ZA200508789B - 3-(1-Naphthyl)-2-cyanopropanoic acid derivatives as estrogen receptor ligands - Google Patents
3-(1-Naphthyl)-2-cyanopropanoic acid derivatives as estrogen receptor ligands Download PDFInfo
- Publication number
- ZA200508789B ZA200508789B ZA200508789A ZA200508789A ZA200508789B ZA 200508789 B ZA200508789 B ZA 200508789B ZA 200508789 A ZA200508789 A ZA 200508789A ZA 200508789 A ZA200508789 A ZA 200508789A ZA 200508789 B ZA200508789 B ZA 200508789B
- Authority
- ZA
- South Africa
- Prior art keywords
- naphthyl
- methyl
- methoxyphenyl
- cyano
- propanoate
- Prior art date
Links
- 102000015694 estrogen receptors Human genes 0.000 title description 10
- 108010038795 estrogen receptors Proteins 0.000 title description 10
- 239000003446 ligand Substances 0.000 title description 5
- NUSBDSQULWMBEU-UHFFFAOYSA-N 2-cyano-3-naphthalen-1-ylpropanoic acid Chemical class C1=CC=C2C(CC(C(=O)O)C#N)=CC=CC2=C1 NUSBDSQULWMBEU-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 245
- 125000004432 carbon atom Chemical group C* 0.000 claims description 105
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 95
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- PHRABVHYUHIYGY-UHFFFAOYSA-N 1-methylnaphthalene Chemical group C1=CC=C2C([CH2])=CC=CC2=C1 PHRABVHYUHIYGY-UHFFFAOYSA-N 0.000 claims description 50
- -1 Het Chemical group 0.000 claims description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 30
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 25
- 239000000126 substance Substances 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 229910052786 argon Inorganic materials 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 208000023275 Autoimmune disease Diseases 0.000 claims description 10
- 230000002757 inflammatory effect Effects 0.000 claims description 10
- 201000001320 Atherosclerosis Diseases 0.000 claims description 9
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 9
- 206010019280 Heart failures Diseases 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 206010003246 arthritis Diseases 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 208000010125 myocardial infarction Diseases 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000004001 thioalkyl group Chemical group 0.000 claims description 8
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000006413 ring segment Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000005127 aryl alkoxy alkyl group Chemical group 0.000 claims description 4
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 4
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 4
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229960002179 ephedrine Drugs 0.000 claims description 4
- CNKCDDUMEAKBMY-UHFFFAOYSA-N ethyl 2-cyano-3-(2,4-dimethoxyphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=C(OC)C=C1OC CNKCDDUMEAKBMY-UHFFFAOYSA-N 0.000 claims description 4
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical class C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- BCMHUBAKWXCWES-UHFFFAOYSA-N ethyl 2-cyano-3-(2-methoxyphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=CC=C1OC BCMHUBAKWXCWES-UHFFFAOYSA-N 0.000 claims description 3
- KIQFYXQRTULPSW-UHFFFAOYSA-N ethyl 2-cyano-3-naphthalen-1-yl-3-naphthalen-2-ylpropanoate Chemical compound C1=CC=C2C(C(C=3C=C4C=CC=CC4=CC=3)C(C#N)C(=O)OCC)=CC=CC2=C1 KIQFYXQRTULPSW-UHFFFAOYSA-N 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- ZYXRUBZPGKMZIQ-NAKRPHOHSA-N tert-butyl (2r,3r)-2-cyano-2-methyl-3-naphthalen-1-yl-3-(2-propan-2-ylphenyl)propanoate Chemical compound CC(C)C1=CC=CC=C1[C@@H]([C@](C)(C#N)C(=O)OC(C)(C)C)C1=CC=CC2=CC=CC=C12 ZYXRUBZPGKMZIQ-NAKRPHOHSA-N 0.000 claims description 3
- FNNBTMYOIIUTFI-UHFFFAOYSA-N tert-butyl 2-cyano-3-(2-methoxyphenyl)-3-naphthalen-1-ylpropanoate Chemical compound COC1=CC=CC=C1C(C(C#N)C(=O)OC(C)(C)C)C1=CC=CC2=CC=CC=C12 FNNBTMYOIIUTFI-UHFFFAOYSA-N 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- DHFVMONEBPBPJQ-UHFFFAOYSA-N ethyl 2-cyano-3-(2,5-dimethoxyphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC(OC)=CC=C1OC DHFVMONEBPBPJQ-UHFFFAOYSA-N 0.000 claims description 2
- HAWZLUYUKKDNQT-UHFFFAOYSA-N ethyl 2-cyano-3-(2,6-dichlorophenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=C(Cl)C=CC=C1Cl HAWZLUYUKKDNQT-UHFFFAOYSA-N 0.000 claims description 2
- ICMDEXFWAQWPAT-UHFFFAOYSA-N ethyl 2-cyano-3-(2-methylphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=CC=C1C ICMDEXFWAQWPAT-UHFFFAOYSA-N 0.000 claims description 2
- XEJUPNISYVEWOR-UHFFFAOYSA-N ethyl 2-cyano-3-naphthalen-1-yl-3-(2-propan-2-ylphenyl)propanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=CC=C1C(C)C XEJUPNISYVEWOR-UHFFFAOYSA-N 0.000 claims description 2
- JODISYZHJHSRQM-UHFFFAOYSA-N ethyl 3-(4-chlorophenyl)-2-cyano-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=C(Cl)C=C1 JODISYZHJHSRQM-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- OUXYXEGUGBCCDD-UHFFFAOYSA-N tert-butyl 2-cyano-3-(2,6-dimethylphenyl)-2-methyl-3-naphthalen-1-ylpropanoate Chemical compound CC1=CC=CC(C)=C1C(C(C)(C#N)C(=O)OC(C)(C)C)C1=CC=CC2=CC=CC=C12 OUXYXEGUGBCCDD-UHFFFAOYSA-N 0.000 claims description 2
- LUIUWFWPBAGLHR-XDFJSJKPSA-N (2s,3s)-2-[4-(3-chlorophenyl)piperazine-1-carbonyl]-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanenitrile Chemical compound COC1=CC=CC=C1[C@@H]([C@@](C)(C#N)C(=O)N1CCN(CC1)C=1C=C(Cl)C=CC=1)C1=CC=CC2=CC=CC=C12 LUIUWFWPBAGLHR-XDFJSJKPSA-N 0.000 claims 1
- PYUXCEVGIQTTRI-UHFFFAOYSA-N 2-[4-(3-chloro-2-methylphenyl)piperazine-1-carbonyl]-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanenitrile Chemical compound COC1=CC=CC=C1C(C(C)(C#N)C(=O)N1CCN(CC1)C=1C(=C(Cl)C=CC=1)C)C1=CC=CC2=CC=CC=C12 PYUXCEVGIQTTRI-UHFFFAOYSA-N 0.000 claims 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 claims 1
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 238000002296 dynamic light scattering Methods 0.000 claims 1
- BLZUWOJBIVZAFB-UHFFFAOYSA-N ethyl 2-cyano-3-naphthalen-1-yl-3-(2-phenylphenyl)propanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=CC=C1C1=CC=CC=C1 BLZUWOJBIVZAFB-UHFFFAOYSA-N 0.000 claims 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- IPZOUOZDIYMKQO-BVAGGSTKSA-N tert-butyl (2r,3r)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanoate Chemical compound COC1=CC=CC=C1[C@H]([C@](C)(C#N)C(=O)OC(C)(C)C)C1=CC=CC2=CC=CC=C12 IPZOUOZDIYMKQO-BVAGGSTKSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 108
- 239000011541 reaction mixture Substances 0.000 description 105
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 93
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 64
- 238000005160 1H NMR spectroscopy Methods 0.000 description 59
- 239000007787 solid Substances 0.000 description 57
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
- 239000012267 brine Substances 0.000 description 44
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 40
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 38
- 230000003197 catalytic effect Effects 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 238000001953 recrystallisation Methods 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 239000003921 oil Substances 0.000 description 24
- 239000013078 crystal Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- 238000010992 reflux Methods 0.000 description 22
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- 229940086542 triethylamine Drugs 0.000 description 19
- 239000007789 gas Substances 0.000 description 18
- 239000007788 liquid Substances 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- 239000012258 stirred mixture Substances 0.000 description 17
- 239000007858 starting material Substances 0.000 description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 15
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 108010063738 Interleukins Proteins 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 12
- 102000015696 Interleukins Human genes 0.000 description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 11
- 238000010998 test method Methods 0.000 description 11
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 10
- 125000003636 chemical group Chemical group 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 210000000988 bone and bone Anatomy 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 7
- 229940011051 isopropyl acetate Drugs 0.000 description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 7
- 238000001665 trituration Methods 0.000 description 7
- OLFLGDVJYKREPU-RBBKRZOGSA-N (2s,3s)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanoic acid Chemical compound COC1=CC=CC=C1[C@@H]([C@@](C)(C#N)C(O)=O)C1=CC=CC2=CC=CC=C12 OLFLGDVJYKREPU-RBBKRZOGSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- 102000004420 Creatine Kinase Human genes 0.000 description 6
- 108010042126 Creatine kinase Proteins 0.000 description 6
- 108060001084 Luciferase Proteins 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 108010057466 NF-kappa B Proteins 0.000 description 5
- 102000003945 NF-kappa B Human genes 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229930195734 saturated hydrocarbon Natural products 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- PZIIGUMPOSVMSD-UHFFFAOYSA-M [Br-].C1=CC=C2C([Mg+])=CC=CC2=C1 Chemical compound [Br-].C1=CC=C2C([Mg+])=CC=CC2=C1 PZIIGUMPOSVMSD-UHFFFAOYSA-M 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001500 aryl chlorides Chemical class 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 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 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 238000009164 estrogen replacement therapy Methods 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 229910001623 magnesium bromide Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- DASYJICSSLWYAG-UHFFFAOYSA-N 2-cyanopropanamide Chemical compound N#CC(C)C(N)=O DASYJICSSLWYAG-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 3
- FCPRDUXJWIUVPZ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=CC=[C-]1 FCPRDUXJWIUVPZ-UHFFFAOYSA-M 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- NFBCKIYRAVMXKN-UHFFFAOYSA-N 1-(2,3-dihydro-1h-inden-4-yl)piperazine;hydrochloride Chemical compound Cl.C=12CCCC2=CC=CC=1N1CCNCC1 NFBCKIYRAVMXKN-UHFFFAOYSA-N 0.000 description 2
- SHOLVQVIKRVCGQ-UHFFFAOYSA-N 1-(2,3-dimethylphenyl)piperazin-4-ium;chloride Chemical compound Cl.CC1=CC=CC(N2CCNCC2)=C1C SHOLVQVIKRVCGQ-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 238000010240 RT-PCR analysis Methods 0.000 description 2
- 241000219061 Rheum Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 210000002403 aortic endothelial cell Anatomy 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001543 aryl boronic acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000007640 basal medium Substances 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000004305 biphenyl Chemical group 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- LKIMUVKEQPRZFV-GXDHUFHOSA-N ethyl (e)-2-cyano-3-naphthalen-1-ylprop-2-enoate Chemical compound C1=CC=C2C(/C=C(C(=O)OCC)\C#N)=CC=CC2=C1 LKIMUVKEQPRZFV-GXDHUFHOSA-N 0.000 description 2
- RRDOGGURDLJRMR-UHFFFAOYSA-N ethyl 2-cyano-3,3-dinaphthalen-1-ylpropanoate Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4C=CC=3)C(C#N)C(=O)OCC)=CC=CC2=C1 RRDOGGURDLJRMR-UHFFFAOYSA-N 0.000 description 2
- FTSXTKLDGMGCEN-UHFFFAOYSA-N ethyl 2-cyano-3-(2,6-dimethoxyphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=C(OC)C=CC=C1OC FTSXTKLDGMGCEN-UHFFFAOYSA-N 0.000 description 2
- LKIMUVKEQPRZFV-UHFFFAOYSA-N ethyl 2-cyano-3-naphthalen-1-ylprop-2-enoate Chemical compound C1=CC=C2C(C=C(C(=O)OCC)C#N)=CC=CC2=C1 LKIMUVKEQPRZFV-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 159000000003 magnesium salts Chemical class 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
- NIXOIRLDFIPNLJ-UHFFFAOYSA-M magnesium;benzene;bromide Chemical compound [Mg+2].[Br-].C1=CC=[C-]C=C1 NIXOIRLDFIPNLJ-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 125000003431 oxalo group Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 description 2
- 229960005235 piperonyl butoxide Drugs 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- BOWLEFLERZIKSG-DHZHZOJOSA-N tert-butyl (e)-2-cyano-3-[2-(trifluoromethyl)phenyl]prop-2-enoate Chemical compound CC(C)(C)OC(=O)C(\C#N)=C\C1=CC=CC=C1C(F)(F)F BOWLEFLERZIKSG-DHZHZOJOSA-N 0.000 description 2
- IYZKSQINJIJKKF-UHFFFAOYSA-N tert-butyl 2-cyano-3-naphthalen-1-yl-3-(2-propan-2-ylphenyl)propanoate Chemical compound CC(C)C1=CC=CC=C1C(C(C#N)C(=O)OC(C)(C)C)C1=CC=CC2=CC=CC=C12 IYZKSQINJIJKKF-UHFFFAOYSA-N 0.000 description 2
- BFNYNEMRWHFIMR-UHFFFAOYSA-N tert-butyl 2-cyanoacetate Chemical compound CC(C)(C)OC(=O)CC#N BFNYNEMRWHFIMR-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- DCCPNFFQPPRMAK-BHDXBOSCSA-N (2s,3s)-2-[4-(2,3-dichlorophenyl)piperazine-1-carbonyl]-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanenitrile Chemical compound COC1=CC=CC=C1[C@@H]([C@@](C)(C#N)C(=O)N1CCN(CC1)C=1C(=C(Cl)C=CC=1)Cl)C1=CC=CC2=CC=CC=C12 DCCPNFFQPPRMAK-BHDXBOSCSA-N 0.000 description 1
- DUAHHJADGMHDAK-XDFJSJKPSA-N (2s,3s)-2-[4-(2-chlorophenyl)piperazine-1-carbonyl]-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanenitrile Chemical compound COC1=CC=CC=C1[C@@H]([C@@](C)(C#N)C(=O)N1CCN(CC1)C=1C(=CC=CC=1)Cl)C1=CC=CC2=CC=CC=C12 DUAHHJADGMHDAK-XDFJSJKPSA-N 0.000 description 1
- RDYVLJXNUNCGGT-UZNNEEJFSA-N (2s,3s)-2-[4-(3,5-dimethoxyphenyl)piperazine-1-carbonyl]-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanenitrile Chemical compound COC1=CC(OC)=CC(N2CCN(CC2)C(=O)[C@](C)(C#N)[C@H](C=2C(=CC=CC=2)OC)C=2C3=CC=CC=C3C=CC=2)=C1 RDYVLJXNUNCGGT-UZNNEEJFSA-N 0.000 description 1
- ITWQRJZKAATYDR-CQTOTRCISA-N (2s,3s)-2-[4-(4-chlorophenyl)-3,6-dihydro-2h-pyridine-1-carbonyl]-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanenitrile Chemical compound COC1=CC=CC=C1[C@@H]([C@@](C)(C#N)C(=O)N1CC=C(CC1)C=1C=CC(Cl)=CC=1)C1=CC=CC2=CC=CC=C12 ITWQRJZKAATYDR-CQTOTRCISA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- VNICFCQJUVFULD-UHFFFAOYSA-N 1-(1-naphthalenyl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=CC=CC=C12 VNICFCQJUVFULD-UHFFFAOYSA-N 0.000 description 1
- CYQFNNSFAGXCEC-UHFFFAOYSA-N 1-(2,3-dichlorophenyl)piperazine;hydrochloride Chemical compound [Cl-].ClC1=CC=CC(N2CC[NH2+]CC2)=C1Cl CYQFNNSFAGXCEC-UHFFFAOYSA-N 0.000 description 1
- GUTWDZXWTKMXPI-UHFFFAOYSA-N 1-(2-chlorophenyl)piperazin-4-ium;chloride Chemical compound Cl.ClC1=CC=CC=C1N1CCNCC1 GUTWDZXWTKMXPI-UHFFFAOYSA-N 0.000 description 1
- JVQOFQHGEFLRRQ-UHFFFAOYSA-N 1-(2-fluorophenyl)piperazine;hydrochloride Chemical compound Cl.FC1=CC=CC=C1N1CCNCC1 JVQOFQHGEFLRRQ-UHFFFAOYSA-N 0.000 description 1
- LZNYIWJDVYCKDU-UHFFFAOYSA-N 1-(2-methylphenyl)piperazine;hydrochloride Chemical compound Cl.CC1=CC=CC=C1N1CCNCC1 LZNYIWJDVYCKDU-UHFFFAOYSA-N 0.000 description 1
- COWMQOCYJSUFSB-UHFFFAOYSA-N 1-(3,5-dimethoxyphenyl)piperazine Chemical compound COC1=CC(OC)=CC(N2CCNCC2)=C1 COWMQOCYJSUFSB-UHFFFAOYSA-N 0.000 description 1
- QFKKVCPQBPIHKZ-UHFFFAOYSA-N 1-(3-chloro-2-methylphenyl)piperazine;hydrochloride Chemical compound Cl.CC1=C(Cl)C=CC=C1N1CCNCC1 QFKKVCPQBPIHKZ-UHFFFAOYSA-N 0.000 description 1
- MHXPYWFZULXYHT-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazin-1-ium;chloride Chemical compound Cl.ClC1=CC=CC(N2CCNCC2)=C1 MHXPYWFZULXYHT-UHFFFAOYSA-N 0.000 description 1
- JSUGMCBUCXRCMG-UHFFFAOYSA-N 1-(3-propan-2-ylphenyl)piperazine Chemical compound CC(C)C1=CC=CC(N2CCNCC2)=C1 JSUGMCBUCXRCMG-UHFFFAOYSA-N 0.000 description 1
- ORKOLISAYPZGHP-UHFFFAOYSA-N 1-(4-chlorophenyl)piperazine-1,4-diium;dichloride Chemical compound Cl.Cl.C1=CC(Cl)=CC=C1N1CCNCC1 ORKOLISAYPZGHP-UHFFFAOYSA-N 0.000 description 1
- LZIYAIRGDHSVED-UHFFFAOYSA-N 1-(bromomethyl)-3-chlorobenzene Chemical compound ClC1=CC=CC(CBr)=C1 LZIYAIRGDHSVED-UHFFFAOYSA-N 0.000 description 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- RNWGKWOKMIHZOQ-UHFFFAOYSA-N 1-[4-chloro-3-(trifluoromethyl)phenyl]-2h-pyridine;hydrochloride Chemical compound Cl.C1=C(Cl)C(C(F)(F)F)=CC(N2C=CC=CC2)=C1 RNWGKWOKMIHZOQ-UHFFFAOYSA-N 0.000 description 1
- HVKCZUVMQPUWSX-UHFFFAOYSA-N 1-bromo-2,3-dichlorobenzene Chemical compound ClC1=CC=CC(Br)=C1Cl HVKCZUVMQPUWSX-UHFFFAOYSA-N 0.000 description 1
- LECYCYNAEJDSIL-UHFFFAOYSA-N 1-bromo-2-propan-2-ylbenzene Chemical compound CC(C)C1=CC=CC=C1Br LECYCYNAEJDSIL-UHFFFAOYSA-N 0.000 description 1
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 1
- OEHHXVIJMCMYGM-UHFFFAOYSA-N 1-chloro-3-iodo-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1I OEHHXVIJMCMYGM-UHFFFAOYSA-N 0.000 description 1
- MWZDIEIXRBWPLG-UHFFFAOYSA-N 1-methyl-1,2,4-triazole Chemical compound CN1C=NC=N1 MWZDIEIXRBWPLG-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- FGYADSCZTQOAFK-UHFFFAOYSA-N 1-methylbenzimidazole Chemical compound C1=CC=C2N(C)C=NC2=C1 FGYADSCZTQOAFK-UHFFFAOYSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- PQEQIKPDWGEXER-UHFFFAOYSA-N 2,6-dichloro-2-pyridin-4-ylpiperazine Chemical compound ClC1(NC(CNC1)Cl)C1=CC=NC=C1 PQEQIKPDWGEXER-UHFFFAOYSA-N 0.000 description 1
- PDFGFQUSSYSWNI-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1CBr PDFGFQUSSYSWNI-UHFFFAOYSA-N 0.000 description 1
- ZDVRPKUWYQVVDX-UHFFFAOYSA-N 2-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=CC=C1C=O ZDVRPKUWYQVVDX-UHFFFAOYSA-N 0.000 description 1
- OXECFVGUMUCEQO-UHFFFAOYSA-N 2-cyano-3,3-dinaphthalen-1-ylpropanamide Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4C=CC=3)C(C#N)C(=O)N)=CC=CC2=C1 OXECFVGUMUCEQO-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- KJZPSLZQMISKHY-UHFFFAOYSA-N 4-(4-chlorophenyl)piperidine;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1C1CCNCC1 KJZPSLZQMISKHY-UHFFFAOYSA-N 0.000 description 1
- RJFISGALWPADNA-UHFFFAOYSA-N 4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(C=2CCNCC=2)=C1 RJFISGALWPADNA-UHFFFAOYSA-N 0.000 description 1
- IPKSNWXGEIHOMR-UHFFFAOYSA-N 4-[3-(trifluoromethyl)phenyl]piperidine Chemical compound FC(F)(F)C1=CC=CC(C2CCNCC2)=C1 IPKSNWXGEIHOMR-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- XILPCSMEKCBYFO-UHFFFAOYSA-N 4-methyl-1,2,4-triazole Chemical compound CN1C=NN=C1 XILPCSMEKCBYFO-UHFFFAOYSA-N 0.000 description 1
- ZAPXMYJBUSBVRC-UHFFFAOYSA-N 4-piperazin-1-yl-1h-indole;hydrochloride Chemical compound Cl.C1CNCCN1C1=CC=CC2=C1C=CN2 ZAPXMYJBUSBVRC-UHFFFAOYSA-N 0.000 description 1
- MJAMUSZUMAHFLH-UHFFFAOYSA-N 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-one Chemical compound FC1=CC=CC=C1C(C(=O)C1CC1)N1CC2=CC(=O)SC2CC1 MJAMUSZUMAHFLH-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000005641 Adenomyosis Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 206010002650 Anorexia nervosa and bulimia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 102100040214 Apolipoprotein(a) Human genes 0.000 description 1
- 101710115418 Apolipoprotein(a) Proteins 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 238000010639 Bodroux reaction Methods 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 125000006414 CCl Chemical group ClC* 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical compound ClC1=CC=C([Mg]Br)C=C1 CDEMHJCJMMOFMB-UHFFFAOYSA-M 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 208000031953 Hereditary hemorrhagic telangiectasia Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 208000013038 Hypocalcemia Diseases 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 102000057248 Lipoprotein(a) Human genes 0.000 description 1
- 108010033266 Lipoprotein(a) Proteins 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 229910019906 NaxSOy Inorganic materials 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- ZMBUGGZBEPQTNV-UHFFFAOYSA-M [Br-].C(C)(C)C1=C(C=CC=C1)[Mg+].C(#N)C(C(=O)OCC)C(C1=CC=CC2=CC=CC=C12)C1=C(C=CC=C1)C(C)C Chemical compound [Br-].C(C)(C)C1=C(C=CC=C1)[Mg+].C(#N)C(C(=O)OCC)C(C1=CC=CC2=CC=CC=C12)C1=C(C=CC=C1)C(C)C ZMBUGGZBEPQTNV-UHFFFAOYSA-M 0.000 description 1
- HAFKDFYJKIZMCD-UHFFFAOYSA-M [Br-].C1=CC=C2C(F)=CC=C([Mg+])C2=C1 Chemical compound [Br-].C1=CC=C2C(F)=CC=C([Mg+])C2=C1 HAFKDFYJKIZMCD-UHFFFAOYSA-M 0.000 description 1
- GWICKWUOSJJCNO-UHFFFAOYSA-M [Br-].CC1=CC=CC([Mg+])=C1C Chemical compound [Br-].CC1=CC=CC([Mg+])=C1C GWICKWUOSJJCNO-UHFFFAOYSA-M 0.000 description 1
- VLEJARWZYYUFHU-UHFFFAOYSA-M [Br-].FC(F)(F)C1=CC=CC=C1[Mg+] Chemical compound [Br-].FC(F)(F)C1=CC=CC=C1[Mg+] VLEJARWZYYUFHU-UHFFFAOYSA-M 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000004062 acenaphthenyl group Chemical group C1(CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000000923 atherogenic effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000011803 breast fibrocystic disease Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical class OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000005115 demineralization Methods 0.000 description 1
- 230000002328 demineralizing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- PQZTVWVYCLIIJY-UHFFFAOYSA-N diethyl(propyl)amine Chemical group CCCN(CC)CC PQZTVWVYCLIIJY-UHFFFAOYSA-N 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000005435 dihydrobenzoxazolyl group Chemical group O1C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 125000005049 dihydrooxadiazolyl group Chemical group O1N(NC=C1)* 0.000 description 1
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005053 dihydropyrimidinyl group Chemical group N1(CN=CC=C1)* 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000005058 dihydrotriazolyl group Chemical group N1(NNC=C1)* 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 208000016018 endometrial polyp Diseases 0.000 description 1
- 201000009274 endometriosis of uterus Diseases 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- WLXUQTCLMCEXML-SOFGYWHQSA-N ethyl (e)-2-cyano-3-(2,6-dichlorophenyl)prop-2-enoate Chemical compound CCOC(=O)C(\C#N)=C\C1=C(Cl)C=CC=C1Cl WLXUQTCLMCEXML-SOFGYWHQSA-N 0.000 description 1
- MPLHNBVWRMUPEA-CSKARUKUSA-N ethyl (e)-2-cyano-3-(2,6-dimethoxyphenyl)prop-2-enoate Chemical compound CCOC(=O)C(\C#N)=C\C1=C(OC)C=CC=C1OC MPLHNBVWRMUPEA-CSKARUKUSA-N 0.000 description 1
- VIUZRBURZORUGU-UHFFFAOYSA-N ethyl 2-cyano-3,3-bis(2-methoxyphenyl)propanoate Chemical compound C=1C=CC=C(OC)C=1C(C(C#N)C(=O)OCC)C1=CC=CC=C1OC VIUZRBURZORUGU-UHFFFAOYSA-N 0.000 description 1
- NEYPVTGUZSVTET-UHFFFAOYSA-N ethyl 2-cyano-3-(2,4-dimethoxyphenyl)prop-2-enoate Chemical compound CCOC(=O)C(C#N)=CC1=CC=C(OC)C=C1OC NEYPVTGUZSVTET-UHFFFAOYSA-N 0.000 description 1
- OXWQNXNRBGZYJW-UHFFFAOYSA-N ethyl 2-cyano-3-(2,5-dimethoxyphenyl)prop-2-enoate Chemical compound CCOC(=O)C(C#N)=CC1=CC(OC)=CC=C1OC OXWQNXNRBGZYJW-UHFFFAOYSA-N 0.000 description 1
- LXZSBCQFZFCBFP-UHFFFAOYSA-N ethyl 2-cyano-3-(2-methoxyphenyl)prop-2-enoate Chemical compound CCOC(=O)C(C#N)=CC1=CC=CC=C1OC LXZSBCQFZFCBFP-UHFFFAOYSA-N 0.000 description 1
- CZPQZBRWWGSHSL-UHFFFAOYSA-N ethyl 2-cyano-3-(2-nitrophenyl)prop-2-enoate Chemical compound CCOC(=O)C(C#N)=CC1=CC=CC=C1[N+]([O-])=O CZPQZBRWWGSHSL-UHFFFAOYSA-N 0.000 description 1
- QHHMWJQNJCIYCE-UHFFFAOYSA-N ethyl 2-cyano-3-(3-methoxyphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=CC(OC)=C1 QHHMWJQNJCIYCE-UHFFFAOYSA-N 0.000 description 1
- KNDHLMAUUOISSV-UHFFFAOYSA-N ethyl 2-cyano-3-(4-methoxyphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=C(OC)C=C1 KNDHLMAUUOISSV-UHFFFAOYSA-N 0.000 description 1
- CZWGNLKMGONOQT-UHFFFAOYSA-N ethyl 2-cyano-3-(4-methylphenyl)-3-naphthalen-1-ylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=C(C)C=C1 CZWGNLKMGONOQT-UHFFFAOYSA-N 0.000 description 1
- QSQIOLZIBXSXMS-UHFFFAOYSA-N ethyl 2-cyano-3-naphthalen-1-yl-3-[2-(trifluoromethyl)phenyl]propanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=CC=C1C(F)(F)F QSQIOLZIBXSXMS-UHFFFAOYSA-N 0.000 description 1
- KNVTZIDAGQXKIV-UHFFFAOYSA-N ethyl 2-cyano-3-naphthalen-1-yl-3-phenylpropanoate Chemical compound C=1C=CC2=CC=CC=C2C=1C(C(C#N)C(=O)OCC)C1=CC=CC=C1 KNVTZIDAGQXKIV-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 206010049444 fibromatosis Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 208000002566 gonadal dysgenesis Diseases 0.000 description 1
- 210000000224 granular leucocyte Anatomy 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 102000052611 human IL6 Human genes 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000000705 hypocalcaemia Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 208000027138 indeterminate colitis Diseases 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000006301 indolyl methyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZUBZATZOEPUUQF-UHFFFAOYSA-N isopropylhexane Natural products CCCCCCC(C)C ZUBZATZOEPUUQF-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000023404 leukocyte cell-cell adhesion Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 description 1
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 1
- BVUQKCCKUOSAEV-UHFFFAOYSA-M magnesium;methylbenzene;bromide Chemical compound [Mg+2].[Br-].CC1=CC=[C-]C=C1 BVUQKCCKUOSAEV-UHFFFAOYSA-M 0.000 description 1
- YAMQOOCGNXAQGW-UHFFFAOYSA-M magnesium;methylbenzene;bromide Chemical compound [Mg+2].[Br-].CC1=CC=CC=[C-]1 YAMQOOCGNXAQGW-UHFFFAOYSA-M 0.000 description 1
- JWQLJPBJNSPKSG-UHFFFAOYSA-M magnesium;phenylbenzene;bromide Chemical compound [Mg+2].[Br-].C1=CC=CC=C1C1=CC=[C-]C=C1 JWQLJPBJNSPKSG-UHFFFAOYSA-M 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- PJFPVGFPENNCND-KPKJPENVSA-N methyl (e)-2-cyano-3-quinolin-3-ylprop-2-enoate Chemical compound C1=CC=CC2=CC(/C=C(C(=O)OC)\C#N)=CN=C21 PJFPVGFPENNCND-KPKJPENVSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- VKTOBGBZBCELGC-UHFFFAOYSA-M methyl(triphenoxy)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1O[P+](OC=1C=CC=CC=1)(C)OC1=CC=CC=C1 VKTOBGBZBCELGC-UHFFFAOYSA-M 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- WLBYPRUBXWTYBC-UHFFFAOYSA-N n-(2-methylphenyl)piperazine-1-carboxamide Chemical compound CC1=CC=CC=C1NC(=O)N1CCNCC1 WLBYPRUBXWTYBC-UHFFFAOYSA-N 0.000 description 1
- KQBMEKDIBGGRLE-UHFFFAOYSA-N n-(3-methoxyphenyl)piperazine-1-carboxamide Chemical compound COC1=CC=CC(NC(=O)N2CCNCC2)=C1 KQBMEKDIBGGRLE-UHFFFAOYSA-N 0.000 description 1
- LIZJGQANTCERJA-UHFFFAOYSA-N n-(4-ethoxyphenyl)piperazine-1-carboxamide Chemical compound C1=CC(OCC)=CC=C1NC(=O)N1CCNCC1 LIZJGQANTCERJA-UHFFFAOYSA-N 0.000 description 1
- CQLSOBHHDIYRAO-UHFFFAOYSA-N n-(4-methylphenyl)piperazine-1-carboxamide Chemical compound C1=CC(C)=CC=C1NC(=O)N1CCNCC1 CQLSOBHHDIYRAO-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- IPZOUOZDIYMKQO-JYFHCDHNSA-N tert-butyl (2s,3s)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-naphthalen-1-ylpropanoate Chemical compound COC1=CC=CC=C1[C@@H]([C@@](C)(C#N)C(=O)OC(C)(C)C)C1=CC=CC2=CC=CC=C12 IPZOUOZDIYMKQO-JYFHCDHNSA-N 0.000 description 1
- IYCKRNGFYLPCLF-RVDMUPIBSA-N tert-butyl (e)-2-cyano-3-naphthalen-1-ylprop-2-enoate Chemical compound C1=CC=C2C(/C=C(C(=O)OC(C)(C)C)\C#N)=CC=CC2=C1 IYCKRNGFYLPCLF-RVDMUPIBSA-N 0.000 description 1
- FMUSBYFVRQZJTK-UHFFFAOYSA-N tert-butyl 2-cyano-3,3-dinaphthalen-1-ylpropanoate Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4C=CC=3)C(C#N)C(=O)OC(C)(C)C)=CC=CC2=C1 FMUSBYFVRQZJTK-UHFFFAOYSA-N 0.000 description 1
- NOFLSPNCSWNKMK-UHFFFAOYSA-N tert-butyl 2-cyano-3-(2,6-dimethylphenyl)-3-naphthalen-1-ylpropanoate Chemical compound CC1=CC=CC(C)=C1C(C(C#N)C(=O)OC(C)(C)C)C1=CC=CC2=CC=CC=C12 NOFLSPNCSWNKMK-UHFFFAOYSA-N 0.000 description 1
- IAMKOTFMXMLXGS-UHFFFAOYSA-N tert-butyl 2-cyano-3-[2-(trifluoromethoxy)phenyl]prop-2-enoate Chemical compound CC(C)(C)OC(=O)C(C#N)=CC1=CC=CC=C1OC(F)(F)F IAMKOTFMXMLXGS-UHFFFAOYSA-N 0.000 description 1
- IYCKRNGFYLPCLF-UHFFFAOYSA-N tert-butyl 2-cyano-3-naphthalen-1-ylprop-2-enoate Chemical compound C1=CC=C2C(C=C(C(=O)OC(C)(C)C)C#N)=CC=CC2=C1 IYCKRNGFYLPCLF-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- TZBUFYPRATZGDD-UHFFFAOYSA-N thianthrene Chemical compound C1=CC=C2SC3=C=CC=C[C]3SC2=C1 TZBUFYPRATZGDD-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical group CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 201000007954 uterine fibroid Diseases 0.000 description 1
- 206010046811 uterine polyp Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Description
2-CYANOPROPANOIC ACID AMIDE AND ESTER DERIVATIVES
AND METHODS OF THEIR USE
This application claims the benefit of U.S. Application No. 60/466,567, filed
April 30, 2003 and U.S. Application No. ___ filed April 28, 2004, the entire disclosures of both are incorporated herein by reference.
This invention relates to ligands for the estrogen receptor (ER), and specifically relates to 2-cyanopropanoic acid amide and ester derivatives useful for the treatment of the inflammatory component of diseases and are particularly useful in treating atherosclerosis, myocardial infarction, congestive heart failure, inflammatory bowel disease, arthritis, type Il diabetes, and autoimmune diseases. such as multiple sclerosis and rheumatoid arthritis.
The ability of ligands for the estrogen receptor to inhibit inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes provides a means to treat the inflammatory component of diseases such as atherosclerosis, myocardial infarction (MI), congestive heart failure (CHF), inflammatory bowel disease and arthritis. Other potential therapeutic indications for these type of molecules include type II diabetes (Cefalu, J Womens
Health & Gender-based Med., 2001, 10, 241 & Yuan et al., Science, 2001, 293, 1673), osteoarthritis (Pelletier et al., Arthi. & Rheum., 2001, 44:1237 and Felson et al., Gurr Opinion Rheum, 1998, 10, 269) asthma (Chin-Chi Lin et.al., Immunol. Lett, 2000, 73, 57), Alzheimer’s disease (Roth, A. et. al.,; J. Neurosci. Res., 1999, 57, 399) and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
A common component of these chronic inflammatory conditions. is polymorphonuclear leukocyte and monocyte infiltration into the site of damage through increased expression of cytokines and adhesion molecules responsible for their recruitment. Overproduction of the cytokine interleukin (IL-6) has been associated with states of chronic inflammation (Bauer M. A. Herrmann F., Ann.
Hematol., 1991, 62, 203). Synthesis of the IL-6 gene is induced by the transcription factor, nuclear factor xB (NF-kB). Interference at this step in the inflammatory process can effectively regulate the uncontrolled proliferative process that occurs in these chronic conditions. in endothelial cells, 17p-estradiol (E2) inhibits IL-1 induced NF-kB reporter activity and IL-6 expression in an ER dependent fashion (Kurebayashi S. et. al, J.
Steroid Biochem. Molec. Biol., 1997, 60, 11). This correlates with anti-inflammatory action of E2 in vivo as confirmed in different animal models of inflammation. in models of atherosclerosis, E2 was shown to protect endothelial cell integrity and function and to reduce leukocyte adhesion and intimal accumulation (Adams, M. R. et al., Arterio., 1990, ,1051, Sullivan, T. R. et al. J. Clin. Invst., 1995, 96, 2482,
Nathan, L. et. al., Circ. Res., 1999, 85, 377). Similar effects of estrogen on the vascular wall have also been demonstrated in animal models of myocardial infarction (Delyani, J. A. et al, J. Molec. Cell. Cardiol., 1996, 28, 1001) and congestive heart failure. Clinically, estrogen replacement therapy (ERT) has been demonstrated to reduce the risk of mortality in patients with both CHF (Reis et. al., J.
Am. Coll. Cardio., 2000, 36, 529) and Mi (Grodstein, F. et. al., Ann. Int. Med., 2000, 133, 633, Alexander et. al., J. Am. Coll. Cardio., 2001, 38, 1 and Grodstein F. et. al.,
Ann. Int. Med, 2001, 1351). In ERT, clinical studies demonstrated an influence of
E2 on the decrease in the production of B-amyloid 1-42 (AB42), a peptide central for the formation of senile plaques in Alzheimer's disease (Schonknecht, P. et. al,
Neurosci. Lett., 2001, 307, 122).
However, 17-p-estradiol also strongly stimulates: creatine kinase expression.
Thus, in ERT some potential unwanted side effects, such as an increase risk of cardiovascular events in the first year of use, have been demonstrated (Hulley, S. et. al., J. Am. Med. Assoc., 1998, 280, 605) as well as proliferative effects on uterine and breast tissue.
In one embodiment, the invention is directed to compounds of formula I:
Ry fo
Sls 0 0] as
WX
So Ri ~~ R2 wherein
B and D are independently CH or N, provided that B and D are not both N;
R,, R,, R, are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl, alkylthio of 1-6 carbon atoms, CF,, -OCF,, -NRRq, or hydroxy; or Rq and R; together with carbon atoms to which they are attached form a fused benzene ring, the naphthalene ring so formed being optionally substituted by halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalky! of 1-8 carbon atoms, aryl, alkyithio of 1-6 carbon atoms, CF, -OCF;, -NR.R,, or hydroxy;
R, is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkenyl of 2.7 carbon atoms, cycloalkyimethyl of 3-8 carbon atoms in the cycloalkyl moiety, arylalkoxyalkyl, alkoxyalkyl, dialkylaminoalkyl having 1-6 carbon atoms in the alkyl moieties, or Het-alkyl having 1-6 carbon atoms in the alkyl moiety;
> /N\ /~\/ is-NRgRg, “ORg, — y— y— N-A * —N +N—A '
Ry is-NRsRs, “ORs { {) N A 0) .
NH
—N Pp 0
Oe Tg OU oO . lo /\ i /\ ~\ Q —N N-CH)—C—-N_ 0 | — \-cH—t-N \ :
Q
Ra H
OE 0% (X —N N-C— , WN \—/ A
Qo
OH N —N \ NH —N SS Ire
SV YY
N EAR WF or A, wherein any phenyl ring in Ry is optionally substituted with R7;
Rg and Ry are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, arylalkyl having 1-6 carbon atoms in the alkyl moiety, Het-alkyl having 1-6 carbon atoms in the alkyl moiety, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
R, is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, nitro, cyano, alkylthio of 1-6 carbon atoms, thioalky! of 1-6 carbon atoms, CF,, or -OCF;
Rg is alkyl of 1-6 carbon atoms;
A is hydrogen, cycloalkyl of 3-8 carbon atoms, alkoxyalkyl having 1-6 carbon atoms in the alkyl and alkoxy moieties, dialkylaminoalkyl having 1-6 carbon atoms in the alkyl moieties, aryl, Het, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6 carbon atoms, Het-alkyl having 1-6 carbon atoms in the alkyl moiety, arylalkyl having 1-6 carbon atoms in the alkyl moiety, or he
Zz
W is aryl, -Y-aryl, or Het or -Y-Het;
Y is -O- or -NH-;
ZisOorS;
Het is a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system having 4-12 ring atoms and 1-3 heteroatoms selected from N, O, or S, that may be optionally substituted with 1-3 R, groups; aryl is an aromatic ring or ring system having 6-14 carbon atoms in the ring or ring system, that may be optionally substituted with 1-3 R, groups; with the proviso that at least one of the R,, R,,, or R, groups is not hydrogen, or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention is directed to pharmaceutical compositions, comprising: a pharmaceutical carrier, and a compound of formula | or a pharmaceutically acceptable salt thereof. in further embodiments, the invention is directed to methods of treating the inflammatory component of a disease, comprising the step of: administering an effective amount of a compound of formula | or a pharmaceutically acceptable sait thereof.
The disease include atherosclerosis, myocardial infarction, congestive heart failure, inflammatory bowel disease, arthritis, type Il diabetes, and autoimmune disease (such as multiple sclerosis or rheumatoid arthritis). : In yet further embodiments, the invention is directed to processes for preparing a compound of formula I.
In yet other embodiments, the invention is directed to process for preparing a substantially pure enantiomer of a compound of formula |.
The invention provides substituted 2-cyanopropanoic acid amide and ester derivatives represented by formula | that are useful for the treatment of the inflammatory component of diseases and are particularly useful in treating atherosclerosis, myocardial infarction, congestive heart failure, inflammatory bowel disease, arthritis, type Il diabetes, and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
This invention provides compounds of formula | having the structure
Ry Fo
QL
0 x
Ng iS {AX
Ria 2 wherein
B and D are independently CH or N, provided that B and D are not both N;
R, R;, R, are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl, alkylthio of 1-6 carbon atoms, CF, -OCF,, -NR,R,, or hydroxy; or Ry and R, together with carbon atoms to which they are attached form a fused benzene ring, the naphthalene ring so formed being optionally substituted by halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl, alkyithio of 1-6 carbon atoms, CF,, -OCF,, -NR,R,, or hydroxy;
R, is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkenyl of 2-7 carbon atoms, cycloalkylmethyt of 3-8 carbon atoms in the cycloalkyl moiety, arylalkoxyalkyl, alkoxyalkyl, dialkylaminoalkyl having 1-6 carbon atoms in the alkyl moieties, or Het-alkyl having 1-6 carbon atoms in the alkyl moiety;
O-
R4 is-NRsRe. -ORe. —~ —_ »—N NAN N=n
Q
NH
—N Pp
O~ Fy ON
Oo ’ fo} /\ SAR —\ Q —N N-CH—C—-N ~~ O | —N vont) .
Q
OE 0% X —N N—C \ ' , -—N ' _/ A
OH N — \ NH —N SE ¢ GR? a ~~
N —N \ NH or A, wherein any phenyl ring in Ry is optionally substituted with Rz;
R, and Rg are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, arylalkyl having 1-6 carbon atoms in the alkyl moiety, Het-alkyl having 1-6 carbon atoms in the alkyl moiety, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalky! of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
R, is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, nitro, cyano, alkylthio of 1-6 carbon atoms, thioalky! of 1-6 carbon atoms, CF, or -OCF;
Rg is alkyl of 1-6 carbon atoms;
A is hydrogen, cycloalkyl of 3-8 carbon atoms, alkoxyalkyl having 1-6 carbon atoms in the alkyl and alkoxy moieties, dialkylaminoalkyl having 1-6 carbon atoms in the alkyl moieties, aryl, Het, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6 carbon atoms, Het-alkyl having 1-8 carbon atoms in the alkyl moiety, arylalkyl having 1-6 carbon atoms in the alkyl moiety, or he z
W is aryl, -Y-aryl, or Het or -Y-Het;
Y is -O- or -NH-;
ZisOorS;
Het is a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system having 4-12 ring atoms and 1-3 heteroatoms selected from N, O, or S, that may be optionally substituted with 1-3 R, groups; aryl is an aromatic ring or ring system having 6-14 carbon atoms in the ring or ring system, that may be optionally substituted with 1-3 R, groups; with the proviso that at least one of the R,, Ry, OF R, groups is not hydrogen; : or a pharmaceutically acceptable salt thereof.
The term “alkyl”, employed alone, is defined herein as, unless otherwise stated, either a (C4-Cg) straight chain or branched-chain monovalent saturated hydrocarbon moiety. It is preferred that the alkyl moiety contains 1-6 carbon atoms.
Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term “cycloalkyl”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbon moiety of 3-8 carbon atoms.
Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl, adamantyl, spirof4.5]decanyl, and homologs, isomers, and the like.
The terms “halo” or “halogen”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a fluorine, chlorine, bromine, or jodine atom.
The term “aryl”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an aromatic carbocyclic moiety of up to 14 carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. Any suitable ring position of the aryl moiety may be covalently linked to the defined chemical structure. Examples of aryl moieties include, but are not limited to, chemical groups such as phenyl, 1- naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and the like.
The term “arylalkyl”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an aryl, as herein before defined, suitably substituted on any open ring position with an alkyl moiety wherein the alkyl chain is either a (Cy-Ce) saturated hydrocarbon moiety. Examples of arylalkyl moieties include, but are not limited to, chemical groups such as benzyl, 1- phenylethyl, 2-phenylethyl, diphenylmethyl, 3-phenyipropyl, 2-phenyipropyl, fluorenylmethyl, and homologs, isomers, and the like.
The term "Het", employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an heterocyclic ring system having 4-14 ring atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. The rings may contain from one to four hetero atoms selected from nitrogen (N), oxygen (O), and sulfur (S), wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of unsaturated Het moieties include, but are not limited to, heterocycles such as furan, thiophene, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, imidazole, N-methylimidazole, oxazole, isoxazole, thiazole, isothiazole, 1H-tetrazole, 1-methyitetrazole, 1,3,4- oxadiazole, 1H-1,2,4-triazole, 1-methyl-1,2,4-triazole 1,3,4-triazole, 1-methyl-1,3,4- triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzoxazole, benzisoxazole, benzothiazole, benzofuran, benzothiophene, thianthrene, dibenzolb,d}furan,
dibenzofb,djthiophene, benzimidazole, N-methylbenzimidazole, indole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, 9H-carbazole, B- carboline, and the like.
Het, as defined herein, also includes saturated or partial saturated heterocyclic rings of 4-14 ring atoms, and 1-4 heteroatoms selected from N, O, and
S. Examples of saturated or partially saturated heteroaryl moieties include, but are not limited to, chemical groups such as azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyi, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrobenzoimidazolonyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyt, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrrazinyl, ~ dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyi, dihydroguinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, ~~ dihydro-1 A-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
The term “Het-alkyl”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a heteroaryl, as herein before defined, suitably substituted on any open ring position with an alkyl moiety, wherein the alkyl chain is either a (C1-Ce) straight or branched-chain saturated hydrocarbon moiety.
Examples of heteroarylalkyl moieties include, but are not limited to, chemical groups such as furanyimethyl, thienylethy, indolylmethyl, and the like.
The term “hydroxyalkyl”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a (C4-Cg) straight chain hydrocarbon, terminally substituted with a hydroxyl group. Examples of hydroxyalkyl moieties include chemical groups such as -CH20H, ~CH2CH,0H, -CH2CH,CH,0H, and higher homologs. Similarly, dihydroxyalkyl indicates an alkyl moiety that is substituted by two hydroxyl groups.
The term “alkoxy”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, either a (C4-Ce) straight chain or branched-chain hydrocarbon covalently bonded to an oxygen atom. Examples of alkoxy moieties include, but are not limited to, chemical groups such as methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy, and homologs, isomers, and the like.
The term “alkylthio”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, either a (C4-Cg) straight or branched- chain hydrocarbon covalently bonded to a sulfur atom. Examples of alkylthio moieties include, but are not limited to, chemical groups such as methyithio, ethylthio, isopropylthio, sec-butylthio, tert-butyithio, and homologs, isomers, and the like.
The term “thioalkyl”, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a sulfhydryl group covalently bonded to either a (C1-Cg) straight or branched-chain hydrocarbon. Examples of thioalkyl moieties include, but are not limited to, chemical groups such as thiomethyl, thioethyl, thioisopropyl, and homologs, isomers, and the like.
The term “alkoxyalkyl” is defined herein as, unless otherwise stated, an alkyl, as herein before defined, substituted by an alkoxy group, as herein before defined.
An example of an alkoxyalkyl moiety is methoxyethyl.
The term “arylalkoxyalkyl” is defined herein as, unless otherwise stated, an alkyl, as herein before defined, substituted by an alkoxy group, as herein before defined, wherein the alkoxy is substituted by an aryl, as herein before defined. An example of an arylalkyloxyalkyl moiety is phenylmethoxymethyl.
The term “dialkylaminoalkyl” is defined herein as, unless otherwise stated, an alkyl as herein before defined, substituted by an amino group independently disubstituted with alkyl, as herein before defined. An example of a dialkylaminoalkyl group is dimethylaminoethyl.
Unless otherwise indicated, each of the above terms (e.g., alkyl, aryl, Het) are meant to include unsubstituted, monosubstituted, and polysubstituted forms of the indicated radical or moiety. As described above, the moiety R7 represents typical substituents for the radicals or moieties.
The compounds of the present invention may contain an asymmetric atom, and some of the compounds may contain one or more asymmetric atoms or centers, which may thus give rise to optical isomers (enantiomers) and diastereomers. While shown without respect to the stereochemistry in Formula (1), the present invention includes such optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers may be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diasteromeric salt formation, kinetic resolution, and asymmetric synthesis. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof, which may be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
The compounds of the present invention may contain isotopes of atoms for diagnostic, therapeutic, or metabolic purposes. Such isotopes may or may not be radioactive.
The compounds of this invention include racemates, enantiomers, geometric isomers, or pro-drugs of the compounds shown by formula I.
Pharmaceutically acceptable salts of the compounds of formula | with an acidic moiety can be formed from organic and inorganic bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Intemal salts may furthermore be formed. Similarly, when a compound of the present invention contains a basic moiety, salts can be formed from organic and inorganic acids. For example salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known pharmaceutically acceptable acids. :
As used in accordance with this invention, the term "providing," with respect to providing a compound or substance covered by this invention, means either directly administering such a compound or substance, or administering a pro-drug, derivative, or analog that will form the effective amount of the compound or substance within the body. This invention also covers providing the compounds of this invention to treat the disease states disclosed herein that the compounds are useful for treating.
Preferred compounds of this invention include those of formula | in which: /~\
Ry is -NRsRg, OR, —{ , —{_ , or —N_ NA ;and
A is hydrogen, aryl, or Het; or a pharmaceutically acceptable salt thereof.
More preferred compounds of this invention include those of formula | in which:
On =O
Rqsis —N A ,or —N N-A ; and _—/
A is hydrogen, aryl, or Het; or a pharmaceutically acceptable salt thereof.
In certain preferred embodiments, B and D are both CH. In certain other preferred embodiments, one of B or Dis N. In yet other preferred embodiments, B is N and D is CH. In yet further embodiments, B is CH and Dis N.
Preferred compounds of formula | include: ethyl 2-cyano-3-(2,6-dimethoxyphenyl)-3-(1-naphthyl)propanoate; ethyl 2-cyano-3-(2,6-dichlorophenyi)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-{4-(dimethylamino)phenyi]-3-(1-naphthyl)propanoate; ethyl 2-cyano-3-(1-naphthyl}-3-[2 (trifluoromethyl) phenyl]propanoate; ethyl 2-cyano-3-(2-isopropylphenyl)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-(2,4-dimethoxyphenyl)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-(2,5-dimethoxyphenyt)-3-(1 -naphthyl)propanoate; tert-butyl 2-cyano-3-(1 -naphthyl)-3-{2-(trifluoromethyl) phenyl] propanoate; ethyl 2-cyano-3-(2-methoxyphenyt)-3-(1 -naphthyl)propanoate; ethyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate; tert-butyl 2-cyano-3-(2-isopropyiphenyl)-3-(1-naphthyl)propancate; tert-butyl 2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyi)propanoate; tert-butyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethoxy)phenyil propanoate, ethyl 2-cyano-3-(1 -naphthyl)-3-(2-nitrophenyl)propanoate; tert-butyl 2-cyano-3-(2,6-dimethyiphenyl)-3-(1-naphthyljpropanoate;
tert-butyt (RR,SS)-2-cyano-3-(1 -naphthyl)-3-[2-(trifluoromethyl)phenyl] propanoate; tert-butyl (RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanoate; -) ethyl (SS)-2-cyano-3-(2-methoxyphenyl)-2-methy}-3-(1- naphthyl)propanoate; (+) ethyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanocate; - ethyl (RR,SS)-2-cyano-2-{(2-methoxyphenyl)(1-naphthyl)methyl]-4- pentenoate; ethyl (RR, SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl }-3~(1-naphthyl) propanoate; tert-butyl (RR,SS)-2-cyano-3-~(2-isopropylphenyl )}-2-methyl-3-(1- naphthyl)propanoate; tert-butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2- (trifluoromethyi)phenylpropanoate; tert-butyl (RS, SR)-2-cyano-3-(2,6-dimethylphenyl)-2-methyl-3-(1- naphthyl)propanoate; tert-butyl (RR, SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 - naphthyt)propanoate, tert-butyl (RR, SS)-2-(3-chlorobenzyl)-2-cyano-3-(2-methoxyphenyi)-3-(1- naphthyl)propanoate; tert-butyl (RR,SS)-2-(2-bromobenzyl }-2-cyano-3-(2-methoxyphenyl)-3-(1- naphthyl)propanoate; tert-butyl (RR,SS)-2-(2-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1- naphthyl)propanoate; tert-butyl (RR,SS)-2-cyano-2-(2,6-dichlorobenzyl)-3-(2-methoxyphenyl)-3~(1- naphthyl)propanoate; ethyl (RR,S8)-2-cyano-3-(2,4-dimethoxyphenyl)-2-methyl-3-(1- naphthyl)propanoate; tert-butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyi)-3-[2- (trifluoromethoxy)phenyl]propanoate; ethyl 2-cyano-3~(3-methoxyphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(4-methyiphenyl)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-(2-methylphenyl)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-(1-naphthyl)-3-(2-naphthyl)propanoate; ethyl 2-cyano-3-(4-fluoro-1-naphthyl)-3-(1 -naphthyi)propanoate; ethyl 2-cyano-3-[4-(methylithio)phenyl]-3-(1 -naphthyl)propanoate; ethyl 3-[1,1 *_biphenyll-4-yl-2-cyano-3-(1 -naphthyl)propanoate; ethyl 3-[1,1 _biphenyl]-2-yl-2-cyano-3-(1 -naphthyl)propanoate; ethyl 3-(4-chlorophenyl)-2-cyano-3-(1 -naphthyt)propanoate; ethyl 2-cyano-3-[2-(methylthio)phenyl}-3-(1 -naphthyl)propanoate; ethyl-(RR,SS)- 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanoate; ethyl (RR,SS)-2-cyano-2-methyl-3-[2-(methyithio)phenyl]-3~(1 - naphthyl)propanoate; (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-mathyl-3-(1 -naphthyl)propanoic acid; (RR, SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1 -naphthyl)propanoic acid, (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-{2- : (trifluoromethyl)phenyljpropanoic acid; (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)}-3-(1 -naphthyl)propanoic acid; tert-butyl (R,R)-2-cyano-3-(2-isopropylphenyl )-2-methyl-3-(1- naphthyl)propanoate; tert-butyl (S,S)-2-cyano-3-(2-isopropyiphenyl)-2-methyl-3-(1 - naphthyl)propanoate; tert-butyl (S,S)-2-cyano-3-(2-methoxyphenyl }-2-methyl-3-(1- naphthyl)propanoate; tert-butyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyi-3-(1 - naphthyl)propanoate; (RR,SS)-3-(2-methoxyphenyl }2-methyi-3-(1-naphthyl)-2-(piperazin-1- ylcarbonyl)propanenitrile;
RR.SS)(3-[4-(3-chloro-2-methylphenyl)piperazin-1 -yi}-2-[(2-methoxyphenyi)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile);
(RR,S, S)-3-(2-methoxyphenyl)-2-methyl-2-{14-(2-methylphenyl)piperazin-1 - ylcarbonyl}-3-(1 -naphthyl)propanenitrile; (SS)-3-(2-methoxyphenyl)-2-methyl-2-{4-(2-methylphenyl}-1 - piperazinyi]carbony}-3-(1 -naphthyl)propanenitrile; (R,R)-3-(2-methoxyphenyl }-2-methyl-2-{[4-(2-methylphenyl)piperazin-1 - yllcarbonyl}-3-(1 -naphthyl)propanenitrile; (S, S)-3-(2-methoxyphenyl)-2-methyi-2-{{4-(3-methyl phenyl)piperazin-1- yiJcarbonyl}-3-(1 -naphthyt)propanenitrile; (S)-3-[4-(3 5-dimethoxyphenyl)piperazin-1 -yl]-2-[(S)-(2-methoxyphenyl)(1 - naphthyl)methyf}-2-methyl-3-oxopropanenitrile; (S)3-(4-indan-4-yl-piperazin-1 -yl)-2-[(S)(2-methoxy-phenyl)-na phthalen-1-yl- methyl}-2-methyl-3-oxo-propionitrile; (S,S)-3-(2-methoxyphenyl)-2-methy!-3-(1 -naphthyl}-2-{[4-(1- naphthyl)piperazin-1 -yllcarbonyl}propanenitrile; (S)-3-[4-(3 4-dimethylphenyl)piperazin-1 —yl]-2-[(S)-(2-methoxyphenyl)(1 - naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (RR,SS) 3-[4-(H-indol-4-yl)piperazin-1 ~yl]-2-[(2-methoxyphenyl)(1 - naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(3-chlorophenyl)piperazin-1 ~yll-2-[(S)-(2-methoxyphenyl)(1 - naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (S)-3-{4-(2 .3-dimethylphenyl)piperazin-1 yI}2-[(S)-(2-methoxyphenyl)(1 - naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(4-chlorophenyl)piperazin-1 ~yi]-2-{(S)-(2-methoxyphenyl)(1 - naphthyl)methyl]-2-methyi-3-oxopropanenitrile; (S)-3-[4-(1H-i ndol-4-yl)-piperazin-1 ~yl}-2-{(S)}-(2-methoxy-phe nyl)-naphthalen- 1 _yl-methyl}-2-methyl-3-oxo-propionitrile; (S, 8)-3-(2-methoxypheny!)-2-methyl-3-(1 -naphthyl)-2-({4-[3- (trifluoromethyl)phenyl] piperidin-1 -yl}carbonyt)propanenitrile; (S)-3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1 -yl}-2-[(S)-(2-methoxy- phenyl)-naphthalen-1 -yl-methyl]-2-methyl-3-oxo-propionitrile; (S,S)-3-(2-methoxy-phenyl)-2-methy}-3-naphthalen-1 yl-2-[4~(3- trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1 -carbonyi]-propionitrile;
(SS)2-{4-(4-Chloro-phenyl)-piperidine-1 _carbonyl]-3-(2-methoxy-phenyl)-2- methyl-3-naphthalen-1 -yl-propionitrile; (RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)-2-({4-[3- (trifluoromethyl)phenyl]piperidin-1 -yl}carbonyl)propanenitrile; (RR, SS)-3-(2-methoxyphenyt)-2-methyl-3-(1 -naphthyl)-2-(piperidin-1- ylcarbonyl)propanenitrile; (RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanamide; (RR, SS)-2-cyano-N-ethyl-3-(2-methoxyphenyl)-2-methyi-3-(1 - naphthyl)propanamide; (RR, SS)-N-(fert-butyl)-2-cyano-3-(2-methoxyphenyl )-2-methyl-3-(1- naphthyl)propanamide; (RR,SS)-2-cyano-3-(2-methoxyphenyl )-N,N,2-trimethyl-3-(1- naphthyl)propanamide; (RR, $S)-2-cyano-N-methoxy-3-(2-methoxyphenyl )-N,2-dimethyi-3-(1- naphthyl)propanamide; (RR,SS)-2-benzyl-3-[4-(3 ,5-dichloro-4-pyridiny)-1 -piperazinyl}-2-[(2- methoxyphenyl)(1 -naphthyl)methyl]-3-oxopropanenitrile; (R,S)-3-[4-(2,3-dimethyiphenyl)piperazin-1 -yl]-2-[(R,S)~(2-methoxyphenyl)(1 - naphthy!)methyl]-2-methyl-3-oxopropanenitrile; (R,S)-3-[4-(3-isopropylphenyl)piperazin-1 -yi]-2-{(R, S)-(2-methoxyphenyl)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (RR, SS)-3-[4~(3,5-dichloropyridin-4-yl)piperazin-1 -yi)-2-[(2-methoxyphenyl)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (2SS)-3-[4~(3-chloro-2-methylphenyl)piperazin-1 -yl]-2-[(2-methoxyphenyl)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(2-fluorophenyl)piperazin-1 -yi}-2-{(S)-(2-methoxyphenyl)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(2-chlorophenyl)piperazin-1 ~yl}-2-[(8)-(2-methoxyphenyl)(1- naphthyl)methyf]-2-methyl-3-oxopropanenitrile; (S, S)-3-(2-methoxyphenyl)-2-{[4-(3-methoxyphenyl)piperazin-1 -ylJcarbonyl}-2- methyl-3-(1-naphthyl)propanenitrile; (R, S)-3-[4~(3-chloropyridin-4-yl)piperazin-1 -yi]-2-[(R,S)~(2-methoxyphenyl)(1- naphthyl)methyf]-2-methyl-3-oxopropanenitrile;
(S)-3-[4-(2,3-d ichlorophenyl)piperazin-1 -yl]-2-[(S)-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (28)-3-[4-[4-chloro-3-(trifluoromethyl)phenyl}-3,6-dihyd ropyridin-1(2H)-yl]-2- [(S)-(2-methoxyphenyl)(1 _naphthyl)methyl]-2-methyi-3-oxopropanenitrile; (2S)-3-{4-[4-chloro-3-(trifluoromethyl)phenyljpiperidin-1 -yI}-2-[(S)-(2- methoxyphenyl)(1 -naphthyl)methyl}-2-methyl-3-oxopropanenitrile; (RRI SS)-3-(2-methoxy-phenyi)-2-methyl-3-naphthalen-1 -yl-2-(4-oxy-4-o-tolyl- piperazine-1 -carbonyl)-propionitrile; (RR, SS)-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl}-2-({4-[3- (trifluoromethoxy)phenyllpiperazin-1 -yl}carbonyl)propanenitrile; (R,S)-3-[4-(2,3-difluorophenyl )piperazin-1-yil-2-[(R, S)-(2-methoxyphenyl)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (R, S)-3-[4-(3-fluorophenyl)piperazin-1 ~yi}-2-{(R,S)-(2-methoxyphenyl)(1- naphthyl methyi]-2-methyi-3-oxopropanenitrile; (RR, SS)-3-(2-methoxyphenyl)-2-methyi-3-(1 -naphthyl)-2-[(4-pyridin-3- ylpiperazin-1-yl)carbonyl]propanenitrile; (RR,SS)-3-[4~(2 ,3-dichlorophenyl)piperazin-1 -yl}-2-[(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyi-3-oxopropanenitrile; (RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazin-1 - ylicarbonyi}-3-(1-naphthyl)propanenitrile; (RR,SS)-3-(2-methoxyphenyi)-2-methyl-3-(1 -naphthyl)-2-(pyrrolidin-1- ylcarbonyl)propanenitrile; (RR, SS)-3-(2-methoxyphenyl)-2-methyl-2-(morpholin-4-yicarbonyl }-3-(1- naphthyl)propanenitrile; (RR,SS)-3-[4-(2-hydroxyethyl)piperazin-1 -yli}-2-[(2-methoxyphenyl)(1- naphthyl)methyi}-2-methyl-3-oxopropanenitrile; (RR,SS)-3-(2,6-dimethylmorpholin-4-yl)-2-[(2-methoxyphenyl)(1 - naphthyl)methyl}-2-methyl-3-oxopropanenitrile; (RR,SS)-2-cyano-N,N-d iethyl-3~(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide; (RR,SS)-2-cyano-N-[2-hydroxy-1 ~(hydroxymethyl)ethyl]-3-(2-methoxyphenyl)- 2-methyl-3-(1-naphthyl)propanamide;
(RR,SS)-3-azetidin-1 -yl-2-[(2-methoxyphenyl)(1 -naphthyl)methyll-2-methyl-3- oxopropanenitrile; (RR, SS)-2-cyano-N,N-diisopropyl-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanamide; (RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthy!)-2-[(3,3,5- trimethylazepan-1 -yl)carbonylipropanenitrile; (RR,SS)-3-(2,3-dihydro-H-indol-1 ~yI}-2-[(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (RR, SS)-3-(2-methoxyphenyl}-2-methyl-3-(1 -naphthyl)-2-(thiomorpholin-4- yicarbonyl)propanenitrile; ((RR,SS)-3-azepan-1 -yl-2-[(2-methoxyphenyl)(1 -naphthyl)methyl}-2-methyl-3- oxopropanenitrile; (RR, SS)-2-cyano-N-cyclohexyl-3-(2-methoxyphenyl)}-N ,2-dimethyl-3-(1- naphthyl)propanamide; (RR, SS)-2-cyano-3-(2-methoxyphenyl)-N ,2-dimethyl-3-(1- naphthyl)propanamide; (RR,SS)-3-(4-benzylpiperazin-1 -yl)}-2-[(2-methoxyphenyl)(1 -naphthyl)methyl]- 2-methyl-3-oxopropanenitrile; (RR,SS)-3-(3,4-dihydroisoquinolin-2(H)-yl)-2-[(2-methoxyphenyl)(1 - : naphthyl)methyl]-2-methyi-3-oxopropanenitrile; (RR,SS)-3-(2-methoxyphenyi)-2-methyl-2-{[4-(4-methylpheny piperazin-1- yllcarbonyl}-3-(1-naphthyl)propanenitrile; (RR,SS)-N,N-dibenzyl-2-cyano-3-(2-methoxyphenyl )-2-methyl-3-(1- naphthyl)propanamide; (RR,SS)-3-azocan-1 -yl-2-[(2-methoxyphenyl)(1 -naphthyl)methyl]-2-methyl-3- oxopropanenitrile; 4-chlorophenyl 4-[(RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyi-3-(1- naphthyl)propanoyl]piperazine-1-carboxylate; 2-nitrophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl )-2-methyl-3-(1- naphthyl)propanoyllpiperazine-1 -carboxylate; 4-(methoxycarbonyi)phenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2- methyl-3-(1-naphthyl)propanoyl]piperazine-1 -carboxylate;
4-methylphenyl 4-[(RR, SS)-2-cyano-3-(2-methoxyphenyl }-2-methyi-3-(1- naphthyl)propanoyijpiperazine-1 -carboxylate; 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyi-3-(1 -naphthyl)propanoyl}-
N-(2-methylphenyl)piperazine-1-carboxamide; 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoyl}-
N-[2-(trifluoromethyl)phenyllpiperazine-1 carboxamide; 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoyl]-
N-(3-methoxyphenyl)piperazine-1-carboxamide; 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoyi}-
N-(4-ethoxyphenyl)piperazine-1 -carboxamide;
N-(2-bromophenyl}4-[(RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanoyl]piperazine-1 -carboxamide; 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoyi]-
N-(4-methylphenyl)piperazine-1 -carboxamide; : 4-fluorophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyi)propanoyllpiperazine-1-carboxylate; phenyl 4-{(RR,SS)-2-cyano-3-(2-methoxyphenyl }2-methyi-3-(1- naphthyl)propanoyl]piperazine-1-carboxylate; (RR,SS)-3-{4-(4-bromobenzoyl )piperazin-1 -yi}-2-{(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile;
N-(4-chlorophenyl}4-[(RR,SS)-2-cyano-3-(2-methoxyphenyt)-2-methyl-3~(1- naphthyl)propanoyllpiperazine-1-carboxamide; methyl (2E)-2-cyano-3-(quinolin-3-yl)prop-2-enoate; and pharmaceutically acceptable salts thereof.
This invention also provides processes for preparing the compounds of formula | as defined herein, which processes preferably comprise steps (a)-(d) or (e), (f), or (g): (a) reacting a compound of formula 0
Reo NC N
Ar wherein Rg is as defined hereinabove excepting hydrogen and Ar is a group of formula (A), (B), or (C): or 7X X X
R, R2 Ria Ria (A) 8) (©) where R; ,Rz and Ry, are as defined hereinabove; with a compound of formula Ar{MX wherein M is a metal such as Mg, X is a halogen such as Cl or Br, and Ary is a group of formula (A) or (B) providing Ar and Ary are not both of formula (A) or (B) to give a compound of formula wherein R, is ORe where Rs is defined hereinabove excepting hydrogen and
Rs is hydrogen; (b) alkylating a compound of formula: 0
Foor
AA wherein Re, Ar, and Ar are as defined above providing Rs is other than hydrogen, with an alkylating agent of formula RsL where L is a leaving group and Rj; is as defined in claim 1 excepting hydrogen to give a corresponding compound of formula | as defined in claim 1; (c) hydrolyzing an ester of formula oR
Feo
Ary” Ar wherein Ar, Ary, R; and Rg are as defined hereinabove providing Rs is other than hydrogen, to give a corresponding compound of formula | wherein
R, is ORg where Rs is hydrogen; (d) reacting an activated acid compound of formula:
HQ Rs _ oT
Ary” Ar wherein Ar, Ary, and Rj are as defined hereinabove, with an amine of formula HNRsRe,
Opn mn = {Or / N_/ \_/ 0,
NH
—N Pp
Oe x 200 0) co /\ NAR — —N N—CH;—C—N O . —N ort) .
IVa ig NI a \ / AN , A : or Ao
OH N —N \ nt _ Rr "Ir atE ~
FP ,
N — \ NH or (e) reacting a compound of formula 0
Rong hn =N wherein Rg is as defined hereinabove excepting hydrogen, in the presence of strong base with an halide of formula
ArArCHX where Ar and Ar, are as defined herein and X is halogen to give a corresponding compound of formula | wherein Rs is hydrogen, or ) converting a compound of formula | as defined hereinabove having a reactive substituent group or site to give a different compound of formula I; or (@) converting a compound of formula | to a pharmaceutically acceptable salt thereof.
The compounds of the present invention can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B.; March, J. March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 5 ed.: John Wiley & Sons: New York, 2001; and Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 39 ed.;
John Wiley & Sons: New York, 1999 are useful and recognized reference textbooks of organic synthesis known to those in the art. The foilowing synthetic schemes are designed to illustrate, but not limit, general procedures for the preparation of compounds of formula 1.
The compounds used in the present invention may be prepared by the method described in Scheme 1.
0) ArCHO § —
Re J = — Re Ne 1,4 addition ~o0 Knoevenagel -_— condensation 1
Ar o Oo
Rs NT . Rex of N hydrolysis ~o alkylation Oo 3) (2) Ary Ar Ar of o lo} a8 Condensation wy N
HO —— @ Af A ® at A
Scheme 1
Condensation of a malonic acid derivative with an optionally substituted aromatic or heteroaromatic aldehyde or ketone in the presence of a catalyst provides the intermediate (1). This reaction is known to one skilled in the art as the
Knoevenagel! reaction. The catalyst can be an ammonium salt derived from an amine and a carboxylic acid. (G. Jones, Organic Reactions (1967) 15, 204; Y.
Sumida, Polymer Journal (1981) 13, 521), Lewis acid such as titanium tetrachloride in pyridine (W. Lehnert, Tetrahedron Lett. (1970), 54, 4723) or a amine immobilized on a resin (J. Simpson, Tetrahedron Lett., (1999), 40, 7031). Michael addition of an aryl Grignard or Gilman reagent (N. Laitif, Egypt J. Chem (1974) 17, 879; C.
Cativieia, Tetrahedron, (1994) 50, 9837) provides 2-cyano propionate (2). Alkylation of the anion of (2) with an alkyl halide or sulfonate (AA Fadda, Ind. J. Chem (1990) 298, 171) provides ester (3). Subsequent hydrolysis of the ester under either acidic or basic conditions provides acid (4). Activation of the acid using reagents familiar to one skilled in the art, such as thionyl or oxalyl chloride, cyanuric chloride, pivaloyl chloride, diphenylphosphoryl azide, diethyl cyanophosphate, diethyl azodicarboxylate/triphenylphosphine, dicyclohexylcarbodimide, hydroxbenzotriazole, and subsequent reaction with an amine provides an amide.
In the case where the amine is piperazine an optionally substituted aryl or optionally substituted heteroaryl group can be attached to the piperazine ring using a
Pd or Ni catalyst, with or without a ligand, a base such as sodium t-butoxide in a solvent and an aryl chloride, bromide, iodide sulfonate or siloxane (D. Baranano,
Current Org. Chem. (1997) 1, 287; B. H. Yang, J. Organomet. Chem. (1999), 376, 125; E. Brenner, Tetrahedron (1999) 55, 12829). Alternatively a Cu catalyst, a base and an aryl chloride, bromide, iodide sulfonate, an aryl boronic acid or aryl siloxane (P.Y.S. Lam, J. Am Chem. Soc (2000)122, 7600; D.J. Cundy, Tetrahedron Letters (1998)39, 7979) can be used. The N-oxide of the substiruted piperazines can be prepared by oxidation of the basic nitrogen with reagents known to one skilled in the art (e.g., 3-chloro perbenzoic acid, trifluoroacetic peracid).
The amide can also be prepared directly from ester (3) by a modification of the Bodroux reaction in which the ester is converted directly into an amide by reaction with the magnesium salt of an amine (Dolling, Uf H.; EP-A-599376) as shown in Scheme 2 o 0
Ap 1) i-PrMgBr Ap
MeO RsReN
RsRgNH
Ary Ar Arf Ar
Scheme 2
Another route to the substituted piperazines amides involves the synthesis of the piperazine amide and using a metal catalyzed coupling with a Pd or Ni catalyst, with or without a ligand, a base such as sodium t-butoxide in a solvent and an aryl chloride, bromide, iodide sulfonate or siloxane (D. Baranano, Current Org. Chem. (1997) 1, 287; B. H. Yang, J. Organomet. Chem (1999), 376, 125; E. Brenner,
Tetrahedron (1999) 55, 12829). Alternatively a Cu catalyst, a base and an aryl chloride, bromide, iodide sulfonate, an aryl boronic acid or aryl siloxane (P.Y.S. Lam,
J. Am Chem. Soc. (2000)122, 7600; D.J. Cundy, Tetrahedron Letters (1998)39, 7979) can be used.
In those cases where the amine used in the condensation reaction with acid, 4 , is an acylated piperazine, the piperazine, if not commercially available, was prepared by monoacylation of an excess of piperazine with an acid chloride, chloroformate or isocyanate in the presence of a base using methods known to one skilled in the art. Alternatively, the piperazine amide can be prepared by condensation of acid 4 with an excess of piperazine to generate a monoacyl piperazine. Subsequent reaction with activated (optionally substituted) (heterro) aryl : acid derivatives, isocyanates, isothiocyanates or (optionally substituted) (hetero) aryl chioroformates under conditions familiar to one skilled in the art produces the disubstituted amide. This route is illustrated in Scheme 3.
Scheme 3 0 oO
Rs =N Condensation Rs ==N
HO —_— ow (5) 4) Af TA oo mn Ar; Ar 0}
Acylate > 6 —_— N
Arq Ar
Zz
Z2=0,S
W = O(optionally substituted)(hetero)Aryl,
NH(optionally substituted)(hetero)Aryl, (optionally substituted)(hetero) Aryl
An alternative synthesis of the 3-(1 -naphthyl)-3-phenyl-2-cyanopropanoic acid ester (intermediate 2), involves the synthesis of a naphthyl aryl methyl halide and its use in a subsequent alkylation of a cyanoacetic acid derivative. This route, based on the work of L. Voegtli (Helv. Chim Acta. 38 (1955) 46, is shown in Scheme 4.
Scheme 4
OH X
ALCHO+AM ~~ oh, — re
Arq Ar Arq Ar
M = MgX. Li, K, Na, Zn
X = Cl, Br, |, 0S0,Me, OSO2Ar, OSOCF3; :
o 0
Re A= EE er RA ry 0] 2)diaryimethy! halide 2) Ar Ar
The alcohol could be converted into a leaving group familiar to one skilled in the art using methods familiar to one skilled in the art (eg PhaP/CCls, PhaP/CBra, methyltriphenoxy- phosphonium iodide, TsCI/Pyr, MsCI/TEA, AcO/Pyr).
The substantially pure enantiomers of the compounds of formula | may be resolved by forming a ephedrine, cinchonidine, or quinidine salt of a compound of claim 1 or a pharmaceutically acceptable salt thereof: and extracting said ephedrine, cinchonidine, or quinidine salt with solvent. As used herein, “substantially pure enantiomer’ means an enantiomer present it a mixture with other enantiomer at a proportion of at least about 90%, by weight, based on the total weight of all enantiomers of the compound, preferably at least about 95%, by weight, and, more preferably at least about 99%, by weight.
The compounds of this invention are useful in the treatment of the inflammatory component of diseases and are therefore particularly useful in treating atherosclerosis, myocardial infarction, congestive heart failure, arthritis, inflammatory bowel! disease, type Il diabetes, osteoarthritis, asthma and any other autoimmune disease in humans or other mammals which comprises administering to a human or other mammal an antiinflammatory effective amount of a compound of the present invention.
Representative compounds of this invention were evaluated in the following standard pharmacological test procedures that demonstrated the antiinflammatory activity for the compounds of this invention. The test procedures used and the results obtained are briefly described below.
Test procedures:
Cells
T-175 flasks of 100% confluent HAECT-1 cells (immortalized human aortic endothelial cells) were washed with 8 mL of HBSS (HEPES buffered saline solution) and infected for four hours with 6 mL of a 1:10 dilution of Ad5-wt-hERa virus (an adenovirus transfection vector that mediates CMV promoter driven expression of human ERa) in phenol red free Endothelial Cell Basal medium (Clonetics, San
Diego CA, Catalog # CC-3129) containing 0.25% bovine serum albumin (EBM-BSA).
After four hours, cells were washed with EBM-BSA and incubated overnight in the same medium. Following overnight incubation, cells were washed with EBM-BSA and infected for 2 hours with 6 mL of a 1:10 dilution of Ad5-3x(NFxB).Luc virus (Adenovirus luciferase expression vector driven by 3 repeats of the MHC NF«b site to the thymidine kinase promoter) in EBM-BSA. After two hours, cells were washed and incubated at 34°C for 1 hour. Cells were then washed, trypsinized, counted and resuspended in 95%FBS / 5% dimethylsulfoxide at a concentration of 4x10° cells/mL, frozen as 1 or 5 mL aliquots in cryo-vials and stored at —150 °C.
Control (no ER infection) cells were processed as above without Ad5-wt-hERa. virus infection.
A representative compound selected from the compounds of Examples 1-130 was evaluated in the test procedure described below. iL-6 and Creatine Kinase (CK)Test Procedure
ERG, infected HAECT-1 cells or control cells were thawed, diluted 42x in warm
EBM-BSA, plated into 96-well plates at 0.1 mL/well and incubated for 4 hours at 34 °C. Test compounds were added to the cells as 2x stocks in EBM-BSA containing 2 ng/mL IL-1 (R&D Systems) and the 96-well plates were returned to the incubator (34 °C). After 15-20 hours, 100 ul aliquots of media were removed from the cells and assayed for IL-6 content using a BioSource human IL-6 ELISA Kit. Cells were subsequently washed with 300 pL of Dulbecco's phosphate buffered saline and lysed in 50 uL of Cell Culture Lysis Reagent (Promega). Luciferase was determined on a Wallac Victor Luminometer (Gaithersburg, MD) using 10 pL of lysate and mixing with 100 pL of Promega Luciferase Assay reagent. Creatine kinase was determined from the rate of increase in Ass following addition of 100 pL of CK assay reagent (Sigma, cat. No 47-10) to the remainder of the cell lysate.
Data Analyses
For IC, and ECs calculations, mean IL-6, luciferase or CK values versus log,, of the compound concentration were fitted to a four parameter logistic equation. The ICgy/ ECs value, "Hill slope’, upper and lower limits of the curve were iteratively estimated.
Mice
Ovariectomized C57BL/6 mice (16-20 g) (Taconic) were separated into groups of eight mice each. After 5-7 days of recuperation, the mice were fed a chow diet or an atherogenic diet (15.75% fat, 1.25% cholesterol and 0.5% sodium cholate) (Purina diet #21539). EE or test compound was administered once daily by gavage in a methylcelluloseftween vehicle (0.1 ml per mouse) for 5 weeks. At the end of the experimental period, the liver was collected and uterine wet weight was recorded.
RNA Analysis
Liver total RNA was prepared by using Trizol reagent (BRL). Estrogen and compound regulation of NF-kB target genes were verified by real time reverse transcriptase-polymerase chain reaction (RT-PCR) using an ABI PRISM 7700
Sequence Detection System according to the manufacturer's protocol (Applied
Biosystems). The data was analyzed using the Sequence Detector v1.7 software (Applied Biosystems) and normalized to GAPDH using the Applied Biosystems primer set. .
The following table summarizes the results obtained in the standard pharmacological test procedures described above using a representative compound of this invention.
Table 1:
Effects of tested compounds on ER/NF-kB, IL-6 and CK expression in Ad5-wt-
ERa. infected HAECT-1 cells
ICs Efficacy |1Cso Efficacy | ECso Efficacy le J Jn [0 fn Jw 101 92 173 58
CEE TLE
92 |86 222 100 *Efficacy values are relative to the maximal inhibition (ER/NF-xB or IL-6 test procedure) or stimulation (CK test procedure) observed with E2.
E2 inhibits NF-xB and IL-6 expression in Ad5-wt-ER infected HAECT-1 cells with an ICs, value around 1 nM and induces expression of creatine kinase in the same cells with similar potency (5.8 nM) (Table 1). In contrast, compounds of the present invention potently and efficaciously inhibit NF-xB and IL-6 expression in
Ad5-wt-ER infected HAECT-1 cells but do not induce CK expression (Table 1) in an
ER-dependent manner. The ability of compounds of the present invention to inhibit
NF-kB and IL-6 expression without inducing CK activity (as shown for a representative compound in Table 1) is demonstrates anti-inflammatory activity in the absence of classic estrogenic activity.
Representative compounds selected from the compounds of Examples 131- 230 were evaluated in the test procedure described below.
Test procedures:
Cells
T-175 flasks of 100% confluent HAECT-1 cells (immortalized human aortic endothelial cells) were washed with 8 mi of HBSS (HEPES buffered saline solution) and infected for fours hours with 6 mi of a 1:10 dilution of Ad5-wt-hERa virus (an adenovirus transfection vector that mediates CMV promoter driven expression of human ERa) in phenol red free Endothelial Cell Basal medium (Clonetics, San
Diego, CA, Catalog # CC-3129) containing 0.25% bovine serum albumin (EDM-
BSA). After four hours, cells were washed with EDM-BSA and incubated overnight in the same medium. Following overnight incubation, cells were washed with EDM-
BSA and infected for 2 hours with 6 ml of a 1:10 dilution of Ad5-3x(NF«B).Luc virus (Adenovirus luciferase expression vector driven by three repeats of the MHC NF«b sites 5 to the thymidine kinase promoter) in EDM-BSA. After two hours, cells were washed and incubated at 34 °C for one hour. Cells were then washed, trypsinized, counted, and resuspended in 95% FBS/5% dimethylsulfoxide at a concentration of 4x10® cells/ml, frozen as 1 or 5 ml aliquots in cryo-vials and stored at -150°C.
Control (no ER infection) cells were processed as above without Ad5-wt-hERa virus infection. iL-6 and Creatine Kinase Assays
ERga infected HAECT-1 cells or control cells were thawed, diluted 42x in warm
EBM-BSA, plated into 96-well plates at 0.1 ml/well and incubated for 4 hours at 34 oC. Test compounds were added to the cells at 2x stocks in EBM-BSA containing 2 ng/ml IL-18 Ad6-IL-6(1250bp).Luc virus and plates were retuned to the incubator (34 °C). After 15 to 10 hours, cells were lysed with 50 pl of Promega Cell Culture
Lysis reagenet for about 5 minutes at room temperature on a shaker. After lysing, pl of lysate is transferred to luminometer plates for luciferase determination.
Luciferase activity is evaluated using a Perkin Elmer Victor2 1420 multilabel counter.
Creatine kinase was determined from the rate of increase in Asso following addition of 100 pl of CK assay reagent (Sigma catalog no. 47-10) to the remainder of the cell lysate.
Data Analyses
For ICs and ECs calculations, mean IL-6, luciferase or CK values versus logs of the compound concentration were fitted to a four parameter logistic equation. The ICs/ECso value, ‘Hill slope,’ upper and lower limits of the curve were iteratively estimated. [wwe [we ok [OK 131 15 119 212 48 132 122 92 298 57 133 206 81 134 612 85 135 65 119 136 63 142 137 33 163 138 156 131 34 49 139 113 98 140 324 125
TT wew | ew [XK [OC]
Earle | TC W)_| Wea 08) | EC | HEA (4) 141 3.2 123 20 39 142 69 103 143 39 91 74 38 144 7 103 19 29 145 9.1 102 146 5.5 135 147 12 148 257 149 18 102 150 150 64 151 5.5 141 13.5 30 152 : 152 19 130 85 14 153 149 150 15 154 6 87 155 2 105 6 33 156 312 73 157 23 110 -100 158 45 121 55 23 159 273 95 162 546 126 4 163 2.95 -32 12 165 21 22 166 353 77 13 167 1229 72 -16 168 37 68 169 331 97 8 170 577 89 171 337 54 wee | ewe [ok [Oo] 172 114 149 -13 173 72 124 -13 174 1815 49 34
175
176 413 71
177 1152 91 -32 178 94 137 -100 179 151 128
180 200 | 119 -6 181 389 104 2 182 45 74
183 361 196 481 63 184 445 88
185 288 116
186 2461 60 11 187 21 134 50 48 188 63 107 39 189 348 103
190 113
191 586
192 44 176 415 61 193
194 132 150
195 710 74
196 70 142
197 39 46
198
199
200 157 162 320 13 201 1093 45
EE 1 NS 202 3 202 43 203 26 203 9.93 28 204 ” 204 117 23 205 334 58 35 206 345 83 207 4002 63 16 208 13 50 209 87 116 311 2 210 16 132 211 268 78 212 59 113 138 22 213 5.6 103 64 26 214 276 136 315 12 215 216 51 21 217 203 12 37 218 103 101 12 219 1405 74 220 344 128 6 221 170 245 38 12 221 92 174 82 33 221 62 159 1 222 222 304 170 33 57 223 38 154 318 24 204 832 77 4 225 1598 83 42 wwe | ew [OC [OK
Bare | TC (W_| Fefioaoy (4) | Eom OW) _| HEeacy 00) 226 220 115 138 18 160 1255 82 -10 161 798 122 5 164 32 48
Based on the results obtained in the standard pharmacological test procedures, the compounds of this invention are selective antiinflammatory compounds described herein useful for the treatment and prevention of chronic inflammatory diseases without stimulating uterine and breast cell proliferation as found with classic estrogens.
Accordingly, the compounds of this invention are useful in treating or inhibiting osteoporosis and in the inhibition of bone demineralization, which may result from an imbalance in an individual's formation of new bone tissues and the resorption of older tissues, leading to a net loss of bone. Such bone depletion results in a range of individuals, particularly in post-menopausal women, women who have undergone bilateral oophorectomy, those receiving or who have received extended corticosteroid therapies, those experiencing gonadal dysgenesis, and. those suffering from Cushing's syndrome. Special needs for bone, including teeth and oral bone, replacement can also be addressed using these compounds in individuals with bone fractures, defective bone structures, and those receiving bone- related surgeries and/or the implantation of prosthesis. In addition to those conditions described above, these compounds can be used in treatment or inhibition of osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple myeloma and other forms of cancer having deleterious effects on bone tissues.
The compounds of this invention are also active in the brain and are therefore useful for inhibiting or treating Alzheimer's disease, cognitive decline, decreased libido, senile dementia, neurodegenerative disorders, depression, anxiety, insomnia, schizophrenia, and infertility. The compounds of this invention are also useful in treating or inhibiting benign or malignant abnormal tissue growth including,
glomerulosclerosis, prostatic hypertrophy, uterine leiomyomas, breast cancer, scleroderma, fibromatosis, endometriosis, endometrial cancer, polycystic ovary syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostate cancer, cancers of the colon, CNS cancers, such as glioma or astioblastomia.
The compounds of this invention are cardioprotective and are antioxidants, and are useful in lowering cholesterol, triglycerides, Lipoprotein (a) (Lp(a)), and low density lipoprotein (LDL) levels; inhibiting or treating hypercholesteremia, hyperlipidemia, cardiovascular disease, atherosclerosis, peripheral vascular disease, restenosis, and vasospasm, and inhibiting vascular wall damage from cellular events leading toward immune mediated vascular damage.
The compounds of this invention are also useful in treating disorders associated with inflammation or autoimmune diseases, including inflammatory bowel disease (Crohn’s disease, ulcerative colitis, indeterminate colitis), arthritis (rheumatoid . arthritis, spondyloarthropathies, osteoarthritis), pleurisy, ischemia/reperfusion injury (e.g. stroke, transplant rejection, myocardial infarction, etc.), asthma, giant cell arteritis, prostatitis, uveitis, psoriasis, multiple sclerosis, systemic lupus erythematosus and sepsis.
The compounds of this invention are also useful in treating or inhibiting ocular disorders including cataracts, uveitis, and macular degeneration and in treating skin conditions such as aging, alopecia, and acne.
The compounds of this invention are also useful in treating or inhibiting metabolic disorders such as disorders of lipid metabolism, appetite (e.g. anorexia nervosa and bulimia), or type-ll diabetes.
Compounds in this invention are also useful in treating or inhibiting bleeding disorders such as hereditary hemorrhagic telangiectasia, dysfunctional uterine bleeding, and combating hemorrhagic shock.
The compounds of this invention are useful in disease states where amenorrhea is advantageous, such as leukemia, endometrial ablations, chronic renal or hepatic disease or coagulation diseases or disorders.
It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. It is projected that compounds of this invention will be administered at an oral daily dosage of from about 0.05 mg to about 30 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form. For most large mammals, the total daily dosage is from about 3.5 mg to about 2100 mg, preferably from about 3.5 to about 5 mg. In the case of a 70 kg human adult, the total daily dose will generally be from about 3.5 mg to about 2100 mg and may be adjusted to provide the optimal therapeutic result.
The compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. The pharmaceutical carrier may be solid or liquid.
A solid carrier can include one or more substances that may also act as flavoring agents, sweetening agents, lubricants, solubilizers, suspending agents, . fillers, glidants, compression aids, binders, or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient.
Solid dosage unit forms or compositions such as tablets, troches, pills, capsules, powders, and the like, may contain a solid carrier binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of. the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
Liquid carriers are used in preparing liquid dosage forms such as solutions, suspensions, dispersions, emulsions, syrups, elixirs and pressurized compositions.
The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives,
sweeteners, ‘flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution); alcohols, including monohydric alcohols such as ethanol and polyhydric alcohols such as glycols and their derivatives; lethicins, and oils such as fractionated coconut oil and arachis oil. For parenteral administration, the liquid carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carmier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.
A liquid pharmaceutical composition such as a syrup or elixir may contain, in addition to one or more liquid carriers and the active ingredients, a sweetening agent such as sucrose, preservatives such as methyl and propyl parabens, a pharmaceutically acceptable dye or coloring agent, or a flavoring agent such as : cherry or orange flavoring.
Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered intraocularly or parenterally, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy. injectability exists. It must be : stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing a liquid carrier, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The liquid carrier may be suitably mixed with a surfactant such as hydroxypropyiceliulose.
The compounds of the present invention may also be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may be administered topically, or also transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, which is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
The following describes the preparation of representative compounds of this invention. Compounds described as homogeneous were determined to be 98% or greater a single peak (exclusive of enantiomers) by analytical reverse phase chromatographic analysis with 254 nM UV detection. Melting points are reported as uncorrected in degrees centigrade. The infrared data is reported as wavenumbers at maximum absorption, vmax, in reciprocal centimeters, cm’. Mass spectral data is reported as the mass-to-charge ratio, m/z; and for high resolution mass spectral data, the calculated and experimentally found masses, [M+H]’, for the neutral formulae M are reported. Nuclear magnetic resonance data is reported as 3 in parts per million (ppm) downfield from the standard, tetramethylsilane; along with the solvent, nucleus, and field strength parameters. The spin-spin homonuclear coupling constants are reported as J values in hertz; and the multiplicities are reported as a: s, singlet; d, doublet; t, triplet; q, quartet; quintet; or br, broadened. Italicized elements or groups are those responsible for the chemical shifts. °C NMR chemical shift assignments were made by reasonable comparison to a full chemical shift assignment determination for Example 1, Step a. The yields given below are for informational purposes and may vary according to experimental conditions or individual techniques.
Example 1, Part1
Ethyl (E)-2:cyano-3-(2,6-dimethoxyphenyl)prop-2-enoate
A solution of ethyl cyanoacetate (817mg,7.22mmol), 2,6- (dimethoxy)benzaldehyde (19, 6.0 mmol), piperidinium acetate (0.430 mg, 3.0 mmol) in toluene (25mL.) is refluxed for four hours under a Dean Stark trap. The reaction is cooled, diluted with isopropyl acetate (25mL) and washed with iN HCl, saturated bicarbonate solution, and brine. The sample was evaporated to a solid.
Recrystallization from ethanol provided the title compound as white crystals mp 99-101 °C; 'H NMR (DMSO-D6): & 0.79 (t, J=7.08 Hz, 3 H), 3.84 (s, 6H), 4.29 (q, J=7.08 Hz, 2
H), 6.77 (d, J=8.55 Hz, 2 H), 7.50 (t, J=8.55 Hz, 1 H), 8.28 (s,1H)
MS (APCI) m/z [M+H]+ (262);
Anal. calcd for C14H1sNO4: C:64.36 H:5.79 N:5.36 Found: C:64.13 H:5.71 N:5.31.
Example 1 Part 2
Ethyl 2-cyano-3-(2,6-dimethoxyphenyl)-3-(1 -naphthyl)propanoate
Ethyl (E)-2-cyano-3-(2,6-dimethoxyphenyl)prop-2-enoate (522 mg, 2 mmol) was disolved in 20 mL dry tetrahydrofuran (THF) and stirred under argon at room temperature while 0.25 M 1-naphthyi magnesium bromide (9.6 mL, 2.4 mmol) was added dropwise. The reaction was stirred 2 hrs., quenched with 1 N HCI, taken up in ethyl acetate, washed with NaHCOs, brine, dried with MgSO, filtered, and "evaporated. The crude reaction mixture was recrystallized from ethyl acetate/hexanes to yield 390 mg. 1H NMR (400 MHz, DMSO-D6) & 0.79 (t, J=7.08 Hz, 1 H) 0.90 (t, J=7.08 Hz, 1 H) 3.79 (d, J=10.49 Hz, 4 H) 3.92 (m, 1 H) 5.18 (d, J=11.23 Hz, 1 H) 5.26 (d, J=11.23
Hz, 1 H) 5.84 (d, J=11.47 Hz, 1 H) 5.94 (d, J=11.23 Hz, 1 H) 6.60 (d, J=8.54 Hz, 1
H) 6.67 (d, J=8.30 Hz, 1 H) 7.17 (t, J=8.30 Hz, 1 H) 7.22 (t, J=8.42 Hz, 1 H) 7.49 (m, 2 H) 7.72 (d, J=6.59 Hz, 1 H) 7.80 (dd, J=17.33, 8.30 Hz, 1 H) 7.89 (m, 1 H) 8.30 (d,
J=8.79 Hz, 1 H)
MS (APC) m/z 390 ([M+H]+);
MS (APCI) m/z 407 ((M+NH4]+);
Anal. calcd for CaqH2sNO4: C:74.02 H:5.95 N:3.60 Found: C:73.73 H:5.78 N:3.57.
Example 2
Ethyl 2-cyano-3-(2,6-dichlorophenyl)-3-(1-naphthyl)propanoate
Ethyl (E)-2-cyano-3-(2,6-dichlorophenyl)prop-2-enoate (540 mg, 2 mmol) was dissolved in 20 mL dry THF and stirred under argon at room temperature while 0.25
M 1-naphthyl magnesium bromide (9.6 mL, 2.4 mmol) was added dropwise. The reaction was stirred 2 hours quenched with 4 N HCI, taken up in ethyl acetate, washed with NaHCOa, brine, dried with MgSO, filtered, and evaporated. The crude reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to yield 450 mg the title compound as a yellowish oil. 1H NMR (400 MHz, DMSO-D6) 5 0.97 (t, J=7.08 Hz, 1 H) 1.07 (, J=7.08 Hz, 1 H) 4.04 (m, 1 H) 4.16 (dd, J=7.08, 4.15 Hz, 1 H) 5.41 (d, J=9.27 Hz, 1 H) 5.58 (d,
J=11.23 Hz, 1 H) 6.01 (d, J=9.03 Hz, 1 H) 6.10 (d, J=11.47 Hz, 1 H) 7.36 (m, 1 H) 7.47 (m, 2 H) 7.53 (d, J=7.81 Hz, 1 H) 7.59 (t, J=7.81 Hz, 1 H) 7.66 (d, J=8.30 Hz, 1
H) 7.74 (d, J=7.57 Hz, 1 H) 7.81 (m, 1 H) 7.90 (d, J=8.05 Hz, 1 H) 7.85 (m, 1 H)
MS (APCI) m/z 398 ([M+H]+);
MS (APCI) m/z 415 ([M+NH4]+);
Anal. calcd for C22H17CI2NO2: C:66.34 H:4.30 N:3.52 Found: C:66.18 H:4.35 N:3.48.
Example 3
Ethyl 2-cyano-3-[4-(dimethylamino)phenyl}-3-(1 -naphthyl)propanoate . Ethyl (E)-2-cyano-3-[4-(dimethylamino)phenyl)]prop-2-enoate (489 mg, 2 mmol) was disolved in 20 mL dry THF and stirred under argon at room temperature while 0.25 M 1-naphthyl magnesium bromide (9.6 mL, 2.4 mmol) was added dropwise. The reaction was stirred 2 hrs., quenched with 1 N HCI, taken up in ethyl acetate, washed with NaHCO3, brine, dried with MgSOa, filtered, and evaporated.
The crude reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to yield 125 mg the title compound as a yellowish oil which became a hard foam upon high vaccum. "H NMR (400 MHz, DMSO-D6) 8 0.92 (dt, J=12.93, 7.08 Hz, 3 H) 2.79 (s, 3H) 2.82 (s, 3H) 4.01 (m, 1 H) 5.19 (d, J=0.76 Hz, 0.5 H) 5.26 (d, J=9.27 Hz, 0.5 H) 5.38 (m, 1 H) 6.58 (d, J=8.79 Hz, 1 H) 6.62 (d, J=8.79 Hz, 1 H) 7.15 (d, J=8.79 Hz, 1 H) 7.29 (m, 1.33 H) 7.49 (m, 3 H) 7.58 (d, J=7.32 Hz, 0.5 H) 7.69 (d, J=7.08 Hz, 0.5 H) 7.88 (m, 3 H) 8.12 (m, 0.66 H) 8.23 (d, J=8.30 Hz, 0.5 H)
MS (APCI) m/z 373 ([M+H]+);
Anal. calcd for CagHasN2O2: C:77.39 H:6.49 N:7.52 Found: C:77.31 H:5.90 N:6.90.
Example 4
Ethyl 2-cyano-3-(1-naphthyl)-3-[2-(triflucromethyl)phenyllpropanoate 2-(trifluoromethyl)phenyt magnesium bromide (550 mg, 2 mmol) taken up in mL dry THF with magnesium (59 mg, 2 mmol) overnight. To this was added ethyl (E)-2-cyano-3-(1-naphthyl)prop-2-enoate (502 mg, 2 mmol) in THF (10 mL). The reaction mixture allowed to stir overnight. The reaction was stirred 2 hrs., quenched with 1 N HCI, taken up in ethyl acetate, washed with NaHCOs, brine, dried with
MgSO, filtered, and evaporated. The crude reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to yield 692 mg of the title compound as a yellow oil. 'H NMR (400 MHz, DMS0-D6) 8 0.76 (t, J=7.08 Hz, 1 H) 0.92 (t, J=7.08 Hz, 1 H) 3.87 (m, 1 H) 4.02 (q, J=7.08 Hz, 0.5 H) 4.07 (q, J=7.08 Hz, 0.5 H) 5.23 (d, J=7.32
Hz, 0.5 H) 5.36 (d, J=8.30 Hz, 0.5 H) 5.87 (d, J=7.32 Hz, 0.5 H) 5.94 (d, J=8.30 Hz, 0.5 H) 7.27 (d, J=6.59 Hz, 0.5 H) 7.58 (m, 5H) 7.80 (m, 1.5 H) 7.94 (m, 3 H) 8.13 (d, J=8.79 Hz, 0.5 H)8.18 (d, J=7.81 Hz, 0.5 H)
MS (APCI) m/z 398 ((M+H]+);
Anal. calcd for CasH1aFaNO2: C:69.52 H:4.57 N:3.52 Found: C:68.50 H:4.09 N:3.22.
Example 5
Ethyl 2-cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate 2-(isopropyl)phenyl magnesium bromide (502mg, 2 mmol) taken up in 10 mL dry THF with magnesium (59 mg, 2 mmol) overnight. To this was added ethyl (E)-2- cyano-3-(1-naphthyl)prop-2-enoate (502 mg, 2 mmol) in THF (10 mL). The reaction mixture allowed to stir overnight. The reaction was stirred 2 hours, quenched with 1
N HC, taken up in ethyl acetate, washed with NaHCO3, brine, dried with MgSOa, filtered, and evaporated. The crude reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to yield 302 mg of the title compound as a yellow oil. "MH NMR (400 MHz, DMSO-D86) 8 0.66 (d, J=6.59 Hz, 1.66 H) 0.83 (t, J=7.08 Hz, 1.66 H) 0.93 (t, J=7.08 Hz, 0.33 H) 1.00 (d, J=6.59 Hz,0.33 H) 1.20 (d, J=6.83 Hz, 2.33 H) 1.26 (d, J=6.83 Hz, 0.66 H) 1.34 (t, J=7.20 Hz, 0.66 H) 2.94 (dt, J=13.54, 6.89 Hz, 0.66 H) 3.93 (qd, J=7.12, 1.59 Hz, 1.33 H) 4.05 (q, J=7.08 Hz, 0.66 H) 4.37
(a, J=7.08 Hz, 0.33 H) 5.14 (d, J=7.81 Hz, 0.33 H) 5.23 (d, J=8.05 Hz, 0.66 H) 5.82 (t, J=7.69 Hz, 1 H) 7.11 (t, J=8.18 Hz, 0.33 H) 7.29 (m, 4 H) 7.44 (, J=7.81 Hz, 0.66
H) 7.55 (m, 2 H) 7.69 (m, 2.33 H) 7.87 (t, J=8.42 Hz, 1 H) 7.95 (d, J=8.30 Hz, 0.33
H) 7.99 (d, J=7.81 Hz, 1 H) 8.07 (d, J=7.81 Hz, 0.66 H) 8.14 (d, J=7.32 Hz, 0.33 H) 8.20 (m, 1 H)
MS (APCI) miz 370 (IM-H]-);
Anal. calcd for CosHasNO,: C:80.83 H:6.78 N:3.77 Found: C:79.13 H:6.07 N:3.94.
Example 6
Ethyl 2-cyano-3-(2,4-dimethoxyphenyl)-3-(1 -naphthyl)propanoate
A solution of 2-cyano-3-(2,4-dimethoxy-phenyl)-acrylic acid ethyl ester (522 mg, 2 mmol) in THF (20mL) was treated dropwise with 1-naphthyl magnesium bromide (9.6mL, 2.4mmol) at room temperature. The reaction was stirred for 3 hours, quenched with 1N HCl and diluted with ethyl acetate (40mL). The organic layer was separated and was washed sequentially with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over Na;SOa, filtered and was concentrated in vacuo. Chromatography over silica gel (20% ethyl acetate/hexanes) yielded 421 mg of the title compound as an off white solid. 'H NMR (400 MHz, DMSO-D6) § 0.90 (td, J=7.08, 1.71 Hz, 3 H) 3.68 (s, 1.5 H) 3.71 (s, 1.5 H) 3.84 (s, 1.5 H) 3.94 (s, 1.5 H) 4.00 (m, 2 H) 5.08 (d, J=8.30 Hz, 0.5 H) 5.20 (d, J=9.27 Hz, 0.5 H) 5.74 (d, J=8.54 Hz, 0.5 H) 5.78 (d, J=9.27 Hz, 0.5 H) 6.36 (dd,
J=8.54, 2.44 Hz, 0.5 H) 6.45 (dd, J=8.66, 2.32 Hz, 0.5 H) 6.60 (dd, J=8.18, 2.32 Hz, 1 H) 6.80 (d, J=8.54 Hz, 0.5 H) 7.20 (d, J=8.54 Hz, 0.5 H) 7.51 (m, 3 .5H) 7.64 (d,
J=6.83 Hz, 0.5 H) 7.88 (m, 3.5 H) 8.06 (d, J=8.54 Hz, 0.5 H)
MS (APCH) m/z 390 ([M+H]+);
Anal. calcd for CosHasNOg: C:74.02 H:5.95 N:3.60 Found: C:73.84 H:5.91 N:3.54.
Example 7
Ethyl 2-cyano-3-(2,5-dimethoxyphenyl)-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 6 using 2-cyano-3- (2,5-dimethoxy-phenyl)-acrylic acid ethyl ester as the starting material. This provided 309 mg of the tite compound as a yellow powder.
1H NMR (400 MHz, DMSO-D6) 8 0.87 (t, J=7.20 Hz, 1.5 H) 0.91 (t, J=7.20 Hz, 1.5
H) 3.54 (s, 1.5 H) 3.62 (s, 1.5 H) 3.79 (s, 15H) 3.88 (s, 1.5 H) 3.99 (m, 2 H) 5.16 (d,
J=8.79 Hz, 0.5 H) 5.30 (d, J=9.52 Hz, 0.5 H) 5.81 (d, J=8.79 Hz, 0.5 H) 5.85 (d,
J=9.76 Hz, 0.5 H) 6.54 (d, J=2.93 Hz, 0.5 H) 6.79 (ddd, J=8.79, 5.13, 3.17 Hz, 1H) 6.97 (m, 1.5 H) 7.54 (m, 3 H) 7.67 (d, J=6.83 Hz, 0.5 H) 7.90 (m, 3 H) 8.13 (d,
J=8.30 Hz, 0.5 H)
MS (APCH) m/z 390 ([M+H]+);
Anal. calcd for Co4H2aNO4: C:74.02 H:5.95 N:3.80 Found: C:73.79 H:6.09 N:3.85.
Example 8 -- Part 1 tert-Butyl (E)-2-cyano-3-[2-(trifluoromethyl)phenyl]-2-propenoate
A mixture of 2-trifluoromethyl benzaldehyde (13.1 gmL, 100mmol), t- butylcyanoacetate and piperazine resin (350mg) in toluene was heated under a Dan
Stark trap for 2 hours. The reaction was cooled, diluted with ethyl acetate and filtered. The solution was concentrated in vacuo to yield the tittle compound as a clear oil. 'H NMR (500 MHz,DMSO-D6 & 1.52 (s, 9H), 7.78 (t, J=7.63 Hz, 1H), 7.88 (t, J= 7.79Hz,1H), 7.92 (d, J=7.79Hz,1H), 8.05 (d, J=7.63Hz, 1H), 8.46 (d, J=1.36Hz,1H)
MS (ESI) m/z 315 ([M+NH4]+);
Anal. calcd for C1sH1aFaNO2: C:60.61 H:4.75 N:4.71 Found: C:60.59 H:4.68 N:4.72.
Example 8 — Part 2 tert-Butyl 2-cyano-3-(1 -naphthyl)-3-[2-(trifluoromethyl)phenyi]propanoate
The title compound was prepared according to example 6 using tert-butyl (E)-2-cyano-3-[2-(trifluoromethyl)phenyl]-2-propenoate prepared in part A as the starting material. This provided the title compound as a white foam. 1H NMR (500 MHz, DMSO-D6) 8 1.08 (s, 4.5 H) 1.14 (s, 4.5 H) 5.09 (d, J=7.63 Hz, 0.5 H) 5.26 (d, J=7.94 Hz, 0.5 H)5.84 (d, J=7.79 Hz, 0.5 H) 5.91 (d, J=7.94 Hz, 0.5
H) 7.23 (d, J=7.33 Hz, 0.5 H) 7.45 (m, 0.5 H) 7.54 (m, 1.56 H) 7.59 (m, 1.5 H) 7.67 (m, 1 H) 7.71 (td, J=7.71, 1.22 Hz, 0.5 H) 7.81 (m, 1.5 H) 7.94 (m, 3 H) 8.13 (d,
J=8.55 Hz, 0.5 H) 8.17 (d, J=7.94 Hz, 0.5 H)
MS (ESI) m/z 443 ([M+NH4]+);
Anal. calcd for CasHaoFaNO,: C:70.58 H:5.21 N:3.29 Found: C:70.64 H:5.35 N:3.19.
Example 9 Part 1 tert-Butyl (E)-2-cyano-3-(1 -naphthyl)prop-2-encate 1-naphthaldehyde (17.4 mL, 128.06 mmol), tert-butyl cyano acetate (21.8 mL, 153.67 mmol), piperidinium acetate (64 mmol), toluene (250 mL), and ethanol (20mL) were combined in a flask fitted with a Dean-Stark apparatus and refluxed with removal of water for 4 hrs. The reaction was cooled, taken up in isopropyl acetate, washed twice with 1 N HCI, once with saturated aqueous NaHCOg, brine, dried with MgSOy, filtered, and evaporated. Reaction yielded 33g of the title compound as an oil. The oil crystallized (thick needles) after standing for a prolonged period (4 months) at room temperature. mp 51-53 °C; 1H NMR (400 MHz, DMSO-D6) § 1.55 (s, 9 H) 7.62 (m, 3 H) 8.00 (m, 2H) 8.10 (s, 1
H) 8.12 (s, 1H) 8.95 (s, 1 H)
MS (APC!) m/z 280 ([M+H]+);
Anal. calcd for CqgH7NO,: C:77.40 H:6.13 N:5.01 Found: C:76.30 H:5.95 N:4.81.
Example 9 Part 2 tert-Butyl 2-cyano-3,3-di(1-naphthyl)propanoate
Tert-butyl (E)-2-cyano-3-(1-naphthyi)prop-2-enoate (559 mg, 2 mmol) was disolved in 15 mL dry THF and stirred under argon at room temperature while 0.25
M 1-naphthyl magnesium bromide (9.6 mL, 2.4 mmol) was added dropwise. The reaction was stimed 2 hrs., quenched with 1 N HCI, taken up in ethyl acetate, washed with NaHCO, brine, dried with MgSO, filtered, and evaporated. The crude reaction mixture was purified via crystallization from ethanol to yield 480 mg of the title compound as a crystalline solid. mp 156-157 °C; 1H NMR (400 MHz, DMSO-D6) 5 1.06 (s, 8 H) 5.26 (d, J=8.06 Hz, 1 H) 6.27 (d,
J=8.06 Hz, 1 H) 7.31 (dd, J=7.32, 1.22 Hz, 1 H) 7.40 (m, 2 H) 7.47 (m, 1 H)7.61 (m, 2 H) 7.71 (ddd, J=8.48, 6.90, 1.46 Hz, 1 H) 7.90 (m, 5 H) 8.00 (dd, J=8.18, 1.10 Hz, 1 H) 8.39 (d, J=8.54 Hz, 1 H)
MS (APCI) m/z 406 ([M-H}-); :
Anal. calcd for CogHasNO,: C:82.53 H:6.18 N:3.44 Found: C:81.44 H:5.93 N:3.39.
Example 10
Ethyl 2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 6 using 2-cyano-3- naphthalen-1-yl-acrylic acid ethyl ester and 2-methoxyphenyl magnesium bromide as starting materials. This provided the title compound as a low melting solid which
NMR shows to be a 50:50 mixture of diastereomers 1H NMR (400 MHz, DMSO-D6) 5 0.88 (m, 3 H) 3.84 (s, 1.5 H) 3.94 (s, 1.5 H) 3.99 (m, 2 H) 5.15 (d, J=8.30 Hz, 0.5 H) 5.25 (d, J=9.27 Hz, 0.5 H) 5.84 (d, J=8.30 Hz, 0.5 H) 5.88 (d, J=0.52 Hz, 0.5 H) 6.78 (td, J=7.44, 0.98 Hz, 0.5 H) 6.88 (td, J=7.38, 0.85 Hz, 0.5 H) 6.95 (dd, J=7.69, 1.59 Hz, 0.5 H) 7.05 (t, J=7.69 Hz, 1 H) 7.23 (ddd,
J=15.68, 7.99, 1.71 Hz, 1 H) 7.35 (dd, J=7.81, 1.71 Hz, 0.5 H) 7.52 (m, 3 H) 7.60 (d,
J=7.81 Hz, 0.5 H) 7.65 (d, J=7.08 Hz, 0.5 H) 7.83 (d, J=8.30 Hz, 0.5 H) 7.90 (m, 3 H) 8.11 (d, J=8.79 Hz, 0.5 H)
MS (El) m/z M+. (359);
Anal. calcd for Ca3H24NO3: C:76.86 H:5.89 N:3.90 Found: C:76.51 H:5.85 N:3.83.
Example 11
Ethyl (RR, SS)-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate
Fractional crystallization of the solid from example 10 in ethyl acetate/hexanes provided colorless needles of the title compound. mp 123-126 °C; 1H NMR (500 MHz, DMSO-D6) 5 0.89 (t, J=7.10 Hz, 3 H) 3.94 (s, 3 H) 4.01 (ddd,
J=14.16, 7.06, 1.07 Hz, 2 H) 5.15 (d, J=8.40 Hz, 1 H) 5.85 (d, J=8.55 Hz, 1 H) 6.78 (td, J=7.52, 0.99 Hz, 1 H) 6.96 (dd, J=7.64, 1.68 Hz, 1 H) 7.06 (dd, J=8.25, 0.92 Hz, 1 H) 7.22 (ddd, J=7.33, 1.83, 0.61 Hz, 1 H) 7.48 (m, 2 H) 7.59 (dd, J=8.17, 7.41 Hz, 1H)7.91 (m, 4H)
MS (ESI) m/z 377 ([M+NH4]+);
Anal. calcd for Co3H21NO3 . 0.15 H20: C:76.29 H:5.93 N:3.87 Found: C:76.33 H:5.82
N:3.70.
Example 12 tert-Butyl 2-cyano-3-(2-isopropylphenyl)-3-(1 -naphthyl)propanoate
A mixture of Cul (681mg, 3.58mmol) in THF (10mL), cooled to 0°, was treated with a cold, 0°, solution of 2-isopropyl lithium (from 1.43g of 1-bromo-2-isopropyl- benzene and nBuli (4.48mL, 1.6M in hexane) in THF (10mL). This mixture was added to a cold solution of 2-cyano-3-naphthalen-1-yl-acrylic acid tert-butyl ester in
THF (10mL). The reaction was stirred and allowed to warm to room temperature over an hour. The reaction was quenched with ammonium chloride and diluted with ether. The aqueous layer was washed twice with ether and the organic layers were combined and washed with saturated ammonium chloride and brine. The sample was dried over Na,SO, and was filtered and evaporated to a solid. Trituration of the solid with provided the title compound as a white powder. 1H NMR (500 MHz, DMSO-D6) 8 0.64 (d, J=6.72 Hz, 1.5 H) 1.00 (d, J=6.72 Hz, 1
H) 1.11 (s, 4.5 H) 1.18 (s, 4.5 H) 1.22 (d, J=6.72 Hz, 1.5 H) 1.27 (d, J=6.57 Hz, 1 H) 2.96 (m, 0.5 H) 5.00 (d, J=8.25 Hz, 0.5 H) 5.11 (d, J=7.94 Hz, 0.5 H) 5.77 (d, J=7.94
Hz, 0.5 H) 5.78 (d, J=8.09 Hz, 0.5 H) 7.12 (t, J=8.09 Hz, 0.5 H) 7.31 (m, 3.5 H) 7.44 (t, J=7.71 Hz, 0.5 H) 7.52 (m, 1 H) 7.59 (t, J=7.41 Hz, 0.5 H) 7.70 (m, 0.5 H) 7.75 (m, 0.5 H)7.87 (t, J=8.78 Hz, 1 H) 7.95 (d, J=7.94 Hz, 0.5 H) 8.01 (m, 1 H) 8.22 (d,
J=8.70 Hz, 0.5 H)
MS (ESI) m/z 417 ((M+NH4]+);
Anal. calcd for Ca7HooNO,: C:81.17 H:7.32 N:3.51 Found: C:81.05 H:7.34 N:3.49.
Example 13 tert-Butyl 2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate
Tert-butyl (E)-2-cyano-3-(1-naphthyl)prop-2-enoate (2.23g, 8 mmol) was dissolved in 40 mL dry THF and stirred under argon at room temperature while 1 M 2-methoxyphenyl magnesium bromide (9.6 mL, 9.6 mmol) was added dropwise.
The reaction was stirred 2 hrs., quenched with 1 N HCI, taken up in ethyl acetate, washed with NaHCO3, brine, dried with MgSO, filtered, and evaporated. The crude reaction mixture was purified on silica gel (20% ethyl acetate/hexanes) to yield a yellowish oil which recrystallized from ethanol to yield 1.661 g product as a crystalline polymorphic solid. 1H NMR (400 MHz, DMSO-D6) 8 1.04 (s, 4.5 H) 1.09 (s,4.5H) 3.83 (s, 1.5 H) 3.95 (s, 1.5 H) 5.06 (d, J=8.79 Hz, 0.5 H) 5.11 (d, J=10.49 Hz, 0.5 H) 5.81 (d, J=8.79 Hz, 0.5 H) 5.86 (d, J=10.74 Hz, 1.5H) 6.80 (t, J=7.08 Hz, 0.5 H) 6.92 (t, J=7.44 Hz, 0.5
H) 7.03 (m, 1.5 H) 7.23 (m, 1 H) 7.50 (m, 2 H) 7.59 (m, 1 H) 7.65 (d, J=6.59 Hz, 0.5
H) 7.82 (d, J=8.05 Hz, 0.5 H) 7.92 (m, 3 H) 8.22 (d, J=8.54 Hz, 0.5 H)
MS (APCI) m/z 388 ([M+H]+);
Anal. calcd for CosHasNOg: C:77.49 H:6.50 N:3.61 Found: C:77.40 H:6.25 N:3.57
Example 14 tert-Butyl 2-cyano-3-(1 -naphthyl)-3-[2-(trifluoromethoxy)phenyllpropanoate
The title compound was prepared according to example 6 using 2-cyano-3-(2- trifluoromethoxy-phenyl)-acrylic acid tert-butyl ester as the starting material. The crude product was chromatographed on silica using 25% ethyl acetate/ hexanes.
Recrystallization from methylene chloride/ hexane provided the title compound as a crystalline solid. mp 115-118 °C 1H NMR (500 MHz, DMSO-D6) § 1.04 (s, 5 H) 1.16 (s, 3 H) 5.19 (d, J=9.32 Hz, 0.4
H) 5.25 (d, J=9.47 Hz, 0.6 H) 5.76 (d, J=9.16 Hz, 0.4 H) 5.80 (d, J=9.62 Hz, 0.6 H) 7.46 (m, 6.4 H) 7.65 (ddd, J=8.44, 6.99, 1.22 Hz, 0.6 H) 7.82 (d, J=7.18 Hz, 0.4 H) 7.87 (dd, J=5.65, 3.66 Hz, 0.6 H) 7.91 (d, J=8.09 Hz, 0.4 H) 7.97 (d, J=7.94 Hz, 1 H) 7.99 (dd, J=7.56, 1.91 Hz, 0.6 H) 8.04 (d, J=8.40 Hz, 0.4 H) 8.19 (d, J=8.70 Hz, 0.6
H)
MS (ESI) m/z 440 ([M-H]-);
Anal. calcd for CasHaoFaNO3: C:68.02 H:5.02 N:3.17 Found: C:67.88 H:5.04 N:3.11.
Example 15
Ethyl 2-cyano-3-(1 -naphthyl)-3-phenylpropanoate
A solution of 2-cyano-3-naphthalen-1-yl-acrylic acid ethyl ester (0.502mg,2mmol) in THF(15mL) was ‘treated with phenyl magnesiun bromide (1.2mL,2M in THF) dropwise with stirring under nitrogen. After one hour the reaction was quenched with 1N HCL. The solution was diluted with isopropyl acetate (15mL) and the organic layer was isolated. The organic layer was washed with bicarbonate solution and brine. Chromatography over silica gel (15% MTBE/hexane) provided the tite compound as an oil from which solidified on standing. NMR suggests a 6:1 ratio of diastereomers.
1H NMR (400 MHz, DMSO-D6) 5 0.89 (dt, J=9.70, 7.11 Hz, 3 H) 4.00 (ddd,
J=14.28, 7.08, 1.10 Hz, 2 H) 5.33 (d, J=9.76 Hz, 0.8 H) 5.40 (d, J=9.76 Hz, 0.2 H) 5.51 (d, J=9.76 Hz, 0.8 H) 5.55 (d, J=9.76 Hz, 0.2 H) 7.25 (m, 3.2 H) 7.40 (d, J=7.08
Hz, 1.8 H) 7.52 (m, 2.6 H) 7.60 (t, J=7.81 Hz, 1 H) 7.72 (d, J=7.08 Hz, 0.2 H) 7.84 (d, J=8.79 Hz, 0.2 H) 7.90 (d, J=8.05 Hz, 1 H) 7.94 (m, 1.8 H) 8.18 (m, 0.8 H) 8.30 (d, J=7.57 Hz, 0.2 H)
MS (El) m/z M+. (329);
Anal. calcd for CaoHyoNO>: C:80.22 H:5.81 N:4.25 Found: C:80.03 H:5.94 N:4.21.
Example 16
Ethyl 2-cyano-3,3-bis(2-methoxyphenyl)propanoate
A solution of 2-cyano-3-(2-methoxy-phenyl}-acrylic acid ethyl ester (2mmol) in
THF (10mL) is treated with 2-methoxyphenyl magnesium bromide (2.4mmol,1M
THF) at room temperature. The reaction is stirred for 3 hours, quenched with 1N HCI and diluted with isopropyl acetate (15mL). The aqueous layer is removed and the organic layer is washed with bicarbonate then brine and is dried over Na;S04.
Evaporation of the sample yields an oil which is chromatographed on silica gel (25% ethyl acetate hexane) to yield the title compound as a viscous oil. 1H NMR (DMSO-D6): 80.93 (t, J=7.20 Hz, 3 H), 3.71 (s, 3 H), 3.79 (s, 3H), 4.00 (ddd, J=14.15 Hz, 7.08 Hz, 1.22 Hz, 2H), 4.98 (d, J=8.79 Hz, 1H), 5.35 (d, J=8.79
Hz, 1H), 6.85 (td, J=7.44 Hz, 0.98 Hz, 1H), 6.97 (m, 3H), 7.07 (dd, J=7.57 Hz,
J=1.71 Hz, 1H), 7.24 (m, 2H), 7.45 (dd, J=7.57 Hz, 1.46 Hz, 1H)
MS (APCI) m/z [M+NH4]+ (357);
Anal. calcd for CogH21NO4: C:70.78 H:6.24 N:4.13 Found: C:70.64 H:6.07 N:4.03.
Example 17
Ethyl 2-cyano-3-(1 -naphthyl)-3-(2-nitrophenyl)propanoate
The ‘title compound was prepared using 2-cyano-3-(2-nitro-phenyl)-acrylic acid ethyl ester according to example 6.The title compound was a sticky viscous oil 1H NMR (DMSO-D86): 0.92 (td, J=7.08 Hz, 3.66 Hz, 2.5 H), 1.05 (t, J=7.08 Hz, 0.5
H), 3.44 (m, 0.5H), 4.02 (m, 1.5H), 4.35 (t, J=5.13 Hz, 0.5H), 5.41 (d, J=2.20 Hz, 0.5H), 5.43 (d, J=2.93 Hz, 0.5H), 6.25 (t, J=8.18 Hz, 1H), 7.41 (m, 1.5H), 7.50 (m,
2.5H), 7.61 (m, 1.5H), 7.82 (m, 0.5 H), 7.91 (d, J=8.05 Hz, 1.5H), 7.96 (m, 1.5 H), 8.01 (dd, J=8.05 Hz, 1.22 Hz, 0.5 H), 8.05 (d, J=8.30 Hz, 0.5H), 8.10 (dd, J=8.05 Hz, 1.22 Hz, 0.5H)
MS (APC) m/z 375 ([M+H]+);
Anal. calcd for CxHgN204: C:70.58 H:4.85 N:7.48 Found: C:69.19 H:4.87 N:6.97.
Example 18 tert-Butyl 2-cyano-3-(2,6-dimethyiphenyl)-3-(1 -naphthyl)propanoate 2,6 (Dimethyl)phenyl magnesium bromide (50mL , 1.0M in THF) was added dropwise to a a stirred solution of 2-cyano-3-naphthalen-1-yl-acrytic acid tert-butyl ester (11.6g,41.5mmol) in THF (170mL) under Nz . The reaction was stirred overnight during which time a precipitate formed. The reaction was then treated with HC) (250ml, 1N) and diluted with ethyl acetate (500mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate ((250mL). The organic layers were combined and were washed with saturated brine (250mL.), dried over Na;SO, and concentrated in vacuo to yield 16.1 g of a solid.
Recrystallization of the crude product yielded 12.4 g of the title compound mp 124-128 °C; 1H NMR (500 MHz, DMSO-D6) 8 1.23 (s,9 H) 1.33 (s, 6 H) 5.10 (d, J=6.57 Hz, 1 H) 5.44 (d, J=11.76 Hz, 0.5 H) 5.58 (d, J=6.87 Hz, 1.5 H) 7.00 (s, 1 H) 7.07 (m, 1 H) 7.35 (m, 1 H) 7.44 (m, 1 H) 7.53 (m, 0.5 H) 7.59 (t, J=7.79 Hz, 1 H) 7.64 (d, J=7.48
Hz, 0.5 H) 7.87 (t, J=6.95 Hz, 1 H) 7.92 (dd, J=11.53, 8.17 Hz, 2 HY
MS (ESI) m/z 403 ([M+NH4]+); Anal. calcd for CzsHzzNO2: C:81.01 H:7.06 N:3.63
Found: C:80.67 H:7.08 N:3.55.
Example 19 tert-Butyl (RR,SS)-2-cyano-3-(1 -naphthyl)-3-[2-(trifluoromethyl)phenyi]propanoate
A solution of 2-(trifluoromethyl)phenyl magnesium bromide in THF was prepared (J. Med. Chem. 33 (1990) 1452) this material was used in the procedure described in example 18 to yield the title compound as a reddish solid.
Chromatography over SiO using 105 to 40% ethyl acetate/hexanes yielded the title compound as a white solid.
mp 120.5-125.0 °C; 1H NMR (500 MHz, DMSO-D6) 5 1.08 (s, 5 H) 1.14 (s, 3 H) 5.09 (d, J=7.79 Hz, 0.4 H) 5.26 (d, J=7.94 Hz, 0.6 H) 5.85 (d, J=7.79 Hz, 0.4 H) 5.91 (d, J=7.79 Hz, 0.6 H) 7.23 (d, J=7.18 Hz, 0.5 H) 7.45 (t, J=7.64 Hz, 0.5 H) 7.56 (m, 3
H) 7.69 (m, 1.5 H) 7.81 (m, 1.5 H) 7.94 (m, 3 H) 8.15 (dd, J=16.49, 8.25 Hz, 1 H);
MS (ESI) m/z 443 ([M+NHA4]+); Anal. calcd for CasHzoF3NO2: C:70.58 H:5.21 N:3.29
Found: C:70.62 H:5.14
Example 20 teri-Butyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
A solution of 2-cyano-3-(2-methoxy-phenyl)-3-naphthalen-1-yl-propionic acid tert-butyl ester in THF ( 25mL) was treated at room temperature with potassium bistrimethylsilyl amide (3.64mL, 2.4mmol, 0.66M in toluene). The reaction was stirred for two hours and then methyl iodide was added (0.5mL, 8mmotl). The reaction was stirred at room temperature for one hour and was quenched with 1N
HCI. The reaction was diluted with ethyl acetate and the organic layer was isolated.
The organic layer was washes with saturated sodium bicarbonate solution and brine.
The organic layer was dried over NaxSOy, filtered and was concentrated in vacuo.
Trituration of the resulting solid with ethanol provided 700mg of the title compound as a white powder. 1H NMR (400 MHz, DMSO-D6) § 1.02 (s, 9 H) 1.62 (s, 3 H) 4.04 (s, 3 H) 5.76 (s, 1
H) 6.83 (td, J=7.50, 1.10 Hz, 1 H) 7.21 (m, 3 H) 7.47 (m, 2 H) 7.60 (t, J=7.32 Hz, 1
H) 7.89 (m, 3 H) 8.06 (d, J=7.08 Hz, 1 H) :
MS (APCI) m/z 402 ([M+H]+);
Anal. calcd for CagHayNOs: C:77.78 H:6.78 N:3.49 Found: C:77.41 H:6.84 N:3.67.
Example 21 Part 1 (-) Ethyl (SS)2-cyano-3-(2-methoxyphenyl)-2-methyi-3-(1-naphthyl)propanoate
A sample of ethyl (RR,SS)cyano-3-(2-methoxyphenyl)-2-methyl-3~(1- naphthyl)propanoate was dissolved in methanol and was resolved by chromatography on a preparative HPLC system using a Chiralcel OD (25 x 5cm) column and 8:2 methanol:water as the eluant. The title compound was the first peak to elute. Recrystallization from ethanol provided the title compound as colorless crystals.
mp 134.5-135.5 °C; [alo® = -297.79° (1%, CHCl);
Example 21 Part 2 (+) Ethyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyljpropanoate
The title compound was the second peak to elute in example 21 part 1.
Recrystallization from ethanol provided the title compound as colorless crystals. mp 134.5-135.5 °C; [aJp? = +289.80° (1%,CHCla);
Example 22
Ethyl (RR,SS)-2-cyano-2-[(2-methoxyphenyl)(1 -naphthyl)methyl]4-pentenoate
The title compound was prepared according to example 20 using allyl bromide. Recrystallization of the crude product from methanol provided the title compound as an off white solid. 1H NMR (500 MHz, DMSO-D6) 8 0.73 (t, J=7.10 Hz, 3 H) 2.43 (dd, J=13.74, 6.72
Hz, 1 H) 2.94 (dd, J=13.90, 7.94 Hz, 1 H) 3.92 (m, 2 H) 4.06 (s, 3 H) 5.18 (dd,
J=11.07, 1.60 Hz, 1 H) 5.21 (d, J=3.05 Hz, 1 H) 5.71 (m, 1 H) 5.88 (s, 1 H) 6.84 (t,
J=7.02 Hz, 1 H) 7.16 (d, J=8.25 Hz, 1 H) 7.25 (m, 2 H) 7.47 (m, 2 H) 7.58 (m, 1 H) 7.85 (d, J=8.25 Hz, 1 H) 7.88 (m, 1 H) 7.93 (m, 1 H) 8.08 (d, J=7.02 Hz, 1 H)
MS (ESI) m/z 417 (IM+NH4]+);
Anal. calcd for CogH2sNO3: C:78.17 H:6.31 N:3.51 Found: C:78.53 H:6.31 N:3.48.
Example 23 :
Ethyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 20 using benzyl bromide. Recrystallization of the crude product from methanol provided the title compound as a white solid. 1H NMR (500 MHz, DMSO-D6) 8 0.58 (t, J=7.10 Hz, 3 H) 2.90 (d, J=13.44 Hz, 1 H) 3.57 (d, J=13.59 Hz, 1 H) 3.79 (m, 2 H) 4.09 (s, 3 H) 6.05 (s, 1 H) 6.89 (t, J=7.86 Hz, 1 H) 7.10 (m, 2 H) 7.19 (d, J=7.94 Hz, 1 H) 7.30 (m, 5 H) 7.49 (m, 2 H) 7.56 (m, 1 H) 7.84 (d, J=8.25 Hz, 1 H) 7.89 (d, J=9.47 Hz, 1 H) 8.00 (d, J=8.09 Hz, 1 H) 8.07 (d,
J=7.18 Hz, 1 H)
MS (ESI) m/z 467 ((M+NH4]+);
Anal. calcd for CaoHz7NO3: C:80.15 H:6.05 N:3.12 Found: C:79.99 H:6.00 N:3.04.
Example 24 tert-Butyl (RR, S$S)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 20 using tert-butyl 2- cyano-3-(2-isopropylphenyl)-3-(1-naphthyl)propanoate as the starting material.
Recrystallization from MeOH provided the title compound. 1H NMR (500 MHz, DMSO-D6) & 0.26 (d, J=6.72 Hz, 3 H) 1.19 (d, J=6.72 Hz, 2 H) 1.21 (s, 9 H) 1.54 (s, 3 H) 2.95 (m, 1 H) 5.62 (s, 1 H) 7.26 (m, 2 H) 7.33 (m, 1 H) 7.44 (m, 2 H) 7.58 (m, 1 H) 7.72 (t, J=7.18 Hz, 1 H) 7.88 (d, J=7.79 Hz, 1 H) 7.99 (dd, J=7.79, 4.28 Hz, 2 H) 8.47 (d, J=8.70 Hz, 1 H)
MS (ESI) m/z 370 ((M+H]+),
Anal. calcd for CogHaiNO2: C:81.32 H:7.56 N:3.39 Found: C:81.23 H:7.54 N:3.38 :
Example 25 Part 1 tert-Butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-(trifluoromethyi) phenyli]propanoate
The tile compound was prepared according to example 20 using tert-butyl 2- cyano-3-(2- trifluoromethyl )phenyl)-3-(1-naphthyl)propanoate as the starting material.
Fractional recrystallization of the solid from MeOH provided the title compound as a white solid. mp 159-161 °C; 1H NMR (500 MHz, DMSO-D6) 8 1.14 (s, 9 H) 1.57 (s, 3H) 5.78 (s, 1 H) 7.48 (8,
J=7.71 Hz, 1 H) 7.54 (m, 1 H) 7.57 (t, J=7.56 Hz, 2 H) 7.70 (ddd, J=8.47, 6.95, 1.22
Hz, 1 H) 7.74 (d, J=7.79 Hz, 1 H) 7.91 (m, 2 H) 7.98 (d, J=7.48 Hz, 1 H) 8.30 (d,
J=8.70 Hz, 1 H) 8.40 (d, J=7.94 Hz, 1 H)
MS (ESI) m/z 457 ([M+NH4]+);
Anal. calcd for CogHaaF3NO2: C:71.06 H:5.50 N:3.19 Found: C:71.08 H:5.42 N:3.19.
Example 25 Part 2 tert-Butyl(R,R/SS)2-cyano-2-methyl-3-(1-naphthyl)-3-[2-(trifluoromethyl) phenyl]propanoate
The mother liquors from example 25 part 1 were separated on a Primesphere
C18 (25x5cm) column in 1:4 water:methanol. This provided the title compound as a white solid. mp 136-138 °C; 1H NMR (500 MHz, DMSO0-D6) 8 0.94 (s, © H) 1.58 (s, 3 H) 5.81 (s, 1 H) 7.51 {,
J=7.41 Hz, 1 H) 7.58 (m, 3 H) 7.79 (d, J=7.79 Hz, 1 H) 7.82 (d, J=7.63 Hz, 1 H) 7.93 (dd, J=10.69, 8.55 Hz, 2 H) 8.08 {t, J=8.17 Hz, 2 H) 8.22 (d, J=7.94 Hz, 1 H)
MS (ESI) m/z 457 ([M+NH4]+);
Anal. calcd for CosHasF3NO2: C:71.06 H:5.50 N:3.19 Found: C:71.10 H:5.48 N:3.03.
Example 26 tert-Butyl (RS,SR)-2-cyano-3-(2,6-dimethyiphenyl)-2-methyi-3-(1- naphthyl)propanoate
The title compound was prepared according to example 20 using 2-cyano-3-(2,6-dimethyl-phenyl)-3-naphthalen-1-yl-propionic acid tert-butyl ester as the starting material. Recrystallization from MeOH provided the title compound as a white solid. mp 155-156 °C; 1H NMR (500 MHz, DMSO-D6) 8 1.28 (s, 9 H) 1.68 (s, 3H) 1.74 (s,3H) 2.78 (s, 3
H) 5.52 (s, 1 H) 6.82 (d, J=7.48 Hz, 1 H) 7.11 (t, J=7.64 Hz, 1 H) 7.28 (d, J=7.33 Hz, 1 H) 7.34 (td, J=7.71, 1.07 Hz, 1 H) 7.44 (4, J=7.41 Hz, 1 H) 7.48 (d, J=8.70 Hz, 1 H) 7.61 (t, J=7.79 Hz, 1 H) 7.91 (dd, J=11.30, 8.09 Hz, 2 H) 8.01 (d, J=7.33 Hz, 1 H)
MS (APC) m/z 400 ([M+H]+);
Anal. calcd for CorH2gNO2: C:81.17 H:7.32 N:3.51 Found: C:81.03 H:7.27 N:3.46.
Example 27 tert-Butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 20 using benzyl bromide. Trituration of the solid in methanol provided the title compound as a white powder. mp 208 °C;
1H NMR (500 MHz, DMSO0-D6) 8 0.85 (s, 9 H) 2.89 (d, J=13.44 Hz, 1 H) 3.53 (d,
J=13.59 Hz, 1 H) 4.09 (s, 3 H) 6.00 (s, 1 H) 6.90 (td, J=7.52, 0.99 Hz, 1 H) 7.17 (m, 3 H) 7.29 (m, 4 H) 7.36 (dd, J=7.79, 1.53 Hz, 1 H) 7.50 (m, 2 H) 7.59 (m, 1 H)7.85 (d, J=8.25 Hz, 1 H) 7.90 (dd, J=8.09, 1.07 Hz, 1 H) 8.03 (d, J=8.40 Hz, 1H) 8.14 (d,
J=7.18 Hz, 1 H)
MS (ESI) m/z 495 ([M+NH4]+);
Anal. calcd for CazHaiNO3: C:80.48 H:6.54 N:2.93 Found: C:80.48 H:6.42 N:2.93.
Example 28 tert-Butyl (RR, SS)-2-(3-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1- : naphthyl)propanoate
The title compound was prepared according to example 20using tert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate and 3- chloro-benzyl bromide as the starting materials. Trituration with methanol provided the title compound as a white solid. mp 175-179 °C; 1H NMR (500 MHz, DMSO-D6) 3 0.87 (s, 9 H) 2.91 (d, J=13.59 Hz, 1 H) 3.56 (d,
J=13.74 Hz, 1 H) 4.08 (s, 3 H) 5.99 (s, 1 H) 6.89 (t, J=7.56 Hz, 1 H) 7.15 (d, J=7.18
Hz, 1 H) 7.19 (m, 2 H) 7.29 (td, J=7.83, 1.30 Hz, 1 H) 7.36 (m, 3 H) 7.50 (m, 2 H) 7.59 (t, J=7.79 Hz, 1 H) 7.86 (d, J=8.25 Hz, 1 H) 7.90 (dd, J=7.86, 1.15 Hz, 1 H) 8.01 (d, J=8.25 Hz, 1 H) 8.12 (d, J=7.18 Hz, 1 H)
MS (APCI) m/z 529 ([M+NHA4]+);
Anal. calcd for CazHzoCINO3: C:75.06 H:5.91 N:2.74 Found: C:74.84 H:5.81 N:2.72.
Example 29 tert-Butyl (RR, SS)-2-(2-bromobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1 - naphthyi)propanoate
The title compound was prepared according to example 20using tert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3(1-naphthyl)propanoate and 2- bromo-benzy! bromide as the starting materials. Chromatography on silica gel with 25% ethyl acetate/hexanes as the eluant provided the tite compound as a white solid.
1H NMR (500 MHz, DMSO-D6) & 0.89 (s, 9 H) 3.36 (d, J=14.35 Hz, 1 H) 3.75 (d,
J=14.51 Hz, 1 H) 4.11 (s, 3 H) 6.01 (s, 1 H) 6.90 (t, J=7.33 Hz, 1 H) 7.32 (m, 6 H) 7.54 (m, 4 H) 7.86 (d, J=8.09 Hz, 1 H) 7.90 (d, J=7.79 Hz, 1 H) 8.06 (d, J=8.55 Hz, 1
H) 8.17 (d, J=7.02 Hz, 1 H)
MS (ESI) m/z 575 ([M+NHA4]+);
Anal. calcd for CaoHaoBrNO3: C:69.07 H:5.43 N:2.52 Found: C:69.16 H:5.42 N:2.50.
Example 30 tert-Butyl (RR,SS)-2-(2-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-(1 - naphthyl)propanoate
The title compound was prepared according to example 20using tert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate and 2- chiorobenzyl bromide as the starting materials. Trituration with methanol provided the title compound as a white solid. 1H NMR (500 MHz, DMSO-D6) 8 0.89 (s, 9 H) 3.32 (d, J=13.29 Hz, 1 H) 3.71 (d,
J=14.35 Hz, 1 H) 4.10 (s, 3 H) 6.01 (s, 1 H) 6.90 (td, J=7.56, 1.07 Hz, 1 H) 7.20 (dd,
J=8.32, 0.84 Hz, 1 H) 7.30 (m, 4 H) 7.42 (m, 2 H) 7.51 (m, 2 H) 7.59 (m, 1 H) 7.86 (d, J=8.25 Hz, 1 H) 7.90 (dd, J=8.02, 1.30 Hz, 1 H) 8.06 (d, J=8.40 Hz, 1 H) 8.16 (d,
J=7.02 Hz, 1 H)
MS (ESI) m/z 529 ([M+NH4]+);
Anal. calcd for CapHsoCINO3 . 0.15 H20: C:74.67 H:5.93 N:2.72 Found: C:74.63
H:5.87 N:2.66.
Example 31 tert-Buty! (RR,SS)-2-cyano-2-(2,6-dichlorobenzyl)-3-(2-methoxyphenyl)-3-(1 - naphthyl)propanoate
The title compound was prepared according to example 20using tert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate and 2,6- dichlorobenzyl bromide as the starting materials. Trituration with methanol provided the title compound as a white solid. 1H NMR (500 MHz, DMSO-D6) 5 0.80 (s, 9 H) 3.61 (d, J=14.35 Hz, 1 H) 3.83 (d,
J=14.35 Hz, 1 H) 4.11 (s, 3 H) 6.05 (s, 1 H) 6.89 (td, J=7.56, 1.07 Hz, 1 H) 7.18 (dd,
J=8.40, 0.92 Hz, 1 H) 7.30 (m, 2 H) 7.42 (m, 2 H) 7.53 (m, 4 H) 7.86 (d, J=8.25 Hz, 1
H) 7.90 (dd, J=8.09, 1.07 Hz, 1 H) 8.17 (t, J=7.86 Hz, 2 H)
MS (ESI) m/z 562 ((M+NH4]+);
Anal. calcd for CaHagCLNO; . 0.30 HO: C:69.64 H:5.41 N:2.54 Found: C:69.57
H:5.44 N:2.44.
Example 32
Ethyl (RR,SS)-2-cyano-3-(2,4-dimethoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 20 using ethyl 2- cyano-3-(2,4-dimethoxyphenyl)-3-(1 -naphthyl)propanoate. Chromatography on silica gel using 25% ethyl acetate/hexanes as eluant provided the title compound as a white powder. 1H NMR (500 MHz, DMSO-D6) & 0.75 (t, J=7.02 Hz, 3 H) 1.64 (s, 3 H) 3.70 (s, 3 H) 3.97 (m, 2 H) 4.04 (s, 3 H) 5.68 (s, 1 H) 6.42 (dd, J=8.70, 2.44 Hz, 1 H) 6.69 (d,
J=2.44 Hz, 1 H) 7.03 (d, J=8.70 Hz, 1 H) 7.46 (dq, J=9.62, 0.92 Hz, 2 H) 7.56 (t,
J=7.48 Hz, 1 H) 7.83 (d, J=8.25 Hz, 1 H) 7.87 (m, 2 H) 8.00 (d, J=7.18 Hz, 1 H)
MS (ESI) m/z 404 ([M+H]+);
Anal. calcd for CosHasNO4: C:74.42 H:6.25 N:3.47 Found: C:73.77 H:6.32 N:3.31.
Example 33 tert-Buty! (RS,SR)-2-cyano-2-methyl-3-(1 -naphthyt)-3-[2- (trifluoromethoxy)phenyli]propanoate
The title compound was prepared according to example 20 using tert-butyl 2- cyano-3-(1 -naphthyl)-3-[2-(trifluoromethoxy)phenyllpropanoate as the starting material. Recrystallization from ethanol provided the title compound as a crystalline solid. mp 150-153 °C; 1H NMR (500 MHz, DMSO-D6) § 1.25 (s, 9 H) 1.48 (s, 3 H) 5.70 (s, 1 H) 7.29 (d,
J=8.40 Hz, 1 H) 7.46 (ddd, J=8.09, 7.33, 1.07 Hz, 1 H) 7.49 (m, 2 H) 7.58 (td,
J=7.25, 5.65 Hz, 2 H) 7.69 (t, J=7.41 Hz, 1 H) 7.91 (dd, J=6.41, 2.90 Hz, 1 H) 7.99 (d, J=8.09 Hz, 1 H) 8.18 (dd, J=7.86, 0.99 Hz, 1 H) 8.36 (d, J=8.70 Hz, 1 H)
MS m/z 00-E1394P;
Anal. calcd for CagHz4F3NO3: C:68.56 H:5.31 N:3.08 Found: C:68.36 H:5.24 N:2.96.
Example 34
Ethyl 2~cyano-2-methyl-3,3-di(1-naphthyl)propanoate
A solution of 2-cyano-3,3-di-naphthalen-1-yl-propionic acid ethyl ester was dissolved in THF (3mL) and treated with sodium bis-trimethylsilyl amide (39ul, 1M in
THF) at room temperature. After 5 minutes methyl iodide was added (Sul) and the reaction was stirred for 4 hours. The reaction was quenched with 1N HCI (3m) and was diluted with isopropyl acetate (3mL). The organic layer was washed with bicarbonate then brine; dried over Na;SOs, filtered and evaporated to yield the title compound as a crystalline material. mp 186-188 °C; 1H NMR (400 MHz, DMSO-D6) § 0.81 (t, J=7.08 Hz, 3 H) 1.66 (s, 3 H) 4.01 (m, 2H) 6.19 (s, 1 H) 7.32 (td, J=7.69, 1.22 Hz, 1 H) 7.43 (q, J=7.57 Hz, 2 H) 7.57 (d, J=7.32
Hz, 1 H) 7.62 (td, J=7.69, 3.90 Hz, 2 H) 7.77 (td, J=7.69, 0.98 Hz, 1 H) 7.89 (m, 4 H) 8.01 (d, J=7.32 Hz, 1 H) 8.10 (d, J=7.08 Hz, 1 H) 8.76 (d, J=8.54 Hz, 1 H)
MS (El) m/z M+. (393);
Anal. calcd for CarHaaNO,: C:82.42 H:5.89 N:3.56 Found: C:82.20 H:5.84 N:3.52.
Example 35
Ethyl 2-cyano-3-(3-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 3-methoxy- phenyl magnesium bromide. The sample is a viscous oil. 1H NMR (400 MHz, DMS0-D6) 5 0.85 (t, J=7.08 Hz, 1.5 H) 0.90 (t, J=7.20 Hz, 1.5
H) 2.04 (s, 1 H) 3.66 (s, 1.5 H) 3.67 (s, 1.5 H) 3.97 (m, 2 H) 5.30 (d, J=9.52 Hz, 0.5
H) 5.38 (d, J=10.01 Hz, 0.5 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.50 (d, J=9.76 Hz, 0.5 H) 6.76 (m, 1 H) 6.89 (d, J=8.30 Hz, 0.5 H) 6.97 (t, J=1.95 Hz, 0.5 H) 7.10 (m, 1 H) 7.16 (t, J=7.93 Hz, 0.5 H) 7.20 (t, J=7.93 Hz, 0.5 H) 7.49 (m, 1.5 H) 7.57 (t, J=7.69 Hz, 0.5 H) 7.70 (d, J=7.08 Hz, 0.5 H) 7.81 (d, J=8.05 Hz, 0.5 H) 7.90 (m, 2 H) 8.16 (d,
J=9.52 Hz, 0.5 H) 8.30 (d, J=8.05 Hz, 0.5 H)
MS (El) m/z M+. (359);
Anal. calcd for CasHa1NO;: C:76.86 H:5.89 N:3.90 Found: C:75.45 H:5.83 N:3.58 )
Example 36
Ethyl 2-cyano-3-(4-methoxyphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4-methoxy- phenyl magnesium bromide. The sample is a viscous oil 1H NMR (400 MHz, DMSO-D6) § 0.91 (dt, J=13.97, 7.05 Hz, 3 H) 3.66 (s, 1.5 H) 3.69 (s, 1.5 H) 4.01 (m, 2 H) 5.26 (d, J=9.76 Hz, 0.5 H) 5.33 (d, J=9.52 Hz, 0.5 H)
5.45 (d, J=9.76 Hz, 0.5 H) 5.49 (d, J=9.76 Hz, 0.5 H) 6.69 (m, 0.5 H) 6.84 (ddd,
J=14.52, 6.71, 1.95 Hz, 2 H) 7.30 (d, J=8.79 Hz, 1 H) 7.48 (m, 3 H) 7.58 (t, J=7.57
Hz, 0.5 H) 7.71 (d, J=7.57 Hz, 0.5 H) 7.83 (d, J=8.30 Hz, 0.5 H) 7.91 (m, 2 H) 8.14 (dd, J=5.74, 4.03 Hz, 0.5 H) 8.26 (d, J=8.30 Hz, 0.5 H)
MS (EI) m/z M+. (359);
Anal. calcd for CasHayNO4: C:76.86 H:5.89 N:3.90 Found: C:75.32 H:5.89 N:3.53.
Example 37
Ethyl 2-cyano-3-(4-methylphenyl)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4-methyl- phenyl magnesium bromide. The sample is a viscous oil. 1H NMR (400 MHz, DMSO-D6) 8 0.90 (dt, J=12.45, 7.08 Hz, 3 H) 2.06 (s, 3 H) 2.19 (s, 1.5 H) 2.22 (s, 1.5 H) 4.00 (ddd, J=13.85, 7.02, 4.03 Hz, 2 H) 5.28 (d, J=9.52 Hz, 0.5 H) 5.35 (d, J=9.52 Hz, 0.5 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.50 (d, J=9.52 Hz, 0.5
H) 7.09 (dd, J=15.13, 7.81 Hz, 2 H) 7.26 (d, J=8.30 Hz, 1 H) 7.41 (d, J=8.30 Hz, 1H) 7.52 (m, 2.5 H) 7.70 (d, J=6.59 Hz, 0.5 H) 7.83 (d, J=8.05 Hz, 0.5 H) 7.91 (m, 1 H) 8.14 (dd, J=5.13, 4.39 Hz, 0.5 H) 8.26 (d, J=8.54 Hz, 0.5 H)
MS (El) m/z M+. (343);
Anal. calcd for CosH21NO2: C:80.44 H:6.16 N:4.08 Found: C:78.76 H:6.32 N:3.81.
Example 38 -.
Ethyl 2-cyano-3-(2-methylphenyt)-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 2-methyl- phenyl magnesium bromide. The sample is a viscous oil. 1H NMR (400 MHz, DMSO-D6) & 0.81 (t, J=7.08 Hz, 1.5 H) 0.92 (t, J=7.08 Hz, 1.5
H) 2.13 (s, 3 H) 3.88 (m, 1 H) 4.05 (q, J=7.08 Hz, 1 H) 5.22 (t, J=8.18 Hz, 1 H) 5.62 (d, J=7.57 Hz, 0.5 H) 5.67 (d, J=8.79 Hz, 0.5 H) 7.20 (m, 3.5 H) 7.48 (m, 1.5 H) 7.57 (m, 1 H) 7.65 (m, 1.5 H) 7.77 (d, J=6.83 Hz, 0.5 H) 7.89 (m, 2 H) 7.97 (dd, J=8.05, 0.98 Hz, 0.5 H) 8.22 (d, J=8.54 Hz, 0.5 H)
MS (APC) m/z [M+H]+ (344),
Anal. calcd for CagH2iNO2: C:80.44 H:6.16 N:4.08 Found: C:78.56 H:6.10 N:3.91.
Example 39
Ethyl 2-cyano-3-(1-naphthyl)-3-(2-naphthyl)propanoate
The title compound was prepared according to example 15, using 2-naphthy! magnesium bromide. The sample is a viscous oil. 1H NMR (400 MHz, DMSO-D6) 6 0.82 (t, J=7.08 Hz, 1.5 H) 0.89 (t, J=7.08 Hz, 1.5
H) 3.99 (m, 2 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.51 (d, J=9.76 Hz, 0.5 H) 5.70 (d,
J=9.76 Hz, 0.5 H) 5.74 (d, J=9.76 Hz, 0.5 H) 7.51 (m, 5 H) 7.64 (m, 1 H) 7.83 (m, 4
H) 7.93 (m, 2 H) 8.02 (d, J=7.08 Hz, 0.5 H) 8.15 (d, J=1.46 Hz, 0.5 H) 8.25 (m, 0.5
H) 8.38 (d, J=8.54 Hz, 0.5 H)
MS (APCI) m/z 380 ([M+H]+);
Anal. calcd for CagHasNO,: C:82.30 H:5.58 N:3.69 Found: C:81.94 H:5.55 N:3.43.
Example 40
Ethyl 2-cyano-3-(4-filuoro-1-naphthyl)-3-(1-naphthyf)propanoate
The title compound was prepared according to example 15, using 4-fluoro-(1- naphthyl) magnesium bromide. The sample is a white foam. 1H NMR (400 MHz, DMSO0-D6) § 0.83 (m, 3 H) 3.93 (m, J=17.51, 14.15, 7.14, 3.66
Hz, 2 H) 5.37 (d, J=2.20 Hz, 0.5 H) 5.39 (d, J=2.20 Hz, 0.5 H) 6.30 (d, J=7.81 Hz, 1
H) 7.25 (d, J=8.05 Hz, 1 H) 7.31 (dd, J=7.32, 0.98 Hz, 0.5 H) 7.41 (m, 1 H) 7.47 (m, 1 H) 7.53 (ddd, J=8.48, 6.89, 1.46 Hz, 0.5 H) 7.60 (m, 1.5 H) 7.67 (m, 0.5 H) 7.73 (d, J=7.32 Hz, 0.5 H) 7.83 (m, 2.5 H) 7.97 (m, 2 H) 8.09 (dd, J=8.30, 0.98 Hz, 0.5 H) 8.13 (dd, J=8.18, 1.10 Hz, 0.5 H) 8.35 (d, J=8.54 Hz, 0.5 H) 8.46 (d, J=8.79 Hz, 0.5
H)
MS (APCI) m/z 398 ([M+H]+);
Anal. calcd for CogHaoFNO2: C:78.57 H:5.07 N:3.52 Found: C:77.65 H:4.97 N:3.43.
Example 41
Ethyl 2-cyano-3-[4-(methylthio)phenyi]-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4- (thiomethyl)phenyl magnesium bromide. The sample is a white foam 1H NMR (400 MHz, DMSO-D6) § 0.91 (dt, J=14.34, 7.11 Hz, 3 H) 2.39 (d, J=9.76
Hz, 3 H) 4.01 (m, 2 H) 56.31 (d, J=9.52 Hz, 0.5 H) 5.39 (d, J=9.52 Hz, 0.5 H) 5.49 (d,
J=9.52 Hz, 0.5 H) 5.52 (d, J=9.76 Hz, 0.5 H) 7.17 (m, 2 H) 7.33 (d, J=8.30 Hz, 1 H)
7.50 (m, 3.5 H) 7.59 (dd, J=8.30, 7.32 Hz, 0.5 H) 7.72 (d, J=6.59 Hz, 0.5 H) 7.84 (d,
J=8.30 Hz, 0.5 H) 7.92 (m, 2 H) 8.15 (m, 0.5 H) 8.27 (d, J=8.54 Hz, 0.5 H)
MS (El) m/z M+. (375);
Anal. calcd for CosH2NO,S: C:73.57 H:5.64 N:3.73 Found: C:73.45 H:5.44 N:3.71.
Example 42
Ethyl 3-[1,1-biphenyl}-4-yl-2-cyano-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 15, using 4-biphenyl magnesium bromide. The sample is a white foam 1H NMR (400 MHz, DMS0-D6) 8 0.90 (q, J=7.08 Hz, 3 H) 4.01 (m, 2 H) 5.39 (d,
J=9.76 Hz, 0.5 H) 5.46 (d, J=9.76 Hz, 0.5 H) 5.58 (d, J=9.76 Hz, 0.5 H) 5.62 (d,
J=10.01 Hz, 0.5 H) 7.32 (m, 1 H) 7.42 (m, 2 H) 7.57 (m, 9 H) 7.78 (d, J=6.59 Hz, 0.5
H) 7.85 (d, J=8.30 Hz, 0.5 H) 7.94 (m, 2 H) 8.23 (m, 0.5 H) 8.35 (d, J=8.30 Hz, 0.5
H)
MS (APC!) m/z 404 ([M-H]-);
Anal. calcd for CasHasNO,: C:82.94 H:5.72 N:3.45 Found: C:82.84 H:5.71 N:3.38.
Example 43
Ethyl 3-[1,1"-biphenyl]-2-yl-2-cyano-3-(1 -naphthyl)propanoate
The title compound was prepared according to example 15, using 2-biphenyl magnesium bromide. The sample is a white foam 1H NMR (400 MHz, DMSO-D6) & 0.73 (t, J=7.08 Hz, 1.5 H) 0.90 (t, J=7.08 Hz, 1.5
H) 3.82 (m, 1 H) 4.02 (q, J=7.08 Hz, 1 H) 5.23 (d, J=8.30 Hz, 0.5 H) 5.31 (d, J=9.52
Hz, 0.5 H) 5.55 (d, J=8.30 Hz, 0.5 H) 5.66 (d, J=9.52 Hz, 0.5 H) 7.03 (d, J=8.79 Hz, 1.5 H) 7.18 (m, 2.5 H) 7.40 (m, 7.5 H) 7.62 (m, 1 H) 7.82 (m, 2 H) 8.05 (d, J=7.57
Hz, 0.5 H)
MS (APCI) m/z 404 ([M-H]-);
Anal. calcd for CogHsNO2: C:82.94 H:5.72 N:3.45 Found: C:82.40 H:5.94 N:3.39.
Example 44
Ethyl 3-(4-chlorophenyl)-2-cyano-3-(1-naphthyl)propanoate
The title compound was prepared according to example 15, using 4- chlorophenyl magnesium bromide. The sample is a sticky oil. 1H NMR (400 MHz, DMSO-D6) 5 0.89 (dt, J=16.60, 7.08 Hz, 3 H) 2.42 (s, 1.5 H) 2.63 (s, 1.5 H) 4.01 (m, 2 H) 5.12 (d, J=7.08 Hz, 0.5 H) 5.26 (d, J=8.79 Hz, 0.5 H) 5.83 (d, J=7.32 Hz, 0.5 H) 5.92 (d, J=8.79 Hz, 0.5 H) 7.02 (m, 1 H) 7.28 (m, 1.5) 7.39 (t, J=8.30 Hz, 1 H) 7.56 (m, 3 H) 7.88 (m, 3 H) 8.24 (d, J=8.54 Hz, 0.5 H)
MS (APC) m/z [M+H]+ (364);
Anal. calcd for CaHqsCINO,: C:72.63 H:4.99 N:3.85 Found: C:71.56 H:4.95 N:3.65.
Example 45
Ethyl 2-cyano-3-[2-(methylthio)phenyl}-3~(1 -naphthyl)propanoate
The title compound was prepared according to example 15 using 2- (thiomethyl)phenyl magnesium bromide. The sample is a sticky white foam 1H NMR (400 MHz, DMSO-D6) & 0.91 (dt, J=16.23, 7.14 Hz, 3 H) 4.01 (m, 2 H) 5.36 (d, J=9.52 Hz, 0.5 H) 5.43 (d, J=9.76 Hz, 0.5 H) 5.56 (d, J=9.52 Hz, 0.5 H) 5.60 (d, J=10.01 Hz, 0.5 H) 7.39 (m, 3 H) 7.55 (m, 4 H) 7.72 (d, J=6.83 Hz, 0.5 H) 7.85 (d,
J=8.30 Hz, 0.5 H) 7.92 (m, 2 H) 8.17 (m, 0.5 H) 8.29 (d, J=8.54 Hz, 0.5 H)
MS (APCI) m/z [M+H]+ (376);
Anal. calcd for CasH21NO,S: C:73.57 H:5.64 N:3.73 Found: C:73.58 H:5.88 N:3.58.
Example 46
Ethyl-(RR,SS)- 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
A solution of 2-cyano-3-(2-methoxy-phenyl)-3-naphthalen-1-yl-propionic acid ethyl ester (205mg, 0.57mmol) in THF (10mL) is cooled in a dry ice ethanol bath. A solution of KHMDS (1.04ml, 0.68mmol, 0.66M toluene) is added dropwise. The bath is removed and the reaction is warmed to room temperature over an hour. To this is added methyl iodide (162mg, 1.14mmol) and the reaction is stirred at room temperature for 30 minutes. The reaction is quenched with 1NHCI and is diluted with ethyl acetate. The organic layer is isolated and is washed with saturated bicarbonate solution then brine. The organic layer is dried with Na,SO, , is filtered and evaporated to a solid. Chromatography over silica gel (20%ethyl acetate/hexane) yields the title compound as a solid. Recrystallization from MeOH yields the title compound (80mg) as white crystals.
mp 134.5-135.5 °C; 1H NMR (400 MHz, DMS0-D6) & 0.75 (t, J=7.08 Hz, 3 H) 1.65 (s, 3 H) 3.98 (m,
J=17.79, 10.65, 7.08, 3.78 Hz, 2 H) 4.05 (s, 3 H) 5.81 (s, 1 H) 6.83 (td, J=7.50, 1.10
Hz, 1 H) 7.16 (dt, J=7.87, 1.56 Hz, 1 H) 7.26 (td, J=7.81, 1.71 Hz, 1 H) 7.46 (m, 1 H) 7.58 (dd, J=8.18, 7.44 Hz, 1 H) 7.85 (d, J=8.54 Hz, 1 H) 7.89 (m, 1 H) 8.03 (d,
J=7.08 Hz, 1 H)
MS (APCI) m/z [M+H]+ (374);
Anal. calcd for CpgH2aNO3: C:77.19 H:6.21 N:3.75 Found: C:77.05 H:6.24 N:3.74.
Example 47
Ethyl (RR,SS)-2-cyano-2-methyl-3-[2-(methyithio)phenyl]-3-(1 -naphthyl)propanoate
The title compound is prepared from 2-cyano-3-(2-methyisulfanyl-phenyl}-3- naphthalen-1-yl-propionic acid ethyl ester according to example 46. The title compound is obtained as white crystals from MeOH. mp 154-156 °C; 1H NMR (400 MHz, DMSO0-D6) 8 0.75 (t, J=7.08 Hz, 3 H) 1.71 (s, 3H) 2.70 (s, 3H) 3.96 (m, 2 H) 5.81 (s, 1 H) 7.11 (td, J=7.69, 1.22 Hz, 1 H) 7.29 (Wd, J=7.57, 1.46 Hz, 1 H) 7.34 (dd, J=7.93, 1.34 Hz, 1 H) 7.48 (dt, J=6.53, 2.96 Hz, 2 H) 7.53 (dd, J=8.05, 0.98 Hz, 1 H) 7.60 (t, J=7.57 Hz, 1 H) 7.89 (m, 2 H) 8.05 (d, J=7.08 Hz, 1 H) 8.15 (d,
J=9.52 Hz, 1 H)
MS (APCI) m/z [M+H]+ (390);
Anal. calcd for CasHa3NO,S: C:74.01 H:5.95 N:3.60 Found: C:73.97 H:5.91 N:3.55.
Example 48 (RR,SS)-2-Cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoic acid
Ethyl-(RR,SS)- 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoate (12.42g, 33.33 mmol) was dissolved in 100 mL THF to which was added 2.5 M NaOH (18 mL). Reaction mixture heated to reflux for 8 hrs, allowed to cool and stir overnight. The reaction mixture was acidified with 1 N HCI, taken up in ethyl acetate, washed with brine, dried with MgSOs, filtered, evaporated, and recrystallized from ethanol to tyield 11.44 g the title compound as a crystalline solid. mp 229 °C (dec);
1H NMR (400 MHz, DMSO-D6) § 1.62 (s, 2 H) 4.05 (s, 2 H) 5.77 (s, 1 H) 6.80 (td,
J=7.50, 1.10 Hz, 1 H) 7.11 (dd, J=7.69, 1.59 Hz, 1 H) 7.15 (dd, J=8.30, 0.98 Hz, 1 H) 7.23 (td, J=7.81, 1.71 Hz, 1 H) 7.44 (m, 1 H) 7.59 (m, 1 H) 7.84 (d, J=8.30 Hz, 1 H) 7.89 (m, 1 H) 8.10 (d, J=7.32 Hz, 1 H)
MS (APCI) m/z 344 ([M-H]-);
Anal. calcd for CaoHigNO; e 0.35 HO: C:75.13 H:5.65 N:3.98 Found: C:75.16
H:5.61 N:3.76.
Example 49 (RR,SS)-2-Cyano-3-(2-isopropylphenyl)-2-methyl-3-(1 -naphthyl)propanoic acid
A sample of tert-butyl (RR,SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1- naphthyl)propanoate (3.99, 9.4mmol) was dissolved in CHxCl; (40mL). The sample was treated with trifluoroacetic acid (40mL) and was stirred for 2 hours. The mixture was evaporated to a solid. Recrystallization from ethyl acetate/hexanes provided the title compound as white powder. mp 214 °C(dec); 1H NMR (500 MHz, DMSO-D6) 5 0.33 (d, J=6.72 Hz, 3 H) 1.17 (d, J=6.87 Hz, 3 H) 1.52 (s, 3 H) 2.97 (m, 1 H) 5.68 (s, 1 H) 7.25 (m, 2 H) 7.32 (td, J=7.22, 2.21 Hz, 1 H) 7.41 (dd, J=7.33, 1.22 Hz, 1 H) 7.47 (t, J=7.71 Hz, 1 H) 7.58 (m, 1 H) 7.70 (d,
J=7.71, 1.07 Hz, 1 H) 7.87 (d, J=7.79 Hz, 1 H) 7.99 (dd, J=8.17, 0.69 Hz, 1 H) 8.05 (d, J=7.63 Hz, 1 H) 8.46 (d, J=8.70 Hz, 1 H) 14.01 (bs, 1H)
MS (ESI) m/z 375 ((M+NH4]+);
Anal. calcd for CagHosNO2: C:80.64 H:6.49 N:3.92 Found: C:80.75 H:6.54 N:3.87.
Example 50 (RS,SR)-2-Cyano-2-methyl-3-(1 -naphthyl)-3-[2-(trifluoromethyl)phenyl}propanoic acid
The title compound was prepared according to example 49 using tert-butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2-(trifluoromethyl) phenyl] propanoate as the starting material. Recrystallization from ethyl acetate/hexane provided the title compound as a white solid. mp 220 °C (dec);
1H NMR (500 MHz, DMSO-D6) 3 1.54 (s, 3 H) 5.83 (s, 1 H) 7.52 (m, 4 H) 7.69 (m, 2
H) 7.90 (m, 2 H) 7.97 (d, J=7.94 Hz, 1 H) 8.32 (d, J=8.70 Hz, 1 H) 8.48 (d, J=8.09
Hz, 1 H) 14.08 (bs, 1 H)
MS (ESI) m/z 401 ([M+NH4]+);
Anal. calcd for CapH1gF3NO2: C:68.93 H:4.21 N:3.65 Found: C:68.93 H:4.20 N:3.61.
Example 51 (RR,SS)-2-Benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoic acid
The title compound was prepared according to example 49 using tert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoate as the starting material. Trituration with heptane provided the tite compound as a white solid. mp 230-233 °C; 1H NMR (500 MHz, DMSO-D6) 8 2.81 (d, J=13.29 Hz, 1 H) 3.55 (d, J=13.44 Hz, 1
H) 4.08 (s, 3 H) 6.01 (s, 1 H) 6.87 (td, J=7.52, 0.69 Hz, 1 H) 7.14 (dd, J=7.18, 2.29
Hz, 2 H) 7.18 (d, J=8.25 Hz, 1 H) 7.29 (m, 5 H) 7.47 (m, 2H) 7.57 (m, 1 H) 7.84 (d,
J=8.25 Hz, 1 H) 7.88 (dd, J=7.18, 2.75 Hz, 1 H) 8.01 (dd, J=7.48, 1.68 Hz, 1 H) 8.18 (d, J=7.18 Hz, 1 H)
MS (ESI) m/z 422 ([M+H]+);
Anal. calcd for CgHosNO; . 0.30 H20: C:78.78 H:5.57 N:3.28 Found: C:78.84 H:5.50
N:3.28.
Example 52 Part 1 tert-Butyl (R,R)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1 -naphthyl)propanoate
A sample of tert-butyl (RR, SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1- naphthyl)propanoate was dissolved in methanol and was resolved by chromatography on a preparative HPLC system using a Chiralcel OD (25 x 5cm) column and 8:2 methanal:water as the eluant. The title compound was the first peak to elute. Recrystallization from ethanol provided the title compound as colorless crystals [o}p?® = -439.8° (1%, CHCla);
Example 52 Part 2 tert-butyl (S,8)-2-cyano-3-(2-isopropylphenyl)-2-methyi-3-(1-naphthyl)propanoate
The title compound is the second peak to elute in example 51 part 1.
Recrystallization from methanol provided the tite compound as colorless needles. [a]o® = +434.2° (1%, CHCl);
Example 53 Part 1 tert-butyl (S,8)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoate
A sample of tert-butyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanoate was dissolved in methanol and was resolved by chromatography on a preparative HPLC system using a Chiralcel OD (25 x 5cm) column and 8:2 methanol:water as the eluant. The title compound was the first peak to elute. Recrystallization from ethanol provided the title compound as colorless crystals [o]p®® = -283.8° (0.5%, CHCl3); 1H NMR (500 MHz, DMS0-D6) § 1.03 (s, 9 H) 1.63 (s, 3 H) 4.06 (s, 3 H) 5.78 (s, 1
H) 6.85 (td, J=7.48, 1.07 Hz, 1 H) 7.17 (d, J=8.25 Hz, 1 H) 7.22 (dd, J=7.71, 1.60 Hz, 1 H) 7.26 (ddd, J=8.63, 6.95, 1.68 Hz, 1 H) 7.48 (m, 2 H) 7.62 (t, J=7.48 Hz, 1 H) 7.87 (d, J=8.25 Hz, 1 H) 7.92 (m, 2 H) 8.08 (d, J=7.18 Hz, 1 H)
Anal. calcd for C2sH27NO3: C:77.78 H:6.78 N:3.49 Found: C:76.93 H:6.86 N:3.47.
Example 53 Part2 tert-butyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyi-3-(1 -naphthyl)propanoate
The title compound is the second peak to elute in example 53 part 1.
Recrystallization from methanol provided the title compound as colorless needles. [a]o® = +272.0° (0. 5%, CHCl3); 1H NMR (500 MHz, DMSO-D6) 5 1.03 (s, 9 H) 1.63 (s, 3 H) 4.06 (s, 3 H) 5.78 (s, 1
H) 6.85 (td, J=7.48, 1.07 Hz, 1 H) 7.17 (d, J=8.25 Hz, 1 H) 7.22 (dd, J=7.71, 1.60 Hz, 1 H) 7.26 (ddd, J=8.63, 6.95, 1.68 Hz, 1 H) 7.48 (m, 2 H) 7.62 (t, J=7.48 Hz, 1 H) 7.87 (d, J=8.25 Hz, 1 H) 7.92 (m, 2 H) 8.08 (d, J=7.18 Hz, 1 H)
Anal. calcd for CgH27NO3: C:77.78 H:6.78 N:3.49 Found: C:77.31 H:6.86 N:3.48.
Example 54
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(piperazin-1- ylcarbonyl)propanenitrile (RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid(10 g, 28.95 mmol) was dissolved in 250 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxaly! chloride (3.03 mL, 34.72 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 50 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chioride ‘was dissolved in 500 mL CHCl; and placed under nitrogen. In a separate flask piperazine (3g, 34.74 mmol) was dissolved in 200 mL
CH,Cl, under nitrogen. To this stirred solution was added a catalytic amount of
DMAP, and triethylamine (14.12 mL, 101.33 mmol). The acid chloride solution was added slowly to this stirred mixture and allowed to react overnight after which water was added fo the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, and purified on silica gel (5% methanol/methylene chloride + 0.5% Et;N) to yield 7.26 g of the title compound as a white foam. 1H NMR 500 MHz (DMSO-D6): 5 7.95 (d, 1H, J=7.18 Hz), 7.85 (m, 2H), 7.78 (d, 1H,
J=8.25 Hz), 7.52 (t, 1H, J=7.48 Hz), 7.41 (m, 2H), 7.21 (td, 1H, J=7.71 Hz, 1.63 Hz), 7.42 (d, 1H, J=8.25 Hz), 7.08 (dd, 1H, J=7.79 Hz, 1.53 Hz), 6.77 (t, 1H, J=7.48 Hz), 5.99 (s, 1H), 4.00 (s, 3H), 3.44 (bs, 4H), 2.62 (bs, 2H), 2.55 (bs, 2H), 1.59 (s, 3H)
MS (ESI) m/z 414 ([M+H]+);
Anal. calcd for CosHzzN3O2 © 0.20 Hp0: C:74.95 H:6.95 N:9.80 Found: C:74.73
H:6.72 N:9.68
Example 55 (RR.SS)(3-[4-(3-chloro-2-methylphenyl)piperazin-1-yl]-2-[(2-methoxyphenyl)(1- naphthyl) methyi]-2-methyi-3-oxopropanenitrile)
A mixture of 2-[(2-methoxy-phenyl)-naphthalen-1-yl-methyl}-2-methyl-3-oxo-3- piperazin-1-yi-propionitrile (442mg, 1.05mmol) , 1-chloro-3-iodo-2-methyl-benzene (258mg, 1.02mmol), NaOtBu (140mg, 1,.45mmol), Pdx(dba)s (27mg, 0.029mmol), racemic BINAP (39mg, 0.06mmol) in toluene (5mL) in a Carius tube was degassed with argon. The tube was sealed and placed in a preheated oil bath (80°) for 21 hours. The sample was cooled, diluted with isopropyl acetate (50mL), washed with brine then water, was dried over Na;SO;, filtered and concentrated to an oil.
Chromatography on silica gel using 15% isopropyl acetate /hexane provided a foam which was recrystallized from ethyl acetate/hexane to provide 220mg of the title compound as an amorphous white powder. 'H NMR 500MHz(DMSO-D6): & 7.99 (d, 1H, J = 7.18Hz), 7.88 (m, 2H), 7.80 (d, 1H,
J = 8.24Hz), 7.55 (t, 1H, J = 7.63Hz), 7.42 (m,.2H), 7.23 (dt, 1H, J = 8.56, 1.53Hz), &.14 (m, 4H), 7.12 (brs, 1H), 6.80 (t, 1h, J = 7.48Hz), 4.01 (s, 3H), 2.26 (s,3H), 1.64, (s.3H); MS (ESI) m/z 5638 ([M+H]+); Anal. calcd for CasHa2CIN3O2: C:73.66 H:5.99
N:7.81 Found: C:73.98 H:6.33 N:7.46.
Example 56 Part 1 (RR,S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylpheny!)piperazin-1- ylcarbonyl}-3-(1-naphthyl)propanenitrile
A solution of (R,RIS,S)2-cyano-3-(2-methoxy-phenyl)-2-methyi-3-naphthalen- 1-yl-propionic acid (1.2g, 347mmol) in THF (40mL) is treated with DMF (2 drops).
Oxalyl chloride (0.4mL, 4.60mmol) is added dropwise in order to control gas evolution; when the gas evolution siopped the soiution is heaied io reflux for & minutes. The solution is cooled, the THF is evaporated in vacuo and the solid is dissolved in dry toluene (15mL) and evaporated to a solid. This procedure is repeated twice. The acid chloride is dissolved in dichloromethane (60mL). 1-o-tolyl- piperazine hydrochloride (830mg, 3.91mmoal) and a crystal of DMAP are added to the solution of acid. This is followed by the dropwise addition of TEA (1.1mL, 7.84mmol). The reaction is stirred overnight. The reaction mixture is diluted with dichloromethane (50mL), washed with aqueous HCI (10mL 0.5N) then saturated
NaHCOs (10mL) and brine (10mL). The sample is dried over NaSQ;, filtered and concentrated in vacuo. This provided 1.7g a tan solid.
MS (ESI) m/z 504 ([M+H]+);
Anal. calcd for C33H33N302: C:78.70 H:6.60 N:8.34 Found: C:78.51 H:6.85 N:7.91.
Example 56 Part 2
(SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methyiphenyl)-1-piperazinyllcarbonyl}- 3-(1-naphthyl)propanenitrile
Preparative chiral HPLC (Chiracel OD, 25x2cm) in 5%methanol/water of (RR,S,S)-3-(2-methoxyphenyl)-2-methyl-2~{{4-(2-methylphenyl)piperazin-1- yljcarbonyl}-3-(1-naphthyl)propanenitrile, prepared in example 56 part 1, provided 570 mg of title compound as the first peak to elute.Recrystallization from ethanol hexane provided off white crystals. mp 175-177 °C; [oJo®® = -188.7° (1%, CHCl); "H NMR 500MHz(DMSO-D6): § 7.99 (d, 1H, J = 7.17Hz), 87.89 (d, 1H, J = 9.78), 7.87 (d, 1H, J = 10.38Hz), 7.80 (d, 1H, J = 8.10H2), 7.55 (t, 1H, J = 7.48Hz), 7.42 (m,2H), 7.23 (t, 1H, J = 7.63Hz), 7.14 (m, 4H), 6.95 (t, 1H, J = 7.18Hz), 6.48 (brs, 1H), 6.79 (t,1H, J = 7.48Hz), 6.02 (s, 1H), 4.01 (s,3H), 3.86 (brs, 3H), 2.68 (brs,3H), 2.22 (s,3H), 1.65 (s,3H)
MS (ESI) m/z: 504 ([M+H]+)
Anal. calcd for CasHasNaO,: C:78.70 H:6.60 N:8.34 Found: C:78.33 H:6.63 N:8.28.
Example 56 Part 3 (R,R)-3-(2-methoxyphenyi)-2-methyi-2-{{4-(2-meihyiphenyi)piperazin-1 -yljcarbonyl}- 3-(1-naphthyl)propanenitrile
The second peak from the preparative HPLC described in example 56 part 2 provided 510mg of the title compound. Recrystallization from ethanol/hexanes yielded a white powder. mp 173-176 °C; [o)o2° = +184.1° (1%, CHCl);
Anal. calcd for CasHaaN3zO2: C:78.70 H:6.60 N:8.34 Found: C:77.93 H:6.63 N:8.13.
Example 57 (S,S)-3-(2-methoxyphenyl)-2-methyl-2{[4-(3-methylphenyl)piperazin-1 ~yljcarbonyl}- 3-(1-naphthyl)propanenitrile
The title compound was prepared according to Example 2B using racemic (RR, SS)(3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazin-1-
yllcarbonyl}-3-(1-naphthyi)propanenitrile as the starting material. Recrystallization from ethanol/ether yielded white crystals. mp 104-105 °C; [odp?® = -175.00° (1%, CHC);
HRMS Calcd for 1.00 CasH33N302; Theory 503.644; Found: 503.257277
Example 58 (S)-3-[4-(3,5-dimethoxyphenyl)piperazin-1-yl}-2-[(S)-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile
A solution of (S,S)2-cyano-3-(2-methoxy-phenyl)-2-methyi-3-naphthalen-1-yl- propionic acid (0.45g, 1.30 mmol) in THF (1 50mL) is treated with DMF (2 drops).
Oxalyl chloride (0.16mL, 1.84 mmol) is added dropwise in order to control gas evolution; when the gas evolution stopped the solution is heated to reflux for 5 : minutes. The solution is cooled, the THF is evaporated in vacuo and the solid is dissolved in dry toluene (15mL) and evaporated to a solid. This procedure is repeated twice. The acid chloride is dissolved in dichloromethane (10mL) this is added to a solution of 1-(3,5-dimethoxy-phenyl)-piperazine (305mg, 1.36 mmol) and a crystal of DMAP in dichloromethane (15mL). This is followed by the dropwise addition of TEA (0.86mi, 4.27 mmol). The reaction is stirred overnight. The reaction mixture is diluted with dichloromethane (50mL), washed with aqueous HCI (10mL 0.5N) then saturated NaHCOa (10mL) and brine (10mL). The sample is dried over NaSO, filtered and concentrated in vacuo. Chromatography on silica gel using 30% ethyl acetate/hexanes provided 510mg the titte compound as a white solid. Recrystallization from ethyl acetate/hexanes yielded colorless needles. mp 186-188 °C; [op?® = -153.91° (1%, CHCl3); 1H NMR 500MHz (DMSO-D6): § 7.96 (d,1H, J = 7.33Hz), 7,86 (m, 2H), 7.78 (d,1H, J = 8.24Hz), 7.53 (t, 1H, J = 7.94Hz), 7.22 (t, 1H, J=7.48Hz), 7.12 (m, 2H), 6.79 (t,1H,
J = 7.49Hz), 6.01 (m, 4H), 4.01 (s,3H), 3.68 (s,6H), 3.05 (brs,4H), 1.63 (s,3H) (ES!) m/z 550 ([M+H]+);
Anal. calcd for CasHasN3O,4: C:74.29 H:6.42 N:7.64 Found: C:74.10 H:6.35 N:7.87.
Example 59
(S)3-(4-Indan-4-yl-piperazin-1-yt}-2-[ (S) (2-methoxy-phenyl)-naphthalen-1-yl- methyl]-2-methyl-3-oxo-propionitrile
The title compound was prepared in 77% yield according to Example 58 using 1-indan-4-yl-piperazine hydrochloride. Recrystallization from ethanol/ether yielded white crystals. mp 188-190 °C; [oJp® = -180.0° (1%,CHCls); H NMR 500MHz (DMSO-D6): 57.98 (d, 1H, J = 7.07Hz), 7.87 (m, 2H), 7.79(d, 1H, J = 8.17Hz), 7.54 (t, 1H, J = 7.78Hz), 7.43 (m, 2H), 7.23 (t, 1H, J = 7.38Hz), 7.13 (m, 2H), 7.03 (t, 1H, J =7.63Hz), 6.88 (d,1H, J = 7.33Hz), 6.79 ( t,1H, J = 7.63Hz), 6.57 (brs,1H), 6.02 (s,1H), 4.01 (s, 3H), 2.79 ({t, 2H, J = 7.18Hz), 2.74 (1, 2H, J =7.03Hz), 1.94 (giun, 2H, J = 7.18 Hz), 1.64 (s, 3H);
MS (ESI) m/z 530 ([M+H]+), Anal. calcd for CasHasN3Oa: C:79.37 H:6.66 N:7.93
Found: C:78.82 H:6.76 N:7.81
Example 60 (S.S)-3-(2-methoxyphenyi)-2-methyl-3-(1-naphthyl)-2-{{4-(1-naphthyl)piperazin-1- yijcarbonyi}propanenitrile
The title compound was prepared as a white powder, according to Example 58, using 1-naphth-4-yl-piperazine hydrochioride. foo® = -156.06° (1%, CHCl); 'H NMR 500MHz (DMSO-D6): § 8.13 (d,1H, J = 8.86Hz), 8.03 (d, 1H, J = 7.33Hz), 7.89 (m, 2H), 7.81 d,1H, J = 8.26Hz), 7.61 (d, 1H, J = 8.09Hz), 7.57 (t,1H, J = 8.09Hz), 7.49 (quin,2H, J = 3.82Hz), 7.43 (quin, 2H, J = 3.82Hz), 7.42 D(t, 1H, J = 8.25Hz), 7.23 (t, 1H, J = 7.33Hz), 7.14 (s,1H), 7.13 (d, 1H, J = 4.29Hz), 6.98 (brs,2H), 6.80 (t, 1H, J = 7.78Hz), 4.02 (s, 3H), 2.88 (brs, 2H), 1.67 (s, 3H)
MS (ESI) m/z 540 ([M+H]+);
Anal. calcd for CagHasNaOo: C:80.12 H:6.16 N:7.79 Found: C:79.37 H:6.42 N:7.25.
Example 61 (S)-3-{4-(3,4-dimethylphenyl)piperazin-1-yl}-2-[(S)-(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyi-3-oxopropanenitrile
The title compound was prepared in 25% yield according to Example 58 using 1-indan-4-yl-piperazine hydrochloride. Recrystallization from ethyl acetate/hexane yielded a white solid. mp 181-183 °C; [o]p? = -180.07° (1%, CHCl3); H NMR 500MHz (DMSO-D6): § 7.97 (d,1H, J = 6.99
Hz), 7.86 (m, 2H), 7.78 (d, 1H, J = 7.97Hz), 7.52 (t, 1H, J = 7.3%Hz), 7.42 (m, 2H),7.23 (dt, 1H, J = 8.36, 1.60Hz), 7.12 (m,2H), 6.95 (d,1H, J = 8.36Hz), 6.79 (t, 1H, J = 7.57Hz), 6.70 (s,1H), 6.61 (d, 1H, J = 7.38Hz), 6.01 (s,1H), 4.01 (s, 3H), 3.67 (brs, 3H), 2.97 (brs, 3H), 2.14 (s,3H), 2.10 (s,3H), 1.63 (s,3H)
MS (ESI) m/z 518 ((M+H]+);
Anal. calcd for CagHasN3O2: C:78.89 H:6.81 N:8.12 Found: C:77.36 H:6.59 N:7.85.
Example 62 (RR,SS) 3-{4-(H-indol-4-yl)piperazin-1 -yl]-2-{(2-methoxyphenyl)(1-naphthyl)methyl]- 2-methyl-3-oxopropanenitrile
The title compound was prepared in 74% Yield according to Example 58 using 4-piperazin-1-yl-1H-indole hydrochloride and (RR,SS)2-cyano-3-(2-methoxy-phenyl)- 2-methyl-3-naphthalen-1-yl-propionic acid. Recrystallizaton from ethyl acetate/hexane yielded pink crystals. : mp 225-226 °C; 'H NMR 500MHz (DMSO-D6): 5 11.03 (s,1H), 7.98 (d, 1H] = 2.08Hz), 7.85 (m,2H), 7.77 (d, 1H,J = 8.17Hz), 7.53 (t,1H, J = 7.45Hz), 7,42 (m,2H), 7.21 (m 2H), 7.11 (t, 2H, J = 8.42Hz), 7.00 (t, 1H, J = 8.06Hz), 6.78 (t,1H, J = 7.57Hz), 6.38 (s,1H), 6.34 (m,1H), 6.02 (s,1H), 3.73 (brm,3H), 2.97(brm,3H0, 1.64 (s,3H)
MS (ESI) m/z 529 (IM+H]+);
Anal. calcd for CagH32N4O2: C:77.25 H:6.10 N:10.60 Found: C:76.86 H:6.13 N:10.43.
Example 63 (S)-3-[4-(3-chlorophenyl)piperazin-1-yl]-2-{(S)-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile
The title compound was prepared in 72% yield according to Example 58 using 1-(3-chlorophenyl)-piperazine hydrochloride. ~~ Recrystallization from ethyl acetate/hexane yielded white crystals.
mp 174-176 °C; []o? = -146.5° (1% , CHCl); "H NMR 500MHz (DMSO-D6): 5 7.97 (d, 1H, J = 7.33Hz), 7.86 (m, 2H), 7.78 (d, iH J = 8.24Hz), 7.52 (t, 1H, J = 7.63Hz), 7.41 (m, 2H), 7.23 (m, 2H), 7.13 (d,1H, J = 9.47Hz), 7.11 (dd, 1H, J = 6.11,1.68 Hz), 6.91 (s,1H),6.86 (dd,1H J = 8.40, 1.83Hz), 6.80 (d,1H, J = 7.64Hz, 6.78 (dt,1H, J = 7.33, 1.06 Hz), 6.01 (s,1H), 4.01 (s, 3H), 3.75 (brm,3H), 3.12 (brm,3H), 1.63 (s,3H)
MS (ESI) m/z 524 ([M+H]+),
Anal. calcd for CaHaoCIN3O2: C:73.34 H:5.77 N:8.02 Found: C:73.71 H:6.23 N:7.51.
Example 64 (S)-3-4-(2,3-dimethylphenyl)piperazin-1 -yl]-2-{(S)-(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyl-3-oxopropanenitrile
The title compound was prepared in 67% yield according to Example 58 using 1-(2,3-dimethylphenyl)-piperazine hydrochloride. Recrystallization from ethyl acetate/hexane yielded white crystals. mp 194-195 °C; [edo = -180.00° (1%, CHCl);
H NMR 500MHz (DMSO-D6): § 7.99 (d,1H, J = 7.33Hz), 7.88 (m,1H), 7.81 (d,1H, J = 8.09Hz), 7.56 (t,1H, J = 7.63Hz), 7.43 (quin,2H, J = 1.83Hz), 7.23 (t1H, J = 6.88Hz), 7.13 (d,2H, J = 8.09Hz), 7.01 (t,1H, J = 7.64Hz), 6.87 (d,1H, J = 7.48Hz), 6.80 (t,1H, J = 7.63Hz), 6.71 (brs,1H), 6.03 (s,3H), 4.01 (s,3H), 3.65 (brm,3H), 2.65 (brm,3H), 2.19 (s,3H), 2.14 (s,3H), 1.65 (s,3H),
MS (ESI) m/z 518 ([M+H]+);
Anal. calcd for CagHasN3Oz : C:78.01 H:6.76 N:8.12 Found: C:78.48 H:6.88 N:8.00.
Example 65 (S)-3-[4-(4-chlorophenyl)piperazin-1 -yl}-2-[(S)-(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyl-3-oxopropanenitrile
The title compound was prepared in 35% yield according to Example 58 using 1-(4-chloro-phenyl)-piperazine dihydrochloride. Recrystallization from ethyl acetate/hexane yielded white crystals. mp 178-180 °C;
(odo? = -1565.6° (1%, CHC); '"H NMR 500MHz (DMSO-D6): 5 7.98 (d,1H, J = 7.33Hz),7.87 (m,2H), 7.88 (d,1H, J = 8.25Hz), 7.53 (tH, J = 7.63Hz), 7.43 (d,1H, J = 9.32Hz), 7.43 (quin,AH, J = 4.54Hz), 7.24 (m,3H), 7.14 (t,2H, J = 8.25Hz), 6.80 (t,1H, J = 7.48Hz), 6.01 (s,1H), 4.01 (s,3H), 3.65 (brs,3H), 3.09 (brm,4H), 1.64 (s,3H)
MS (ESI) m/z 524 ([M+H]+),
Anal. calcd for CaoHaCINaO,: C:73.34 H:6.77 N:8.02 Found: C:72.8 H:5.97 N:7.67
Example 66 (S)-3-[4-(1H-Indol-4-yl)-piperazin-1 ~yl]-2-[(S)-(2-methoxy-phenyl }-naphthalen-1-yi- methyl]-2-methyl-3-oxo-propionitrile
The title compound was prepared in 67% yield according to Example 58 using of (S, S)2-cyano-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-propionic acid .
Recrystallization from ethyl acetate/hexane yielded white crystals. mp 174-176 °C; [a]? =-191.9° (1% , CHCla);
MS (ESI) m/z 529 ([M+H]+);
Anal. calcd for CasH3N,O2: C:77.25 H:6.10 N:10.60 Found: C:75.4 H:6.31 N:10.16
Example 67 (S.8)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3-(trifluoromethyl)phenyl] piperidin-1-yl}carbonyi)propanenitrile
The title compound was prepared in 75% yield according to Example 58 using 4-(3- trifluoromethyl-phenyl)-piperidine. ~~ Recrystallization from ethyl acetate/hexane yielded white crystals mp 123-127 °C; [oa]? = -144.4° (1%, CHCl);
H NMR 500MHz (DMSO-D6): § 8.02 (d,1H, J = 7.03Hz), 7.88 (m,2H), 7.82 (d,1H, J = 8.25Hz), 7.56 (t,1H, J = 7.79Hz),7.51 (brm,2H), 7.42 (d,1H, J = 7.48Hz), 7.42 (quin,1H, J = 3.51Hz), 7.23 (t,1H, J = 7.03Hz), 7.14 (m,2H), 6.80 (t,1H, J = 7.48Hz), 6.02 (s,1H),4.37 (brm, 2H), 4.01 (s, 3H), 2.88 (brm, 2H), 1.66 (s, 3H)
MS (ESI) m/z 557 ([M+H]+);
Anal. calcd for CasHaiFaN20,: C:73.35 H:5.61 N:5.03 Found: C:73.99 H:6.00 N:4.72
Example 68 (S)-3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-2-{(S)-(2-methoxy-phenyl)- naphthalen-1-yl-methyl}-2-methyl-3-oxo-propionitrile
The title compound was prepared in 75% yield according to Example 58 using 4-(4-chloro-phenyt)-1 ,2,3,6-tetrahydro-pyridine.. Recrystallization from ethyl acetate/hexane yielded white crystals. mp 118-122 °C; [odo = -129.1° (1%, CHCl); 'H NMR 500MHz (DMSO-D6): 5 7.94 (d ,1H, J = 7.17Hz), 7.92 (d ,1H, J = 8.70Hz), 7.79 (brm,1H), 7.76 (d ,1H, J = 8.26Hz), 7.49 (t ,1H, J = 7.64Hz), 7.39 (m,6H), 7.23 (t AH, J = 7.18Hz),7.18 (brd,1H, J = 6.24Hz), 7.12 (d JAH, J = 8.40Hz), 6.82 (d ,1H, J = 7.48Hz), 6.11 (brs, 1H), 6.03 (s,1H3.99 (s,1H), 1.64 (s,3H)
MS (ESI) m/z 521 ([M+H]+);
Anal. calcd for CasHagCIN2O,: C:76.07 H:5.61 N:5.38 Found: C:75.51 H:5.63 N:5.19
Example 69 (S,S)-3-(2-Methoxy-phenyl)-2-methyl-3-naphthalen-1-yi-2-[4-(3-trifluoromethyl- phenyl)-3,6-dihydro-2H-pyridine-1-carbonyi}-propionitriie
The title compound was prepared in 49% yield, as a white solid, according to
Example 58 using 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahyd ro-pyridine hydrochloride. [oJp® = -123.5° (1% , CHCl) 4 NMR 500MHz (DMSO0-D6): § 7.97 (d, 1H, J = 3.30Hz), 7.91 (d, 1H, J = 8.70Hz), 7.76 (d, 1H, J = 3.30H2),7.76 (brs,1H), 7.75 (d, 1H, J = 8.24Hz),7.65 (brs, 1H), 7.62 (d, 1H, J = 7.63Hz), 7.58 (d, 1H, J = 7.60Hz), 7.50 (t, 1H, J =7.64Hz), 7.42 (t, 1H, J = 7.48Hz), 7.38 (brm,1H), 7.24 (t, 1H, J = 7.18Hz), 7.22, (brm, 1H), 7.12 (d, 1H, J =8.25 Hz), 6.82 (t,1H, J = 7.64Hz), 6.21 (brs, 1H), 6.03 (s,1H), 4.01 s,3H), 1.65 (s, 3H)
MS (ESI) m/z 555 ([M+H]+)
Anal. calcd for CaaHzgF3N202: C:73.63 H:5.27 N:5.05 Found: C:73.45 H:5.51 N:5.06.
Example 70
(SS)2-[4-(4-Chioro-phenyl)-piperidine-1-carbonyl]-3-(2-methoxy-phenyl)-2-methyl-3- naphthalen-1-yl-propionitrile
The title compound was prepared in 97% yield, as a white solid, according to
Example 58 using 4-(4-chlorophenyl)piperidine hydrochloride mp 156-158 °C; [a]p?® = -174.89°, (1%, CHC); 'H NMR (DMSO-D6): & 8.01 (d,1H, J = 6.87Hz), 7.88 (t2H, J = 10.09Hz), 7.83 (d,1H, J = 8.25Hz), 7.56 (tH, J = 7.63Hz), 7.42 (quin,2H, J = 9.05Hz), 7.30 (brm, 1H), 7.23 (t,1H, J = 7.18Hz), 7.13 (d,2H, J = 8.24Hz), 6.80 (41H, J = 7.38H2), 6.01 (s,1H), 4.01 (s,3H),1.64 (s,3H)
MS (ESI) m/z 523 ((M+H]+);
Anal. calcd for CasHa1CIN2O,: C:75.78 H:5.97 N:5.36 Found: C:75.58 H:5.99 :N: 5.07
Example 71 (RR, SS)-3-(2-methoxyphenyl)-2-methyl-3-( 1-naphthyl)-2-({4-[3-(trifluoromethyl) phenyl]piperidin-1 -yl}carbonyl)propanenitrile
The title compound was prepared in 35% yield according to Example 56 using racemic 4-(3-trifluoromethyphenyl)piperidine hydrochloride.
MS (ES!) m/z 595 (IM+K]+);
Anal. calcd for C34H31F3N202: C:73.37 H:5.61 N:5.03 Found: C:73.31 H:5.88
N:4.78.
Example 72 : (RR,SS)-3-(2-methoxyphenyl)-2-methyi-3-(1-naphthyl)-2-(piperidin-1- ylcarbonyl)propanenitrile (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid( g, 2.89 mmol) was dissolved in 50 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.303 mL, 3.47 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 50 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CHCl, and placed under nitrogen. In a separate flask piperidine (0.49 mL, 4.91 mmol) was dissolved in 50 mL CHCl, under nitrogen. To this stirred solution was added a catalytic amount of
DMAP, and triethylamine (0.69 mL, 4.91 mmol). The acid chloride in CH2Cl2 was added rapidly to this stirred mixture and allowed to react for 2 hours after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSOs, filtered, evaporated to dryness, and recrystallized from ethanol to yield 851 mg of the title compound as a crystalline solid. mp 194-196 °C; 1H NMR 400 MHz (DMSO0-D6): § 7.94 (d, 1H, J=7.32 Hz), 7.85 (m, 2H), 7.78 (d, 1H,
J=8.30 Hz), 7.52 (t, 1H, J=7.32 Hz), 7.40 (m, 2H), 7.21 (td, 1H, J=7.75 Hz, 1.71 Hz), 7.12 (dd, 1H J=8.30 Hz, 0.98 Hz), 7.06 (dd, 1H, J=7.81 Hz, 1.71 Hz), 6.77 (td, 1H,
J=7.57 Hz, 0.98 Hz), 5.99 (s, 1H) 4.01 (s, 3H), 3.49 (bs, 4H), 1.58 (s, 1H), 1.41 (bs, 6H)
MS (APCI) m/z 413 ([M+H]+);
Anal. calcd for CorHasN20O2: C:78.61 H:6.84 N:6.79 Found: C:78.32 H:6.86 N:6.69.
Example 73 (RR, SS)-2-cyano-3-(2-methoxyphenyt)-2-methyl-3-(1 -naphthyl)propanamide (RR, SS) 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyljpropanoic acid(345 mg, 1 mmol) was dissolved in 10 mL THF. A catalytic amount of DMF was added to the reaction mixture. Thionyl chloride (131 mg, 1.1 mmol) was added slowly. The reaction mixture was stirred 2 hours. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 10 ml toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 5 mL CHCl, and placed under nitrogen. in a separate flask, methanolic ammonia (2M 1.5 mL, 3 mmol) was dissolved in 10 mL CHCl, under nitrogen. To this stirred ‘solution was added a catalytic amount of DMAP, and triethylamine (0.35 mL, 2.5 mmol). The acid chloride in CH,Cl, was added rapidly to this stirred mixture and allowed to react for 2 hours after which water was added to the reaction mixture.
The organic layer was separated and washed with brine, dried over MgSOs, filtered, evaporated to dryness, and purified on silica gel (30% ethyl acetate/hexanes) to yield 66 mg of the title compound.
1H NMR 500 MHz (DMSO-D6): & 8.07 (d, 1H, J=7.18 Hz), 7.94 (m, 1H), 7.85 (m, 1H), 7.79 (m, 2H), 7.53 (t, 1H, J=7.79 Hz), 7.41 (m, 2H), 7.35 (s, 1H), 7.20 (td, 1H,
J=7.55 Hz, 1.53 Hz), 7.11 (d, 1H, J=7.94 Hz), 7.08 (dd, 1H, J=7.78 Hz, 1.53 Hz), 6.76 (t, 1H, J=7.17 Hz), .85 (s, 1H), 4.03 (s, 3H), 1.57 (s, 3H).
MS (ESI) m/z 362 (M+NH4]+);
Anal. calcd for CogH2oN202: C:76.72 H:5.85 N:8.13 Found: C:76.68 H:5.83 N:8.13.
Example 74 (RR.SS)-2-cyano-N-ethyl-3-(2-methoxyphenyi)-2-methyl-3-(1-naphthylpropanamido (RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthylpropanoic acid(345 mg, 1 mmol) was dissolved in 10 mL THF. A catalytic amount of DMF was added to the reaction mixture. Thionyl chloride (131 mg, 1.1 mmol) was added slowly. The reaction mixture was stirred 2 hours. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 10 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in
CH,Cl> (5 mL) and placed under nitrogen. In a separate flask, ethyl amine (135 mg, 3 mmol) was dissolved in 10 mL CHCl, under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.35 mL, 2.5 mmol). The acid chloride in CH2Cl, was added rapidly to this stiited mixture and allowed to react for 2 hours after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, and purified on silica gel (30% ethyl acetate/hexanes) fo yield 89 mg of the title compound. 'H NMR 500 MHz (DMSO-D8): 3 8.27 {t, 1H, J=5.65 Hz), 8.01 (d, 1H, J=7.33 Hz), 7.94 (m, 1H), 7.84 (m, 1H), 7.79 (d, 1H, J=8.25 Hz), 7.51 (t, 1H, J=7.64 Hz), 7.41 (m, 2H), 7.21 (td, 1H, J=7.79 Hz, 1.60 Hz), 7.13 (m, 2H), 7.78 (id, 1H, 7.48 Hz, 0.91 Hz), 5.86 (s, 1H), 4.02 (s, 3H), 2.89 (q, 1H, J=7.02 Hz), 2.87 (a, 1H, J=7.02 Hz), 1.55 (s, 3H), 0.58 (t, 3H, J=7.18 Hz)
MS (ESI) m/z 373 ((M+H]+);
Anal. calcd for CasHasN2O2: C:77.39 H:6.49 N:7.52 Found: C:77.37 H:6.65 N:7.59.
Example 75
(RR,SS)-N-(tert-butyl)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyljpropanoic acid (345 mg, 1 mmol) was dissolved in 10 mL THF. A catalytic amount of DMF was added to the reaction mixture. Thionyl chloride (131 mg, 1.1 mmol) was added slowly. The reaction mixture was stirred 2 hours. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 10 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 5 mL CH,Cl, and placed under nitrogen. In a separate flask, tert-butyl amine (219 mg, 3 mmol) was dissolved in 10 mL CH,Cl, under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.35 mL, 2.5 mmol). The acid chloride in CH.Cl, was added rapidly to this stirred mixture and allowed to react for 2 hours after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSOa, filtered, evaporated to dryness, and purified on silica gel (30% ethyl acetate/hexanes) to yield 135 mg of the title compound.
H NMR 500 MHz (DMSO-D6): 58.02 (d, 1H, J=7.18 Hz), 7.95 (m, 1H), 7.84 (m, 1H), 7.78 (d, 1H, J=8.256 Hz), 7.52 (t, 1H, J=7.94 Hz), 7.41 (m, 2H), 7.22 (s, 1H), 7.20 (dd, 1H, J=7.48 Hz, 1.07 Hz), 7.15 (dd, iH, J=7.70 Hz, 1.68 Hz), 7.11 (d, 1H,
J=7.64 Hz), 6.78 (td, 1H, J=7.48 Hz, 0.92 Hz), 5.86 (s, 1H), 4.02 (s, 3H), 1.59 (s, 3H), 0.94 (s, 9H)
MS (ESI) m/z 399 ([M-H]-);
Anal. calcd for CogHasN202: C:77.97 H:7.05 N:6.99 Found: C:77.80 H:7.19 N:6.84.
Example 76 (RR,SS)-2-cyano-3-(2-methoxyphenyl)-N,N.2-trimethyl-3-(1 -naphthyl)propanamide (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-( 1-naphthyl)propanocic acid(345 mg, 1 mmol) was dissolved in 10 mL THF. A catalytic amount of DMF was added to the reaction mixture. Thionyl chloride (131 mg, 1.1 mmol) was added slowly. The reaction mixture was stirred 2 hours. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 10 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 5 mL CHCl, and placed under nitrogen. In a separate flask, dimethyl amine (135 mg, 3 mmol) was dissolved in 10 mL CHCl» under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.35 mL, 2.5 mmol). The acid chloride in CH,Cl, was added rapidly to this stirred mixture and allowed to react for 2 hours after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, and purified on silica gel (30% ethyl acetate/hexanes) to yield 129 mg of the title compound. 'H NMR 500 MHz (DMSO-D86): 3 7.91 (d, 1H, J=7.18 Hz), 7.86 (t, 1H, J=6.41 Hz), 7.85 (t, 1H, J=7.18 Hz), 7.78 (d, 1H, J=8.25 Hz), 7.52 {t, 1H, J=7.64 Hz), 7.41 (m, 2H), 7.21 (td, 1H, J=7.79 Hz, 1.63 Hz), 7.12 (d, 1H, J=7.64 Hz), 7.08 (dd, 1H, J=6.26
Hz, 1.53 Hz), 6.77 (td, 1H, J=7.48 Hz, 0.84 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 2.95 (bs, 6H), 1.60 (s, 3H)
MS (ES!) m/z 373 ([IM+H]+);
Anal. calcd for CasHasN202: C:77.39 H:6.49 N:7.52 Found: C:77.00 H:6.65 N:7.46.
Example 77 : (RR, SS)-2-cyano-N-methoxy-3-(2-methoxyphenyi)}-N,2-dimethyl-3-(1- naphthyl)propanamide : (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyi-3-(1-naphthyl)propanoic acid(1 g, 2.89 mmol) was dissolved in 50 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.303 mL, 3.47 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 50 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CHCl, and placed under nitrogen. In a separate flask N-O-dimethyl-hydroxyl amine hydrochloride (424 mg, 4.34 mmol) was dissolved in 50 mL CHCl under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.69 mL, 4.91 mmol).
The acid chloride in CH.Cl, was added rapidly to this stirred mixture and allowed to react for 2 hours after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO;, filtered, evaporated to dryness, and recrystallized from methanol to yield 644 mg of the title compound as a crystalline solid. mp 151-153 °C;
"H NMR 500 MHz (DMSO-D6): & 7.79 (d, 1H, J=7.18 Hz), 7.85 (m, 2H), 7.79 (d, 1H,
J=8.25 Hz), 7.54 (t, 1H, J=7.79 Hz), 7.41 (m, 2H), 7.21 (id, 1H, J=8.86 Hz, 1.68 Hz), 7.43 (d, 1H, J=8.25 Hz), 7.06 (dd, 1H, J=7.79 Hz, 1.37 Hz), 6.76 (t, 1H, J=7.48 Hz), 6.01 (s, 1H), 4.03 (s, 3H), 3.82 (s, 3H), 3.00 (s, 3H), 1.59 (s, 3H)
MS (ESI) m/z 389 ([M-+H]+),
MS (ESI) m/z 406 ([M+NH4]+);
Anal. calcd for CogHa4N2O3: C:74.21 H:6.23 N:7.21 Found: C:73.82 H:6.20 N:7.02.
Example 78 (RR,SS)-2-benzyl-3-{4-(3,5-dichloro-4-pyridinyl)-1 -piperazinyl]-2-[(2- methoxyphenyl)(1-naphthyl)methyl]-3-oxopropanenitrile (RR, SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl)propanoic acid (250 mg, mmol) was dissolved in 10 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.062 mL, 0.712 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 20 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 5 mL CHCl; and placed under nitrogen. In a separate fiask i~{3,5-dichioropyridin-4-yi)piperazine (207 mg, 0.820 mmol) was dissolved in 15 mL CHCl, under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.250 mL, 1.78 mmol). The acid chloride in CH2Cl, was added rapidly to this stirred mixture and allowed to react for 2 hours after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSOQ, filtered, evaporated to dryness, and purified on silica gel (20% ethyl acetate/Hexanes +1% NH4OH) to yield 140 mg of the title compound as a white foam. 'H NMR (DMSO-D8): & 8.42 (s, 1H), 8.02 (d, 1H, J=6.37 Hz), 7.95 (d, 1H, J=4.41
Hz), 7.87 (d, 1H, J=5.43 Hz), 7.82 (d, 1H, 8.19 Hz), 7.57 (t, 1H, J=7.63 Hz), 7.47 (m, 2H), 7.35 (m, 3H), 7.28 (m, 3H), 7.19 (m, 3H), 6.86 (t, 1H, J=7.54 Hz), 6.36 (s, 1H), 4.07 (s, 3H)
MS (ESI) m/z 635 ([M+H]+);
Anal. calcd for Ca7Ha2ClaN4O, © 0.20 CgHyq: C:70.28 H:5.37 N:8.58 Found: C:70.03
H:5.04 N:8.26.
Example 79 : (R,S)-3-[4-(2,3-dimethylphenyl)piperazin-1 -yl}-2-[(R,S)-(2-methoxyphenyl)(1 - naphthyl)methyl]-2-methyl-3-oxopropanenitrile (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoic acid(5 g, 14.47 mmol) was dissolved in 50 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyi chloride (1.52 mL, 17.36 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 50 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 50 mL CH.Cl, and placed under nitrogen. In a separate flask 1-(2,3-Dimethyl-phenyl)-piperazine hydrochloride (5.58 g, 24.60 mmol) was dissolved in 100 mL CHxClz under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (6.87 mL, 49.20 mmol). The acid chloride in CHCl, was added rapidly to this stirred mixture and allowed to react for 2 hours after which water was added to the reaction mixture.
The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, and recrystallized from ethyl acetate/hexanes to yield 2.37 g of the title compound as a crystalline solid. mp 219 °C; 1H NMR 500 MHz (DMSO-D6): & 8.00 (d, 1H, J=7.18 Hz), 7.88 (m, 2H), 7.80 (d, 1H,
J=8.25Hz), 7.55 (t, 1H, J=7.64 Hz), 7.42 (m, 2H), 7.23 (id, 1H, J=8.70 Hz, 1.68 Hz), 7.13 (dd, 2H, J=7.94 Hz, 1.68 Hz), 7.00 (t, 1H, J=7.79 Hz), 6.80 (t, 1H, J=7.94 Hz), 6.70 (bs, 1H), 6.02 (s, 1H), 4.01 (s, 3H), 3.70 (bs, 4H), 2.62 (bs, 4H), 2.18 (s, 3H), 2.13 (s, 3H), 1.65 (s, 3H)
MS (ESI) m/z 518 ([M+H]+);
Anal. calcd for CaqHasNsO,: C:78.89 H:6.81 N:8.12 Found: C:78.76 H:6.93 N:7.94.
Example 80 (R,S)-3-[4-(3-isopropylphenyi)piperazin-1 -yi]-2-[(R,S)-(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyl-3-oxopropanenitrile (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid(0.25 g, 0.72 mmol) was dissolved in 10 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.075 mL, 0.87 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 20 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CHCl, and placed under nitrogen. In a separate flask 1-(3-isopropyl-phenyl)-piperazine (178 mg, 0.087 mmol) was dissolved in 10 mL CHClz under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.35 mL, 2.53 mmol). The acid chloride in CHCl, was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, and purified on silica gel (35% ethyl acetate/hexanes) to yield 150 mg of the title compound as a white powder. : ~ '"H NMR 500 MHz (DMSO-D8): 8 7.97 (d, 1H, J=7.18 Hz), 7.88 (m, 1H), 7.84 (m, 1H), 7.78 (d, 1H, J=8.09 Hz), 7.52 (t, 1H, J=7.64 Hz), 7.42 (m, 2H), 7.23 (td, 1H,
J=7.79 Hz, 1.53 Hz), 7.12 (m, 3H), 6.79 (t, 1H, J=7.48 Hz), 6.69 (d, 2H, J=7.64 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.68 (bs, 4H), 3.03 (bs, 4H), 2.79 (sep, 1H, J=6.87 Hz), 1.64 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H)
MS (ESI) m/z 532 ([M+H]+);
Anal. calcd for CasHazN3O2 e 0.10 H20 eo 0.15 CoH: C:78.91 H:7.25 N:7.69 Found:
C:78.91 H:7.49 N:7.48.
Example 81 - - (RR,SS)3-[4-(3 ,5-dichioropyridin-4-yl)piperazin-1 -yl]-2-{(2-methoxyphenyl)(1- naphthyl )methyl]-2-methyl-3-oxopropanenitrile (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid(1.5 g, 4.34 mmol) was dissolved in 50 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.46 mL, 5.21 mmol) was added slowly. The reaction mixture was stirred untii no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and , evaporated. 50 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 20 mL CHCl, and placed under nitrogen. In a separate flask 2,6-dichloro-4-pyridyl-piperazine (1.51 g, 6.51 mmol)
was dissolved in 20 mL CH.Clz under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (1.81 mL, 13.02 mmol). The acid chloride in CH,Cl, was added rapidly to this stirred mixture and allowed to react ovemight after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, and recrystallized from ethanol to yield 1.92 g of the title compound as a crystalline solid. mp 242-243 °C; 'H NMR 500 MHz (DMSO-D6): 8 8.44 (s, 2H), 8.00 (d, 1H, J=33 Hz), 7.87 (m, 2H), 7.80 (d, 1H, J=8.25 Hz), 7.55 (t, 1H, J=7.64 Hz), 7.42 (m, 2H), 7.23 (td, 1H, J=7.79
Hz, 1.53 Hz), 7.14 (m, 2H), 6.80 (td, 1H, J=7.48, 0.92 Hz), 6.02 (s, 1H), 4.01 (s, 3H), 3.65 (bs, 4H), 3.27 (bs, 4H), 1.66 (s, 3H)
MS (ESI) m/z 559 (IM+H]+);
Anal. calcd for CaiH2sCLNsO2: C:66.55 H:5.04 N:10.01 Found: C:66.29 H:4.79
N:9.76
Example 82 (2S8)-3-[4-(3-chloro-2-methyiphenyl)piperazin-1-yl]-2-{(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyi-3-oxopropanenitrile (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoic acid(12 g, 34.74 mmol) was dissolved in 500 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (3.64 mL, 41.69 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 250 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 250 mL CHCl, and placed under nitrogen. In a separate flask 1-(3-chloro-2-methylphenyl)piperazine hydrochloride (10.67 g, 41.69 mmol) was dissolved in 250 mL CH.Cl> under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (21.80 mL, 156.33 mmol). The acid chloride in CHCl; was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture.
The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, purified on silica gel (20% hexanes/CH2Cl), the purified fractions were evaporated and recrystallized from ethyl acetate/hexanes to yield 12.58 g of the title compound as a crystalline solid. mp 150-153 °C; [oJp® = -167.9° (1% , CHCI3); 1H NMR 500 MHz (DMSO-D6): § 8.00 (d, 1H, J=7.33 Hz), 7.88 (m, 2H), 7.86 (d(1H,
J=8.25 Hz), 7.55 (t, 1H, J=7.64 Hz), 7.43 (m, 2H), 7.23 (td, 1H, J=7.79 Hz, 1.37 Hz), 7.14 (m, 3H), 6.86 (bs, 1H), 6.80 (t, 1H, J=7.48 Hz), 6.02 (s, 1H), 4.01 (s, 3H), 3.69 (bs, 4H), 2.70 (bs, 4H), 2.27 (s, 3H), 1.65 (s, 3H)
MS (ES!) m/z 538 ([M+H]+);
Anal. calcd for CazHaCIN3O2: C:73.66 H:5.99 N:7.81 Found: C:73.33 H:6.04 N:7.72.
Example 83 (S)-3-[4-(2-fluorophenyl)piperazin-1-yi}-2-[(S)-(2-methoxypheny!)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid(450 mg, 1.30 mmol) was dissolved in 20 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chioride (0.160 mL, 1.82 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 25 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CHCl; and placed under nitrogen. In a separate flask 1-(2-flouro- phenyl)piperazine hydrochloride (247 mg, 1.37 mmol) was dissolved in 15 mL CHzCl> under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.82 mL, 5.86 mmol).
The acid chloride in CHCl, was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO, filtered, evaporated to dryness, and recrystallized from methanol to yield 480 mg of the title compound as a crystalline solid. mp 145-148 °C; [o]o? = -172.15° (1% , CHCI3);
H NMR 500 MHz (DMSO-D6): § 7.98 (d,1H, J=7.33 Hz), 7.87 (m, 2H), 7.79 (d, 1H,
J=8.25 Hz), 7.54 (t, 1H, J=7.94 Hz), 7.42 (m, 2H), 7.23 (td, 1H, J=8.86 Hz, 1.53 Hz),
7.12 (m, 4H), 6.98 (m, 1H), 6.93 (bs, 1H), 6.79 (t, 1H, J=7.33 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.69 (bs, 4H), 2.88 (bs, 4H), 1.64 (s, 3H)
MS (ESI) m/z 508 ((M+H]+);
Anal. calcd for CaHaFN3O2 e 0.25 HO: C:75.05 H:6.00 N:8.21 Found: C:75.02
H:6.07 N:8.23.
Example 84 (S)-3-[4-(2-chlorophenyl)piperazin-1-yl}-2-{(S)-(2-methoxyphenyl)(1 -naphthyl) methyl]-2-methyl-3-oxopropanenitrile (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoic acid(450 mg, 1.30 mmol) was dissolved in 20 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.160 mL, 1.82 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 25 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CH2Cl, and placed under nitrogen. In a separate flask 1-(2-chloro- phenyl)piperazine hydrochloride (269 mg, 1.37 mmol) was dissolved in 15 mL CHCl, under nitrogen. To this stirred solution was added a cataiytic amount of DMAP, and triethylamine (0.82 ml, 5.85 mimo).
The acid chloride in CH2Cl» was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture. The organic - layer was separated and washed with brine, dried over MgSO.,, filtered, evaporated to dryness, and recrystallized from methanol to yield 430 mg of the title compound as a crystalline solid. : mp 145-147 °C; [oo = -168.03° (1% solution, CHCla); 1H NMR 500 MHz (DMS0-D6): § 7.98 (d,1H, J=7.18 Hz), 7.87 (m, 2H), 7.79 (d, 1H,
J=8.25 Hz), 7.54 (t, 1H, J=7.94 Hz), 7.42 (m, 3H), 7.28 (t, 1H, J=7.33 Hz), 7.23 (t, 1H, J=7.18 Hz), 7.12 (m, 2H), 6.80 (t, 1H, J=7.64 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.69 (bs, 4H), 2.88 (bs, 4H), 1.64 (s, 3H)
MS (ESI) m/z 524 (IM+H]+);
Anal. calcd for CazHaoCIN;O2 » 0.20 HO: C:72.84 H:5.81 N:7.96 Found: C:72.79
H:5.88 N:7.92.
Example 85 (S,S)-3-(2-methoxyphenyl)-2-{[4-(3-methoxyphenyl)piperazin-1 -yijcarbonyl}-2- methyl-3-(1-naphthyl)propanenitrile (S ,8)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)propanoic acid(450 mg, 1.30 mmol) was dissolved in 20 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.160 mL, 1.82 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 25 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CHCl, and placed under nitrogen. In a separate flask 1-(3-methoxy- phenyl)piperazine dihydrochloride (593 mg, 1.37 mmol) was dissolved in 15 mL CHCl» under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.82 mL, 5.86 mmol). The acid chloride in CHzCl> was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSOs,, filtered, evaporated to dryness, and recrystallized from ethanol/diethy! ether to yield 530 mg of the title compound as a crystalline solid. mp 147-148 °C; [o]o® = -160.87° (1% , CHCI3); 1H NMR 500 MHz (DMSO-D6): § 7.97 (d, 1H, J=7.33 Hz), 7.87 (m, 1H), 7.84 (m, 1H), 7.78 (d, 1H, J=8.25 Hz), 7.52 (t, 1H, J=7.79 Hz), 7.41 (m, 2H), 7.23 (td, 1H,
J=7.79 Hz, 1.53 Hz), 7.12 (m, 3H), 6.79 (t, 1H, J=7.33 Hz), 6.48 (d, 1H, J=8.40 Hz), 6.42 (s, 1H), 6.38 (dd, 1H, J=8.09 Hz, 1.83 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.70 (s, 3H), 3.67 (bs, 4H), 3.08 (bs, 4H), 1.63 (s, 3H)
MS (ESI) m/z 520 ([M+H]+);
Anal. calcd for CasHasN3sOs: C:76.28 H:6.40 N:8.09 Found: C:76.06 H:6.39 N:8.06.
Example 86 (R,S)-3-[4-(3-chloropyridin-4-yf)piperazin-1 -yl}-2-{(R,S)-(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyl-3-oxopropanenitrile
(R,S)-3-[4-(3,5-dichloropyridin-4-yl)piperazin-1 -yil-2-[(R,S)-(2- methoxyphenyt)(1-naphthyl)methyl}-2-methyl-3-oxopropanenitrile (600 mg), 10% palladium on carbon (50 mg), triethyl amine (1 mL) were dissolved in THF (20 mL), evacuated and placed under one atmosphere of hydrogen overnight. The reaction mixture was filtered and evaporated to dryness. Purification of silica gel (650% ethyl acetate/CH,Cl,) afforded 167 mg of the title compound as an off white solid 'H NMR 400 MHz (DMSO-D8): § 8.41 (s, 1H), 8.32 (d, 1H, J=5.44 Hz), 7.97 (d, 1H,
J=7.19 Hz), 7.87 (m, 2H), 7.79 (d, 1H, 8.16 Hz), 7.54 (t, 1H, J=7.87 Hz), 7.42 (m, 2H), 7.23 (m, 1H), 7.12 (m, 2H), 7.00 (s, 1H), 6.80 (t, 1H, J=6.80 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.71 (bs, 4H), 3.25 (bs, 4H), 1.64 (s, 3H); MS (ESI) m/z 525 ((M+H]+);
Anal. calcd for Ca1H2gCIN4O2 © 0.30 CgH1s © CH,Cl: C:70.22 H:5.99 N:9.94 Found:
C:70.31 H:5.86 N:9.81.
Example 87 (S)-3-[4-(2,3-dichlorophenyl)piperazin-1-yl}-2-[(S)-(2-methoxyphenyl)(1- : naphthyl)methyi]-2-methyi-3-oxopropanenitrile (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid (450 mg, 1.30 mmol) was dissolved in 20 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.160 mL, 1.82 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 25 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CHCl, and placed under nitrogen. In a separate flask 1-(2,3-dichloro- phenyl)piperazine hydrochloride (367 mg, 1.37 mmol) was dissolved in 156 mL CHCl. under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.82 mL, 5.86 mmol). The acid chloride in CHxCl, was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO,, filtered, evaporated to dryness. Purification of silica gel (CH2Cl,) afforded 462 mg of the title compound as a powder. [o]o?® = -159.1° (1% , CHCI3);
H NMR 500 MHz (DMSO-D8): & 799 (d, 1H, J=7.33 Hz), 7.87 (m, 2H), 7.79 (d, 1H, 8.25 Hz), 7.55 (t, 1H, J=7.79 Hz), 7.42 (m, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 7.13 (d, 2H, J=8.09 Hz), 7.02 (bs, 1H), 6.80 (t, 1H, J=7.48 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.67 (bs, 4H), 2.85 (bs, 4H), 1.64 (s, 3H)
MS (ES!) m/z 558 ([M+H]+);
Anal. calcd for CasHaoCloN3O2 e 0.25 CgHag: C:69.37 H:5.65 N:7.24 Found: C:69.61
H:5.53 N:7.24.
Example 88 (2S)-3-[4-[4-chloro-3-(trifluoromethyl)phenyi]-3,6-dihydropyridin-1 (2H)yW)-2-[(S)-(2- methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile (S,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid(500 mg, 1.45 mmol) was dissolved in 20 mL THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chloride (0.152 mL, 1.73 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 25 mL toluene was added and the reaction mixture was evaporated to dryness. The acid chloride was dissolved in 10 mL CHCl, and placed under nitrogen. In a separate flask 1-(4-chloro-3-triflourometnyi phenyi}-3,6- dihydropyridine hydrochloride (520 mg, 1.73 mmol) was dissolved in 15 mL CH2Cl> under nitrogen. To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.91 mL, 6.51 mmol). The acid chloride in CH.Cl, was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over MgSO., filtered, evaporated to dryness. Purification of silica gel (20% hexanes /
CH,Cl,) afforded 406 mg of the title compound.
H NMR 500 MHz (DMSO-D6): & 7.95 (d, 1H, J=7.18 Hz), 7.91 (d, 1H, J=8.70 Hz), 7.71 (m), 7.49 (t, 1H, J=7.79 Hz), 7.42 (m, 1H), 7.37 (bs, 1H), 7.24 (m, 1H), 7.22 (bs, 1H), 7.12 (d, 1H, J=8.25 Hz), 6.83 (t, 1H, J=7.48 Hz), 6.22 (bs, 1H), 6.02 (s, 1H), 3.98 (s, 3H), 3.60 (2H,bs), 1.65 (s, 3H)
MS (ESI) m/z 587 ([M-H]-);
Anal. calcd for CasHosCIFaN2O2: C:69.33 H:4.79 N:4.76 Found: C:69.06 H:4.87
N:4.65.
Example 89 (2S)-3-{4-{4-chioro-3-(trifluoromethyl)phenyllpiperidin-1-yi}-2-{(S)-(2- methoxyphenyl)(1-naphthyl)methyll-2-methyl-3-oxopropanenitrile (8,S)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyljpropanoic acid(500 mg, 1.45 mmol) was dissolved in 20 mL. THF. A catalytic amount of DMF was added to the reaction mixture. Oxalyl chioride (0.152 mL, 1.73 mmol) was added slowly. The reaction mixture was stirred until no more evolution of gas was observed. The reaction mixture was rapidly heated to reflux, then cooled and evaporated. 25 mL toluene was added and the reaction mixture was evaporated to dryness. . The acid chloride was dissolved in 10 mL CHCl, and placed under nitrogen. In a separate flask 1-(4-chloro-3-triflouromethyl phenyl)-pyridine hydrochloride (520 mg, 1.73 mmol) was dissolved in 15 mL CHzCl, under nitrogen.
To this stirred solution was added a catalytic amount of DMAP, and triethylamine (0.91 mL, 6.51 mmol). The acid chloride in CHCl, was added rapidly to this stirred mixture and allowed to react overnight after which water was added to the reaction mixture. The organic layer was separated and washed with brine, dried over
MgSO,, filtered, evaporated to dryness. Purification of silica gel (20% hexanes/CH,Cl,) afforded 510 mg of the title compound.
TH NMR 500 MHz (DMSO0-D6): 5 8.02 (d, 1H, J=7.02 Hz), 7.88 (dd, 2H, J=6.18 Hz, 2.52 Hz), 7.81 (d, 1H, J=8.40 Hz), 7.61 (bs, 2H), 7.56 (t, 1H, J=7.79 Hz), 7.42 (m, 2H), 7.23 (td (1H, J=6.87 Hz, 1.37 Hz), 7.14 (m, 2H), 6.80 (t, 1H, J=7.48 Hz), 6.02 (s, 1H), 4.35 (bs, 1H), 4.01 (s, 3H), 2.89 (bs, 4H), 1.75 (bs, 4H), 1.65 (s, 3H)
MS (ESI) m/z 649 ({[M+CH3COO]-);
Anal. calcd for CasHaoCIFsN2O2: C:69.09 H:5.12 N:4.74 Found: C:69.21 H:5.13
N:4.62.
Example 90 2-cyano-3,3-di(1-naphthyl)propanamide
Ethyl 2-cyano-3,3-di(1-naphthyl)propanoate (250 mg, 0.66 mmol) was disolved in THF (2 mL) to which concentrated ammonium hydroxide (5 mL) was added. The reaction mixture was allowed to stir overnight, then taken up in ethyl acetate, washed with saturated NaHCO3, Brine, dried with MgSO, evaporated, and purified on silica gel to yield 38 mg of the title compound. 'H NMR 400 MHz (DMSO-D6): § 8.27 (m, 2H), 7.83 (m, 3H), 7.81 (m, 2H), 7.65 (d, 1H, J=7.65 Hz), 7.50 (m, 8H), 6.35 (d, 1H, J=9.76 Hz), 4.90m (d, 1H, J=9.76 Hz).
MS (APCI) m/z 368 ([M+NH4]+);
Anal. calcd for CosH1sNoO eo 0.5 HO e 0.25 Cea: C:80.39 H:5.95 N:7.35 Found:
C:80.27 H:5.69 N:7.11.
Example 91 (RRISS)- 3-(2-Methoxy-phenyl)-2-methyl-3-naphthalen-1 -yi-2-(4-oxy-4-o-tolyl- " piperazine-1-carbonyl)-propionitrile
A solution of (RR,SS)-3-(2-methoxyphenyl)-2-methyl-2-{{4-(2-methylphenyl) piperazin-1-yllcarbonyl}-3-(1-naphthyl)propanenitrie (256mg, 0.50mmol) in dichloromethane (5mL) is treated with 3- chloroperoxybenzoic acid (86mg, 0.5mmol) at reflux for 53 hours (approximately 35% conversion by LC/MS). The sample is cooled and quenched with saturated aqueous sodium bicarbonate. The organic layer is washed with water dried over Na,SO,, Filtered and concentrated in vacuo.
Chromatography over silica using 5% methanol in dichloromethane yielded 80mg of the title compound. Recrystallization from hexane/ethyl acetate provided the title compound as a white crystal. mp 178-180 °C dec; 'H NMR 500MHz (CDCls): § 8.01 «d, 1H, J = 7.17Hz),7.88 (m, 2H), 7.81 (d, 1H, J = 8.24Hz), 7.56 (t, 1H, J = 7.63Hz), 7.44 (quin, 2H, J = 4.12Hz), 7.28 (brm, 2H), 7.81 (t, 2H, J = 7.18Hz), 7.14 (d, 1H, J = 8.24Hz), 7.13 (t,1H, J = 4.59Hz), 6.03 (s,1H), 7.81 (d, 1H, J = 8.24Hz), 4.02 (s, 3H), 3.63 (brs, 3H), 3.23 (brs, 3H), 2.72 (brs, 3H), 3.63 (brs, 3H), 1.68 (s, 3H), :
MS (ESI) m/z 520 ([M+H]+),
Anal. calcd for CasHasN3sOs: C:76.28 H:6.40 N:8.09 Found: C:75.19 H:6.53 N:7.86.
Example 92 (RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3- (trifluoromethoxy)phenyl]piperazin-1 -yl}carbonyl)propanenitrile
(RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-(piperazin-1- ylcarbonyl)propanenitrile (377 mg, 0.913 mmol), meta-trifluoromethoxy bromobenzene (200 mg, 0.830 mmol), sodium tert-butoxide (111 mg, 1.16 mmol), tris (dibenzylideneacetone) dipalladium (0) (22.8 mg, 0.025 mmol), racemic BINAP (31 mg, 0.05 mmol), and toluene (3 mL) were combined in a Carius fube, vacuum degassed, placed under an argon atmosphere, sealed and heated to 80°C ovemight. The reaction was cooled, taken up in diethyl ether, filtered, washed with water, saturated aqueous sodium bicarbonate, brine, dried over MgSO, filtered, evaporated, and purified on slica gel (10% hexanes/CHzCl2) to yield 255 mg of the title compound as a white powder. 'H NMR 500 MHz (DMSO-D6): & 7.97 (d, 1H, J=7.18 Hz), 7.88 (m, 1H), 7.84 (m, 1H), 7.78 (d, 1H, J=8.25 Hz), 7.52 (t, 1H, J=7.48 Hz), 7.41 (m, 2H), 7.30 (t, 1H,
J=8.25 Hz), 7.23 (td, 1H, J=7.79 Hz, 1.68 Hz), 7.12 (m, 2H), 6.91 (dd, 1H, J=8.40
Hz, 1.68 Hz), 6.79 (m, 2H), 6.72 (d, 1H, J=8.09 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.68 (bs, 4HO, 3.16 (bs, 4H) 1.63 (s, 3H)
MS (ESI) m/z 574 ([M+H]+);
Anal. calcd for Ca3H3oF3N303 o 0.35 CgHis: C:69.82 H:5.83 N:6.96 Found: C:69.81
H:5.91 N:6.74.
Example 93 (R,S)-3-[4-(2,3-difluorophenyhpiperazin-1-yi}-2-[(R,S)-(2-methoxyphenyl)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile (RR,SS)-3-(2-methoxyphenyl)-2-methyi-3-(1 -naphthyl)-2-(piperazin-1- ylcarbonyl)propanenitrile (471 mg, 1.14 mmol), 2,3-diflucrobromobenzene (200 mg, 1.04 mmol), sodium tert-butoxide (139 mg, 1.45 mmol), tris (dibenzylideneacetone) dipalladium (0) (28 mg, 0.031 mmol), racemic BINAP (39 mg, 0.062 mmol), and toluene (3 mL) were combined in a Carius tube, vacuum degassed, placed under an argon atmosphere, sealed and heated to 80°C overnight. The reaction was cooled, taken up in diethyl ether, filtered, washed with water, saturated aqueous sodium bicarbonate, brine, dried over MgSO, filtered, evaporated, and purified on slica gel (10% hexanes/CHzCl2) to yield 280 mg of the title compound as an off-white crystal solid. mp 198-200 °C;
H NMR 500 MHz (DMSO-D6): § 7.98 (d, 1H, J=7.33 Hz), 7.86 (m, 2H), 7.79 (d, 1H,
J=8.25 Hz), 7.54 (t, 1H, J=7.64 Hz), 7.42 (m, 2H), 7.23 (t, 1H, J=7.64 Hz), 7.12 (m, 2H), 7.08 (m, 1H), 7.00 (q, 1H, J=9.01 Hz), 6.79 (m, 2H), 6.01 (s, 1H), 4.01 (s, 3H), 3.73 (bs, 4H), 2.96 (bs, 4H), 1.64 (s, 3H)
MS (ESI) m/z 526 ([M+H]+);
Anal. calcd for CaoHagFaN3O2 © 0.20 H20: C:72.63 H:5.60 N:7.94 Found: C:72.65
H:5.58 N:7.79.
Example 94 (R,S)-3-{4-(3-flucrophenyl)piperazin-1-yl]-2-[(R,S)-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile (RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)-2-(piperazin-1- yicarbonyl)propanenitrile (519 mg, 1.25 mmol), 3-fluorobromobenzene (200 mg, 1.14 mmol), sodium tert-butoxide (154 mg, 1.60 mmol), tris (dibenzylideneacetone) dipalladium (0) (31 mg, 0.034 mmol), racemic BINAP (42 mg, 0.068 mmol), and toluene (3 mL) were combined in a Carius tube, vacuum degassed, placed under an argon atmosphere, sealed and heated to 80°C overnight. The reaction was cooled, taken up in diethyl ether, filtered, washed with water, saturated aqueous sodium bicarbonate, brine, dried over MgSO, filtered, evaporated, and purified on slica gel (10% hexanes/CH,Cl,) to yield 295 mg of the titte compound as a white powder. 'H NMR 500 MHz (DMSO0-D6): & 7.96 (d, 1H, J=7.18 Hz), 7.88 (m, 1H), 7.83 (m, 1H), 7.52 (t, 1H, J=7.48 Hz), 7.41 (m, 2H), 7.21 (Mm, 2H), 7.12 (m, 2H)< 6.79 (td, 1H,
J=7.48 Hz, 0.84 Hz), 6.72 (m, 2H), 6.56 (td, 1H, J=8.40 Hz, 1.68 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.68 (bs, 4H), 3.14 (bs, 4H), 1.63 (s, 3H)
MS (ESI) m/z 508 ([M+H]+);
Anal. calcd for CaaHaoFN3O2 e 0.20 HO: C:75.18 H:5.99 N:8.22 Found: C:75.15
H:5.95 N:8.02.
Example 95 (RR,SS)-3-(2-methoxyphenyi)-2-methyl-3-(1-naphthyl)-2-[(4-pyridin-3-ylpiperazin-1- yl)carbonyl)propanenitrile (RR, SS)-3~(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)-2-(piperazin-1- ylcarbonyl)propanenitrile (576 mg, 1.39 mmol), 3-bromopyridine (200 mg, 1.27 mmol), sodium fert-butoxide (170 mg, 1.77 mmol), tris (dibenzylideneacetone) dipalladium (0) (35 mg, 0.038 mmol), racemic BINAP (47 mg, 0.076 mmol), and toluene (3 mL) were combined in a Carius tube, vacuum degassed, placed under an argon atmosphere, sealed and heated to 80°C overnight. The reaction was cooled, taken up in diethyl ether, filtered, washed with water, saturated aqueous sodium bicarbonate, brine, dried over MgSO, filtered, evaporated, and purified on slica gel (5% methanolliso-propyl acetate) to yield 234 mg of the title compound which was recrystallized from ethanol to yield 158 mg of the tite compound as a crystal solid. mp 186-188 °C; 'H NMR 500 MHz (DMSO-D6): &§ 8.26 (d, 1H, J=2.75 Hz), 8.01 (dd, 1H, J=4.43 Hz, 1.07 Hz), 7.97 (d, 1H, J=7.18 Hz), 7.88 (m, 1H), 7.78 (d, 1H, J=8.25 z), 7.53 (t, 1H, 7.64Hz), 7.42 (m, 2H), 7.28 (dd, 1H, J=8.40 Hz, 1.53 Hz), 7.22 (m, 2H), 7.12 (t, 2H,
J=7.79 Hz), 6.79 (t, 1H, J=7.79 Hz), 6.01 (s, 1H), 4.01 (s, 3H), 3.62 (bs, 4H), 3.17 (bs, 4H), 1.64 (s, 3H)
MS (ESI) m/z 491 (M+H]+);
Anal. calcd for CaiHaoN4O2: C:75.89 H:6.16 N:11.42 Found: C:75.70 H:6.22 N:11.32.
Example 96 (RR,SS)-3-[4-(2,3-dichlorophenyl)piperazin-1-yl}-2-[(2-methoxyphenyi)(1- naphthyl)methyl]-2-methyi-3-oxopropanenitrile (RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyi)-2-(piperazin-1- yicarbonyl)propanenitrile (403 mg, 0.97 mmol), 2,3-dichlorobromobenzene (200 mg, 0.89 mmol), sodium fert-butoxide (119 mg, 1.24 mmol), tris (dibenzylideneacetone) dipalladium (0) (24 mg, 0.027 mmol), racemic BINAP (33 mg, 0.053 mmol), and toluene (3 mL) were combined in a Carius tube, vacuum degassed, placed under an argon atmosphere, sealed and heated to 80°C ovemight. The reaction was cooled, taken up in diethyl ether, filtered, washed with water, saturated aqueous sodium bicarbonate, brine, dried over MgSOy, filtered, evaporated, and purified on slica gel (10% hexanes/CHzCl,) and recrystallized from ethanol to yield 228 mg of the title compound as a crystal solid. mp 220-222 °C; 1H NMR 500 MHz (DMSO0-D6): § 7.99 (d, 1H, J=7.33 Hz), 7.87 (m, 2H), 7.80 (d, 1H,
J=8.25 Hz), 7.55 (t, 1H, J=7.64 Hz), 7.43 (m, 2H), 7.31 (m, 2H), 7.23 (td, 1H, J=8.55
Claims (21)
1. A compound of formula | having the structure Ry Rs =n oO QELS gy AN Ria Re l wherein B and D are independently CH or N, provided that B and D are not both N; R, R,, R, are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl, alkylthio of 1-6 carbon atoms, CF,, -OCF,, -NR.R,, or hydroxy; or R; and R; together with carbon atoms to which they are attached form a fused benzene ring, the naphthalene ring so formed being optionally substituted by halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, nitro, cyano, thioalkyl of 1-6 carbon atoms, aryl, alkylthio of 1-6 carbon atoms, CF,, -OCF,, -NR,R,, or hydroxy; R, is hydrogen, alkyl of 1-6 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkenyl of 2-7 carbon atoms, cycloalkyimethyt of 3-8 carbon atoms in the cycloalkyl moiety, arylalkoxyalkyl, alkoxyalkyl, dialkylaminoalkyl having 1-6 carbon atoms in the alkyl moieties, or Het-alky! having 1-6 carbon atoms in the alkyl moiety;
/\ \ R4 is-NRsRg, -ORg, -— (> ~~) — N—A —N N—A > Nn" / N_/ Nw Q OLS —N Ox -00 . —N (o] ’ 9 ’ an NONE VAR — 0 lo) OED - 0 OL —nN N—-C— ' N , ' Nn A I — [ _ == Oa oH \ N™ A / \ ’ OH N —_ —N SE d ARy R 1) YY N —N \ NH or A, wherein any phenyl ring in Ry is optionally substituted with Rz;
R, and R; are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, arylatkyl having 1-6 carbon atoms in the alkyl moiety, Het-alkyl having 1-6 carbon atoms in the alkyl moiety, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6 carbon atoms, or cycloalkyl! of 3-8 carbon atoms;
R, is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, nitro, cyano, alkylthio of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, CF, or -OCF,; Rg is alkyl of 1-6 carbon atoms; A is hydrogen, cycloalkyl of 3-8 carbon atoms, alkoxyalkyl having 1-6 carbon atoms in the alkyl and alkoxy moieties, dialkylaminoalkyl having 1-6 carbon atoms in the alkyl moieties, aryl, Het, hydroxyalkyl of 1-6 carbon atoms, dihydroxyalkyl of 1-6 carbon atoms, Het-alkyl having 1-6 carbon atoms in the alkyl moiety, arylaiky! having 1-6 carbon atoms in the alkyl moiety, or oN Zz W is aryl, -Y-aryl, or Het or -Y-Het; Y is -O- or -NH-; ZisOorsS; Het is a saturated, unsaturated, or partially unsaturated heterocyclic ring or ring system having 4-12 ring atoms and 1-3 heteroatoms selected from N, O, or S, that may be optionally substituted with 1-3 R, groups; aryl is an aromatic ring or ring system having 6-14 carbon atoms in the ring or ring system, that may be optionally substituted with 1-3 R; groups; with the proviso that at least one of the R;, R,,, or R, groups is not hydrogen; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R4 is -NRsRs, ORs, —{_ a , —{_ , or N Na ; and / A is hydrogen, aryl, or Het; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein : Ry is —{ Ha , or N\A ; and \/
A is hydrogen, aryl, or Het; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, wherein B and D are CH.
5. The compound according to claim 1, which is ethyl 2-cyano-3-(2,6-dimethoxyphenyi)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-(2,6-dichlorophenyl)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-[4-(dimethylamino)phenyl}-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-(1-naphthyl)-3-[2 (trifluoromethyl) phenyi]propanoate; ethyl 2-cyano-3-(2-isopropylphenyl)-3-(1 -naphthyl)propanoate; ethyl 2-cyano-3-(2,4-dimethoxyphenyl)-3-(1-naphthyl)propanoate; ethyl 2-cyano-3-(2,5-dimethoxyphenyl)-3-(1 -naphthyl)propanoate; tert-butyl 2-cyano-3-(1 -naphthyt)-3-[2-(trifluoromethyl) phenyl] propanoate; ethyl 2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate; ethyl (RR,SS)-2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate; tert-butyl 2-cyano-3-(2-isopropylphenyt)-3-(1 -naphthyli)propanoate; tert-butyl 2-cyano-3-(2-methoxyphenyl)-3-(1 -naphthyl)propanoate; tert-butyl 2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethoxy)phenyl] propanoate; ethyl 2-cyano-3-(1 -naphthyl)-3-(2-nitrophenyl)propanoate; tert-butyl 2-cyano-3-(2,6-dimethyiphenyl)-3-(1 -naphthyl)propanoate; tert-butyl (RR, SS)-2-cyano-3-(1-naphthyl)-3-[2-(trifluoromethyl)phenyl] propanoate; tert-butyl (RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methy!-3-(1 - naphthyl)propanoate; -) ethyl (SS)-2-cyano-3-(2-methoxypheny!)-2-methyl-3-(1- naphthyl)propanoate; (+) ethyl (R.R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoate;
ethyl (RR,SS)-2-cyano-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-4- pentenoate;
ethyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1-naphthyl) propanoate;
tert-butyl (RR,SS)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3~(1- naphthyl)propanoate;
tert-butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)-3-[2- (trifluoromethyl)phenyl]lpropanoate;
tert-butyl (RS,SR)-2-cyano-3-(2,6-dimethylphenyl)-2-methyl-3-(1- naphthyl)propanoate;
tert-butyl (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1- naphthyl)propanoate;
tert-butyl (RR, SS)-2-(3~chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3- (1-naphthyl)propanoate;
tert-butyl (RR,SS)-2-(2-bromobenzyl)-2-cyano-3-(2-methoxyphenyl)-3-
(1-naphthyl)propanoate;
tert-butyl (RR,SS)-2-(2-chlorobenzyl)-2-cyano-3-(2-methoxyphenyl)-3- (1-naphthyl)propanoate;
tert-butyl (RR,SS)-2-cyano-2-(2,6-dichlorobenzyl)-3-(2-methoxyphenyi)- 3-(1-naphthyt)propanoate;
ethyl (RR,SS)-2-cyano-3-(2,4-dimethoxyphenyl)-2-methyl-3-(1- naphthyl)propanoate;
tert-butyl (RS,SR)-2-cyano-2-methyl-3-(1-naphthyl)}-3-[2- . (trifluoromethoxy)phenyl]propanoate;
ethyl 2-cyano-3-(3-methoxyphenyl)-3-(1-naphthyi)propanoate;
ethyl 2-cyano-3-(4-methyiphenyl)-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(2-methylphenyl}-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-(1-naphthyl)-3-(2-naphthyl)propanoate;
ethyl 2-cyano-3-(4-fluoro-1-naphthyl)-3-(1-naphthyi)propanoate;
ethyl 2-cyano-3-[4-(methyithio)phenyl]-3-(1-naphthyl)propanoate;
ethyl 3-{1,1'-biphenyi}-4-yl-2-cyano-3-(1-naphthyl)propanoate;
ethyl 3-[1,1-biphenyl]-2-yl-2-cyano-3-(1-naphthyl)propanoate;
ethyl 3-(4-chlorophenyl)-2-cyano-3-(1-naphthyl)propanoate;
ethyl 2-cyano-3-[2-(methylthio)phenyl}-3-(1 -naphthyl)propanoate; ethyl-(RR,SS)- 2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanoate; ethyl (RR,SS)-2-cyano-2-methyl-3-[2-(methyithio)phenyl]-3-(1 - naphthyl)propanoate; (RR, SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanoic acid; (RR,SS)-2-cyano-3-(2-isopropylphenyl }-2-methyl-3-(1- naphthyl)propanoic acid; (RS,SR)-2-cyano-2-methyi-3-(1 -naphthyl})-3-[2- (trifluoromethyl)phenyi]propanoic acid; (RR,SS)-2-benzyl-2-cyano-3-(2-methoxyphenyl)-3-(1 - naphthyl)propanoic acid; tert-butyl (R,R)-2-cyano-3-(2-isopropylphenyl)-2-methyl-3-(1 - naphthyl)propanoate; tert-butyl (8,S)-2-cyano-3-(2-isopropylphenyl }-2-methyl-3-(1- naphthyl)propanoate; tert-butyl (S, S)-2-cyano-3-(2-methoxyphenyl)-2-methyi-3-(1 - naphthyl)propanoate; tert-butyl (R,R)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1 - naphthyl)propanoate; (RR, SS)-3-(2-methoxyphenyl)-2-methyl-3-(1 -naphthyl)-2-(piperazin-1- yicarbonyl)propanenitrile;
RR.SS)(3-[4-(3-chloro-2-methylphenyl)piperazin-1 -yl]-2-[(2- methoxyphenyl)(1 -naphthyl)methyl]-2-methyl-3-oxopropanenitrile); (RR,S,S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2- methylphenyl)piperazin-1 -yijcarbonyl}-3-(1 -naphthyl)propanenitrile; (SS)-3-(2-methoxyphenyl)-2-methyl-2-{j4-(2-methylpheny)-1 - piperazinyljcarbonyl}-3-(1 -naphthyl)propanenitrile; (R, R)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(2-methylphenyl)piperazin-1 - yi]carbonyl}-3-(1 -naphthyl)propanenitrile; (S, S)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(3-methylphenyl)piperazi n-1- yijcarbonyl}-3-(1 -naphthyl)propanenitrile;
(S)-3-[4-(3,5-dimethoxyphenyi)piperazin- 1-yi}-2-[(S)-(2- methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (8)3-(4-indan-4-yi-piperazin-1-y)-2-[(S)(2-methoxy-phenyl)-naphthalen- 1-yl-methyl]-2-methyl-3-oxo-propionitrile; (S,S)-3-(2-methoxyphenyl)-2-methyi-3-(1-naphthyl)-2-{[4-(1- naphthyl)piperazin-1-yljcarbonyl}propanenitrile; (S)-3-[4-(3,4-dimethylphenyl)piperazin-1-yl}-2-[(S)-(2- methoxyphenyl)(1-naphthyl)methyli}-2-methyl-3-oxopropanenitrile; (RR,SS) 3-[4-(H-indol-4-yl)piperazin-1-yl}-2-[(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(3-chlorophenyl)piperazin-1-yl]-2-[(S)-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(2,3-dimethylphenyl)piperazin-1-yl}-2-[(S)-(2- methoxyphenyl)(1-naphthyl)methyi]-2-methyi-3-oxopropanenitrile; (S)-3-[4-(4-chlorophenyl)piperazin-1-yi]-2-[(S)-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(1H-Indol-4-yl)-piperazin-1-yl}-2-[(S)-(2-methoxy-phenyl)- naphthalen-1-yl-methyl]-2-methyl-3-oxo-propionitrile; (S,S)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3- (trifluoromethyl)phenyl] piperidin-1-yl}carbonyt)propanenitrile; (S)-3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-[(S)-(2- methoxy-phenyl)-naphthalen-1-yl-methyl}-2-methyl-3-oxo-propionitrile; (S,S)-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-2-[4-(3- trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl}-propionitrile; (SS)2-{4-(4-chloro-phenyl)-piperidine-1-carbonyl]-3-(2-methoxy- phenyl)-2-methyl-3-naphthalen-1-yl-propionitrile; (RR, SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyi)-2-({4-[3- (trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)propanenitrile; . (RR,SS)-3-(2-methoxyphenyl}-2-methyl-3-(1-naphthyl)-2-(piperidin-1- ylcarbonyl)propanenitrile; (RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide;
(RR, SS)-2-cyano-N-ethyl-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide; (RR,SS)-N-(tert-butyl}-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide; (RR,SS)-2-cyano-3-(2-methoxyphenyl)-N,N,2-trimethyl-3-(1- naphthyl)propanamide; (RR,SS)-2-cyano-N-methoxy-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1- naphthyl)propanamide; (RR, SS)-2-benzyl-3-[4-(3,5-dichloro-4-pyridinyl)-1-piperazinyl)-2-{(2- methoxyphenyl)(1-naphthyl)methyl]-3-oxopropanenitrile; (R,S)-3-[4-(2,3-dimethylphenyl)piperazin-1-yi}-2-[(R,S)-(2- methoxyphenyl)(1-naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (R,S)-3-[4-(3-isopropylphenyl)piperazin-1-yl]-2-[(R,S)-(2- methoxyphenyl)(1-naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (RR, SS)-3-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl]-2-[(2- methoxyphenyl)(1-naphthyl)methyi}-2-methyl-3-oxopropanenitrile; (2SS)-3-[4-(3-chloro-2-methylphenyl)piperazin-1-yi]-2-[(2- methoxyphenyl)(1-naphthyl)methyl]-2-methyi-3-oxopropanenitrile; (S)-3-[4-(2-fluorophenyl)piperazin-1-yl}-2-[( S)}-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (S)-3-[4-(2-chlorophenyl)piperazin-1-yi}-2-[( S)-(2-methoxyphenyl)(1- naphthyl)methyi}-2-methyl-3-oxopropanenitrile; (S,S)-3-(2-methoxyphenyl)-2-{[4-(3-methoxyphenyl)piperazin-1- * ylJcarbonyl}-2-methyi-3-(1-naphthyl)propanenitrile; (R,S)-3-[4-(3-chloropyridin-4-yi)piperazin-1-yl]-2-[(R,S)-(2- methoxyphenyl)(1-naphthyl)methyi}-2-methyl-3-oxopropanenitrile; (S)-3-[4-(2,3-dichlorophenyl)piperazin-1-yi]-2-[(S)-(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (2S)-3-[4-[4-chloro-3-(trifluoromethyl )phenyl]-3,6-dihydropyridin-1(2H)- yi}-2-[(S)-(2-methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (2S)-3-{4-[4-chloro-3-(trifluoromethyl )phenyl]piperidin-1-yl}-2-[(S)-(2- methoxyphenyl)(1-naphthyl)methyi]-2-methyl-3-oxopropanenitrile;
(RR/SS)-3-(2-methoxy-phenyt)-2-methyl-3-naphthalen-1-yl-2-(4-oxy-4- o-tolyl-piperazine-1-carbonyl)-propionitrile; (RR,SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-({4-[3- (trifluoromethoxy)phenyl}piperazin-1-yl}carbonyl)propanenitrile; (R,S)-3-[4-(2,3-difluorophenyl)piperazin-1-yl}-2-[(R, S)-(2- methoxyphenyl)(1-naphthyl)methyl}-2-methyl-3-oxopropanenitrile; (R,S)-3-[4-(3-fluorophenyl)piperazin-1-yl}-2-[(R,S)-(2- methoxyphenyi)(1-naphthyl)methyl}-2-methyi-3-oxopropanenitrile; (RR,SS)-3-(2-methoxyphenyli)-2-methyl-3-(1-naphthyl)-2-[(4-pyridin-3- ylpiperazin-1-yl)carbonyl]propanenitrile; (RR,SS)-3-[4-(2,3-dichlorophenyl)piperazin-1-yl]-2-[(2- methoxyphenyl)(1-naphthyl)methyl]-2-methyl-3-oxopropanenitrile; (RR, SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4~(3- : methylphenyl)piperazin-1-yl]carbonyl}-3-(1-naphthyl)propanenitrile; (RR, SS)-3-(2-methoxyphenyl)-2-methyi-3-(1-naphthyl)-2-(pyrrolidin-1- ylcarbonyl)propanenitrile; (RR, SS)-3-(2-methoxyphenyl)-2-methyl-2-(morpholin-4-ylcarbonyt)-3- (1-naphthyl)propanenitrile; (RR, SS)-3-[4-(2-hydroxyethyl)piperazin-1-yl]-2-[(2-methoxyphenyi)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile; (RR,SS)-3-(2,6-dimethylmorpholin4-y1)-2-[(2-methoxyphenyl)(1- naphthyl)methyi]-2-methyl-3-oxopropanenitrile; : (RR,SS)-2-cyano-N,N-diethyl-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide; (RR,SS)-2-cyano-N-[2-hydroxy-1-(hydroxymethyl)ethyi]-3-(2- methoxyphenyi)-2-methyl-3-(1-naphthyl)propanamide; (RR,SS)-3-azetidin-1-yl-2-[(2-methoxyphenyl)(1-naphthyl)methyl]-2- methyl-3-oxopropanenitrile; (RR, SS)-2-cyano-N,N-diisopropyl-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide; (RR, SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2-[(3,3,5- trimethylazepan-1-yl)carbonyi]propanenitrile;
(RR,SS)-3-(2,3-dihydro-H-indol-1-yl)-2-[(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyl-3-oxopropanenitrile;
(RR, SS)-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)-2- (thiomorpholin-4-ylcarbonyl)propanenitrile;
(RR,SS)-3-azepan-1-yl-2-[(2-methoxyphenyl)( i-naphthyl)methyl]-2- methyl-3-oxopropanenitrile;
(RR, SS)-2-cyano-N-cyclohexyl-3-(2-methoxyphenyi)-N,2-dimethyl-3-(1- naphthyl)propanamide;
(RR, SS)-2-cyano-3-(2-methoxyphenyl)-N,2-dimethyl-3-(1- naphthyl)propanamide;
(RR,SS)-3-(4-benzylpiperazin-1-yl)-2-[(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyl-3-oxopropanenitrile;
(RR, SS)-3-(3,4-dihydroisoquinalin-2(H)-yl)-2-[(2-methoxyphenyl)(1- naphthyl)methyl}-2-methyl-3-oxopropanenitrile;
(RR, SS)-3-(2-methoxyphenyl)-2-methyl-2-{[4-(4- methylphenyl)piperazin-1-yljcarbonyl}-3-(1-naphthyl)propanenitrile;
(RR,SS)-N,N-dibenzyl-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanamide;
(RR,SS)-3-azocan-1-yi-2-{(2-methoxyphenyi)(i-naphnthyi)methyij-2- methyi-3-oxopropanenitrile;
4-chlorophenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3- (1 -naphthyi)propanoyl]piperazine-1-carboxylate;
2-nitrophenyl 4-[(RR,SS)-2-cyano-3-~(2-methoxyphenyl)-2-methyi-3-(1- : naphthyl)propanoyi]piperazine-1-carboxylate;
4-(methoxycarbonyl)phenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)- 2-methyl-3-(1-naphthyl)propanoyl]piperazine-1-carboxylate;
4-methylphenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyi-3- (1-naphthyl)propanoyl]piperazine-1-carboxylate;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoyl]-N-(2-methylphenyl)piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoyi]-N-[2-(trifluoromethyl)phenyi]piperazine-1-carboxamide;
4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoyi]-N-(3-methoxyphenyl)piperazine-1-carboxamide; 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoyl]-N-(4-ethoxyphenyl)piperazine-1-carboxamide; N-(2-bromophenyl)-4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl- 3-(1-naphthyl)propanoyllpiperazine-1-carboxamide; 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoyl]-N-(4-methylphenyl)piperazine-1-carboxamide; 4-fluorophenyi 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoyllpiperazine-1-carboxylate; phenyl 4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(1- naphthyl)propanoyl]piperazine-1-carboxylate; : (RR,SS)-3-[4~(4-bromobenzoyl)piperazin-1-yi]-2-[(2-methoxyphenyl)(1- naphthyl)methyl]-2-methyl-3-oxopropanenitrile; N-(4-chlorophenyl)-4-[(RR,SS)-2-cyano-3-(2-methoxyphenyl)-2-methyl- 3-(1-naphthyl)propanoyl]piperazine-1-carboxamide; methyl (2E)-2-cyano-3-(quinolin-3-yi)prop-2-enoate; or a pharmaceutically acceptable salt thereof.
6. A compound selected from group consisting of: methyl-(SS,RR)-2-cyano-3-(2-methoxyphenyl)-2-methyl-3-(quinolin-3- : yl)propanoate; 3-(2-methoxyphenyl)-2-methyl-3-quinolin-3-yi-2-({4-[3- (trifluoromethyl)phenyi] piperidin-1-yl}carbonyl)propanenitrile; methyl (2S*,3R*)-2-cyano-2-(methoxymethyl)-3-(2-methoxyphenyl)-3- quinolin-3-ylpropanoate; and pharmaceutically acceptable salts thereof.
7. A pharmaceutical composition, comprising: a pharmaceutical carrier; and a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
. 'PCT/US04/013360
8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating the inflammatory component of a disease.
g. Use according to claim 8, wherein said disease is selected from the group consisting of atherosclerosis, myocardial infarction, congestive heart failure, inflammatory bowel disease, arthritis, type Il diabetes, and autoimmune disease.
10. Use according to claim 9, wherein said autoimmune disease is multiple sclerosis or rheumatoid arthritis.
11. A process for preparing a compound of formula | as claimed in claim 1 which comprises steps (a)-(d) or (e), (f): (a) reacting a compound of formula Oo Rg —N Ar wherein Rg is as defined in claim 1 excepting hydrogen and Ar is a group of formula (A), (B), or (C): ’ , or P SX 2X 2X R3 Ria Ria ® A) (8) (©) AMENDED SHEET
A PCT/US04/013360 where Ry ,R; and Ry, are as defined in claim 1; with a compound of formula Ar{MX wherein Arjis a group of formula (A) or (B) providing Ar and Ar’ are not both of formula (A) or (B) to give a compound of formula | wherein Ry is ORg where Rg is defined in claim 1 excepting hydrogen and Rs is hydrogen; (b) alkylating a compound of formula: 0] eo Ary Ar wherein Re, Ar, and Ar are as defined above providing Re is other than hydrogen, with an alkylating agent of formula RiL where L is a leaving group and Rj is as defined in claim 1 excepting hydrogen to give a corresponding compound of formula | as defined in claim 1; (c) hydrolyzing an ester of formula Re~ Ag oO Ary” Ar wherein Ar, Ars, Rs and Rg are as defined hereinabove providing Rs is other than hydrogen, to give a corresponding compound of formula | wherein R4 is ORg where Rg is hydrogen; (d) reacting an activated acid compound of formula: HO Rj i. rot Ary” Ar wherein Ar, Ary, and Rj are as defined hereinabove, with an amine of formula HNRsRs, AMENDED SHEET
K PCT/US04/013360 O- Or =O =O =F —N ACTING A + —N N—A *—N +N—A . 0 NH —N Pp! Oo OTE Ou
0 . 0 /\ n/N —\ Q —N N—CH,—C—N o —N Wy Q \ 0 0 Re OM —N wt) ' —N , —{ X . _/ A OH N —N \ NH —N SR ¢ SR 717) N° N —N \ NH or (e) reactinga compound of formula oO Reng An =N wherein Rg is as defined hereinabove excepting hydrogen, in the presence of strong base with an halide of formula AriArCHX AMENDED SHEET
- PCT/US04/013360 where Ar and Ar, are as defined herein and X is halogen to give a corresponding compound of formula | wherein R; is hydrogen, or (f} converting a compound of formula | as defined in claim 1 having a reactive substituent group or site to give a different compound of formula |; or (g) converting a compound of formula | to a pharmaceutically acceptable salt thereof.
12. A process, comprising the steps of: forming a ephedrine, cinchonidine, or quinidine salt of a compound of claim 1 or 6 or a pharmaceutically acceptable salt thereof; and extracting said ephedrine, cinchonidine, or quinidine salt with solvent; to form a substantially pure enantiomer of a compound of claim 1 or 6.
13. A substance or composition for use in a method for treating the inflammatory component of a disease, said substance or composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and said method comprising administering said substance or composition.
14. A substance or composition for use in a method of treatment according to claim 13 wherein said disease is selected from the group consisting of atherosclerosis, myocardial infarction, congestive heart failure, inflammatory bowel disease, arthritis, type ll diabetes, and autoimmune disease. AMENDED SHEET
+ vo PCT/US04/013360
15. A substance or composition for use in a method of treatment according to claim 14, wherein said autoimmune disease is multiple sclerosis or rheumatoid arthritis.
16. A compound according to any one of claims 1 to 6, substantially as herein described and illustrated.
17. A composition according to claim 7, substantially as herein described and illustrated.
18. Use according to any one of claims 8 to 10, substantially as herein described and illustrated.
19. A process according to claim 11 or claim 12, substantially as herein described and illustrated.
20. A substance or composition for use in a method of treatment according to any one of claims 13 to 15, substantially as herein described and illustrated.
21. A new compound, a new composition, a new use of a compound according to any one of claims 1 to 6, a new process for preparing a compound, or a substance or composition for a new use in a method of treatment, substantially as herein described. : AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46656703P | 2003-04-30 | 2003-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200508789B true ZA200508789B (en) | 2007-04-25 |
Family
ID=36845296
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200508789A ZA200508789B (en) | 2003-04-30 | 2005-10-28 | 3-(1-Naphthyl)-2-cyanopropanoic acid derivatives as estrogen receptor ligands |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN1812790A (en) |
CL (1) | CL2004000825A1 (en) |
ZA (1) | ZA200508789B (en) |
-
2004
- 2004-04-16 CL CL2004000825A patent/CL2004000825A1/en unknown
- 2004-04-30 CN CN 200480018402 patent/CN1812790A/en active Pending
-
2005
- 2005-10-28 ZA ZA200508789A patent/ZA200508789B/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN1812790A (en) | 2006-08-02 |
CL2004000825A1 (en) | 2005-01-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1620102B1 (en) | 3-(1-naphthyl)-2-cyanopropanoic acid derivatives as estrogen receptor ligands | |
US7037919B1 (en) | Tetrahydroquinoline derivatives | |
US7351709B2 (en) | Estrogen receptor ligands | |
US6894061B2 (en) | Substituted dihydrophenanthridinesulfonamides | |
PL210615B1 (en) | Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors | |
US7378427B2 (en) | Processes for preparing 6-alkyl-5-arylsulfonyl-dihydrophenanthridines | |
US20050256132A1 (en) | Use of ER selective NF-kB inhibitors for the treatment of sepsis | |
US7598286B2 (en) | [(1H-indazol-3-yl)methyl]phenols and (hydroxyphenyl)(1H-indazol-3-yl)methanones | |
ZA200508789B (en) | 3-(1-Naphthyl)-2-cyanopropanoic acid derivatives as estrogen receptor ligands | |
EP1640373A1 (en) | Process for producing 3-acylaminobenzofuran-2-carboxylic acid derivative | |
US7585871B2 (en) | Phenanthridine carbonyl phenols | |
US20060160815A1 (en) | Pyrrolo[1,2-a]quinoxalin-5-(4H)-yl)sulfonyls and carbonyls and their use as estrogenic agents | |
US7696221B2 (en) | Thienoisoquinoline-phenylsulfonamides and their use as ER-NFκB inhibitors | |
US7425580B2 (en) | (Diaryl-methyl)-malononitriles and their use as estrogen receptor ligands | |
US3119813A (en) | Azetidine derivatives | |
ZA200504531B (en) | Substituted dihydrophenanthridine sulfonamides | |
US7476752B2 (en) | Processes for the preparation of 2-cyano-3-naphthalene-1-yl-3-phenyl-propionic acid alkyl or benzyl esters | |
CS214689B2 (en) | Method of making the phenylethanolamines | |
Moniz et al. | On the relocation of the amino functionality to the ethyl side chain in aminoglutethimide: Synthesis and aromatase‐inhibitory activity of 3‐(2′‐N, N‐diethyl‐amino) ethyl‐3‐phenylpiperidine‐2, 6‐dione |