61,41; H, 4,50.
Primjer 84
Sinteza {8-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 84)
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Korak 1. Priprema metil estera {8-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 84A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom metil estera (8-merkapto-kroman-5-iloksi)-octene kiseline i 79B. MS m/z 519 (M+1).
Korak 2. Priprema {8-[3-(4-Trifluorometil-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 84)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 84A. mp 113-115°C; HPLC: područje % = 97,30, r. t. = 3.140 min, γ = 214 nm, mobilna faza = acetonitril / voda w/0,10% TFA; IR (KBr) cm-1: 2952, 2577, 1742, 1582, 1323, 1120; 400 MHz 1H NMR (DMSO-d6): δ 7,67-7,74 (m, 2H), 7,56-7,63 (m, 2H); 7,13 (t, 1H, J = 7,8 Hz), 6,76-6,93 (m, 4H), 6,22 (d, 1H, J = 8,7 Hz), 5,08 (s, 2H), 4,45 (s, 2H), 4,08 (t, 2H, J = 4,8 Hz), 3,91 (s, 2H), 2,54 (t, 2H, J = 6,6 Hz), 1,82 (pentet, 2H); MS m/z 505 (M+1). Anal. Izrač. za C26H23F3O5S: C, 61,90; H, 4,60; nađeno: C, 61,49; H, 4,44.
Primjer 85
Sinteza {8-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 85)
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Korak 1. Priprema metil estera {8-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 85A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom metil estera (8-merkapto-kroman-5-iloksi)-octene kiseline i 1,4-Dikloro-2-(4-klorometil-fenoksimetil)-benzena priređenog na isti način kao i Primjer 71A. m/z 519 (M+l).
Korak 2. Priprema {8-[4-(2,5-Dikloro-benziloksi)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 85)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 85A. mp 98-100°C; IR (KBr) cm-1: 3038, 2854, 1729, 1508, 1240, 1124; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 7,57-7,62 (m, 1H), 7,39-7,53 (m, 2H); 7,12-7,20 (m, 2H), 6,84-6,96 (m, 3H), 6,26 (d, 1H, J = 8,6 Hz), 5,05 (s, 2H), 4,58 (s, 2H), 4,09 (t, 2H, J = 4,9 Hz), 3,92 (s, 2H), 2,55 (t, 2H, J = 6,5 Hz), 1,83 (pentet, 2H); MS m/z 503 (M-1). Anal. Izrač. za C25H22Cl2O5S: C, 59,41; H, 4,39; nađeno: C, 59,20; H, 4,20.
Primjer 86
Sinteza {8-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 86)
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Korak 1. Metil ester {8-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 86A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom metil estera (8-merkapto-kroman-5-iloksi)-octene kiseline i 18B. MS m/z 490 (M+1).
Korak 2. {8-[4-(5-Trifluorometil-piridin-2-il)-benzilsulfanil]-kroman-5-iloksi}-octena kiselina (spoj 86)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 86A. mp 178-179°C; IR (KBr) cm-1: 3034, 2577, 1707, 1604, 1332, 1111; 400 MHz 1H NMR (DMSO-d6): δ 12,95 (br(s), 1H), 8,97 (s, 1H), 7,99-8,24 (m, 4H), 7,33-7,40 (m, 2H), 6,95 (d, 2H, J = 8,5 Hz), 6,26 (d, 2H, J = 8,6 Hz), 4,57 (s, 2H), 4,11 (t, 2H, J = 4,9 Hz), 4,04 (s, 2H), 2,56 (t, 2H, J = 6,5 Hz), 1,84 (pentet, 2H); MS m/z 476 (M+1). Anal. Izrač. za C24H20F3NO4S: C, 60,63; H, 4,24; N, 2,95; nađeno: C, 60,31; H, 4,24; N, 3,02.
Primjer 87
Sinteza {7-[5-(2-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 87)
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Korak 1. Priprema metil ester {7-[5-(2-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 87A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom komercijalno dostupnog 3-klorometil-5-(2-kloro-fenil)-izoksazola i 12C. MS m/z 430 (M+1).
Korak 2. Priprema {7-[5-(2-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 87)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 87A. mp 161-162°C; IR (KBr) cm-1: 3177, 3065, 1706, 1475, 1432, 1233; 400 MHz 1H NMR (DMSO-d6): δ 13,00 (bs, 1H), 7,78-7,85 (m, 1H), 7,58-7,64 (m, 1H), 7,42-7,53 (m, 2H), 7,15 (d, 1H, J = 8,6 Hz), 6,84 (s, 1H), 6,60 (d, 1H, J = 8,6 Hz), 4,62 (s, 2H), 4,09 (s, 2H), 2,72-2,82 (m, 4H), 1,91 (pentet, 2H); MS m/z 416 (M+1). Anal. Izrač. za C21H18ClNO4S: C, 60,65; H, 4,36; N, 3,37; nađeno: C, 60,56; H, 4,28; N, 3,16.
Primjer 88
Sinteza {7-[3-(2,6-Dikloro-fenil)-5-metil-izoksazol-4-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 88)
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Korak 1. Priprema metil ester {7-[3-(2,6-Dikloro-fenil)-5-metil-izoksazol-4-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 88A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom komercijalno dostupnog 4-bromometil-3-(2,6-dikloro-fenil)-5-metil-izoksazola i 12C. MS m/z 478 (M+1).
Korak 2. Priprema {7-[3-(2,6-Dikloro-fenil)-5-metil-izoksazol-4-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 88)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 88A. mp 151-152°C; IR (KBr) cm-1: 3084, 1743, 1430, 1277, 1245, 1106; 400 MHz 1H NMR (DMSO-d6): δ 12,97 (br(s), 1H), 7,47-7,70 (m, 3H), 6,90 (d, 1H, J = 8,5 Hz), 6,52 (d, 1H, J = 8,5 Hz), 4,63 (s, 2H), 3,58 (s, 2H), 2,75 (t, 2H, J = 7,6 Hz), 2,65 (t, 2H, J = 7,6 Hz), 2,07 (s, 3H), 1,89 (pentet, 2H) MS m/z 464 (M+1). Anal. Izrač. za C22H19Cl2NO4S: C, 56,90; H, 4,12; N, 3,02; nađeno: C, 56, 51; H, 3,96; N, 2,95.
Primjer 89
Sinteza {7-[3-(4-Trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 89)
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Korak 1. Priprema metil ester {7-[3-(4-Trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 89A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 42C i 12C. MS m/z 464 (M+1).
Korak 2. Priprema {7-[3-(4-Trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 89)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 89A. mp 166-168°C; HPLC: područje % = 96,95, r. t. = 3,140 min, γ = 214 nm, mobilna faza = acetonitril / voda w/0,10% TFA. IR (KBr) cm-1: 3140, 3085, 1742, 1322, 1255, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12,96 (br(s), 1H), 7,99 (d, 2H, J = 8,3 Hz), 7,81 (d, 2H, J = 8,3 Hz), 7,14 (d, 1H, J = 8,4 Hz), 6,81 (s, 1H), 6,61 (d, 1H, J = 8,4 Hz), 4,63 (s, 2H), 4,23 (s, 2H), 2,76 (t, 4H, J = 7,5 Hz), 1,91 (pentet, 2H); MS m/z 450 (M+l). Anal. Izrač. za C22H18F3NO4S: C, 58,79; H, 4,04; N, 3,12; nađeno: C, 58,38; H, 3,92; N, 2,95.
Primjer 90
Sinteza {7-[2-(4'-Trifluorometil-bifenil-4-il)-etilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 90)
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Korak 1. Priprema metil ester {7-[2-(4'-Trifluorometil-bifenil-4-il)-etilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 90A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 12C i 4-(2-bromo-etil)-4'-trifluorometil-bifenila (spoj 22B). MS m/z 487 (M+1).
Korak 2. Priprema {7-[2-(4'-Trifluorometil-bifenil-4-il)-etilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 90)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 90A. mp 170-172°C; IR (tanki sloj) cm-1: 1724, 1471, 1327, 1239, 1175, 1110; 400 MHz 1H NMR (DMSO-d6) δ 12,96 (br s, 1H), 7,82 (d, 2H, J = 8,3 Hz), 7,74 (d, 2H, J = 8,3 Hz), 7,61 (d, 2H, J = 8,3 Hz), 7,31 (d, 2H, J = 8,3 Hz), 7,12 (d, 2H, J = 8,5 Hz), 6,62 (d, 1H, J = 8,5 Hz), 4,63 (s, 2H), 3,08 (t, 2H, J = 7,6 Hz), 2,80 (m, 6H), 1,96 (m, 2H); MS m/z 471 (M-1). Anal. Izrač. za C26H23F3O3S: C, 66,09; H, 4,91; nađeno: C, 65,95; H, 4,63.
Primjer 91
Sinteza {7-[2-(4'-Trifluorometil-bifenil-4-il)-etil]-indan-4-iloksi}-octene kiseline (spoj 91)
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Korak 1. Priprema metil estera (Indan-4-iloksi)-octene kiseline (spoj 91A)
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Spoj 91A je priređen iz indan-4-ol i metil estera bromo-octene kiseline na isti način kao i Primjer 1C. 400 MHz 1H NMR (DMSO-d6) δ 7,00 (t, 1H, J = 7,8 Hz), 6,79 (d, 1H, J =7,3 Hz), 6,56 (d, 1H, J =8,1 Hz), 4,74 (s, 2H), 3,63 (s, 3H), 2,77 (m, 4H), 1,95 (m, 2H).
Korak 2. Priprema (4'-Trifluorometil-bifenil-4-il)-octene kiseline (spoj 91B)
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Smjesa (4-bromo-fenil)-octene kiseline (10,2 g, 47,4 mmol), 4-trifluorometilfenilborne kiseline (10,0 g, 52,7 mmol), i 50% vodom namočenog 5% paladija s drvenim ugljenom kao katalizatorom (4,6 g) u 50 ml vode i 8,0 ml 2-propanola se tretira kap po kap preko 30 minuta s otopinom natrijevog karbonata (6,8 g, 64,2mmol) u 18 ml vode. Smjesa se zagrijava 3 h na 65-70°C, zatim ohladi na 40°C i tretira s 13,0 ml otopine 2-propanol/voda/2,0 N vodena otopina natrijevog hidroksida (70/15/1). Reakcijska smjesa se filtrira kroz podlogu Celite filtera, i filter naslaga se ispere 5x s gore navedenim 2-propanol/voda/2,0 N vodena otopina natrijevog hidroksida. Sjedinjeni filtrati se razrijede s 125 ml vode, i otopina se razgradi na parnoj kupelji s drvenim ugljenom i filtrira. Filtrat se razrijedi s dodatnih 150 ml vode i jako zakiseli dodatkom 4,0 N klorovodične kiseline. Produkt koji istaloži se filtrira i suspendira u 350 ml vode plus 50 ml metanola. Nova smjesa se miješa nekoliko sati i ponovo filtrira. Nepročišćeni produkt se rekristalizira iz vodenog acetonitrila. Uzorak koji je rekristaliziran po drugi put iz vodenog acetonitrila ima mp 158-160°C; MS m/z 280 (M).
Korak 3. Priprema (4'-Trifluorometil-bifenil-4-il)-acetil klorida (spoj 91C)
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Suspenzija 91B (2,0 g, 7,1 mmol) i 5 kapi N,N-dimetilformamida u 30 ml diklorometana se rashladi na ledu i tretira kap po kap s otopinom oksalil klorida (0,70 mol, 1,0 g, 8,0 mmol) u 10 ml diklorometana. Ledena kupelj se ukloni, i smjesa se miješa na sobnoj temperaturi 3 h. Otopina se filtrira, i filtrat ispari. Ostatak brzo kristalizira kako bi se iskoristila kloridna kiselina kao intermedijer, jer se rabi odmah u sljedećem koraku.
Korak 4. Priprema metil estera {7-[2-(4'-Trifluorometil-bifenil-4-il)-acetil]-indan-4-iloksi}-octene kiseline (spoj 91D)
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Otopina 91C (2,1 g, 7,0 mmol) u 25 ml 1,2-dikloro-etana se rashladi na ledu i tretira s bezvodnim željeznim kloridom (1,2 g, 7,4 mmol). Smjesa se miješa, i otopina 91A (1,5 g, 7,3 mmol) u 10 ml 1,2-dikloro-etana se doda kap po kap. Smjesa se miješa na sobnoj temperaturi 18 h. Reakcijska smjesa se doda u 300 g leda i slane vode i ekstrahira s etil acetatom (4x100 ml). Sjedinjeni ekstrakti se isperu s 5% vodenom otopinom natrijevog bikarbonata (4x250 ml) i slane vode (1x250 ml), zatim osuše preko bezvodnog natrijevog sulfata i koncentriraju. Nepročišćeni produkt se pročisti kromatografijom na normalnoj fazi. Uzorak rekristaliziran iz etil acetat/heksana ima mp 141-143°C; MS m/z 467 (M-l).
Korak 5. Priprema metil estera {7-[2-(4'-Trifluorometil-bifenil-4-il)-etil]-indan-4-iloksi}-octene kiseline (spoj 91E)
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Otopina 91D (1,0 g, 2,1 mmol) u 10,0 ml trifluorooctene kiseline se tretira kap po kap s trietilsilanom (1,5 ml, 1,1 g, 9,4 mmol). Smjesa se miješa 3 h na sobnoj temperaturi i zatim doda u 200 g leda i vode. Istaložena krutina se esktrahira s etil acetatom (4x 100 ml). Sjedinjeni ekstrakti se isperu sa slanom vodom (1x250 ml), 5% vodenom otopinom natrijevog bikarbonata (4x250 ml), i ponovo sa slanom vodom, zatim osuše preko bezvodnog natrijevog sulfata i koncentriraju. Nepročišćeni produkt se pročisti kromatografijom na normalnoj fazi. 400 MHz 1H NMR (DMSO-d6) δ 7,82 (d, 2H, J = 8,3 Hz), 7,75 (d, 2H, J = 8,3 Hz), 7,61 (d, 2H, J = 8,3 Hz), 7,30 (d, 2H, J = 8,3 Hz), 6,90 (d, 1H, J = 8,3 Hz), 6,53 (d, 1H, J = 8,3 Hz), 4,71 (s, 2H), 3,63 (s, 2H), 2,77 (m, 8H), 1,94 (m, 2H).
Korak 6. Priprema {7-[2-(4'-Trifluorometil-bifenil-4-il)-etil]-indan-4-iloksi}-octene kiseline (spoj 91)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 91E. mp 188-190°C; IR (tanki sloj) cm-1: 1745, 1322, 1252, 1170, 1112, 1071; 400 MHz 1H NMR (DMSO-d6) δ 12,89 (br s, 1H), 7,83 (d, 2H, J = 8,1 Hz), 7,74 (d, 2H, J = 8,5 Hz), 7,61 (d, 2H, J = 8,1 Hz), 7,30 (d, 2H, J = 8,3 Hz), 6,90 (d, 1H, J = 8,3 Hz), 6,51 (d, 1H, J = 8,3 Hz), 4,58 (s, 2H), 2,75 (m, 8H), 2,45 (m, 2H); MS m/z 439 (M-1). Anal. Izrač. za C26H23F3O3: C, 70,90; H, 5,26; nađeno: C, 70,92; H, 5,01.
Primjer 92
Sinteza {5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-2,3-dihidro-benzofuran-4-iloksi}-octene kiseline (spoj 92)
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Korak 1. Priprema metil estera {5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-2,3-dihidro-benzofuran-4-iloksi}-octene kiseline (spoj 92A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 18B i metil estera 7-merkapto-5-metil-2,3-dihidro-benzofuran-4-iloksi)-octene kiseline (priređenog na isti način kao što je opisano za Primjer 12C). mp 94-95°C; MS m/z 490 (M+l).
Korak 2. Priprema {5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-2,3-dihidro-benzofuran-4-iloksi}-octene kiseline (spoj 92)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 92A. mp 155-157 °C; IR (tanki sloj) cm-1: 1732, 1587, 1416, 1331, 1211, 1129; 400 MHz 1H NMR (DMSO-d6) δ 12,89 (br s, 1H), 8,97 (m, 1H), 8,21 (dd, 1H, J = 2,0, 8,5 Hz), 8,12 (d, 1H, J =8,3 Hz), 8,02 (d, 2H, J = 8,3 Hz), 7,34 (d, 2H, J = 8,5 Hz), 6,83 (s, 1H), 4,56 (s, 2H), 4,48 (t, 2H, J = 8,7 Hz), 4,08 (s, 2H), 3,24 (t, 2H, J = 8,7 Hz), 2,02 (s, 3H); MS m/z 474 (M-1). Anal. Izrač. za C24H20F3NO4S: C, 60,63; H, 4,24; N, 2,95; nađeno: C, 60,54; H, 4,19; N, 2,94.
Primjer 93
Sinteza [8-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-kroman-5-iloksi]-octene kiseline (spoj 93)
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Korak 1. Priprema metil estera [8-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-kroman-5-iloksi]-octene kiseline (spoj 93A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 18B i metil estera (8-merkapto-kroman-5-iloksi)-octene kiseline. mp 122-124°C; MS m/z 489 (M+1).
Korak 2. Priprema [8-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-kroman-5-iloksi]-octene kiseline (spoj 93)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 93A. mp 170-172°C; IR (tanki sloj) cm-1: 1717, 1584, 1473, 1330, 1231, 1118; 400 MHz 1H NMR (DMSO-d6) δ 12,94 (br s, 1H), 7,82 (d, 2H, J = 8,1 Hz), 7,74 (d, 2H, J = 8,5 Hz), 7,60 (d, 2H, J = 8,3 Hz), 7,34 (d, 2H, J = 8,3 Hz), 6,96 (d, 2H, J = 8,8 Hz), 6,28 (d, 2H, J = 8,8 Hz), 4,58 (s, 2H), 4,11 (t, 2H, J = 5,0 Hz), 4,03 (s, 2H), 2,56 (t, 2H, J = 6,5 Hz), 1,84 (m, 2H); MS m/z 473 (M-1). Anal. Izrač. za C25H21F3O4: C, 63,28; H, 4,46; nađeno: C, 63,28; H, 4,26.
Primjer 94
Sinteza {8-[5-(4-Trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 94)
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Korak 1. Priprema metil estera {8-[5-(4-Trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 94A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 42C i metil estera (8-merkapto-kroman-5-iloksi)-octene kiseline. mp 122-124 °C; MS m/z 480 (M+1).
Korak 2. Priprema {8-[5-(4-Trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 94)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 94A. Nepročišćeni produkt rekristalizira iz etil acetat/heksana kako bi se dobio konačan produkt. mp 171-173°C; IR (tanki sloj) cm-1: 1722, 1432, 1322, 1232, 1103,1065; 400 MHz 1H NMR (DMSO-d6) δ 12,94 (br s, 1H), 8,01 (d, 2H, J = 8,1 Hz), 7,84 (d, 2H, J = 8,3 Hz), 7,09 (s, 1H), 7,03 (d, 1H, J = 8,5 Hz), 6,29 (d, 1H, J = 8,5 Hz), 4,59 (s, 2H), 4,08 (t, 2H, J = 5,0 Hz), 4,04 (s, 2H), 2,55 (t, 2H, J = 6,5 Hz), 1,83 (m, 2H); MS m/z 464 (M-1). Anal. Izrač. za C22H18F3NO5S: C, 56,77; H, 3,90; N, 3,01; nađeno: C,56, 80; H, 3,58; N, 3,07.
Primjer 95
Sinteza {8-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 95)
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Korak 1. Priprema metil estera {8-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 95A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 3-klorometil-5-(4-kloro-fenil)-izoksazola i metil estera (8-merkapto-kroman-5-iloksi)-octene kiseline. mp 131-133 C; MS m/z 446(M+1).
Korak 2. Priprema {8-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-kroman-5-iloksi}-octene kiseline (spoj 95)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 95A. mp 181-183°C; IR (tanki sloj) cm-1: 1723, 1612, 1479, 1428, 1231, 1134; 400 MHz 1H NMR (DMSO-d6) δ 12,95 (br s, 1H), 7,82 (m, 2H), 7,54 (m, 2H), 7,02 (d, 1H, J = 8,8 Hz), 6,94 (s, 1H), 6,29 (d, 1H, J = 8,5 Hz), 4,59 (s, 2H), 4,08 (t, 2H, J = 5,0 Hz), 4,01 (s, 2H), 2,55 (t, 2H, J = 6,6 Hz), 1,83 (m, 2H); MS m/z 430 (M-l). Anal. Izrač. za C21H18ClNO5S: C, 58,40; H, 4,20; N, 3,24; nađeno: C, 58,30; H, 3,91; N, 3,28.
Primjer 96
Sinteza {4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 96)
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Korak 1. Priprema metil estera {4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 96A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 3-klorometil-5-(4-kloro-fenil)-izoksazola i 2C. mp 79-80 C; MS m/z 404 (M+1).
Korak 2. Priprema {4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-2-metil-fenoksi}-octene kiseline (spoj 96)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 96A. mp 152-153 C; IR (tanki sloj) cm-1: 1724, 1495, 1433, 1309, 1225, 1196; 400 MHz 1H NMR (DMSO-d6) δ 12,96 (br s, 1H), 7,82 (m, 2H), 7,54 (m, 2H), 7,19 (d, 1H, J = 1,5 Hz), 7,12 (dd, 1H, J = 2,1, 8,4 Hz), 6,97 (s, 1H), 6,72 (d, 1H, J = 8,5 Hz), 4,63 (s, 2H), 4,11 (s, 2H), 2,09 (s, 3H); MS m/z 388 (M-1). Anal. Izrač. za C19H16ClNO4S: C, 58,54; H, 4,14; N, 3,59; nađeno: C, 58,53; H, 4,08; N, 3,50.
Primjer 97
Sinteza {7-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 97)
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Korak 1. Priprema metil estera {7-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 97A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 3-klorometil-5-(4-kloro-fenil)-izoksazola i 12C. mp 112-114 C; MS m/z 430 (M+1).
Korak 2. Priprema {7-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 97)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 97A. mp 157-159°C; IR (tanki sloj) cm-1: 1731, 1612, 1465, 1433, 1231, 1110; 400 MHz 1H NMR (DMSO-d6) δ 7,81 (m, 2H), 7,54 (m, 2H), 7,10 (d, 1H, J = 8,3 Hz), 6,95 (s, 1H), 6,59 (d, 1H, J = 8,5 Hz), 4,62 (s, 2H), 4,06 (s, 2H), 2,77 (m, 4H), 1,92 (m, 2H); MS m/z 414 (M-1). Anal. Izrač. za C21H18ClNO4S: C, 60,65; H, 4,36; N, 3,37; nađeno: C, 60,62; H, 4,10; N, 3,31.
Primjer 98
Sinteza {7-[3-(4-Kloro-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 98)
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Korak 1. Priprema metil estera {7-[3-(4-Kloro-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 98A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 5-klorometil-3-(4-kloro-fenil)-izoksazola i 12C. mp 92-94 C; MS m/z 430 (M+1).
Korak 2. Priprema {7-[3-(4-Kloro-fenil)-izoksazol-5-ilmetilsulfanil]-indan-4-iloksi}-octene kiseline (spoj 98)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 98A. mp 158-160°C; IR (tanki sloj) cm-1: 1741, 1574, 1476, 1429, 1252, 1110; 400 MHz 1H NMR (DMSO-d6) δ 7,78 (m, 2H), 7,51 (m, 2H), 7,13 (d, 1H, J = 8,6 Hz), 6,72 (s, 1H), 6,60 (d, 1H, J =8,5 Hz), 4,62 (s, 2H), 4,20 (s, 2H), 2,76 (m, 4H), 1,91 (m, 2H); MS m/z 414 (M-1). Anal. Izrač. za C21H18ClNO4S: C, 60,65; H, 4,36; N, 3,37; nađeno: C, 60,55;H, 4,17; N, 3,34.
Primjer 99
Sinteza {5-Kloro-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 99)
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Korak 1. Priprema metil estera {5-Kloro-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 99A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 3-klorometil-5-(4-kloro-fenil)-izoksazola i 20C. mp 120-121 C; MS m/z 472 (M+l).
Korak 2. Priprema {5-Kloro-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline (spoj 99)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom 99A. mp 180-182°C; IR (tanki sloj) cm-1: 1743, 1484, 1325, 1236, 1165, 1111; 400 MHz 1H NMR (DMSO-d6) δ 13,03 (br s, 1H), 8,03 (d, 2H, J = 8,1 Hz), 7,84 (d, 2H, J = 8,3 Hz), 7,33 (s, 1H), 7,14 (s, 1H), 6,96 (s, 1H), 4,71 (s, 2H), 4,23 (s, 2H), 2,07 (s, 3H); MS m/z 456 (M-1). Anal. Izrač. za C20H15ClF3NO4S: C, 52,47; H, 3,30; N, 3,06; nađeno: C, 52,39; H, 3,02; N, 2,86.
Primjer 100
Sinteza 2-[2-butil-4-({4-[4-(trifluorometil)fenil]fenil}metiltio)fenoksi]octene kiseline (spoj 100)
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Korak 1. Priprema 2-((1E)buta-1,3-dienil)-1-metoksibenzena (spoj 100A)
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Metiltrifenilfosfonij bromid (42,9 g, 0,12 mol) se suspendira u 400 ml bezvodnog THF u struji dušika i ohladi do -78°C. Natrijev hidrid (60% u mineralnom ulju, 6,0 g, 0,15 mol) se doda po porcijama. Reakcijska smjesa se polako zagrije na sobnu temperaturu i miješa 1 h pri istoj temperaturi, zatim se doda kap po kap na sobnoj temperaturi 2-metoksicinamaldehid (16,2 g, 0,10 mol) u 200 ml THF, miješa 3 h pri istoj temperaturi. Onda se dodaju voda (200 ml) i dietil eter (800 ml). Organski sloj se odvoji, osuši iznad natrijevog sulfata, koncentrira, i pročisti uporabom kromatografije na normalnoj fazi kako bi se dobio spoj iz naslova. 400 MHz 1H NMR (DMSO-d6) δ 7,48-6,56 (m, 7H), 5,32 (d, 1H), 5,16 (d, 1H), 3,84 (s, 3H).
Korak 2. Priprema 2-butil-1-metoksibenzena (spoj 100B)
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Smjesa produkta iz primjera 100A (12,8 g, 0,08 mol) i paladij/ugljika (10%, 50% voda, 12 g) u 400 ml etil acetata se hidrogenira pri 50 psi, na sobnoj temperaturi preko noći, zatim filtrira kroz Celite®, i koncentrira kako bi se dobio 100B. 400 MHz 1H NMR (DMSO-d6) δ 7,16 (m, 2H), 6,85 (m, 2H), 3,81 (s, 3H), 2,61 (m, 2H), 1,57 (m, 2H), 1,38 (m, 2H), 0,92 (t, 3H).
Korak 3. Priprema 2-butilfenola (spoj 100C)
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U otopinu produkta iz primjera 100B (13,1 g, 0,08 mol) u 400 ml diklorometana na -78°C se doda kap po kap uz miješanje otopine bor tribromida (100,2 g, 0,4 mol) u 200 ml diklorometana. Nakon završetka dodavanja bor tribromida, reakcijska smjesa se drži 1 h na -78°C, zatim se zagrijava do sobne temperature i miješa pri istoj temperaturi preko noći. Smjesa se ohladi na 0°C, i pažljivo prelije sa 100 ml vode. Smjesa se ekstrahira s etil acetatom, ispere sa slanom vodom, osuši iznad natrijevog sulfata i koncentrira da se dobije 100C. 400 MHz 1H NMR (DMSO-d6) δ 7,10 (m, 2H), 6,86 (m, 1H), 6,78 (d, 1H), 4,61 (brs, 1H), 2,61 (m, 2H), 1,60 (m, 2H), 1,40 (m, 2H), 0,96 (t, 3H).
Korak 4. Priprema (3-butil-4-hidroksifenil)tiokarbonitrila (spoj 100D)
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Spoj iz naslova je priređen na isti način kao i Primjer 1B s produktom iz primjera 100C (2,38 g, 0,016 mol), natrijevim tiocijanatom (5,14 g, 0,063 mol), natrijevim bromidom (1,63 g, 0,016 mol), i brominom (2,8 g, 0,017 mol) u metanolu. 400 MHz 1H NMR (DMSO-d6) δ 7,30 (m, 2H), 6,81 (d, 1H), 5,49 (brs, 1H), 2,60 (m, 2H), 1,59 (m, 2H), 1,38 (m, 2H), 0,95 (t, 3H).
Korak 5. Priprema metil 2-(2-butil-4-cijanotiofenoksi)acetata (spoj 100E)
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Spoj iz naslova je priređen na isti način kao i Primjer 1C s produktom iz primjera 100D (2,80 g, 0,014 mol), metil bromoacetatom (2,28g, 0,015 mol), i cezijevim karbonatom (6,60 g, 0,020 mol) u 100 ml of acetonitrila. 400 MHz 1H NMR (DMSO-d6) δ 7,38 (m, 2H), 6,72 (d, 1H), 4,66 (s, 2H), 3,80 (s, 3H), 2,67 (m, 2H), 1,57 (m, 2H), 1,38 (m, 2H), 0,98 (t, 3H).
Korak 6. Priprema metil 2-(2-butil-4-sulfanilfenoksi)acetata (spoj 100F)
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Spoj iz naslova je priređen na isti način kao i Primjer 1D s produktom iz primjera 100E (2,79 g, 10,0mmol), ditiotreitolom (3,08 g, 20,0 mmol), i 0,2 M kalijevim dihidrogenfosfatom (15 ml) u 60 ml metanola. 400 MHz 1H NMR (DMSO-d6) δ 7,11 (m, 2H), 6,60 (d, 1H), 4,61 (s, 2H), 3,81 (s, 3H), 3,36 (s, 1H), 2,63 (m, 2H), 1,57 (m, 2H), 1,38 (m, 2H), 0,98 (t, 3H).
Korak 7. Priprema metil 2-[2-butil-4-({4-[4-(trifluorometil)fenil]fenil}metiltio)fenoksi]acetata (spoj 100G)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom 100F i 1-(bromometil)-4-[4-(trifluorometil)fenil]benzena priređenog iz fosfornog tribromida i (4'-trifluorometil-bifenil-4-il)-metanola na isti način kao i Primjer 3B. 400 MHz 1H NMR (DMSO-d6) δ 7,68 (m, 4H), 7,51 (d, 2H), 7,29 (d, 2H), 7,15 (m, 2H), 6,60 (d, 1H), 4,62 (s, 2H), 4,04 (s, 2H), 3,79 (s, 3H), 2,60 (m, 2H), 1,55 (m, 2H), 1,35 (m, 2H), 0,88 (t, 3H).
Korak 8. Priprema 2-[2-butil-4-({4-[4-(trifluorometil)fenil]fenil}metiltio)fenoksi]octene kiseline (spoj 100)
Spoj iz naslova je priređen na isti način kao i Primjer 1 s produktom iz primjera 100G. mp 155-157°C; 400 MHz 1H NMR (DMSO-d6) δ 7,88 (d, 2H), 7,80 (d, 2H), 7,65 (d, 2H), 7,38 (d, 2H), 7,17 (dd, 1H), 7,09 (d, 1H), 6,79 (d, 1H), 4,65 (s, 2H), 4,17 (s, 2H), 2,50 (m, 2H), 1,43 (m, 2H), 1,22 (m, 2H), 0,81 (t, 3H). MS m/z 473 (M-1). Anal. Izrač. za C26H25O3SF3: C, 65,81; H, 5,31; Nađeno: C, 65,95; H, 5,36.
Primjer 101
Priprema {6-metil-8-[4-(4-trifluorometil-benziloksi)-benzil-sulfanil]-kroman-5-iloksi}-octene kiseline (spoj 101)
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Korak 1. Metil ester {6-metil-8-[4-(4-trifluorometil-benziloksi)-benzil-sulfanil]-kroman-5-iloksi}-octene kiseline (spoj 101A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom metil estera (8-merkapto-6-metil-kroman-5-iloksi)-octene kiseline i produkta iz Primjera 14B. MS m/z 533 (M+1).
Korak 2. {6-metil-8-[4-(4-trifluorometil-benziloksi)-benzil-sulfanil]-kroman-5-iloksi}-octena kiselina (spoj 101)
2N otopina KOH (5 ml) se doda uz miješanje u gustu otopinu produkta iz Primjera 101A (0,4g, 0,75 mmol) u 2-3 ml metanola, te se smjesa kratko ugrije na parnoj kupelji dok nije gotovo bistra i zatim miješa na sobnoj temperaturi. Nakon 3 sata se smjesa razrijedi s 15-20 ml hladne vode i zakiseli s H3PO4. Nakon 15 minuta se talog profiltrira, 3x ispere s vodom, i osuši da se dobije spoj iz naslova, ,2g, 51%. 400 MHz 1H NMR (DMSO-d6) δ 7,70 (d, 2H, J = 8 Hz), 7,59 (d, 2H, J = 8 Hz), 7,18 (d, 2H, J = 8,5 Hz), 6,88 (d, 2H, J = 8, 5Hz), 6,83 (s, 1H), 5,14 (s, 2H), 4,21 (s, 2H), 4,06 (t, 2H, J = 4,9Hz), 3,95 (s, 2H), 2,63 (t, 2H, J = 6,3Hz), 2,03 (s, 3H), 1,79 (kvinta, 2H); MS m/z 517 (M-1).
Primjer 102
Priprema {4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-5,6,7,8-tetrahidro-naftalen-1-iloksi}-octene kiseline (spoj 102)
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Korak 1. Metil ester {4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-5,6,7,8-tetrahidro-naftalen-1-iloksi}-octene kiseline (spoj 101A)
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Spoj iz naslova je priređen na isti način kao i Primjer 1F uporabom metil estera (4-merkapto-5,6,7,8-tetrahidro-naftalen-1-iloksi)-octene kiseline i produkta iz Primjera 42C; rekristalizacijom iz metanola se dobije spoj iz naslova. MS m/z 478 (M+1).
Korak 2. {4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-5,6,7,8-tetrahidro-naftalen-1-iloksi}-octena kiselina (spoj 102)
Spoj iz naslova je priređen na isti način kao i Primjer 1 uporabom produkta iz primjera 102A. mp 167-170°C; 400 MHz 1H NMR (DMSO-d6) δ 8,01 (d, 2H, J = 8 Hz), 7,83 (d, 2H, J = 8,3 Hz), 7,14 (d, 2H, J = 8,5 Hz), 7,07 (s, 1H), 6,58 (d, 2H, J = 8,8 Hz), 4,56 (s, 2H), 4,07 (s, 2H), 2,64 (m, 2H), 2,53 (m, 2H), 1,60 (m, 4H, ); MS m/z 464 (M+1).
Spojevi iz ovog izuma se također mogu prirediti uporabom kombiniranih kemijskih postupaka. Konkretno, spojevi iz Primjera 103-134 su priređeni primjenom kombinatorne kemije na isti način kao što je prije opisano u Primjerima 1-102. Kombinirani kemijski postupci korisni za ovaj izum uključuju one u kojima je aktivirani alkohol u kontaktu s tiolom, te slijedi saponifikacija nastalog estera kako bi nastao željeni produkt. Ovakvi postupci se mogu opisati prema prije navedenoj Shemi 1 u kojoj spoj D predstavlja tiol, spoj Y predstavlja aktivirani alkohol, i spoj F predstavlja željeni produkt.
Primjeri 103-134
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Priprema Primjera 103-134 je dalje niže opisana.
Priprema tiola koji se rabe u kombiniranim postupcima
Tiol WW
Priprema 2,5-Dimetil-4-tiocijanato-fenola (spoj WWA)
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Spoj iz naslova je priređen na isti način kao i spoj 1B. 400 MHz 1H NMR (DMSO-d6) δ 10,0 (s, 1H), 7,35 (s, 1H), 6,73 (s, 1H), 2,3 (s, 3H), 2,04 (s, 3H); MS m/z 180 (m+1).
Priprema metil estera (2,5-Dimetil-4-tiocijanato-fenoksi)-octene kiseline (spoj WWB)
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Spoj iz naslova je priređen iz spoja WWA na isti način kao i spoj 1C. 400 MHz 1H NMR (DMSO-d6) δ 7,07 (s, 1H), 6,50 (s, 1H), 4,56 (s, 2H), 3,76 (s, 3H), (s, 1H), 2,26 (s, 3H), 2,17 (s, 3H); MS m/z 252 (m+1).
Priprema metil estera (4-Merkapto-2,5-dimetil-fenoksi)-octene kiseline (spoj WW)
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Spoj iz naslova je priređen iz spoja WWB na isti način kao i spoj 1D. 400 MHz 1H NMR (DMSO-d6) δ 7,07 (s, 1H), 6,50 (s, 1H), 4,56 (s, 2H), 3,76 (s, 3H), 3,07 (s, 1H), 2,26 (s, 3H), 2,17 (s, 3H); MS m/z 227 (M+1).
Tiol XX
Priprema 2,6-Dimetil-4-tiocijanato-fenola (spoj XXA)
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Spoj XXA je priređen iz 2,6-dimetilfenola na sličan način kao što je opisano za spoj 1B. 400 MHz 1H NMR (DMSO-d6) δ 8,96 (s, 1H), 7,22 (s, 2H), 2,13 (s, 6H).
Priprema metil estera (2,6-Dimetil-4-tiocijanato-fenoksi)-octene kiseline (spoj XXB)
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Spoj XXB je priređen iz spoja XXA na sličan način kao što je opisano za spoj 1C da se dobije 2,5 g (46%) spoja iz naslova dovoljne čistoće za sljedeću uporabu. 400 MHz 1H NMR (DMSO-d6) δ 7,11 (s, 2H), 4,41 (s, 2H), 3,63 (s, 3H), 2,14 (s, 6H).
Priprema metil estera (4-Merkapto-2,6-dimetil-fenoksi)-octene kiseline (spoj XX)
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Spoj XX je priređen iz spoja XXB na sličan način kao što je opisano za spoj 1D kako bi se dobilo, nakon pročišćavanja flash kolonskom kromatografijom (gradijent ispiranja: 100% heksan do 30% EtOAc/heksan), 1,8 g (82%) spoja iz naslova. 400 MHz 1H NMR (DMSO-d6) δ 6,90 (s, 2H), 5,51 (s, 1H), 4,39 (s, 2H), 3,66 (s, 3H), 2,10 (s, 6H); MS m/z 225 (M-1).
Tiol YY
Priprema 4-Tiocijanato-5,6,7,8-tetrahidro-naftalen-1-ol (spoj YYA)
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5,6,7,8-Tetrahidro-naftalen-1-ol (1 g, 6,8 mmol) se otopi u 25 ml acetonitrila. Zatim se dodaju natrijev tiocijanat (1,76 g, 22 mmol) i natrijev bromid (0,7 g, 6,8 mmol) i sve se miješa 5 minuta na sobnoj temperaturi. Bromin (1,2 g, 7,48 mmol) se dodaje kap po kap preko 5 minuta. Narandžasta otopina se miješa dva sata. Zatim se doda slana voda i nepročišćeni produkt se dvaput ekstrahira u etil acetat. Sjedinjeni organski ekstrakti se jednom isperu sa slanom vodom, osuše iznad bezvodnog natrijevog sulfata, odvoje i koncentriraju. Kromatografijom na normalnoj fazi se dobije spoja iz naslova, 1,28 g, 92%. 400 MHz 1H NMR (DMSO-d6) δ 11,1 (s, 1H), 7,40 (d, 1H, J = 8,8 Hz), 6,61 (d, 1H, 8,8 Hz), 2,78 (m, 2H), 2,59 (m, 2H), 1,70 (m, 4H). MS m/z 278 (m+1)
Priprema metil estera (4-Tiocijanato-5,6,7,8-tetrahidro-naftalen-1-iloksi)-octene kiseline (spoj YYB)
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Spoj iz naslova je priređen na isti način kao i primjer 1C uporabom spoja YYA. 400 MHz 1H NMR (DMSO-d6) δ 7,4 (d, 1H, J = 8,8 Hz), 6,80 (d, 1H, 8,8 Hz), 4,84 (s, 2H), 3,64 (s, 3H), 2,78 (m, 2H), 2,59 (m, 2H), 1,70 (m, 4H). MS m/z 278 (m+l).
Priprema metil estera (4-Merkapto-5,6,7,8-tetrahidro-naftalen-1-iloksi)-octene kiseline (spoj YY)
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Spoj iz naslova je priređen na isti način kao i primjer 1D uporabom spoja YYB 400 MHz 1H NMR (DMSO-d6) δ 7,08 (d, 1H, J = 8,8 Hz), 6,55 (d, 1H, 8,8 Hz), 4,71 (s, 1H), 4,70 (s, 2H), 3,63 (s, 3H), 2,45 (m, 2H), 2,44 (m, 2H), 1,65 (m, 4H).MS m/z 253 (M+1).
Tiol ZZ
Priprema 4-Tiocijanato-fenola (spoj ZZA)
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Spoj iz naslova je priređen na isti način kao i Primjer 1B uporabom fenola. MS m/z 152 (M+1).
Priprema metil estera [(4-Tiocijanato-fenoksi)-octene kiseline (spoj ZZB)
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Spoj iz naslova je priređen na isti način kao i Primjer 1C uporabom ZZA. MS m/z 224 (M+1)
Priprema metil estera (4-Merkapto-fenoksi)-octene kiseline (spoj ZZ)
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Spoj iz naslova je priređen na isti način kao i Primjer 1D uporabom ZZB. MS m/z 197 (M-1)
Priprema Primjera 103-134
Priprema Alkohola:
Prikladni alkoholi u obliku soli (0,65mmol) se otope u 3,0mL MeOH s malo vode. MP-CO3 (3,21mmol/g, 3,70 ekvivalenata alkohola, 2,41 mmol) se zatim doda u svaku posudicu koja sadrži alkohol i promiješa 3h na sobnoj temperaturi. Uzorci se zatim filtriraju u tarirane posudice i koncentriraju.
Aktivacija Alkohola:
Svaki uzorak alkohola se dalje razrijedi do 0,15M s DCM i 1,0mL svakog se prebaci u reakcijsku cijev. PS-morfolin (4,0 mmol/g, 2 ekvivalenata alkohola, 0,3mmol) i 25 µL metansulfonil klorida se zatim doda u svaku reakcijsku cijev. Reakcijske cijevi se miješaju 16h na sobnoj temperaturi. Uzorci se zatim filtriraju u cijevi za sakupljanje, ostatak se ispere s dva 1,0mL alikvota DCM, i koncentriraju.
Alkilacija:
Primjeri 103-134 su sintetizirani na sljedeći način uporabom bilo tiolnih produkata 2C, 1D, WW, XX, YY ili ZZ i prikladnog aktiviranog alkohola ili alkil halida. Svaki tiol se razrijedi do 0,15M s CH3CN i svaki aktivirani alkohol se razrijedi do 0,15M s CH3CN. 1,0mL alikvota svakog tiola (0,15 mmol) i 1,0mL alikvota svakog aktiviranog alkohola (1,0 ekvivalenata, 0,15mmol) se zatim prebaci u reakcijsku cijev, te se doda 100mg Cs2CO3 (2 ekvivalenata, 0,3mmol). Reakcijske cijevi se miješaju 2,5h na 60°C. Rekacijske smjese se filtriraju u cijevi za sakupljanje, ostatak se ispere s dva 1,0mL alikvota CH3CN, i koncentriraju.
Saponifikacija:
Primjeri 103-134 su sintetizirani na sljedeći način uporabom produkata iz alkilacijskog koraka koji je prethodno opisan. Svaki produkt alkilacije se razrijedi s 3,0mL 0,5M LiOH u 4:1 metoksietanol:H2O, miješa 4h na 60°C i rashladi na sobnu temperaturu. U svaku reakcijsku smjesu se zatim doda 1,0mL 1N HCl i 1,0mL slane vode. Svaka reakcijska smjesa se dvaput ekstrahira s 2,0mL EtOAc, te se organski sloj koncentrira kako bi se dobio željeni produkt.
BIOLOŠKI TESTOVI
Spojevi iz ovog izuma pokazuju sposobnost promjene PPAR aktivnosti u standardnim testovima koji se obično primjenjuju u struci. Prema tome, ovakvi spojevi i pripravci koji sadrže ovakve spojeve su korisni za smanjenje apetita, prilagođavanje razine leptina, i liječenje, prevenciju ili kontrolu hiperkolesterolemije, dislipidemije, gojaznosti, poremećaja u prehrani, hiperglikemije, ateroskleroze, hipertrigliceridemije, hiperinzulinemije i dijabetesa.
A. Selektivna mjerenja
1. Test A. Kratkotrajni test transfekcije uporabom HepG2 stanične linije hepatocelularnog karcinoma.
Transfekcija se provede kratkotrajno na HepG2 stanice s ekspresijskim plazmidima koji kodiraju hPPARα, hPPARβ ili mPPARγ kimerne receptore i receptore koji sadrže kvaščeve gornje aktivacijske sekvence (UAS) iznad viralnog E1B promotora koji kontrolira luciferaza reporter gen. Osim toga, plazmid pRSVβ-gal se rabi za kontrolu uspješnosti transfekcije. HepG2 stanice rastu u DMEM koji je nadopunjen s 10%FBS i 1µM ne-esentcijalnih amino kiselina. Prvi dan se stanice razdvoje u 100mm posudice kao 2,5x106 /posudi i inkubiraju preko noći na 37C°/5% CO2. Drugi dan se kratkotrajno provede transfekcija na stanicama s plazmidom DNA koji kodira kimerni receptor, luciferaza reporter gen; i β-gal. Za svaku 100 mm posudicu, 15 µg luciferaza reporter (PG5E1b) DNA, 15µg Gal4-PPAR kimernog receptora DNA, i 1,5 µg β-gal plasmida DNA se miješa s 1,4ml opti-MEM u cijevi. 28µl reagensa LipoFectamine-2000 se doda u 1,4ml opti-MEM u cijevi, i inkubira 5 min. kod RT. Razrijeđeni reagens Lipofectamine-2000 se poveže s DNA smjesom i inkubira 20 min kod RT. Nakon dodatka svježeg medija u svaku 100mm posudicu sa stanicama se doda kap po kap 2,8ml Lipofectamine2000-DNA smjese u 100mm posudicu koji sadrži 14ml medija, i inkubira preko noći na 37 °C. Danju se tri stanice kojima je dodan tripsin izoliraju s 100 mm posudica i ponovo nanesu na 96 podloge. Stanice se nanose kao 2,5x104 stanica po posudici u 150µl medija, pa se doda 50µl spoja razrijeđenog s medijem. Dodani spoj je u rasponu od 50 µM do 50µM. Nakon dodatka spoja, podloge se inkubiraju na 37C° 24 sata. Nakon toga se stanice jednom isperu sa 100µl PBS, liziraju, i obrade za mjerenje aktivnosti luciferaze i β-gal uporabom Dual-Light luciferaza kita iz Tropix ®, prema preporuci proizvođača, na EG&G Bethold MicroLumat LB96P luminometru. Vrijednosti EC50 su dobivene uporabom GraphPad Prism™ programa. Iznenađujuće, spojevi iz ovog izuma posjeduju aktivnost i za PPARα i za PPARβ. Spojevi iz ovog izuma imaju raspon Hep G2-hBeta EC50‘s ("EC50β") i Hep G2-hAlpha EC50‘s ("EC50α") veći od nule do oko 20µM. Točnije, kao što je prikazano u Tablici 1, Hep G2-hBeta EC50‘s i Hep G2-hAlpha EC50‘s za spojeve iz ovog izuma spadaju u sljedećih 6 skupina:
[image]
Tablica 1
[image] [image] [image] [image]
B. Djelovanje PPAR modulatora na koncentraciju lipida i ljudskog apoproteina A1 u hApoAl transgeničnih miševa
Miševi, transgenični za ljudski apoA1, su nabavljeni iz Jackson laboratorija. Svim životinjama je bilo dopušteno normalno hranjenje (Ralston-Purina) i voda ad libitum u sobama s kontroliranom temperaturom, uz ciklus od 12-h svjetla, 12-h tame s početkom paljenja svjetla u 6 ujutro. Tokom faze tretmana provedenog za ovo istraživanje miševi su primali između 6 i 9 ujutro dnevne doze oralnim kontroliranim hranjenjem uporabom prijenosnog sredstva za suspendiranje od 1,5% karboksimetilceluloze i 0,2 postotnog Tween-20 (CMC/Tween) koji sadrže navedene spojeve. Kontrolne životinje su primale samo prijenosno sredstvo. Volumen prijenosnog sredstva predstavlja 0,25 posto tjelesne mase. Krv iz repa je uzimana svaki tjedan ujutro pod anestezijom u navedene dane istraživanja. Pred kraj su uzeti uzorci tkiva (jetra, probavilo, masnoće, i mišić) kako bi se istražilo djelovanje na gene koji utječu na metabolizam lipida. Svaki od spojeva iz ovog izuma koji su testirani dovode do značajnog porasta HDL preko razina koje su uočene u kontrolnih životinja. Osim toga, ovi spojevi su doveli do sniženja razina triglicerida u odnosu na kontrolu. Spojeva iz ovog izuma koji su testirani u hApoAI transgenskih modelnih miševa daju raspon povišenja HDL-c i sniženja triglicerida kada se primjenjuju kao 30 mg/kg/dnevno. Na primjer, Primjer 4 je povisio HDL-c 97% i snizio trigliceride 65 % u odnosu na kontrolnu skupinu, Primjer 6 je povisio HDL-c 24% i snizio trigliceride 59 % u odnosu na kontrolnu skupinu, i Primjer 3 je povisio HDL-c 9% i snizio trigliceride 70% u odnosu na kontrolnu skupinu.
C. Djelovanje spojeva iz izuma na inzulin otporne ili makaki majmune dijabetičare
Makaki majmuni koji su bili ili inzulin otporni ili dijabetičari (tip II) su tretirani osam tjedana s [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octenom kiselinom uz primjenu sve veće doze (0,1 do 1 mg/kg). Dvaput tjedno im je uzimana plazma i analizirana na glikemike i leptin. Također je u različitim vremenskim intervalima tokom istraživanja mjerena tjelesna masa. Srednja vrijednost tjelesne mase majmuna dijabetičara je prikazana u Tablici 2 a srednja vrijednost tjelesne mase majmuna otpornih na inzulin je prikazana u Tablici 3.
Tablica 2
Srednja vrijednost tjelesne mase majmuna dijabetičara
[image]
Tablica 3
Srednja vrijednost tjelesne mase majmuna otpornih na inzulin
[image]
Vrijednosti plazma leptina, koje su prikazane kao bazične vrijednosti u odnosu na 8-tjendi tretman, su određene ELISA tehnikom i prikazane u Tablici 4. Djelovanje [5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline na vrijednosti plazma leptina u dijebetičara i inzulin otpornih gojaznih makaki majmuna se odražava kao manji porast vrijednosti plazma leptina koji se uočava u tretiranih životinja.
Količina ubrizganog inzulina koji su primili majmuni dijabetičari da bi održali valjanu razinu glukoze, odnosno potreba za dodanim inzulinom, je također prikazana u Tablici 4 kao bazična vrijednost u odnosu na 8-tjendi tretman. Prema definiciji, inzulin otporni majmuni nisu još dijabetičari i ne primaju dodatni inzulin. Smanjenje potreba za dodanim inzulinom je mjera poboljšane osjetljivosti inzulina i kontrole glukoze.
Tablica 4
Leptin i dodani inzulin
[image]
PRIPRAVCI
Spojevi iz ovog izuma se mogu primijeniti sami ili u kombinaciji s jednim ili više terapijskih sredstava. Ona uključuju, na primjer, druga sredstva za liječenje, kontrolu ili prevenciju hiperkolesterolemije, dislipidemije, gojaznosti, hiperglikemije, hiperkolesterolemije, ateroskleroze, hipertrigliceridemije i hiperinzulinemije. Spojevi iz ovog izuma se mogu primijeniti sami ili u kombinaciji s jednim ili više terapijskih sredstava za smanjenje apetita i prilagođavanje leptina.
Spojevi su prema tome dobro prilagođeni za pripravke za uobičajenu primjenu na sisavce kod prevencije i liječenja ovakvih poremećaja.
Sljedeći primjeri prikazuju uobičajene pripravke koji su dobiveni u izumu.
Pripravak 1
[image]
Gornje primjese se pomiješaju i otope u slanoj otopini za IV primjenu na pacijenta.
Pripravak 2
[image]
Gornje primjese se pomiješaju dok ne nastane jednolična smjesa i zgnječe u tabletu koja je prikladna za pacijenta za oralnu primjenu.
Pripravak 3
[image]
Primjese se sjedine i samelju da se dobije prikladan materijal za punjenje tvrdih želatinoznih kapsula koje se primjenjuju na pacijenta.
Pripravak 4
[image]
Primjese se sjedine otapanjem i zatim preliju u kalupe koji sadrže 2,5 g ukupne mase.
Prikazom i opisom dostignuća ovoga izuma nije namjera da se tim dostignućima prikažu i opišu svi mogući oblici izuma. Zapravo, riječi koje se rabe u prikazima su opisne riječi, a ne ograničenja, te se podrazumijeva mogućnost primijene različitih promjena bez udaljavanja od namjene i svrhe izuma.
Claims (15)
1. Spoj formule I:
[image]
i farmaceutski prihvatljive soli, naznačeni time da:
X0 i Xl su neovisno odsutni, O, S, -CH2-, -CH2-CH2-, -CH=CH-, -CH≡CH-, -S(O)2-, ili -S(O)-;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani fenil ili piridinil;
[image]
je odsutan;
R1 i R2 su izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2R5, ili -NR6R7, ili zajedno s atomima na koje su vezani tvore lanac od pet do osam članova;
R3 i R4 izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
uz mogućnost da bar jedan od R1-R4 predstavlja H, niži alkil, niži alkoksi, haloalkil, -O-(CH2)mCF3, halogen, nitro, cijano, -OH, -SH, -CF3, -S(O)palkil, S(O)paril, -(CH2)mOR5, -(CH2)mNR6R7, ili -NR6R7;
R5 je vodik, alkil, alkenil, alkinil, ili aril;
R6 i R7 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, ili R6 i R7 zajedno s atomima na koje su vezani tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
m je 0 do 5;
p je 0, l, ili 2;
q je 0 do 6; i
r je 0 do 6.
2. Spoj iz zahtjeva 1, naznačen time da:
X0 je S;
X1 je odsutan;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani aril;
[image]
je odsutan;
R1 je vodik;
R2 je niži alkil, niži alkoksi, haloalkil, -O-(CH2)mCF3, halogen, nitro, cijano, -OH, -SH, -CF3, -S(O)palkil, S(O)paril, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2R5, ili -NR6R7;
R3 je niži alkil, niži alkoksil, haloalkil, -O-(CH2)mCF3, halogen, nitro, cijano, -OH, -SH, -CF3, -S(O)palkil, S(O)paril, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
R4 je vodik, niži alkil, niži alkoksil, haloalkil, -O-(CH2)mCF3, halogen, nitro, cijano, -OH, -SH, -CF3, -S(O)palkil, S(O)paril, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
R5 je vodik, alkil, alkenil, alkinil, ili aril;
R6 i R7 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, ili R6 i R7 zajedno s atomima na koje su vezani tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
m je 0 do 5;
p je 0, l, ili 2;
q je 1; i
r je 0.
3. Spoj iz zahtjeva 1, naznačen time da:
X0 je S;
X1 je odsutan;
Ar1 je fenil;
Ar2 je supstituirani fenil;
[image]
je odsutan;
R1 je vodik;
R2 je niži alkoksi;
R3 je niži alkil;
R4 je vodik;
q je 1; i
r je 0.
4. Spoj formule II:
[image]
i farmaceutski prihvatljive soli, naznačeni time da:
X0 i Xl su neovisno odsutni, O, S, -CH2-, -CH2-CH2-, -CH=CH-, -CH≡CH-, -S(O)2-, ili -S(O)-;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani aril ili heteroaril, uz uvjete da Arl nije tiazolil ili oksazolil;
[image]
je odsutan; ili ako je prisutan,
[image]
je zasićeni ili nezasićeni ugljikovodikov lanac koji je supstituiran ili nesupstituiran, a spomenuti lanac ima od 1 do 4 atoma tako da
[image]
, Ar1, X1, (CH2)r, i Ar2, zajedno tvore lanac od pet do osam članova;
R3 i R4 izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)mCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, ili -NR6R7;
R5 je vodik, alkil, alkenil, alkinil, ili aril;
R6 i R7 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, SO2alkil, -SO2aril, ili R6 i R7 zajedno s atomima na koje su vezani tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
[image]
zasićeni ili nezasićeni, supstituirani ili nesupstituirani ugljikovodikov lanac ili ugljikovodikov-heteroatomski lanac koji ima od 3 do 6 atoma i u kojem je ugljikov atom na poziciji 2 povezan s ugljikovim atomom na poziciji 3 i tvore lanac od pet do osam članova;
m je 0 do 5;
p je 0 do 2;
q je 0 do 6; i
r je 0 do 6.
5. Spoj iz zahtjeva 18, naznačen time da:
X0 je S;
X1 je O;
Ar1 je fenil;
Ar2 je 4-trifluorometilfenil;
[image]
je odsutan;
R3 je vodik, niži alkil, niži alkoksi;
R4 je vodik, niži alkil, niži alkoksi;
m je 0 do 5;
p je 0, 1 ili 2;
q je 1;
r je 1; i
[image]
je -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-O-CH2-CH2-, -CH2-HC=CH-CH2-, -CH2-HC=CH-, -CH2-CH2-NR4-CH2-, -COCH=CH-O-, -O-CH=CH-CO-, -CH=CH-NR4-, -NR4-CH=CH-, -CH=CH-CH2-, -CH2-CH2-NR4-, -NR4-CH2-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, -CH2-CH2-CH2-NR4-, -NR4-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-.
6. Spoj iz zahtjeva 18, naznačen time da:
[image]
je -CH2CH2CO-O-, -CH2-CH2-O-CO-, -CH2-CH2-CH2-CH2-, -HC=CH-HC=CH-, -N=CH-HC=CH-, -HC=N-HC=CH-, -HC=CH-N=CH-, -HC=CH-HC=N-, -CH2-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-O-CH2-CH2-, -CH2-HC=CH-CH2-, -CH2-HC=CH-, -CH2-CH2-NR4-CH2-, -COCH=CH-O-, -O-CH=CH-CO-, -CH=CH-NR4-, -NR4-CH=CH-, -CH=CH-CH2-, -CH2-CH2-NR4-, -NR4-CH2-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, -CH2-CH2-CO-, -CH2-CO-CH2-, -CO-CH2-CH2-, -CH2-CH2-CH2-CO-, -CO-CH2-CH2-CH2-, -CH2-CO-CH2-CH2-, -CH2-CH2-CO-CH2-, -CH2-CH2-CH2-NR4-, -NR4-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-, -CO-NR4-CH2-CH2-, -NR4CO-CH2-CH2-, -CH2-CH2-NR4-CO-, ili -CH2-CH2-CO-NR4.
7. Spoj naznačen time da je izabran između:
[4-(Bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline;
[4-(2',4'-Dikloro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline;
[5-Metoksi-2-metil-4-(3'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline;
[4-(4'-Fluoro-bifenil-4-ilmetilsulfanil)-5-metoksi-2-metil-fenoksi]-octene kiseline;
[7-(4'-Trifluorometil-bifenil-4-ilmetilsulfanil)-indan-4-iloksi]-octene kiseline;
{5-Metoksi-2-metil-4-[4-(4-trifluorometil-benziloksi)-benzilsulfanil]-fenoksi}-octene kiseline;
[5-Metoksi-2-metil-4-(3'-trifluorometoksi-bifenil-3-ilmetilsulfanil)-fenoksi]-octene kiseline;
{[5-Metoksi-2-metil-4-(4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-fenoksi}-octene kiseline;
{5-Metoksi-2-metil-4-[6-(4-trifluorometil-fenil)-piridin-3-ilmetilsulfanil]-fenoksi}-octene kiseline;
[3-Metoksi-4-(4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline;
{5-Metoksi-2-metil-4-[2-(4'-trifluorometil-bifenil-4-il)-etilsulfanil]-fenoksi}-octene kiseline;
(4-{4-[2-(3-Fluoro-fenil)-vinil]-benzilsulfanil}-5-metoksi-2-metil-fenoksi)-octene kiseline;
[5-Metoksi-2-metil-4-(3-metil-4'-trifluorometil-bifenil-4-ilmetilsulfanil)-fenoksi]-octene kiseline;
{4-[5-(4-Kloro-fenil)-izoksazol-3-ilmetilsulfanil]-5-metoksi-2-metil-fenoksi}-octene kiseline;
{5-Metoksi-2-metil-4-[5-(4-trifluorometil-fenil)-izoksazol-3-ilmetilsulfanil]-fenoksi}-octene kiseline;
{5-Metoksi-2-metil-4-[3-(4-trifluorometil-fenil)-izoksazol-5-ilmetilsulfanil]-fenoksi}-octene kiseline;
[5-Metoksi-2-metil-4-(4'-trifluorometil-bifenil-3-ilmetilsulfanil)-fenoksi]-octene kiseline;
{7-[4-(4-Trifluorometil-benziloksi)-benzilsulfanil]-indan-4-iloksi}-octene kiseline;
{5-Metil-7-[4-(5-trifluorometil-piridin-2-il)-benzilsulfanil]-2,3-dihidro-benzofuran-4-iloksi}-octene kiseline;
i farmaceutski prihvatljivih soli.
8. Farmaceutski pripravak naznačen time da uključuje spoj iz Zahtjeva 1 pomiješan s nosačem, sredstvom za razrjeđivanje, ili ekscipijentom.
9. Postupak za liječenje, prevenciju ili kontrolu inzulin neovisne šećerne bolesti u sisavaca naznačen time da uključuje primjenu spoja iz Zahtjeva 1 na sisavce kojima je potrebna u terapijski djelotvornoj količini.
10. Postupak za liječenje, prevenciju ili kontrolu gojaznosti u sisavaca naznačen time da uključuje primjenu spoja iz Zahtjeva 1 na sisavce kojima je potrebna u terapijski djelotvornoj količini.
11. Postupak za prilagođavanje razina leptina u sisavaca naznačen time da uključuje primjenu spoja iz Zahtjeva 1 na sisavce kojima je potrebna u terapijski djelotvornoj količini.
12. Postupak za liječenje, prevenciju ili kontrolu dislipidemije u sisavaca naznačen time da uključuje primjenu spoja iz Zahtjeva 1 na sisavce kojima je potrebna u terapijski djelotvornoj količini.
13. Postupak za liječenje, prevenciju ili kontrolu hiperkolesterolemije u sisavaca naznačen time da uključuje primjenu spoja iz Zahtjeva 1 na sisavce kojima je potrebna u terapijski djelotvornoj količini.
14. Postupak za pripremu spoja iz zahtjeva 1 ili farmaceutski prihvatljivih soli, naznačen time da uključuje reakciju:
[image]
sa:
[image]
gdje:
X0 je OH ili SH;
X1 je odsutan, O ili S;
Ar1 i Ar2 su svaki neovisno nesupstituirani ili supstituirani aril ili heteroaril;
[image]
je odsutan ili zasićeni ili nezasićeni, supstituirani ili nesupstituirani ugljikovodikov lanac ili ugljikovodikov heteroatomski lanac koji ima od 0 do 3 atoma a prsten od četiri do osam članova nastaje sjedinjavanjem u Ar1 i Ar2 gdje ako je
[image]
odsutan i "---" je veza tada je Ar1 direktno vezan na Ar2;
R1 i R2 su izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)pCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR8, -(CH2)mNR9R10, -COR8, -CO2H, -CO2R8 ili –NR9R10, ili su međusobno povezani i tvore lanac od pet do osam članova;
R3 i R4 izabrani između vodika, nižih alkila, nižih alkoksila, haloalkila, -O-(CH2)pCF3, halogena, nitro, cijano, -OH, -SH, -CF3, -S(O)palkila, S(O)parila, -(CH2)mOR8, -(CH2)mNR9R10, -COR8, -CO2H, -CO2R8, ili -NR9R10;
R5 i R6 su svaki neovisno vodik, alkil, alkenil, alkinil ili aril, ili su međusobno povezani i tvore cikloalkil ili cikoloalkenil od 3 do 7 članova;
R7 i R8 su svaki neovisno vodik, alkil, alkenil, alkinil ili aril;
R9 i R10 su svaki neovisno vodik, alkil, alkenil, alkinil, -COalkil, -COaril, cikloalkil, -CO2alkil, -CO2aril, SO2alkil, -SO2aril, ili su međusobno povezani i tvore lanac od 4 do 7 članova koji ima 1 do 3 heteroatoma;
R11 je niži alkil;
X je vodik;
m je 0 do 5;
p je 0 do 2;
q je 0 do 6; i
r je 0 do 6.
15. Postupak za pripremu spojeva formule I-4, koja je
[image]
naznačen time da obuhvaća:
a) pretvorbu fenola 1A u tiocijanat 1B;
[image]
(b) alkilaciju fenol skupine tiocijanata 1B u acetoksiester 1C;
[image]
(c) redukciju tiocijanatne skupine iz 1C kako bi se dobio tiol 1D;
[image]
(d) alkilaciju tiola 1D s kloridom 3C kako bi se dobio 4a;
[image]
(e) saponifikaciju skupine estera iz 4a kako bi se dobio I-4;
gdje
R1 je vodik ili zajedno s R2 tvori karbociklički prsten od 5 članova;
R2 je metoksi ili zajedno s R1 tvori karbociklički prsten od 5 članova;
R3 je vodik ili metil;
R4 je vodik;
X1 je odsutan ili O; i
r je 0 ili 1.
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US38602602P | 2002-06-05 | 2002-06-05 | |
PCT/IB2003/001121 WO2003084916A2 (en) | 2002-04-05 | 2003-03-24 | Compounds that modulate ppar activity and methods for their preparation |
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US (4) | US6875780B2 (hr) |
EP (1) | EP1494989A2 (hr) |
JP (2) | JP3816922B2 (hr) |
KR (1) | KR100687166B1 (hr) |
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AR (1) | AR039239A1 (hr) |
AU (1) | AU2003212578A1 (hr) |
BR (1) | BR0309169A (hr) |
CA (1) | CA2481246C (hr) |
CO (1) | CO5640080A2 (hr) |
DO (1) | DOP2003000620A (hr) |
EA (2) | EA009518B1 (hr) |
GE (1) | GEP20074244B (hr) |
GT (3) | GT200300075AA (hr) |
HN (1) | HN2003000113A (hr) |
HR (1) | HRP20040916A2 (hr) |
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- 2004-09-17 CO CO04092873A patent/CO5640080A2/es not_active Application Discontinuation
- 2004-09-28 MA MA27877A patent/MA27189A1/fr unknown
- 2004-10-04 TN TNP2004000191A patent/TNSN04191A1/fr unknown
- 2004-10-05 HR HRP20040916 patent/HRP20040916A2/hr not_active Application Discontinuation
- 2004-11-02 US US10/979,617 patent/US6939875B2/en not_active Ceased
- 2004-11-02 US US10/979,629 patent/US6964983B2/en not_active Expired - Fee Related
- 2004-11-04 NO NO20044795A patent/NO20044795L/no not_active Application Discontinuation
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2005
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- 2005-12-14 JP JP2005360431A patent/JP2006151985A/ja not_active Withdrawn
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