HRP960386A2 - Substituted benzylaminopiperidine compounds - Google Patents
Substituted benzylaminopiperidine compounds Download PDFInfo
- Publication number
- HRP960386A2 HRP960386A2 HRPCT/IB95/00683A HRP960386A HRP960386A2 HR P960386 A2 HRP960386 A2 HR P960386A2 HR P960386 A HRP960386 A HR P960386A HR P960386 A2 HRP960386 A2 HR P960386A2
- Authority
- HR
- Croatia
- Prior art keywords
- compound
- salts
- trifluoromethyl
- phenylpiperidine
- amino
- Prior art date
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- QACOELYINOMVBY-UHFFFAOYSA-N n-benzylpiperidin-1-amine Chemical class C=1C=CC=CC=1CNN1CCCCC1 QACOELYINOMVBY-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 234
- 150000003839 salts Chemical class 0.000 claims description 69
- -1 halo C1-C6 alkoxy Chemical group 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 15
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 206010047700 Vomiting Diseases 0.000 claims description 8
- 230000033115 angiogenesis Effects 0.000 claims description 8
- 210000003169 central nervous system Anatomy 0.000 claims description 8
- 208000015114 central nervous system disease Diseases 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 230000008673 vomiting Effects 0.000 claims description 8
- 208000019695 Migraine disease Diseases 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 206010042496 Sunburn Diseases 0.000 claims description 6
- 206010046543 Urinary incontinence Diseases 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 230000002411 adverse Effects 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 206010027599 migraine Diseases 0.000 claims description 5
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 5
- DFLNMCDWRWJNCC-ROUUACIJSA-N (2s,3s)-n-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound FC(F)(F)C1=CC=C(Cl)C(CN[C@@H]2[C@@H](NCCC2)C=2C=CC=CC=2)=C1 DFLNMCDWRWJNCC-ROUUACIJSA-N 0.000 claims description 4
- YKNINAKQXAPIKV-ROUUACIJSA-N (2s,3s)-n-[[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound FC1=CC=C(C(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 YKNINAKQXAPIKV-ROUUACIJSA-N 0.000 claims description 4
- ANSWNMAZMOGQJJ-HKUYNNGSSA-N (2s,3s)-n-[[2-methoxy-5-(trifluoromethyl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC=C(C(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 ANSWNMAZMOGQJJ-HKUYNNGSSA-N 0.000 claims description 4
- LAFDGMMACYWPSJ-UPVQGACJSA-N (2s,3s)-n-[[2-phenoxy-5-(trifluoromethyl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound N([C@@H]1[C@@H](NCCC1)C=1C=CC=CC=1)CC1=CC(C(F)(F)F)=CC=C1OC1=CC=CC=C1 LAFDGMMACYWPSJ-UPVQGACJSA-N 0.000 claims description 4
- HBTHLKHGYLWTGU-HKUYNNGSSA-N (2s,3s)-n-[[5-(1,1-difluoroethyl)-2-(trifluoromethoxy)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound CC(F)(F)C1=CC=C(OC(F)(F)F)C(CN[C@@H]2[C@@H](NCCC2)C=2C=CC=CC=2)=C1 HBTHLKHGYLWTGU-HKUYNNGSSA-N 0.000 claims description 4
- 241000590002 Helicobacter pylori Species 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- PRVMNKWTNJEKFJ-XHRKEWCOSA-N (2s,3s)-n-[[2-methoxy-5-(1,1,1-trifluoropropan-2-yl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC=C(C(C)C(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 PRVMNKWTNJEKFJ-XHRKEWCOSA-N 0.000 claims description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- ZICVNQDAWZSEQP-RXVVDRJESA-N (2s,3s)-n-[[2,4-dimethoxy-5-(2,2,2-trifluoroethyl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC(OC)=C(CC(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 ZICVNQDAWZSEQP-RXVVDRJESA-N 0.000 claims description 2
- GXIYYBXZKMHKPE-ICSRJNTNSA-N (2s,3s)-n-[[2-methoxy-5-(2,2,2-trifluoroethyl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC=C(CC(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 GXIYYBXZKMHKPE-ICSRJNTNSA-N 0.000 claims description 2
- LJZVRCKRTFMNOO-GMAHTHKFSA-N (2s,3s)-n-[[2-methoxy-5-(5,5,5-trifluoro-2-methylpent-3-yn-2-yl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC=C(C(C)(C)C#CC(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 LJZVRCKRTFMNOO-GMAHTHKFSA-N 0.000 claims description 2
- XOHNGGNSGAFTFL-HKUYNNGSSA-N (2s,3s)-n-[[5-(1,1,1,3,3,3-hexafluoropropan-2-yl)-2-methoxyphenyl]methyl]-2-phenylpiperidin-3-amine Chemical group COC1=CC=C(C(C(F)(F)F)C(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 XOHNGGNSGAFTFL-HKUYNNGSSA-N 0.000 claims description 2
- BKILFAAUOLQVPU-ICSRJNTNSA-N (2s,3s)-n-[[5-(1,1-difluoroethyl)-2-methoxyphenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC=C(C(C)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 BKILFAAUOLQVPU-ICSRJNTNSA-N 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000006001 difluoroethyl group Chemical group 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 2
- WUTRELIDULYHSO-FPOVZHCZSA-N (2s,3s)-n-[[2-methoxy-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl]methyl]-2-phenylpiperidin-3-amine Chemical compound COC1=CC=C(C(C)(C)C(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 WUTRELIDULYHSO-FPOVZHCZSA-N 0.000 claims 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 124
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 238000005160 1H NMR spectroscopy Methods 0.000 description 72
- 239000000243 solution Substances 0.000 description 56
- 239000000203 mixture Substances 0.000 description 45
- 239000003921 oil Substances 0.000 description 35
- 235000019198 oils Nutrition 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- 239000012043 crude product Substances 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 239000010410 layer Substances 0.000 description 19
- 238000000746 purification Methods 0.000 description 18
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 17
- 229940125797 compound 12 Drugs 0.000 description 17
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 150000003053 piperidines Chemical class 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
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- 239000005457 ice water Substances 0.000 description 13
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 12
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- 229910002027 silica gel Inorganic materials 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 11
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 11
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- 229940125851 compound 27 Drugs 0.000 description 11
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 10
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
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- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 9
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- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N hydroquinone methyl ether Natural products COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- LOJFBJULPCTMCZ-UHFFFAOYSA-N n-benzyl-2,3,3,4,4,5-hexafluoro-2-propan-2-ylpiperidin-1-amine Chemical class C1C(F)C(F)(F)C(F)(F)C(C(C)C)(F)N1NCC1=CC=CC=C1 LOJFBJULPCTMCZ-UHFFFAOYSA-N 0.000 description 1
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- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
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- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- BWSDNRQVTFZQQD-AYVHNPTNSA-N phosphoramidon Chemical compound O([P@@](O)(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC=1[C]2C=CC=CC2=NC=1)C(O)=O)[C@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@@H]1O BWSDNRQVTFZQQD-AYVHNPTNSA-N 0.000 description 1
- 108010072906 phosphoramidon Proteins 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
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- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- SCWLIHXXYXFUFV-UHFFFAOYSA-M sodium;2,2,3,3,3-pentafluoropropanoate Chemical compound [Na+].[O-]C(=O)C(F)(F)C(F)(F)F SCWLIHXXYXFUFV-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- OIFDSQAQGNEHIL-URXFXBBRSA-N tert-butyl (2s,3s)-3-[[2,4-dimethoxy-5-(2,2,2-trifluoroethyl)phenyl]methylamino]-2-phenylpiperidine-1-carboxylate Chemical compound COC1=CC(OC)=C(CC(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)N(C(=O)OC(C)(C)C)CCC1 OIFDSQAQGNEHIL-URXFXBBRSA-N 0.000 description 1
- ZCGRULLPQMBATK-UPVQGACJSA-N tert-butyl (2s,3s)-3-[[2-methoxy-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl]methylamino]-2-phenylpiperidine-1-carboxylate Chemical compound COC1=CC=C(C(C)(C)C(F)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)N(C(=O)OC(C)(C)C)CCC1 ZCGRULLPQMBATK-UPVQGACJSA-N 0.000 description 1
- QWFNPTQBSCTTFY-UNMCSNQZSA-N tert-butyl (2s,3s)-3-[[5-(1,1-difluoroethyl)-2-(trifluoromethoxy)phenyl]methylamino]-2-phenylpiperidine-1-carboxylate Chemical compound N([C@H]1CCCN([C@H]1C=1C=CC=CC=1)C(=O)OC(C)(C)C)CC1=CC(C(C)(F)F)=CC=C1OC(F)(F)F QWFNPTQBSCTTFY-UNMCSNQZSA-N 0.000 description 1
- HRBAWLDCZIZGIP-GMAHTHKFSA-N tert-butyl (2s,3s)-3-[[5-(1,1-difluoroethyl)-2-methoxyphenyl]methylamino]-2-phenylpiperidine-1-carboxylate Chemical compound COC1=CC=C(C(C)(F)F)C=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)N(C(=O)OC(C)(C)C)CCC1 HRBAWLDCZIZGIP-GMAHTHKFSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- QXXHXTRTGZBOGD-UHFFFAOYSA-M trifluoromethanesulfonate;5-(trifluoromethyl)dibenzothiophen-5-ium Chemical compound [O-]S(=O)(=O)C(F)(F)F.C1=CC=C2[S+](C(F)(F)F)C3=CC=CC=C3C2=C1 QXXHXTRTGZBOGD-UHFFFAOYSA-M 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- JRPGMCRJPQJYPE-UHFFFAOYSA-N zinc;carbanide Chemical compound [CH3-].[CH3-].[Zn+2] JRPGMCRJPQJYPE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Hospice & Palliative Care (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Psychiatry (AREA)
- Otolaryngology (AREA)
- Urology & Nephrology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Područje tehnike
Ovaj se izum odnosi na supstituirane benzilaminopiperidinske spojeve od interesa za one koji rade u području medicinske kemije i kemoterapije. Točnije, odnosi se na niz supstituranih piperidinskih spojeva, uključujući i njihove farmaceutski prihvatljive soli, koji su od posebne vrijednosti imajući u vidu njihovu sposobnost antagoniziranja supstance P. Ovi su spojevi korisni za liječenje poremećaja gastrointestinalnog trakta, poremećaja centralnog živčanog sustava (CNS), inflamatornih oboljenja, povraćanja, nezadržavanja mokrenja, bola, migrene, opekotina od sunca, oboljenja angiogeneza a, poremećaja i nepovoljnih stanja izazvanih bakterijom Helicobacterpylori, ili sličnog, naročito poremećaja CNS kod sisavaca, naročito ljudi.
Poznato stanje tehnike
Supstanca P je prirodni undekapeptid koji pripada porodici peptida, koji su tako nazvani zbog njihovo trenutnog stimulativnog djelovanja na tkivo glatkih mišića. Točnije, supstanca P je jedan farmaceutski aktivni neuropeptid koji se formira kod sisavaca (prvobitno je izdvojen iz crijeva) i ima jednu karakterističnu sekvencu amino kiselina koju su prikazali D.F. Veber i dr. u američkom patentu br. 4680283. Široko učešće supstance P i drugih tahikinina u patofiziologiji brojnih oboljenja potpuno je dokazano. Tako se, na primjer, nedavno pokazalo da supstanca P ima udjela u prijenosu bola ili migrene, kao i kod poremećaja u centralnom živčanom sustavu kao što je anksioznost i šizofrenija, kod oboljenja disajnih organa i upalnih oboljenja kao što su astma i artritis, i kod gastrointestinalnih poremećaja i oboljenja GI trakta kao što je ulcerozni kolitis i Kronova bolest, itd. Također je objavljeno da se tahikininski antagonisti korisni kod liječenja alergijskih stanja, imunoregulacije, vazodilatacije, bronhospazma, refleksne ili neuronske kontrole utrobe i senilne demencije Alzheimer-ovog tipa, povraćanja, opekotina od sunca i Helicobacter pylori infekcija.
Međunarodne publikacije br. WO 93/01170, WO 93/00331 i WO 93/11110 opisuju širok opseg raznih derivata piperidina kao tahikininskih antagonista kao što su antagonisti supstance P.
Kratak opis izuma
Prikazani izum daje supstituirane piperidinske spojeve sljedeće kemijske formule (I):
[image]
i njihovih farmaceutski prihvatljivih soli, pri čemu
R je halo C1-C8 alkil, halo C2-C8 alkenil, halo C2-C8 alkinil ili halo C1-C8 alkil supstituiran s hidroksi ili C1-C8 alkoksi; R1 je vodik, halo ili C1-C8 alkoksi, ili
R i R1, zajedno sa dva ugljikova atoma koje zajednički koriste benzolski prsten i T i R1, upotpunjuju jedan kondenziran C4-C6 cikloalkil, pri čemu je jedan ugljikov atom eventualno zamijenjen kisikom i pri čemu su jedan ili dva ugljikova atoma eventualno supstituirana s do pet supstituenata biranih od halo, C1-C6 alkila i halo C1-C6 alkila;
X je C1-C6 alkoksi, halo C1-C6 alkoksi, fenoksi ili halo; a
Ar je fenil, eventualno supstituiran s halo.
Piperidinski spojevi formule (I), prema prikazanom izumu, iskazuju dobro antagonističke djelovanje prema poremećajima CNS, pa su stoga korisna za liječenje gaostrointestinalnih poremećaja, poremećaja centralnog živčanog sustava, upalnih oboljenja, povraćanja, nezadržavanja mokrenja, bola, migrene, opekotina od sunca, oboljenja angiogeneza a, ili poremećaja i nepovoljnih stanja izazvanih bakterijom Helicobacter pylori kod sisavaca, naročito ljudi.
Na temelju toga, prikazani izum daje farmaceutsku kompoziciju za liječenje poremećaja gastrointestinalnog trakta, poremećaja centralnog živčanog sustava (CNS), inflamatornih oboljenja, povraćanja, nezadržavanja mokrenja, bola, migrene, opekotina od sunca, oboljenja angiogeneza a, poremećaja i nepovoljnih stanja izazvanih bakterijom Helicobacter pylori, ili sličnog, naročito poremećaja CNS kod sisavaca, naročito ljudi, koja sadrži terapeutski djelotvornu količinu jednog spoja formule (I) zajedno s farmaceutski prihvatljivim nosačem.
Detaljan opis izuma
U ovoj specifikaciji,
izraz "halo C1-C8 kako se ovdje koristi podrazumijeva pravi, rašljasti ili ciklični C1-C8 alkil radikal supstituiran s jednim ili više halogena (tj. Cl. F. I ili Br) uključujući, ali ne ograničujući se na na njih, trifluorometil, difluorometil, trifluoroetil, pentafluoroetil, trifluoroizopropil, tetrafluoroizopropil, pentafluoro-izopropil, heksafluoroizopropil ili heptafluoroizopropil i slično;
izraz "halo C2-C8 alkenil" kako se ovdje koristi označava ravni, rašljasti ili ciklični C2-C8 alkenil radikal supstituiran s jednim ili više halogena (tj, Cl, F, I ili Br) uključujući, ali ne ograničavajući se na njih, 3,3,3-trifluoropropenil, 1,1-dimetil-4,4,4-trifluorobutenil i slično,
izraz "halo C2-C8 alkinil" kako se ovdje koristi označava ravni, rašljasti ili ciklični C2-C8 alkinil radikal supstituiran s jednim ili više halogena (tj, Cl, F, I ili Br) uključujući, ali ne ograničavajući se na njih, 3,3,3-trifluoropropinil, 1,1-dimetil-4,4,4-trifluorobutinil i slično,
izraz "halo C1-C8 alkoksi" kako se ovdje koristi označava pravi, rašljasti ili ciklični C1-C8 alkoksi radikal supstituiran s jednim ili više halogena (tj, Cl, F, I ili Br) uključujući, ali ne ograničavajući se na njih, difluorometoksi, trfluoro-metoksi, 2,2,2-trifluoroetoksi i slično.
U kemijskoj formuli (I):
R je poželjno Cr-C6 alkil, hidroksi C1-C6 alkil, C2-C6 alkenil ili C2-C6 alkinil, pri čemu je alkilna, alkenilna i alkinilna jezgra supstituirani s dva do sedam atoma halogena.
Kod preporučljivog izvođenja prikazanog izuma, R je C1-C6 alkil, hidroksi C1-C6 alkil, C2-C6 alkenil ili C2-C6 alkinil, preporučljivo C1-C6 alkil, pri čemu su te grupe supstituirane s dva do tri atoma klora. Primjeri za R su trifluorometil, difluoroetil, trifluoroetil, trifluoroizopropil, trifluoro-terc-butil, trifluoro-1,1-dimetilmetil-3-butinil i 2-hlorotrifluoro izopropil.
Kod jednog drugog preporučljivog izvođenja prikazanog izuma, R je C1-C6 alkil, hidroksi C1-C6 alkil, C2-C6 alkenil ili C2-C6 alkinil, pri čemu su te grupe supstituirane sa četiri do sedam atoma fluora. Primjeri za R su pentafluoroetil, pentafluoropropil, pentafluoroizopropenil, heksafluoroizopropil, heksafluoro-2-hidroksiizopropil i heksafluoro-terc-butil.
R1 je poželjno vodik ili metoksi, poželjnije vodik.
Kod jednog drugog preporučljivog izvođenja prikazanog izuma, R i R1 mogu biti uzeti zajedno s dva ugljikova atoma, zajednička s benzolskim prstenom i R i R1, kako bi se upotpunio kondenzirani C4-C6 cikloalkil. pri čemu je jedan ugljikov atom eventualno zamijenjen kisikom. Jedan ili dva ugljikova atoma C4-C6 cikloalkila mogu biti eventualno supstituirani s do četiri, poželjnije s jednim ili dva, supstituenta birana od atoma fluora i trifluormetila. Poželjnije, R i R1 uzeti zajedno s dva atoma ugljenika, zajednička za benzolski prsten i R i R1, mogu upotpuniti trifluorometilciklopentil, trifluo-rometilcikloheksil, difluorocikloheksil ili difluorodimetilcikloheksil.
R1 je poželjno halo, metoksi, difluorometoksi, trifluorometoksi ili fenoksi, poželjnije metoksi, difluorometoksi ili trifluorometoksi, najpoželjnije metoksi. X je poželjno na položaju 2 na fenilskom prstenu.
Ar je poželjno fenil.
Druga preporučljiva grupa spojeva prema izumu obuhvaća spojeve formule (la):
[image]
pri čenu R1 je vodik, halo ili metoksi; R2 i R3 se neovisno biraju od halo, C1-C6 alkila, C2-C6 alkenila i C2-C6 alkinila, ili R2 i R3 zajedno tvore C2-C6 alkiliden, pri čemu su jezgre alkila, alkenila, alkinila i alkilidena eventualno supstituirane s do sedam halogenih atoma;
ili R1 R2 su uzeti zajedno da tvore jedan kondenziran C4-C6 cikloalkil, pri čemu je jedan ugljikov atom eventualno zamijenjen kisikom, a C4-C6 ci-kloalkil je eventualno supstituiran s do četiri supstituenata biranih od halo, C1-C4 alkila i halo Cr-C4 alkila.
Kod ovih spojeva preporučljiva stereokemija 2-arila i 3-benzil amino je (2S, 3S).
Preporučljiva grupa pojedinačnih spojeva prema ovom izumu je sljedeća:
(2S, 3S)-3-(2-fluoro-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-hloro-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)~3-(2-metoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-fenoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(5-(1,1-difluoroetiI)-2-(trifluorometoksi)benzil)amino-2-fenil-piperidin ili njegove soli;
(2S,3S)-3-(5-(1,1-difluoroetil)-2-metoksibenzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-metoksi-5-(2,2,2-trifluoroetil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-metoksi-5-(1-(trifluorometil)etil)benzil)amino-2-fenilpipe-ridin ili njegove soli;
(2S, 3S)-3-[5-(1,1-dimetil-4,4,4-trifluoro-2-butinil)-2-metoksibenzil]ami-no-2-fenilpiperidin ili njegove soli;
(2S3S)-3-[5-(1,1-dimetil-2.2.2-trifluoroetil)-2-metoksibenzilamino]-2-fe-nilpiperidin ili njegove soli;
(2S, 3S)-3-(2,4-dimetoksi-5-(2,2,2-trifluoroetil)benzil)amino-2-fenilpipe-ridin ili njegove soli; i
(2S,3S)-3-[5-[(1-hloro-1-(trifluorometil)etil]-2-metoksibenzilamino]-2-fe-nilpiperidin ili njegove soli;
Drugu grupu preporučljivih spojeva prema ovom izumu sačinjavaju sljedeći spojevi:
(2S, 3S)-fenil-3-(5-(2,2,2-trifluoro-1-(trifluorometil)etil)-2-metoksiben-zil)aminopiperidin ili njegove soli;
(2S, 3S)-fenil-3-(5-(2,2,2-trifluoro-1-(trifluorometil)etil)-2-metoksiben-zil)aminopiperidin ili njegove soli;
(2S, 3S)-fenil-3-(5-(2,2,2-tetrafluoro-1-(trifluorometil)etil)-2-metoksiben-zil)aminopiperidin ili njegove soli;
(2S, 3S)-3-(2-metoksi-5-(1,1,2,2,2-pentafluoroetil)benzil)amino)-2-fenil-piperidin ili njegove soli;
(2S, 3S)-fenil-3-(5-(2,2,2-trifluoro-1-(metil)-1-(trifluorometil)etil)-2-me-toksibenzil)aminopiperidin ili njegove soli;
(2S, 3S)-3-[5-[2,2-difluoro-1-(trifluorometil)etenil)-2-metoksibenzil]ami-nopiperidin ili njegove soli; i
(2S, 3S)-3-(2-metoksi-5-(2,2,2-trifluoro-1-hidroksi-1-(trifluorometil)etil) benzil)amino-2-piperidin ili njegove soli,
SljedeĆu preporučljivu grupu pojedinačnih spojeva prema ovom izumu sačinjavaju:
(2S, 3S)--3-[5-metoksi-1-(trifluorometil)indan-6-il)metilamino]-2-fenilpi-peridin ili njegove soli;
(2S, 3S)-3-( (6-metoksi-1-( trifluorometil )-l,2,3,4-tetrahidronaflalin-7-il) metil)amino)-2-fenilpiperidin ili njegove soli; i
(2S3S)--3-((2,2-difluoro-6-metoksi-1-1,2,3,4-tetrahidronaftalin-7-il)me-til)amino)-2-fenilpiperidin ili njegove soli.
Opća sinteza
Piperidinski spojevi formule (I) prema ovom izumu mogu se pripremati kako je opisano u sljedećim shemama reakcije.
Ukoliko nije drugačije naznačeno, u sljedećeim shemama reakcije R, X i Ar su takvi kako su naprijed definirani
Šema A-I
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Shema A-1 prikazuje postupak za pripremanje spoja formule (I) redukcijskom aminacijom jednog spoja formule (III) saspojem formule (II). Redukcija se može izvesti katalitičkom hidrogenacijom, ili s nekoliko hibridnih reagensa u nekom reakcijsko-inertnom otapalu. Katalitička hidrogenacija može se izvoditi u prisutnosti metalnog katalizatora kao što je paladij ili Raney nikl. Pogodni hibridni reagensi obuhvaćaju borhidride kako što je na-trijborhidride (NaBH4), natrij cijanoborhidrid (NaBH3CN) i natrij tria-cetoksiborhidrid (NaB(OAc)3H), borani, reagensi na bazi aluminija i trialkil-silani. Pogodna otapala obuhvaćaju polarna otapala kao što su metanol, etanol, metilen klorid, tetrahidrofuran (THF), dioksan i etilacetat. Ova se reakcija obično izvodi na temperaturi od -78°C do temperature refluksiranja otapala, poželjeno od 0°C do 25°C u trajanju od 5 minuta do 48 sati, poželjno od 30 min do 12 sati.
Alternativno, piperidinski spojevi formule (I) prema ovom izumu mogu se pripremati kako je prikazano na sljedećoj shemi A-II.
Shema A-II
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(gdje je Z jedna odlazeća grupa kao što je halo ili sulfonat, uključujući tosilat ili mesilat)
Prema shemi A-II, spojevi formule (I) prema ovom izumu mogu se pripremati reagiranjem spoja formule (IV) s jednim spojem formule (II). Spoj (IV) može se obrađivati sa spojem (II) u prisutnosti jedne baze (na primjer K2CO3 ili Na2CO3) u polarnom otapalu (kao što je, na primjer, metanol, etanol, izopropilalkohol. THF, dioksan, dimetilformamid (DMF) ili dimetilsulfoksid (DMSO)). Ova se reakcija obično izvodi na temperaturi od -78°C do temperature refluksiranja otapala, poželjno od 0°C do 25°C u trajanju od 5 min do 48 sati, poželjno od 30 min do 12 sati.
spojevi (IV) mogu se pripremati reduciranjem jednog aldehida formule (III), pa konverzijom jedne hidroksi grupe dobijenog spoja u odlazeću grupu Z. Reduciranje aldehida (III) može se izvesti korištenjem više raznih sredstava za reduciranje u reakcijsko inertnom otapalu. Pogodni sustavi sredstvo za reduciranje/otapalo obuhvaćaju natrij tetrahidroborat (NaBH4) u metanolu ili etanolu; litij tetrahidroborat (LiBH4) u metanolu ili etanolu; litij tetrahidroborat (LiBH4) u THF ili dietil eteru; litij tetrahidroaluminij (LiAlH4), litij trietoksihidroaluminij (LiAl(OEt)3H), litij terc-buto-ksihidroaluminij (LiAl(OBu/)3H) ili aluminij trihidrid (AlH3) u THF ili dietil eteru; i izobutil aluminij hidrid (i-BuAlH2) ili diizopropil aluminij hidrid (DIBAL-H) i dihlormetanu, THF ili n-heksanu. Ova se reakcija obično izvodi na temperaturi od -20°C do 25°C u trajanju od 5 min do 12 sat. Poslije toga se hidroksi grupa dobijenog spoja pretvara u odlazeću grupu Z (na primjer, halo, kao što je klor, brom, jod ili fluoto, ili sulfonata, uključujući tosilat ili mesi-lat). Pretvaranje hidroksi grupe u odlazeću grupu, Z, može se izvesti postupcima poznatim stručnjacima. Tako, na primjer, kada je Z sulfonat kao što je tosilat ili mesilat, hidroksi spoj se reagira sa sulfonatom u prisutnosti piridina ili trie-tilamina u dihlormetanu. Kada Z je halo kao stoje klor ili brom, hidroksi komponenta se može obraditi sa SOX2 (X je Cl ili Br) u prisutnosti piridina.
Spojevi formule (III) mogu se pripremati kako je prikazano na sljedećoj shemi B-I. Shema B-I
[image]
spoj formule (III) može se pripremiti neposrednom ih posrednom formilacijom (uvođenjem radikala u neki spoj) jednog spoj Formule (V). Može se koristiti svaki postupak za formilaciju poznat stručnjacima, da bi se unijela jedna formil-grupa u benzolski prsten. Tako se, na primjer, neposredna formilacija može ostvariti stavljanjemspoja (V) u dodir s pogodnim sredstvom za formilaciju u prisutnosti pogodnog katalizatora. Pogodni sustavi sredstvo za formilaciju/katalizator obuhvaćaju diklor metil etar/titan (IV) klorid (Cl2CHOCH3/ TiCl4), trifluorooctena kiselina (CF3CO2H) / heksametilentetramin (modificirani Duff-ovi uvjeti) i fosforil triklorid (POCl3)/DMF (Vilsmeier-ovi uvjeti). Posredna formilacija može se postići halogeniziranjem spoja (V), zamjenjujući uvedeni halogenski atom jednom cijano grupom, a potom podvrgavanjem dobijenog cijano-supstituiranog spoja redukciji. Halogenacija, kako se ovdje koristi, može se izvoditi prema poceduri koju su prikazali G.A. Olah i dr., J. Org. Chem.. 58, 3194 (1993). Zamjena halogenskog atoma jednom cijano grupom mo-že se izvesti prema postupcima koje su objavili S.M. Tschaem i dr.. Svnth. Commun.. 24, 887 (1994), K. Takagi i d., 64 Bull.Chem. Soc. Jpn. 64 1118 (1991). Redukcija, kako se ovdje koristi, može se izvesti u prisutnosti diizopropil alumi-nijhidrida (DIBAL-H) u diklormetanu ili Raney nikla u mravljoj kiselini.
Polazni materijali za formulu (V) su poznati spojevi koji su komercijalno dostupni, ili se mogu pripremiti poznatim postupcima. Tako, na primjer, spojevi formule (V) kod kojih X je alkoksi, mogu se pripremati O-alkiliranjem odgovarajućeg spoja (V) kod koga X je hidroksi, u prisutnosti baze (na primjer NaH ili KH) u pogodnom otapalu (na primjer DMSO, DMF i THF)
spoj (V) može se pripremati i drugim postupcima opisanim u literaturi:
(A) trifluorometilacija, J.Am.Che..Soc.. 111, 393-395 (1989)
(B) terc-alkilacija, Angew.Chem.Int.Ed.Engl.. 19, NO. 11 900-901 (1980);
(C) hemoselektivna i položajne specifična metilacija terc-alkil halogenida sa metiltitanom (IV), Angew.Chem.Int.Ed.Engl.. 19, NO. 11 901-902 (1980) i fluo-riniranje ketona, Organic reaction (1988), 35.
Pored toga, R u spoju formule (III) može se prevesti u bilo koji željeni supstituent R" (na primjer CF2CF3 ili CF2CH3) prema tehnikama poznatim stručnjacima, kao što je, na primjer, prikazano na sljedećoj shemi B-II.
Shema B-II
[image]
Na shemi B-II, polazni materijali formule (VI) su poznati spojevi koji se mogu pripremiti procedurama opisanim, na primjer, u Collect.Czech.Chem. Commun.. 52,980 (1987) ili u Bull.Chem.Soc.Jpn.. 57, 2435 (1978).
Tako se, na primjer, spoj formule (VI) kod koga A je CN a R je alkilkarbonil (vidjeti u Collect.Czech.Chem. Commun.. 52,980 (1987)) može podvrgnuti tioketalizaciji, a potom supstituciji da bi se dobilo spoj formule (VII) (videti J. Org. Che.. 57, 3508 (1986)). Spoj formule (VI) kod koga A je acetal a R je halo (videti Bull.Chem.Soc.Jpn.. 57, 2435 (1978) može se podvrgnuti alkilaciji da bi se dobilo spoj formule (VII) (videti Synthetic. Comm.. 75,965 (1988).
Tada se spoj formule (VII) može podvrći solvolizi ili redukciji u pogodnim uvjetima reakcije da bi se dobilo spoj formule (VIII) gde je R prevedeno u R" (na primjer CF2CF3 ili CF2CH3) (vidjeti J.Org.Chem., 24, 627 (1959) i Protective group in organic svnthesis, John Wiley & sons, Inc., 180 i 191 (1991))
Alternativno, spojevi formule (I) mogu se pripremati kako je prikazano u sljedećoj shemi A-III.
Shema A-III
[image]
Shema A-III prikazuje pripremanje spoja formule (I). Prema shemi A-III, N-zaštita spoja formule (IX) (Ar je fenil ili slično) može se izvesti obradom s (t-BuOCO)2O (BoC2O) u prisutnosti baze kao stoje natrij bikarbonat (NaHCO3) ili trietilamin (Et3N) da bi se dobio spoj formule (X). Spoj (X) se podvrgava hidrogenolizi da bi se dobio spoj formule (XI) (gdje Ar je fenil). Alternativan put za N-zaštitu spoja formule (IX) može biti obrada s karbobenzoksi kloridom (Cbz-Cl) u prisutnosti baze kao što je natrij bikarbonat (NaHCO3) ili trietilamin (Et3N), pri čemu Ar je fenil. Hidrogenoliza se može izvesti obradom s H2 ili amonij formijatom (HCO2NH4) u prisutnosti metalnog katalizatora kao što je paladij na drvenom ugljenu (na primjer 20% paladij na drvenom ugljenu) u pogodnom otapalu. Potom se spoj (XI) podvrgava redukcijskoj aminaciji, kako je opisano na shemi A-I. Spoj (XII) može se prevesti u spoj formule (I) obradom s kiselinskim katalizatorom kao što je hidroklorid (HCl) u metanolu, koncentrirana HCl u etilacetatu ili CF3CO2H u dikloretanu.
Spoj formule (I), kao i međuproizvodi prikazani u prikazanim shemama reakcije, mogu se izdvojiti i pročistiti uobičajenim postupcima, kao što je rekristalizacija ili kromatografsko razdvajanje.
Kako piperidinski spojevi prema ovom izumu imaju najmanje dva asimetrična centra, oni se mogu javljati u raznim stereoizomernim oblicima ili konfiguracijama. Zbog toga spojevi mogu postojati u odvojenim (-f-)- i (-)- optički aktivnim oblicima, kao i u njihovim smjesama. Prikazani izum obuhvaća i sve te oblike. Pojedinačni izomeri mogu se dobiti poznatim postupcima kao što je optičko razlaganje, optički selektivna reakcija ili kromatografsko razdvajanje u tijeku pripremanja konačnog proizvoda ili njegovog međuproizvoda.
Kako su piperidinski spojevi prema ovom izumu osnovni spojevi, svi oni mogu tvoriti široku lepezu različitih soli s raznim neorganskim i organskim kiselinama. Iako te soli moraju biti farmaceutski prihvatljive za davanje životinjama, često je u praksi poželjno da se na početku izdvoji spoj na bazi piperidina iz reagirajuće smjese kao farmaceutski neprihvatljiva sol, pa da se potom jednostavno prevede u spoj slobodne baze obradom s nekim alkalnim reagensom, a da se potom slobodna baza prevede u farmaceutski prihvatljivu aditivnu sol kiseline. Aditivne soli kiselina spoja na bazi piperidina, prema ovom izumu, lako se pripremaju obradom osnovnog spoja jednom u suštini ekvivalentnom količinom izabrane mineralne ili organske kiseline u vodenom otapalu ili u pogodnom organskom otapalu kao što je metanol ili etanol. Nakon pažljivog isparavanja otapala, lako se dobija željena čvrsta sol. Kiseline koje se koriste za pripremanje farmaceutski prihvatljivih aditivnih soli kiselina spomenutih spojeva na bazi piperidina, prema ovom izumu, jesu one koje tvore netoksične aditivne soli kiselina, tj, soli koje sadrže farmaceutski prihvatljive anione, kao što su soli hidroklorida, hidrobromida, hidro-jodida, nitrata, sulfata ili bisulfata, fosfata ili kiselog fosfata, acetata, laktata, citrata ili kiselog citrata, tartrata ili bitartrata, sukcinata, maleata, fumarata, glukonata, saharata, benzoata, metansulfonata, etansulfonata, benzensulfonata, p-toluolsulfonata i pamoata (tj. 1,1'-metilen-bis-(2-hidroksi-3-naftoata)).
Piperidinski spojeva prema izumu, koja također imaju kiselinske grupe mogu tvoriti bazne soli s raznim farmaceutski prihvatljivim kationima. Primjeri takvih soli obuhvaćaju soli alkalnih ili zemnoalkalnih metala a posebno soli natrija i kalija. Sve se te soli pripremaju uobičajenim tehnikama.
Kemijske baze koje se koriste kao reagensi za pripremanje farmaceutski prihvatljivih baznih soli prema ovom izumu, jesu one koje tvore netoksične soli baza s opisanim kiselim derivatima piperidina. Te posebne netoksične soli baza obuhvaćaju one izvedene od takvih farmaceutski prihvatljivih kationa ka što su natrij, kaliju kalcij i magnezij, itd. Ove se soli mogu lako pripremiti obradom spomenutih kiselih piperidinskih spojeva s vodenom otopinom koja sadrži željeni farmaceutski prihvatljiv kation, a potom isparavanjem dobijene otopine do suha, poželjno pod sniženim tlakom. Alternativno, one se također mogu pripremati miješanjem nižih alkanojskih otopina kiselinskih spojeva i alkoksida željenog alkalnog metala, a potom isparavanjem dobijene otopine do suha, na isti način kao stoje naprijed opisano. U oba slučaja su preporučljive stehiometrijske količine reagensa da bi se osigurala potpunost reakcije i maksimalni prinosi željenog krajnjeg proizvoda.
Aktivni piperidinski spojevi prema prikazanom izumu pokazuju značajno djelovanje na vezivanju za receptor supstance P, pa su zbog toga korisni kod liječenja široke lepeze kliničkih stanja koja su karakteristična po pretjeranom djelovanju supstance P. Takva stanja obuhvaćaju gastrointestinalne poremećaje, poremećaje centralnog živčanog sustava, upalna oboljenja, povraćanje, nezadržavanje mokrenja, bol, migrenu ili angiogenezu kod sisavaca, posebno kod ljudi. Kod liječenja povraćanja, poželjno je da se ovi spojevi koriste u kombinaciji s nekim antagonistom 5HT3 receptora.
Aktivni piperidinski spojevi formule (I) prema ovom izumu, mogu se sisavcima davati oralnim, parenteralnim ili lokalnim putevima. Općenito, spojevi se najpoželjnije daju ljudima u dozama koje se kreću od 0,3 mg do 750 mg dnevno, iako će se neizbježno javiti varijacije, ovisno od mase i stanja osobe koja se liječi i izabranog puta davanja. Međutim, nivo doziranja koji je u opsegu od oko 0,06 mg do oko 2 mg po kg tjelesne mase na dan, najpoželjnije se koristi. U svakom slučaju, varijacije se opet mogu pojaviti, ovisno od vrste životinje koja se liječi i od individualnog reagiranja na taj lijek, kao i od vrste izabrane farmaceutske formulacije i od vremenskog perioda i intervala u kojima se odvija davanje lijeka.
U nekim slučajevima, nivoi doziranja ispod donje granice naprijed spomenutog opsega mogu biti više nego dovoljni, dok u drugim slučajevima se mogu koristiti još veće doze, bez izazivanja štetnih sporednih djelovanja, pod uvjetom da su ti viši nivoi doziranja prethodno podijeljeni na nekoliko malih doza za davanje u tijeku dana.
Spojevi prema prikazanom izumu mogu se davati sami ili u kombinaciji s farmaceutski prihvatljivim nosačima ili razređivačima za bilo koji od ranije spomenutih puteva, i to se davanje može izvesti pojedinačnim ili višekratnim dozama. Točnije, nova terapeutska sredstva prema izumu mogu se davati u mnoštvu različitih doznih oblika, tj, mogu se kombinirati s raznim farmaceutski prihvatljivim nosačima u vidu tableta, kapsula, pilula, pastila, tvrdih bombona, praškova, sprejeva, krema, masti, supozitorija, želea, gelova, pasta, losiona, melema, vodenih suspenzija, otopina za injekcije, eliksira, sirupa i sličnog. Takvi nosači obuhvaćaju čvrste razredivače ili punioce, sterilne vodene medije i razne netoksične razređivače, itd. Pored toga, oralne farmaceutske kompozicije mogu biti pogodno zaslađene i/ili dobiti određen okus. U cjelini, terapeutski djelotvorni spojevi prema ovom izumu nalaze se u takvim doznim oblicima na nivoima koncentracije u opsegu od oko 5,0% do oko 70% mas.
Za oralno davanje mogu se koristiti tablete koje sadrže razne punioce kao što je mikrokristalna celuloza, natrij citrat, kalcij karbonat, dikalcij fosfat i glicin, zajedno s raznim sredstvima za razlaganje kao što je škrob, poželjno kukuruzni, krumpirov ili škrob od tapioke, alginska kiselina i izvjesni kompleksni silikati, zajedno s vezivima za granuliranje kao što su polivinilpirolidon, saharoza, želatina ili bagrem. Pored toga, sredstva za podmazivanje kao što je magnezij stearat, natrij lauril sulfat i talk, često su veoma korisna u svrhe izrade tableta. Čvrsti spojevi slične vrste mogu se isto tako koristiti kao punioci u želatinskim kapsulama; preporučljivi materijali, s tim u vezi, također obuhvaćaju laktozu ili mliječni šećer kao i polietilen glikole velike molekulske mase. Kada se za oralno davanje žele vodene suspenzije i/ili eliksiri, aktivni sastojak može biti kombiniran s raznim sredstvima za zaslađivanje ili davanje okusa, materijalima za bojenje ili bojama, i, ukoliko se želi, sredstvima za emulgiranje i/ili za pravljenje suspenzija, zajedno s razređivačima kao što je voda, etanol, propilenglikol, glicerin i razne njihove kombinacije.
Za parenteralno davanje mogu se koristiti otopine spoja prema prikazanom izumu bilo u sezamovom ulju, bilo u ulju od kikirikija, ili vodenom propilen glikolu. Vodene otopine trebaju biti pogodno puferirani (poželjno pH> 8) ukoliko je potrebno i da se tekuće otapalo prvo načini izotoničnim. Ovi su vodene otopine pogodne za intravenske injekcije. Uljne otopine su pogodne za injekcije u zglobove, za intramuskularne i potkožne injekcije. Pripremanje svih ovih otopina u sterilnim uvjetima lako se izvodi standardnim farmaceutskim tehnikama, dobro poznatim stručnjacima. Pored toga, spojevi prema prikazanom izumu mogu se davati lokalno kod liječenja upalnih stanja kože, i to se može izvesti kremama, želeima, gelovima, pastama, mastima i sličnim, u skladu sa standardnom farmaceutskom praksom.
Djelovanje spojeva prema prikazanom izumu, kao antagonista supstance P, određen je njihovom sposobnošću da spriječe vezivanje supstance P na njenim receptorskim mjestima u CHO-stanicama koje imaju NK1 receptor ili IM-9 stanice koristeći radioaktivne ligande. Antagonističke djelovanje prema supstanci P naprijed opisanih piperidinskih spoja procjenjuje se koristeći standardnu proceduru ispitivanja koju su opisali M. A. Cascieri i dr., The Journal of Immunologv. 133, 3260 (1984). Ovaj postupak u biti obuhvaća određivanje koncentracije pojedinačnih spojeva potrebnih da se za 50% smanji količina liganada supstance P, obilježenih radioativnim materijama, na mjestima njihovih receptora u spomenutom izoliranom kravljem tkivu ili IM-9 stanicama, čime se dobijaju karakteristične IC50 vrijednosti za svaki ispitivano spoj. Točnije, suzbijanje [3H]SP vezivanja na humane IM-9 stanice od strane spoja određeno je u ispitnom puferu (mM Tris-HCl (pH 7,4), 1 mM MnCl2, 0,02 % albumina iz seruma goveda, bacitracin (40 µg/ml), leupeptin (4 µg/ml), himostatin (2 µg/ml) i fosforamidon (30 µg/ml)). Reakcija je inicirana dodavanjem stanica u ispitni pufer koji je sadržao 0,56 nM[3H]SP i razne koncentracije spoja (ukupna zapremina: 0,5 ml) i puštanjem da inkubira 120 min na 4°C. Inkubacija je završena filtriranjem na GF/B filtrima (prethodno natapanim u 0,1% polietileniminu tijekom 2 sata). Nespecifično vezivanje je definirano kao radioaktivnost koja je ostala u prisutnosti 1 µ SP. Filetri su stavljeni u epruvete i prebrojavani koristeći tkući scintilacioni brojač.
Nepovoljno djelovanje na afinitet za vezivanje Ca2+ kanala određen je proučavanjem vezivanja verapamila u preparatu membrane srca štakora. Točnije, vezivanje verapamila je vršeno kako su ranije opisali Revnolds i dr., (J. Pharmacol. Exp. Ther.. 237, 731, 1986). Ukratko rečeno, inkubacije se iniciraju dodavanjem tkiva u epruvete koje sadrže 0,25 nM [3H]desmetoksiverapamila i različite koncentracije spoja (ukupna zapremina: l ml). Nespecifično vezivanje je definirano kao vezivanje radioliganada koji su ostali u prisutnosti 3-10 µM metoksiverapamila.
Djelovanje spoja prema ovom izumu protiv poremećaja u CNS određuje se ispitivanjem tapkanja nogom kod gerbila (vrsta opitnih glodavaca) izazvanog [Sar9, Met(O2)u]supstancijom P. Točnije, gerbili se lako anesteziraju eterom i otkrije se površina lubanje. [Sar9, Met(O2)11]supstancija P ili nosač daju se neposredno u bočne komore pomoću igle No. 25 umetnute 3,5 mm ispod lambda. Poslije injekcije, gerbili se stavljaju pojedinačno u pehar zapremine 2 l i prati se ponovljeno tapkanje zadnje šape. Neki od spojeva pripremljena u sljedećim primerima ispitivana su prema ovim postupcima ispitivanja. Kao rezultat je utvrđeno da spoja prema prikazanom izumu imaju dobro antagonističke djelovanje prema supstanciji P, posebno prema poremećajima u CNS, sa povoljnim metaboličkim svojstvima.
Točnije, na primjer, usporedbom tri-fluorometil- i heksa-fluoroizopropil-benzilaminopiperidinska spoja (primjeri 3 i 5) s odgovarajućim spojevima koji nisu halo-supstituirana, utvrđeno je da su halo-supstituisani spojevi iskazali neočekivano poboljšano djelovanje protiv poremećaja u CNS.
Poluperiod spoja prema ovom izumu određen je mikrosomskom preparatu humane jetre. Točnije, spoj (1 µM) inkubirano je sa sakupljenim mikrosomima humane jetre (2,0 mg/ml), NADP (1,3 mM), NADH (0,93 mM), glukoza-6-fosfatom (3,3 mM), MgCl2 (3,3 mM) i glokoza-6-fosfat dehidro-genazom (8 jedinica/ml) u ukupnoj zapremini od 1,2 ml 100 nM kalijom fosfatnog pufera, pH 7,4. U raznim trenucima vremena (0,5, 10, 30 i 60 min), uzorak od 100 µl sipan je u otopinu acetonitrila (1,0 ml), što je obuhvaćalo jednu određenu internu kvalitetu. Istaložen protein je podvrgnut centrifugiranju (3000 x g, 5 min). Površinski sloj je analiziran pomoću LC-MS. LC-MS jedinica sastojala se od Hewlett Packard HP 1090 HPLC sustava i Sciex API-III. Uzorci (10 ml) ubrizgavani su pomoću automatskog uređaja za uzimanje uzoraka na Hewlett Packard ODS-Hypersil kolonu (2,1 x 20 mm), Jedna mobilna faza se sastojala od 80% acetonitrila u 10 mM amonij acetatu. Mjerenje API-III analizirano je detekcijom sa višestruko reagiraujućim praćenjem (MRM).
Primjer 1
Pripremanje C2, 3S)-3-(2-fluoro-5-(trifluorometil)benzil)amino-2-fenilpiperidin dihidrohlorida (Spoj 2)
(i) (2S, 3S)-2-fenilpiperidin-3-amin- dihidrohlorid (Spoj 1)
Ovo je spoj pripremljen prema postupku opisanom u EP-558156.
(ii) (2S, 3S)-3-(2-fluoro-5-(trifluorometinbenzil)amino-2-fenilpiperidin dihidro-hlorid (Spoj 2)
Miješanoj suspenziji Spoja 1 (150 mg, 0,60 mmol) i 2-fluoro-5-(trifluorometil)benzaldehida (116 mg, 0,60 mmol) u bezvodnom CH2Cl2 (6 ml) dodan je, po dijelovima, NaBH(OAc)3 (179 mg, 0,84 mmol), u atmosferi azota i na sobnoj temperaturi. Reagirajuća smjesa je miješana na sobnoj temperaturi 6,5 sati. Zatim je olužena sa zasićenim vodenim NaHCO3, ekstrahirana sa CH2Cl2, sušena preko MgSO4, i koncentrirana da bi se dobio sirov (2S, 3S)-3-(2-fluoro-5-(trifluorometil)benzil)amino-2-fenilpiperidin kao bezbojno ulje. Pročišćen je kromatografijom da bi se dobio čist (2S, 3S)-3-(2-fluoro-5-(trifluorometil)benzil)amino-2-feniipiperidin kao bezbojno ulje (75 mg). Otopljen je etil acetatom, dodan je HCl-MeOH, pa je proizvod koncentriran. Bijela čvrsta supstancija je rekristalirana iz MeOH-etera da bi se dobio Spoj 2 u vidu bijelih kristala (67 mg, 26,3 96).
T. t. 195 - 203°C
1H-NMR (CDCl3, slobodna baza) 7,42-7,22 (m, 7H), 6,99 (t, J = 8,8 Hz, 1H), 3,90 (d, J = 2,2 Hz, 1H), 3,61 (d, J = 15,0 Hz, 1H), 3,46 (d, J = 15,0 Hz, 1H), 3,28-3,22 (m, 1H), 2,86-2,76 (m,2H), 2,08-2,03 (m, 1H), 1,95-1,78 (m, 1H), 1,69-1,57 (m, 1H), 1,48-1,44 (m, 1H).
Primjer 2
Pripremanje (2S, 3S)-3-(2-hloro-5-(trifluorometil)benzil)amino-2-fenilpiperidin dihidrohlorida (Spoj 3)
Miješanoj suspenziji Spoja 1 (150 mg, 0,60 m mol) i 2-kloro-5-(trifluorometil)benzaldehida (126 mg, 0,60 mmol) u bezvodnom CH2Cl2 (6 ml) dodan je, po dijelovima, NaBH(OAc)3 (179 mg, 0,84 mmol), u atmosferi azota i na sobnoj temperaturi. Reagiraujuća smjesa je miješana na sobnoj temperaturi 17 sati. Zatim je olužena sa zasićenim vodenim NaHCO3, ekstrahirana sa CH2Cl2, sušena preko MgSO4, i koncentrirana da bi se dobio sirov (2S, 3S)-3-(2-kloro-5-(trifluorometil)benzil)amino-2-fenilpiperidin kao bezbojno ulje. Pročišćen je kromatografijom da bi se dobio čist (2S, 3S)-3-(2-hloro-5-(trifluorometil)benzil)amino-2-fenilpiperidin kao bezbojno ulje (135 mg). Otopljen je etil acetatom, dodan je HCl-MeOH, pa je proizvod koncentriran. Bijela čvrsta supstancija je rekristalirana iz MeOH-etrra da bi se dobio Spoj 3 u vidu bijrelih kristala (64 mg, 24,1 %).
T.t. 200 - 210°C
1H-NMR (CDCl3, slobodna baza) 7,40-7,22 (m, 8H), 3,91 (d, J = 2,2 Hz, 1H), 3,66 (d, J = 15,0 Hz, 1H), 3,50 (d, J = 15,0 Hz, 1H), 3,29-3,23 (m, 1H), 2,86-2,76 (m,2H), 2,10-2,05 (m, 1H), 1,97-1,80 (m, 1H), 1,70-1,58 (m, 1H), 1,51-1,45 (m, 1H).
Primjer 3
Pripremanje (2S, 3S)-3-(2-metoksi-5-(trifluorometil)benzil)amino-2-fenilpiperi-dindihidrohlorida (Spoj 5)
(i) 2-metoksi-5-(trifluorometil)benzaldehid (Spoj 4)
Mijeešanoj i ledeno hladnoj otopini NaOMe (904 mg, 4,68 mmol) dodan je po dijelovima 2-fluoro-5-(trifluorometil)benzaldehid (500 mg, 2,60 mmol). Korišten lijevak za ukapavanje ispran je sa THF. Dobijena suspenzija je miješana 5 sati na sobnoj temperaturi. Reagirajuća je smjesa neutralizirana octenom kiselinom (0,3 ml, 5 mmol), a otapalo je uklonjeno. Čvrstom ostatku je dodana voda i mješavina je ekstrahirana sa CH2Cl2. Kombinirani CH2Cl2 su isprani zasićenim vodenim NaHCO3, sušeni preko MgSO4, pa koncentrirani da bi se dobio sirovi Spoj 4 u vidu čvrste bijele supstancije. Pročišćeno je pripremnom TLC da bi se dobio čisti Spoj 4 u vidu bijelih kristala (363 mg, 68,4 %).
1H-NMR (CDCl3) 10,47 (1, 1H), 8,11 (d, J = 2,2 Hz, 1H), 7,80 (dd, J = 8,8, 2,2 Hz, 1H), 7,10 (d, J = 8,8 Hz, 1H), 4,10 (s, 3H).
(ii) (2S, 3S)-3-(2-metoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin dihidroklorid (Spoj 5)
Miješanoj suspenziji Spoja 1 (150 mg, 0,60 mmol) i Spoja 4 (123 mg, 0,60 mmol) u bezvodnom CH2Cl2 (6 ml) dodan je, po dijelovima, NaBH(OAc)3 (179 mg, 0,84 mmol), u atmosferi azota i na sobnoj temperaturi. Reagirajuća smjesa je miješana na sobnoj temperaturi 3,5 sati. Zatim je olužena zasićenim vodenim NaHCO3, ekstrahirana sa CH2Cl2, sušena preko MgSO4, i koncentrirana da bi se dobio sirov (2S, 3S)-3-(2-metoksi-5-(trifluorometil) benzil)amino-2-fenilpiperidin kao bezbojno ulje. Pročišćen je kromatografijom da bi se dobio čist (2S, 3S)-3-(2-metoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin kao bezbojno ulje (95 mg). Otopljen je etil acetatom, dodan je HCl-MeOH, pa je proizvod koncentriran. Bijela čvrsta supstanca je rekristalirana iz MeOH-etra da bi se dobio Spoj 5 u vidu bijelih kristala (85 mg, 32,4 %).
T.t. 228 - 233°C
1H-NMR (CDCl3, slobodna baza) 7,40 (d, J = 8,8 Hz, 1H), 7,34-7,23 (m. 6H), 6,71 (d, J = 8,8 Hz, 1H), 3,92 (d, J = 2,2 Hz, 1H), 3,66 (d, J = 14,3 Hz, 1H), 3,42 (d, J = 14,3 Hz, 1H), 3,33-3,29 (m, 1H), 2,87-2,77 (m,2H), 2,12-1,90 (m, 2H), 1,66-1,56 (m, 1H), 1,48-1,43 (m, 1H).
Primjer 4
Pripremanje (2S, 3S)-3-(2-fenoksi-5-(trifluorometil)benzil)amino-2-fenilpiperi-dindihidroklorida (Spoj 7)
(i) 2-fenoksi-5-(trifluorornetir)benzaldehid (Spoj 6)
Miješanoj otopini 2-kloro-5-(trifluorometil)bemzaldehida (500 mg, 2,40 mmol) u DMF (5 ml) dodan je fenol (226 mg, 2,40 mmol), K2CO3 (663 mg, 4,79 mmol). Reagirajuća suspenzija je miješana 1 sat na sobnoj temperaturi, pa 1,5 sat na 80°C. Reagirajuća je smjesa neutralizirana octenom kiselinom (0,3 ml, 5 mmol), a otapalo je uklonjeno. Čvrstom ostatku je dodana voda i mješavina je ekstrahirana sa CH2Cl2. Kombinirani CH2Cl2 su isprani zasićenim vodenim NaHCO3, sušeni preko MgSO4, pa koncentrirani da bi se dobio sirovi Spoj 6 kao žuto ulje. Pročišćeno je kromatografijom da bi se dobio čisti Spoj 6 kao žuto ulje (466 mg, 72,9 %).
1H-NMR (CDCl3) 10,58 (l, 1H), 8,21 (d, J = 2,6 Hz, 1H), 7,70 (dd, J = 8,8, 2,6 Hz, 1H), 7,50-7,42 (m, 2H), 7,31-7,25 (m, 1H), 7,16-7,10 (m, 2H), 6,93 (d, J = 8,8 Hz, 1H).
(ii) (2S, 3S)-3-(2-fenoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin dihidroklorid (Spoj 7}
Miješanoj suspenziji Spoja 1 (150 mg, 0,60 mmol) i Spoja 6 (160 mg, 0,60 mmol) u bezvodnom CH2Cl2 (6 ml) dodan je, po dijelovima, NaBH(OAc)3 (179 mg, 0,84 mmol), u atmosferi azota i na sobnoj temperaturi. Reagirajuća smjesa je miješana na sobnoj temperaturi 3 sata. Zatim je olužena sa zasićenim vodenim NaHCO3, ekstrahirana sa CH2Cl2, sušena preko MgSO4, i koncentrirana da bi se dobio sirov (2S, 3S)-3-(2-fenoksi-5-(trifluorometil)ben-zil)amino-2-fenilpiperidin kao žuto ulje. Pročišćen je kromatografijom da bi se dobio čist (2S, 3S)-3-(2-fenoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin kao žuto ulje (135 mg). Otopljen je etil acetatom, dodan je HCl-MeOH, pa je proizvod koncentriran. Bijela čvrsta supstanca je rekristalirana iz MeOH-etra da bi se dobio Spoj 7 u vidu bijelih kristala (108 mg, 36,0 %).
T.t. 190 - 197°C
1H-NMR (CDCl3, slobodna baza) 7,39-7,18 (m, 8H), 7,15-7,09 (m, 2H), 6,79-6,71 (m,3H), 3,90 (d, J = 2,2 Hz, 1H), 3,66 (d, J = 14,7 Hz, 1H), 3,51 (d, J = 14,7 Hz, 1H), 3,28-3,23 (m, 1H), 2,90 (d, J = 2,6 Hz, 1H), 2,66 (d, J = 12,1 Hz, 1H), 2,11-2,06 (m, 1H), 1,98-1,81 (m,1H), 1,69-1,56 (m, 1H), 1,46-1,41 (m, 1H).
Primjer 5
Pripremanje (2S, 3S)-2-fenil-3-(5-(2,2,2-trifluoro-1-(trifluorometil)etil)-2-meto-ksibenzil)aminopiperidin dihidroklorid (Spoj 15)
(i) 4-(2,2,2-trifluoro-1-(trifluorometil)etinanizol (Spoj 8)
Ovo je spoj pripremljen prema proceduri opisanoj u J. Am. Chem. Soc. 820 (972).
(ii) 5-(2,.2,2-trifluoro-1-(trifluorometil)etin-2-metoksibenzaldehid (Spoj 9)
Miješanoj i ledenohladnoj otopini Spoja 8 (650 mg, 2,5 mmol) u suhom CH2Cl2 (15 ml) dodan je čist TiCl4 (950 mg, 5,0 mmol), pa zatim Cl2CHOMe (600 mg, 5,0 mmol). Nakon stoje dodavanje dovršeno, smjesa je miješana 5 sati na sobnoj temperaturi, sipana u H2O (60 ml) i ekstrahirana sa CH2Cl2. Kombinirani ekstrakti su sušeni (Na2SO4) i koncentrirani u vakuumu da bi se dobilo žuto ulje, koje je pročišćeno stubnom kromatografijom na silika gelu da bi se dobio Spoj 9 (650 mg, 90%)
1H-NMR (CDCl3) 7,86-7,08 (m, 3H), 4,05 (hep, J = 8 Hz, 1H), 3,98 (s, 3H).
(iii) (2S,3S)-3-(2-metoksibenzil)amino-2-fenilpiperidin (Spoj 10)
Ovo je spoj pripremljen prema postupku opisanom u WO-93-01170.
(iv) (2S,3S)-1-terc-butoksikarbonil-3-(2-metoksibenzil)aminopiperidin (Spoj 11)
Miješanoj i ledeno hladnoj smjesi spoja 10 (10 g, 27 mmol), 3M NaOH vod. (36 ml, 110 mmol) i terc-BuOH (15 ml) dodan je (terc-BuOCO)2O (7,4 g, 34 mmol). Poslije miješanja na sobnoj temperaturi preko noći, smjesa je ekstrahirana sa AcOEt. Kombinirani AcOEt ekstrakti bili su isprani sa H2O i zasićenim vodenim NaCl, sušeni (Na2SO4), i koncentrirani u vakuumu da bi dali spoj 11 (11 g. kvant.) kao blijedo-žuto ulje.
1H-NMR (CDCl3) 7,58 (br, d, J = 7,3 Hz, 2H), 7,36-7,16 (m, 5H), 6,89 (ddd, J = 7,5, 7,5, 1,1 Hz, 1H), 6,81 (d, J = 8,4, 08 Hz, 1H), 5,47 (br.s, 1H), 3,96 (dm, J = 13,4 Hz, 1H), 3,87 (d, J = 13,6 Hz, 1H), 3,79 (d, J = 13,6 Hz, 1H), 3,70 (s, 3H), 3,10-2,99 (m, 1H), 2,94 (dd, J = 12,5, 3,4 Hz, 1H), 1,87-1,74 (m, 2H), 1,74-1,40 (m, 3H), 1,41 (s, 9H).
Ovaj je proizvod korišten u sljedećem stupnju bez daljnjeg pročišćavanja.
(v) (2S,3S)-3-amino-1-terc-butoksikarbonil-2-fenilpiperidin (Spoj 12)
Smjesa Spoja 11 (11 g), 20% Pd(OH)2 / C (3,1 g), i MeoH (90 ml) miješana je preko noći u atmosferi H2 i na sobnoj temperaturi. Nakon što je dodana sljedeća količina 20% Pd(OH)2 / C (0.55 g), miješanje je nastavljeno u tijeku tri dana u atmosferi H2 i na sobnoj temperaturi. Katalizator je isfiltriran pomoću celita i detaljno ispran sa MeOH. Kombiniran MeOH filtrat i isplaka koncentrirani su u vakuumu da bi se dobio sirovi Spoj 9 (8,6 g, kvant.)
Ovaj je spoj otopljen u EtOH (20 ml), pa je na sobnoj temperaturi odjednom dodana zagrijana otopina fumarne kiseline (1,6 g, 13,5 mmol) u EtOH (20 ml). Istaloženi kristali su sakupljeni filtriranjem, isprani ledeno hladnim EtOH, i sušeni u vakuumu na 50°C da bi se dobio (2S,3S)-3-amino-1-terc-butoksikarbonil-2-fenilpiperidin polufumarat (6,1 g, 68%) u vidu bijelih kratkih igličastih kristala.
Nakon stoje suspenzija polufumarata (1,2 g, 3,7 mmol) u H2O ledeno rashlađena, dodavan je 20% vodeni NaOH sve dok smjesa nije postala bazna. Potom je smjesa ekstrahirana s AcOEt. Kombinirani AcOEt ekstrakti su isprani sa zasićenim vodenim NaCl, sušeni (Na2SO2) i koncentrirani u vakuumu da bi se dobio Spoj 12 (0,95 g, 93%).
1H-NMR (CDCl3) 7,47-7,39 (m, 2H), 7,37-7,23 (m, 5H), 5,19 (br.d, J = 6,2 Hz, 1H), 4,00 (dm, J = 13,0 Hz, 1H), 3,25-3,05 (m, 2H), 1,94-1,83 (m, 1H), 1,83-1,56 (m, 4H), 1,36 (s, 9H), 1,32 (br.s, 2H).
(vi) (2S,3S)-1-terc-butoksikarbonil-2-fenil-3-(5-(22,2,2-trifluoro-1-(trifluorome-til)-2-metoksibenzil)aminopiperidin (Spol 13)
Miješanoj i ledeno hladnoj otopini Spoja 12 (100 mg, 0,3 mmol) i Spoja 9 (100 mg, 0,3 mmol) u bezvodnom CH2Cl2 (10 ml) dodan je odjednom NaBH(OAc)3 (210 mg, 1 mmol). Potom je smjesa miješana 20 sati na sobnoj temperaturi. Smjesa je sipana u vodeni NaHCO3 i ekstrahirana sa CH2Cl2. Kombinirani ekstrakti su sušeni (Na2SO4) i koncentrirani u vakuumu da bi se dobio Spoj 13 kao žuto ulje (170 mg).
1H-NMR (CDCl3) 7,61-6,82 (m, 8H), 5,45 (br, 1H), 4,08-3,65 (m, 3H), 3,74 (s, 3H), 3,10-2,96 (m, 6H), 1,90-1,20 (m, 4H), 1,39 (s, 9H).
Proizvod je korišten u sljedećem stupnju bez daljnjeg pročišćavanja.
(vii) (2S,3S)-2-fenil-3-(5-(2,2,2-trifluoro-1-(trifluorometil)etil)-2-metoksibenzil) aminopiperidin (Spoj 14)
Otopini Spoja 13 (170 mg) u AcOEt (6 ml) dodana je koncentrirana HCl (l ml). Smjesa je miješana 45 min na sobnoj temperaturi. Smjesa je sipana u vodeni NaHCO3 i ekstrahirana sa CH2Cl2. Kombinirani ekstrakti su sušeni (Na2SO4) i koncentrirani u vakuumu da bi se dobio spoj 14 (160 mg) kao žuto ulje.
1H-NMR (CDCl3) 7,36-6,68 (m, 8H), 3,95-3,26 (m, 5H), 3,55 (s, 3H), 2,89-1,40 (m, 6H).
MS 446 (M+)
Proizvod je korišten u sljedećem stupnju bez daljnjeg pročišćavanja.
(viii) (2S,3S)-2-fenil-3-(5-(2.2.2-trifluoro-1-(trifluorometil)etil)-2-metoksibenzil) aminopiperidin dihidroklorid (Spoj 15)
Otopini Spoja 14 (160 mg) u CH2Cl2 dodana je prekomjerna količina 10% HCl-MeOH (6 ml). Nakon što je otapalo ispareno u vakuumu, preostala čvrsta supstancija je rekristalirana iz IPA da bi se dobio Spoj 15 (130 mg, 83%; tri stupnja) u vidu bezbojnog kristala.
t.t.. 290-294°C.
Primjer 6
Pripremanje (2S,3S)-2-fenil-3-(5-(1,2,2,2-tetrafluoro-1-(trifluorometil)etil-2-me-toksibenzil)aminopiperidin diklorida (Spoj 18)
(i) 4-(1,2,2,2,-tetrafluoro-1-(trifluorometil)etil)anizola (Spoj 16)
Ovo je spoj pripremljen prema proceduri opisanoj u Nippon Kagaku Kaishi, 2351 (1973).
(ii) 5-(1,2,2,2-tetrafluoro-1-(trifluorometil)etil)-2-metoksibenzaldehid (Spoj 17)
Ovo je spoj pripremljen od Spoja 16 na isti način kao i Spoj 9.
1H-NMR (CDCl3) 10,49 (s, 1H), 8,13-7,12 (m, 3H), 4,02 (s, 3H).
(iii) (2S,3S)-2-fenil-3-(5-(1,2,2,2-tetrafluoro-1-(trifluorometil)etil-2-metoksiben-zil)aminopiperidin diklorid (Spoj 18)
Ovo je spoj pripremljen od Spoja 1 i Spoja 17 na isti način kao Spoj 2.
t.t. 265 - 270°C
1H-NMR (CDCl3, slobodna baza) 7,44-6,72 (m, 8H), 3,96-2,75 (m, 6H), 3,53 (s, 3H), 2,89-1,40 (m, 4H).
MS (slobodna baza) 446 (M+)
Primjer 7
Pripremanje(2S,3S)-3-(5-(1,1-difluoroetil)-2-(trifluorometoksi)benzil)amino-2-fenilpiperidin dihidroklorida (spoj 28)
(i) 3-jodo-4-(trifluorometoksi)benzaldehid (Spoi 19)
Trifluoreometansulfonska kiselina (18,6 ml, 0,21 mmol) dodana je N-jodosukcinimidu (10,4 g, 46,3 mmol) uz ukapavanje, uz hlađenje na temperaturu leda i u atmosferi N2. U dobijenu tamno plavu smjes dodan je 4-(trifluorometoksi)benzaldehid (4,0 g, 21,0 mmol) ukapavanjem, a na temperatiri ledene vode. Poslije 4 sata mešanja na sobnoj temperaturi, reagiraj uća smjesa je sipana u ledenu vodu '50 ml). Smjesa je ekstrahirana sa CH2Cl2. Kombinirana je otopina isprana vodenim Na2S2O3, vodenim Ma2CO3 i slanom otopinom, sušena (MgSO4), obrađena aktiviranim drvenim ugljenom i koncentriran u vakuumu da bi se dobio grubi Spoj 19 (6,56 g, 99%) kao blijedo-narančasto ulje. Ono se spontano stvrdnulo nakon stajanja u hladnjaku (dug igličast kristal). Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
1H-NMR (CDCl3) 9,95 (s, 1H), 8,39 (d, J = 1,9 Hz, 1H), 7,91 (dd, J = 8,5, 1,9 Hz, 1H), 7,41 (dq, J - 8,5, 1,2 Hz, 1H).
(ii) 3-cijano-4-(trifluorometoksi)benzaldehid (Spoj 20)
Miješanoj suspenziji Spoja 19 (6,85 g, 21,7 mmol) i cink cijanida (4,07 g, 34,7 mmol) u bezvodnom DMF (35 ml) dodan je tetrakis(trifenil-fosfin)paladij(0) (3,00 g, 2,60 mmol) po dijelovima i na sobnoj temperaturi. Reagirajuća je smjesa 9 sati grijana na 100°C. Reagirajuća smjesa je razrijeđena toluolom (100 ml)-vodenim 2M NH3 (100 ml). Organski je sloj izdvojen. Vodeni je sloj razređen toluolom (100 ml), filtriran kroz sloj celita a filterski je kolač ispran toluolom. Organski je sloj izdvojen a vodeni je sloj ektrahiran toluolom. Kombinirana je otopina isprana vodenim 2M NH3 (50 ml) i slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio grub proizvod kao tamno smeđe-žuto ulje.
Sirov je proizvod pročišćen stubnom kromatografijom na silika gelu sa heksan-etil acetatom (10:1-5:1) da bi se dobio spoj 20 (2,87 g, 62%) kao blijedo-žuto ulje.
1H-NMR (CDCl3) 10,04 (s, 1H), 8,26 (d, J = 1,4 Hz, 1H), 8,19 (dd, J = 8,4, 1,4 Hz, 1H), 7,59 (dq, J = 8,4, 1,8 Hz, 1H).
(iii) 5-(1-hidroksietil)2-(trifluorometoksi)benzonitril (Spoj 21)
Miješanoj otopini Spoja 20 (2,59 g, 12,0 mmol) u bezvodnom THF (25 ml) dodan je MeMgBr (4,42 ml, 13,2 mmol, 3,0M u dietil eter otopini) uz hlađenje na temperaturu ledene vode u atmosferi N2. Reagirajuća je smjesa miješana 1 sat na 0°C, a potom 2 sata na sobnoj temperaturi. Smjesa je razblažena vodenim NH4Cl (20 ml) uz hlađenje na temperaturu ledene vode. Smjesa je ekstrahirana eterom. Kombinirana otopina je isprana slanom otopinom, sušena MgSO4) i koncentrirana u vakuumu da bi se dobio sirov Spoj 21 (2,78 g, kvant.) kao žuto ulje. Ono je korišteno u sljedećem stupnju bez daljnjeg pročišćavanja.
1H-NMR (CDCl3) 7,75 (d, J = 2,2 Hz, 1H), 7,66 (dd, J = 8,7, 2,2 Hz, 1H), 7,39 (dq, J = 8,7, 1,7 Hz, 1H), 5,03-4,90 (m, 1H), 2,02 (br.s, 1H), 1,51 (d, J = 6,6 Hz, 3H).
(iv) 3-cijano-4-(trifluorometoksi)acetofenon (Spoj 22)
Miješanoj otopini spoja 21 (2,78 g, 12,0 mmol) u bezvodnom CH2Cl2 (100 ml) dodan je mangan(IV)oksid (aktiviran; 13,9 g) po dijelovima i na sobnoj temperaturi. Smjesa je refluksirana 2,5 sata. Poslije hlađenja na sobnu temperaturu, smjesa je filtrirana kroz sloj celita pa je katalizator ispran sa CH2Cl2. Filtrat i isplaka su koncentrirani u vakuumu da bi se dobio Spoj 22 (2,31 g, 84%) kao žuta čvrsta supstanca.
On je korišten u sljedećem stupnju bez daljnjeg pročišćavanja.
1H-NMR (CDCl3) 8,66 i 8,31 (oba d, J = 2,2 Hz, ukupno 1H), 8,24 i 8,17 (oba dd, J = 8,8, 2,2 Hz, ukupno 1H), 7,54-7,47 i 7,46-7,39 (oba m, ukupno 1H), 2,66 u 2,56 (oba s, ukupno 3H).
(v) 2-metil-2-(3-ciiano-4-(trifluorometoksi)fenil)-1,3-ditiolan (Spoj 23)
Miješanoj otopini Spoja 22 (2,31 g, 10,1 mmol) u bezvodnom CH2Cl2 (30 ml) dodan je 1,2-etanditiol (1,42 g, 15,1 mmol) i bor trifluorid eterat (1,14 g, 8,1 mmol) na sobnoj temperaturi. Reagirajuća smjesa je miješana na sobnoj temperaturi 15 sati. Smjesa je razblažena vodenim 5% NaOH (40 ml) i organski je sloj izdvojen. Vodeni je sloj ekstrahiran s CH2Cl2. Kombinirana otopina je isprana u slanoj otopini, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod kao ulje purpurne boje. Sirov je proizvod pročišćen stubnom hromatografijom na silika gelu sa heksan-etil acetatom (50:1-20:1) da bi se dobio spoj 23 (2,61 g, 85%) kao ulje purpurne boje.
1H-NMR (CDCl3) 8,15 (d, J = 2,6 Hz, 1H), 8,03 (dd, J = 8,8, 2,6 Hz, 1H), 7,32 (dd, J = 8,8, 1,5 Hz, 1H), 3,58-3,44 (m, 2H), 3,43-3,28 (m, 2H), 2,13 (s, 3H).
(vi) 5-(1,1-difluoroetil)-2-(trifluorometoksi)benzonitril (Spoj 24)
Miješanoj suspenziji 1,3-dibromo-3,5-dimetilhidantoina (DBH) (1,07 g, 3,73 mmol) u bezvodnom CH2Cl2 (8 ml) dodan je HF-piridin (0,95 ml, 4,11 mmol) na -78°C (aceton-suhi led). Toj je smjesi dodana otopina spoja 23 (570 mg, 1,87 mmol) u bezvodnom CH2Cl2 (4 ml) na istoj temperaturi. Reagirajuća je smjesa miješana 10 min na -78°C, pa 30 min na sobnoj temperaturi. Smjesa je sipana u zasićeni vodeni NaHCO3 (40 ml) i miješana 15 min na sobnoj temperaturi. Smjesa je filtrirana kroz sloj celita i filtarski kolač je ispran eterom. Organski je sloj izdvojen a vodeni sloj je ekstrahiran eterom. Kombinovana otopina je isprana u vodenoj 10% HCl i u slanoj otopini, sušena (MgSO4), i koncentrirana u vakuumu da bi se dobio sirov proizvod (670 mg). Sirov je proizvod pročišćen pripremnom TLC sa heksan-etil acetatom (5:1) da bi se dobio spoj 24 (408 mg, 87%) u vidu žutog ulja.
1H-NMR (CDCl3) 7,88-7,85 (m, 1H), 7,83-7,76 (m, 1H), 7,51-7,43 (m, 1H), 1,94 (t, J = 18,3 Hz, 3H).
IC (film) 2245, 1619, 1504, 1417, 1391, 1272, 1265, 1212, 1185, 1120, 924, 844.
(vii) 5-(1,1-difluoroetil)-2-(trifluorometoksi)benzilaldehid (Spoj 25)
Miješanoj otopini Spoja 24 (1,31 g, 5,22 mmol) u bezvodnom CH2Cl2 (20 ml) dodana je otopina diizobutilaluminijum hidrida (DIBAL) (6, 20 ml, 6,26 mmol, 1,01M u toluolskoj otopini) uz hlađenje na temperaturu ledene vode. Reagirajuća smjesa je miješana 3 sata na 0°C. Smjesi je dodana H2O (6 ml), a potom vodena 6M HCl (20 ml) pa je miješana 1,5 sat na sobnoj temperaturi. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa CH2Cl2. Kombinirana otopina je isprana zasićenim vodenim NaHCO3 i slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod. Sirov je proizvod pročišćen stubnom kromatografijom na silika gelu sa heksanetil acetatom (50:1-30:1) da bi se dobilo Spoj 25 (1,17 g, 88%) u vidu žutog ulja.
1H-NMR (CDCl3) 10,39 (s, 1H), 8,15-8,08 (m, 1H), 7,86-7,78 (m, 1H), 7,48-7,40 (m, 1H), 1,95 (t, J = 18,3 Hz, 3H).
IC (film) 1702, 1618, 1499, 1390, 1269, 1212, 1180, 1115, 923.
(viii)(2S,3S)-1-terc-butoksikarbonil-3-(5-(1,1-difluoroetil)-2-(trifluorometoksi)benzil)amino-2-fenilpiperidin (Spoj 26)
miješanoj otopini spoja 12 (500 mg, 1,81 mmol) i spoju 25 (552 mg, 2,17 mmol) u bezvodnom CH2Cl2 (10 ml) dodan je po dijelovima natrij triacetoksiborhidrid (1,15 g, 5,43 mmol) a na sobnoj temperaturi. Zatim je na istoj temperaturi dodana octena kiselina (109 mg, 1,81 mmol). Reagirajuća je smjesa miješana 66 sati na sobnoj temperaturi. Reagirajuća smjesa je olužena do pH 10-11 vodenim NaOH na temperaturi ledene vode. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa CH2Cl2. Kombinirana otopina je isprana slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod (1,46 g) u vidu blijedo-žutog ulja. Ono je korišteno u drugom stupnju bez daljnjeg pročišćavanja.
(ix) (2S,3S) -3-(5-(1,1-difluoroetil)-2-(trifluorometoksi)benzil)amino-2-fenilpipe-ridin (Spoj 27}
Miješanoj otopini Spoja 26 (660 mg, 1,25 mmol) u etil acetatu (6 ml) dodana je koncentrirana vodena HCl (2 ml) uz hlađenje na temperaturu ledene vode. Reagirajuća smjesa je miješana 50 min na sobnoj temperaturi. Smjesa je olužena na pH 10-11 vodenim NAOH uz hlađenje na temperaturu ledene vode. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa AcOEt. Kombinirana otopina je isprana slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod u vidu blijedožutog ulja. Sirov je proizvod pročišćen stubnom kromatografijom na silika gelu sa diklormetan-metanolom (20:1) da bi se dobio spoj 27 (360 mg, 70%) u vidu žutog ulja.
1H-NMR (CDCl3) 7,40-7,30 (m, 7H),7,17-7,10 (m, 1H), 3,91 (d, J = 2,2 Hz, 1H), 3,61 (d, J = 15,0 Hz, 1H), 3,47 (d, J = 15,0 Hz, 1H), 3,30-3,20 (m, 1H), 2,89-2,73 (m, 2H), 2,13-2,00 (m, 1H), 1,97-1,71 (m, 1H), l,82 (t, J = 18,1 Hz, 3H), 1,70-1,55 (m, 1H), 1,53-1,40 (m, 1H).
IC (film) 3340, 1605, 1497, 1454, 1419, 1387, 1354, 1309, 1259, 1250, 1221, 1173, 1118, 920, 974, 834,753, 702.
(x) (2S,3S)-3-(5-(1,1-difluoroetiI)-2-trifluorometoksi)benzinamino-2-fenilpiperi-dindihidroklorid (Spoj 28)(
Spoj 27 (360 mg, 0,87 mmol) obrađen je metanol-klor-vodikom (oko 20 ml) pa je otapalo ispareno u vakuumu da bi se dobio sirov proizvod u vidu bijele čvrste supstancije. Sirov proizvod je rekristaliran iz etanol-dietil etera da bi se dobio Spoj 28 (370 mg, 87%) u vidu bijele čvrste supstancije.
1.1. 172-174°C
IC (KBr) 3435, 1607, 1573, 1512, 1458, 1303, 1264, 1208, 1173, 1124, 924, 906, 826, 747, 698.
Primjer 8
Pripremanje (2S,3S)-3-(5-(1,1-difluoroetil)-2-metoksibenzil)amino-2-fenilpipe-ridinmonomandelata (Spoj 37)
(i) 2-bromo-5-(1-hidroksietil)anizol (Spoj 29)
Ovo je spoj pripremljen od 3-bromo-4-metoksibenzaldehida na isti način kao i Spoj 21.
1H-NMR (CDCl3) 7,57 (d, J = 2,2 Hz, 1H), 7,28 (dd, J = 8,4, 2,2 Hz, 1H), 6,88 (d, J = 8,4 Hz, 1H), 4,84 (q, J = 6,2 Hz, 1H), 3,89 (s, 3H), 1,78 (br.s, 1H), 1,47 (d, J = 6,2 Hz, 1H).
(ii) 3-bromo-4-metoksiacetofenon (Spoj 30)
Ovo je spoj pripremljen od Spoja 29 na isti način kao i Spoj 22.
1H-NMR (CDCl3) 8,17 (d, J = 2,2 Hz, 1H), 7,92 (dd, J = 8,4, 2,2 Hz, 1H), 6,92 (d, J = 8,4 Hz, 1H), 3,97 (s, 3H), 2,56 (s, 3H).
(iii) 3-cijano-4-metoksiacetofenon (Spoj 31)
Ovo je spoj je pripremljen od Spoja 30 na isti način kao i Spoj 20.
1H-NMR (CDCl3) 8,21-8,14 (m, 2H), 7,09-7,01 (m, 1H), 4,02 (s, 3H), 2,58 (s, 3H).
(iv) 2-metil-2-(3-cijano-4-metoksifenil)-1,3-ditiolan (Spoj 32)
Ovo je spoj pripremljen od Spoja 31 na isti način kao i Spoj 23.
1H-NMR (CDCl3) 7,98 (d, J = 2,6 Hz, 1H), 7,93 (dd, J = 8,8, 2,6 Hz, 1H), 6,91 (d, J = 8,8 Hz, 1H), 3,93 (s, 3H), 3,53-3,32 (m, 4H), 2,11(s, 3H).
(v) 5-(1,1-difluoroetil)-2-metoksibenzonitoril (Spoj 33)
Miješanoj suspenziji N-jodosukcinimida (12,5 g, 55,7 mmol) u bezvodnom CH2Cl2 (60 ml) dodan je HF piridin (6,81 ml, 30,6 mmol) na -78°C (aceton-suhi led), zatim otopina Spoja 32 (3,50 g, 13,9 mmol) u bezvodnom CH2Cl2 (10 ml) na istoj tempertaturi. Reagirajuća je smjesa miješana 10 min na -78°C, pa 30 min na -10°C (metanol-led). Smjesa je sipana u zasićen vodeni NaHCO3 (100 ml) i miješana 2 sata na sobnoj temperaturi. Smjesa je filtrirana kroz sloj celita a filterski kolač je ispran sa CH2Cl2. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa CH2Cl2: Kombinirana je otopina isprana sa zasićenim vodenim Na2S2O3, 10% vodenom HCli slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod u vidu žutog ulja.
Sirov je proizvod pročišćen stubnom kromatografijom na silika gelu sa he-ksan-etil acetatom (5:1) da bi se dobio Spoj 33 kao bijela čvrsta supstancija.
1NMR (CDCl3) 7,73-7,65 (m, 2H), 7,02 (d, J = 8,4 Hz, 1H), 3,97 (s, 3H), 1,91 (t, J = 18,0 Hz, 3H).
(vi) 5-(1,1-difluoroetil)-2-metoksibenzaldehid (Spoj 34)
Ovo je spoj pripremljen od Spoja 33 na isti način kao i Spoj 25.
1H-NMR (CDCl3) 10.47 (s, 1H), 7,97 (d, J = 2,6 Hz, 1H), 7,72 (dd, J = 8,8, 2,6 Hz, 1H), 7,05 (d, J = 8,8 Hz, 1H), 3,97 (s, 3H), 1,95 (t, J = 18,0 Hz, 3H).
(vii) (2S,3S)-1-terc-butoksikarbonil-3-(5-(1,1-difluoroetil)-2-metoksibenzil) ami-no-2-fenilpiperidin (Spoj 35)
Ovo je spoj pripremljen od Spoja 12 i 34 na isti način kao Spoj 26. Korišten je u sljedećem stupnju bez daljeg pročišćavanja.
(viii) (2S,3S)-3-(5-(1,1-difluoroetil)-2-metoksibenzinamino-2-fenilpiperidin (Spoj 36)
Ovo je spoj pripremljen od Spoja 35 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,35-7,18 (m, 6H), 7,15 (d, J = 2,2 Hz, 1H), 6,68 (d, J = 8,4 Hz, 1H), 3,89 (d, J = 2,2 Hz, 1H), 3,66 (d, J = 13,9 Hz, 3H), 3,49 (s, 3H), 3,41 (d, J = 13,9 Hz, 1H), 3,32-3,20 (m, 1H), 2,86-2,72 (m, 2H), 2,18-2,05 (m, 1H), 2,02-1,81 (m, 1H), 1,86 (t, J = 18,0 Hz, 3H), 1,72 (br.s, 2H), 1,75-1,52 (m, 1H), 1,47-1,35 (m, 1H).
IC (film) 3335, 1614, 1502, 1461, 1386, 1308, 1280, 1252,, 1174, 1123, 1030, 923, 901, 870, 816, 751, 701.
(ix) (2S,3S)-3-(5-(1,1-difluoroetil)-2-metoksibenzil)amino-2-fenilpiperidin mono-mandelat rSpoj 37)
Otopini Spoja 36 (179 mg, 0,50 mmol) u etanolu (3 ml) dodana je (R)-(-)-bademova kiselina (75,4 mg, 0,50 mmol) na sobnoj temperaturi. Nakon što je otapalo ispareno u vakuumu, ostatak je rekristaliran iz etanol-dietiletra da bi se dobio Spoj 37 (168 mg, 66%) u vidu bijele čvrste supstancije.
1.1.; 177-179°C
IC (film) 3400, 1615, 1576, 1506, 1473, 1464, 1399, 1384, 1362, 1245, 1318, 1249, 1172, 1137, 1115, 1054, 1028, 900, 756, 742, 698.
Primjer 9
Pripremanje (2S,3S)-3-(2-metoksi-5-(1,1,2,2,2-pentafluoroetil)benzil)amino-2-fenilpiperidin dihidroklorida (Spoj 43)
(i) 2-(3-bromo-6-metoksifenil)-1,3-dioksan (Spoj (38)
Smjesa 5-bromo-o-anisaldehida (10,0 g, 46,4 mmol), propan01,3-diola (3,90 g, 51,2 mmol) i BF3-Et2O (0,15 ml) u toluolu (50 ml) refluksirana je u Dean-Sark-ovom aparatu tokom 3 sata. Reagirajuća je smjesa ohlađena i razblažena eterom. Organski je sloj ispran redom sa zasićenim vodenim NaHCO3, vodom i slanom otopinom, sušen (MgSO4) i koncentriran u vakuumu da bi se dovio sirov proizvod. Ostatak je destiliran da bi se dobio Spoj 38 (10,7 g, 84%) u vidu bezbojnog ulja t.k.: 124-125°C/0,31-0,33 mbar
1H-NMR (CDCl3) 7,74 (d, J = 2,6 Hz, 1H), 7,39 (d, J = 8,8, 2,6 Hz, 1H), 6,74 (d, J = 8,8 Hz, 1H), 5,81 (s, 1H), 4,31-4,17 (m, 2H), 4,06-3,91 (m, 2H), 3,82 (s, 3H), 2,35-2,10 (m, 1H), 1,50-135 (m, 1H).
(ii) 2-(2-metoksi-5-(1,2,2,2,-pentafluoroetil)fenil)-1,3-dioksan (Spoj 39)
Boca zapremine 50 ml sa okruglim dnom, opremljena Dean-Stark-ovim sifonom i kondenzatorom za refluksiranje, punjena je Spojem 30 (1,0 g, 3,66 mmol), natrij pentafluoropropionatom (1,29 g, 6,95 mmol) i bakar(I) jodidom (1,46 g, 7,69 mmol), DMF (15 ml)-toluolo (6 ml). Smjesa je grijana na 120-140°C (temperatura kupelji) i toluol (6 ml) je izdvojen destiliranjem. Reagirajuća je smjesa grijana na 140°C (unutrašnja temperatura) tokom 15 sati). Smjesa je razrijeđena vodom (40 ml)-toluolom (15 ml)-etil acetatom (60 ml). Smjesa je filtrirana kroz sloj celita i filterski kolač je ispran etil acetatom. Filtrat je ispran vodom pa slanom otopinom, sušen (MgSO4) i koncentriran u vakuumu da bi se dovio sirov proizvod. Sirov proizvod je pročišćen stubnom kromatografijom na silika gelu sa heksan-etil acetatom (10:1-5:1) da bi se dobio Spoj 39 (1,07 g) kao blijedožuto ulje.
1H-NMR (CDCl3) 7,87 (d, J = 2,2 Hz, 1H), 7,53 (dd, J = 8,8, 2,2 Hz, 1H), 6,96 (d, J = 8,8 Hz, 1H), 5,85 (s, 1H), 4,26 (dd, J = 11,0, 4,4 Hz, 2H), 4,00 (d, J = 12,3, 2,2 Hz, 2H), 3,89 (s, 3H), 2,36-2,15 (m, 1H), 1,50-1,38 (m, 1H).
(iii) 2-metoksi-5-(1,2,2,2-pentafluoroetil)benzaldehid (Spoj 40)
Miješanoj otopini Spoja 39 (1,0 g) u acetonu (30 ml) dodana je koncentrirana HCl na sobnoj temperaturi. Reagirajuća je smjesa miješana 5 sati na sobnoj temperaturi. Otapalo je ispareno u vakuumu a ostatak je ekstrahiran eterom. Kombinirana otopina je isprana zasićenim vodenim NaHCO3 i slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod (790 mg) u vidu žute čvrste supstancije. Sirov proizvod je pročišćen stubnom kromatografijom na silika gelu sa heksan-izopropil eterom (10:1-3:1) da bi se dobio Spoj 40 u vidu blijedožute čvrste supstancije.
1H-NMR (CDCl3) 10,48 (s, 1H), 8,09 (d, J = 2,2 Hz, 1H), 7,77 (d, J = 8,8, 2,2 Hz, 1H), 7,13 (d, J = 8,8 Hz, 1H), 4,02 (s, 3H).
(iv)(2S,3S)-1-terc-butoksikarbonil-3-(2-metoksi-5(1,1,2,2,2-pentafluorometil)benzil)amino-2-fenilpiperidin (Spoj 41)
Ovo je spoj pripremljen od Spoja 12 i Spoja 40 na isti način kao i Spoj 26. Korišteno je u sljedećem stupnju bez daljeg pročišćavanja.
(v) (2S,3S)-3-(2-metoksi-5-(1,1,2,2,2-pentafluoroetil)benzil)amino-2-fenilpiridin (Spoj 42)
Ovo je spoj pripremljen od Spoja 41 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,38 (dd, J = 8,4, 2,2 Hz, 1H), 7,34-7,18 (m, 6H), 6,74 (d, J =8,4 Hz, 1H), 3,90 (d, J = 2,2 Hz, 1H), 3,69 (d, J = 14,3 Hz, 3H), 3,53 (s, 3H), 3,40 (d, J = 14,3 Hz, 1H), 3,34-3,24 (m, 1H), 2,88-2,74 (m, 2H), 2,15-1,83 (m, 4H), 1,69-1,83 (m, 4H), 1,69-1,53 (m, 1H), 1,50-1,38 (m, 1H).
IC (film) 3330, 1614, 1501, 1460, 1334, 1304, 1275, 1258, 1203, 1145, 1119, 1096, 1029, 1004, 870, 815, 746, 700.
(vi) (2S,3S)-3-(2-metoksi-5-(1,2,2,2-pentafluoroetil)benzil)amino-2-fenilpipe-ridin dihidroklorid (Spoj 43)
Ovo je spoj pripremljen od Spoja 42 na isti način kao i Spoj 28.
t.t.: 201-202°C
IC(KBr)3455, 1617, 1554, 1506, 1453, 1443, 1416, 1337, 1282, 1258, 1221, 1202, 1180, 1148, 1131, 1091, 1010, 744, 693.
Primjer 10
Pripremanje (2S,3S)-3-(2-metoksi-5-(2,2,2-trifluoretil)banzil)amino-2-fenilpipe-ridindihidroklorida (Spoj 49)
(i) 1-(4-metoksifenil)-2,2,2-trifluoroetil bromid (Spoj 44)
Ovo je spoj pripremljen prema postupku opisanom u J. Am. Chem. Soc.. 111, 1455 (1989).
(ii) 1-(4-metoksifenol)-2,2,2-trifluoroetan (Spoj 45)
Otopina Spoja 44 (1,08 g, 4,00 mmol) u etanolu (20 ml) hidrogen-iziran je preko 10% Pd-C (800 mg) na atmosferskom tlaku u toku 16 sati. Katalizator je isfiltriran kroz sloj celita a filterski kolač je ispran sa CH2Cl2. Kombinirana otopina je isprana poluslanom otopinom i slanom otopinom, sušena (MgSO4) i koncentriran u vakuumu da bi se dobio sirovi Spoj 45 (760 mg, kvant.) u vidu blijedožutog ulja.
1H-NMR (CDCl3) 7,24-7,11 (m, 2H), 6,93-6,84 (m, 2H), 3,81 (s, 3H), 3,30 (q, J = 10,9 Hz, 2H).
(iii) 2-metoksi-5-(2,2,2-trifluoroetil)benzaldehid (Spoj 46)
Miješanoj otopini Spoja 45 (760 mg, 4,00 ,,ol) u bezvodnom CH2Cl2 dodan je kroz brizgalicu TiCl4 (1,67 g, 8,80 mmol) uz hlađenje na temperaturu ledene vode. Poslije 15 min dodana je otopina dihlorometil metil etera (920 mg, 8,00 mmol) u bezvodnom CH2Cl2 (5 ml) na istoj temperaturi. Reagirajuća smjesa je miješana 15 min na 0°C, pa zatim 1,5 sat na sobnoj temperaturi. Smjesa je razrijeđena vodom (20 ml) uz hlađenje na temperaturu ledene vode i miješana 15 min na sobnoj temperaturi. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa CH2Cl2. Kombinirana otopina je isprana zasićenim vodenim NaHCO3 pa sa slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi dao sirov proizvod u vidu žutog ulja. Sirov proizvod je pročišćen stubnom kromatogarfijom na silika gelu sa heksan-etil acetatom (40:1-20:1) da bi se dobio Spoj 46 (500 mg, 57%)
1H-NMR (CDCl3) 10,46 (s, 1H), 7,76 (d, J = 2,2 Hz, 1H), 7,49 (dd, J = 8,8, 2,2 Hz, 1H), 7,00 (d, J = 8,8 Hz, 1H), 3,95 (s, 3H), 3,34 (q, J = 10,6 Hz, 2H).
(iv) (2S,3S)-1-terc-butoksikarbonil-3-(2-metoksi-5-(2,2,2-trifluorometil)benzil)-amino-2-fenilpiperidin (Spoj 47)
Ovo je spoj pripremljen od Spoja 12 i Spoja 46 na isti način kao i Spoj 26. Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
(v) (2S. 3S)-3-(2-metoksi-5-(2.2.2-trinuorometinbenzinamino-2-fenilpiperidin (Spoj 48)
Ovo je spoj pripremljen od Spoja 47 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,35-7,20 (m, 5H), 7,06 (dd, J = 8,4, 1,8 Hz, 1H), 6,84 (d, J = 1,8 Hz, 1H), 6,65 (d, J = 8,4 Hz, 1IH), 3,90 (d, J = 2,2 Hz, 1H), 3,68 (d, J = 14,3 Hz, 1H), 3,49 (s, 3H), 3,42 (d, J = 14,3 Hz, 1H), 3,35-3,24 (m, 1H), 3,20 (q, J = 11,0 Hz, 2H), 2,88-2,73 (m, 2H), 2,20-1,85 (m, 4H), 1,68-1,52 (m, 1H), 1,50-1,37 (m, 1H).
IC (film) 3450, 1614, 1500, 1465, 1445, 1430, 1359, 1328, 1263, 1249, 1237, 1128, 1103, 1074, 1031, 854, 822, 810, 773, 746, 700, 672.
(vi) (2S,3S)-3-(2-metoksi-5-(2,2,2-trifluoretil)banzil)amino-2-fenilpipe-ridindi-hidrohlorid (Spoi 49)
Ovo je spoj pripremljen od Spoja 48 na isti način kao i Spoj 28.
t.t.: 209-210°C.
IC(KBr)3450, 1552, 1506, 1451, 1441, 1415, 1369, 1333, 1260, 1241, 1170, 1132, 1086, 1030, 978, 807, 748, 693.
Primjer 11
Pripremanje (2S,3S)-3-(2-metoksi-5-(1-(trifluorometil)etil)benzil)amino-2-fenil-piperidin dihidroklorida (Spoj 55)
(i) 1-(4-metoksifenil)-1-(trifluorometil)etil bromid (Spoj 50)
Ovo je spoj pripremljen prema postupku iz J. Am.Chem. Soc.. 104, 211 (1892).
(ii) 1-(4-metoksifenil)-1-(trifluorometil)etan (Spoj 51)
Ovo je spoj pripremljen od Spoja 50 na isti način kao i Spoj 45.
1H-NMR (CDCl3) 7,28-7,19 (m, 2H), 6,95-6,84 (m, 2H), 3,81 (s, 3H), 3,48-3,27 (m, 1H), 1,48 (d, J = 7,0 Hz, 3H).
(iii) 2-metoksi-5-(1-(trifluorometil)etil)benzaldehid (Spoj 52)
Ovo je spoj pripremljen od Spoja 51 na isti način kao i spoj 46.
1H-NMR (CDCl3) 10,46 (s, 1H), 7,79 (d, J = 2,6 Hz, 1H), 7,53 (dd, J= 8,8, 2,6 Hz, 1H), 7,00 (d, J = 8,8 Hz, 1H), 3,94 (s, 3H), 3,53-3,32 (m, 1H), 1,50 (d, J = 7,3 Hz, 3H).
(iv) (2S,3S)-1-terc-butoksikarbonil-3-(2-metoksi-5-(1-(trifluorometil)etil) ben-zil)amino-2-fenilpiperidin (Spoj 53)
Ovo je jedinje pripremljen od Spoja 12 i 52 na isti način kao i Spoj 26. Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
(v) (2,S,3S)-3-(2-metoksi-5-(1-(trifluorometil)etil)benzil)amino-2-fenilpiperidin (Spoj 54)
Ovo je spoj pripremljen od Spoja 53 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,35-7,19 (m, 5H), 7,13-7,05 (m, 1H), 6,91-6,86 (m, 1H), 6,68-6,61 (m, 1H), 3,91 (d, J = 2,2 Hz, 1H), 3,75-3,15 (m, 7H), 2,88-2,73 (m, 2H), 2,30-1,85 (m, 4H), 1,70-1,51 (m, 1H), 1,50-1,35 (m, 1H), 1,42 (d, J = 7.3 Hz, 3H).
IC(film) 3330, 1612, 1500, 1462, 1385, 1349, 1331, 1295, 1250, 1171, 1157, 1122, 1082, 1049, 1031, 995, 805, 747, 701.
(vi)2S,3S)-3-(2-metoksi-5-(1 -(trifluorometil)etil)benzil)amino-2-fenil-piperidindihidroklorid (Spoj 55)
Ovo je spoj pripremljen od Spoja 54 na isti način kao i Spoj 28.
t.t.: 217-218°C
IC(Kbr)3450, 1554, 1505, 1465, 1453, 1442, 1417, 1334, 1253, 1169, 1159, 1144, 1120, 1083, 1050, 10030, 748, 693
Primjer 12
Pripremanje (2S,3S)-3-(5-(1,1-dimetil-4,4,4-trifluoro-2-butinil)-2-metoksibenzil] amino-2-fenilpiperidin dihodroklorida (Spoj 60)
(i) 4-(1,1-dimetil-2-propinil)anizol (Spoj 56)
Ovo je spoj pripremljen prema procedurama opisanim u Tetrahedron Lett.. 4163 (1977).
(ii) 4-(1,1-dimetil-4,4,4-trifluoro-2-butinil)anizol (Spoj 57)
Miješanoj otopini Spoja 56 (0,22 g, 1,26 mmol) u THF (8 ml) dodan je n-BuLi (1,69 M u heksanu, 0,82 ml, 1,39 mmol) na -78°C u atmosferi N2, pa je smjesa zagrijana na 0°C i miješana 1 sat. Dodan je S-(trifluorometil)dibenzo-tiofenijum trifluorometan-sulfonat (1,01 g, 2,52 mmol), pa je sve miješano 3 sata na 0°C. Smjesa je ugašena dodavanjem vodenog NaHCO3 i ekstrahirana je sa CH2Cl2. Kombinirani organski slojevi su sušeni preko MgSO4, filtrirani i koncentrirani. Koncentrat je pročišćen SiO2 kromatografijom da bi se dobio Spoj 57 (38 mg, 13%) u vidu bezbojnog ulja.
1H-NMR (CDCl3) 7,37 (d, 1H, J = 8,8 Hz), 6,88 (d, 2H, J = 8,8 Hz), 3,80 (s, 3H), 1,62 (s, 6H).
(iii) 5-(1,1-dimetil-4,4,4-trifluoro-2-butinil)-2-metoksibenzaldehid (Spoj 58)
Ovo je spoj pripremljen od Spoja 57 na isti način kao i Spoj 9.
1H-NMR (CDCl3) 10,47 (s, 1H), 7,87 (d, 1H, J = 2,9 Hz), 7,71 (dd, 1H, J= 8,8, 2,9 Hz), 7,01 (d, 1H, J = 8,8 Hz), 3,94 (s, 3H), 1,64 (s, 6H).
(iv) (2S,3S)-1-terc-butoksikarbonil-3-[5-(1,1-dimetil-4,4,4-trifluoro-2-butinil)-2-metoksibenzinamino-2-fenilpiperidin
(Spoj 59)
Ovo je spoj pripremljen od Spoja 58 i Spoja 12 na isti način kao i Spoj 13.
1H-NMR (CDCl3) 7,62-7,53 (m-2H), 7,36-7,20 (m, 5H), 6,78 (d, 1H, J = 9,2 Hz), 5,53-5,42 (m, 1H), 4,01-3,88 (m, 1H), 3,83 (s, 2H), 3,70 (s, 3H), 3,13-2,93 (m, 2H), 1,92-1,35 (m, 4H), 1,60 (s, 3H), 1,59 (s, 3H), 1,40 (s, 9H).
(v) (2S,3S)-3-[5-(1,1-dimetil-4,4,4-trifluoro-2-butinil)-2-metoksibenzil1 amino-2-fenilpiperidin dihodrohlorid (Spoj 60)
Otopini Spoja 59 (34 mg, 0,064 mmol) u AcOEt (8 ml) dodana je prekomjerna količina HCl - MeOH. Smjesa je miješana 18 sati pa je isparena u vakuumu, čvrst ostatak je rekristaliran iz MeOH-Er2O da bi se dobio spoj 60 (24 mg, 75%) u vidu bijele čvrste supstancije.
t.t.: 227-227°C.
IC(KBr) 3440, 2980, 2935, 2350, 2275, 1558, 1504, 1455, 1416, 1293, 1130 cm1.
1H-NMR (slobodna baza; CDCl3) 7,38-7,25 (m-6H), 7,10 (d, 1H, J = 2,6 Hz), 6,67 (d, 1H, J = 8,4 Hz), 4,04-4,01 (m, IH), 3,78 (d, 1H, J = 13,9 Hz), 3,53-3,38 (m, 2H), 3,45 (s, 2H), 2,96-2,83 (m, 2H), 2,30-1,60 (m, 4H), 1,58 (s, 6H).
Analiza. Proračunato za C25H29F3N2O•2HCl: C, 59,65 %, H, 6,21 &, N, 5,56 %.
Nađeno: C, 59,38 %, H, 6,27 %, N, 5,55%.
Primjer 13.
Pripremanje (2S,3S)-3-[(5-metoksi-1-(trifluorormetil)indan-6-il)metilamino]-2-fenilpiperidin dihidroklorida (Spoj 61) (i) 1-hidroksi-5-metoksi-1-(trifluorometil)indan (Spoj 62)
Miješanoj otopini 3-metoksi-1-indanona (1,00 g, 6,17 mmol) i trifluorometiltrimetilsilana (1,32 g, 9,26 mmol) u bezvodnom THF (15 ml) dodan je 1,0M THF otopine tetrabutilamonij fluorida (0,05 ml) uz hlađenje na temperaturu ledene vode. Reagirajuća je smjesa miješana 21 sat na sobnoj temperaturi. Smjesi je dodana 1N HCl (20 ml) pa je miješana 25 sati na sobnoj temperaturi. Reagirajuća je smjesa razblažena s CH2Cl2-vodom. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa CH2Cl2. Kombinirana otopina je isprana vodom i slanom otopinom, sušena (MgSO4) i koncentriran u vakuumu da bi dala sirov proizvod u vidu tamnožutog ulja. Sirov je proizvod pročišćen stubnom kromatografijom na silika gelu sa heksan-etil acetatom (5:1-3:1) da bi se dobio Spoj 62 (l ,05 g, 73%) u vidu žutog ulja.
1H-NMR (CDCl3) 7,39 (d, J = 8,4 Hz, 1H), 6,88-6,75 (m, 2H), 3,81 (s, 3H), 3,17-2,86 (m, 2H), 2,74-2,57 (m, 1H), 2,43-2,34 (m, 1H), 2,32-2,15 (m, 1H).
(ii) 6-metoksi-3-(trifluorometil)inden (Spoj 63)
Miješanom Spoju 62 (850 mg, 3,66 mmol) dodan je PBr3(9,90 g, 36.6 mmol) uz hlađenje ledenom vodom. Reagirajuća smjesa je miješana 6 sati na 80°C. Smjesa je razrijeđena vodom uz hlađenje ledenom vodom i ekstrahirana sa CH2Cl2. Kombinirana otopina je isprana sa zasićenim NaHCO3 i sa slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod u vidu žutog ulja. Sirov proizvod je pročišćen stubnom kromatografijom na silika gelu sa heksan-etil acetato (50:1-40:1) da bi se dobio spoj 63 (727 mg, 93%) u vidu žutog ulja.
1H-NMR (CDCl3) 7,46-7,38 (m, 1H), 7,10-7,05 (m, 1H), 6,90 (dd, J =8,4, 2,6 Hz, 1H), 6,87-6,81 (m, 1H), 3,84 (s, 3H), 3,50-3,47 (m, 2H).
(iii) 5-metoksi-1-(trifluorometil)indan (Spoj 64)
Otopina Spoja 63 (180 mg, 0,84 mmol) u etanolu (5 ml) hidrogenizirana je preko 10% Pd-C (90 mg) na atmosferskom pritisku, a u trajanju od 4,5 sata. Latalizator je isfiltriran kroz sloj celita a filterski kolač je ipran sa CH2Cl2. Kombinirana otopina je isprana poluslanom otopinom i slanom otopinom, sušena (MgSO4), i koncentriran u vakuumu da bi se dobio sirov spoj 64 (147 mg, 81 %) kao blijedožuto ulje.
1H-NMR (CDCl3) 7,36-7,20 (m, 1H), 6,88-6,69 (m, 2H), 3,90-3,62 (m, 4H), 3,20-2,80 (m, 2H), 2,48-2,19 (m, 2H).
(iv) 6-formil-5-metoksi-l-ftrifluorometil)indan (Spoj 65)
Ovo je spoj pripremljen od Spoja 64 na isti način kao i Spoj 46.
1H-NMR (CDCl3) 10,41 (s, 1H), 7,85 (s, 1H), 6,90 (s, 1H), 3,90-3,70 (m, 1H), 3,24-2,87 (m, 2H), 2,50-2,20 (m, 2H).
(v) (2S,3S)-1-terc-butoksikarbonil-3-[(5-metoksi-1-(trifluorometil)indan-6-il) metilaminol -2-fenilpiperidin (Spoj 66)
Ovo je spoj pripremljen od Spoja 12 i 65 na isti način kao i Spoj 26. On je korišten u sljedećem stupnju bez daljnjeg pročišćavanja.
(vi) (2S,3S)-3-[(5-metoksi-1-(trifluorometil)indan-6-il)metilamino]-2-fenilpipe-ridin (Spoj 67)
Ovo je spoj pripremljen od Spoja 66 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,37-7,17 (m, 5H), 6,99 (br.s, 1H), 6,58 i 6,56 (oba s, ukupno 1H), 3,91 (d, J = 2,2 Hz, 1H), 3,82-3,60 (m, ,2H), 3,44 (s, 3H), 3,39 (d, J = 13,9 Hz, 1H), 3,39-3,24 (m, 1H), 3,10-2,72 (m, 4H), 2,56 (br.s, 2H), 2,43-1,85 (m, 4H), 1,71-1,35 (m, 2H).
(vii) (2S,3S)-3-[(5-metoksi-1-(trifluorormetil)indan-6-il)metilamino1-2-fenilpipe-ridindihidroklorid (Spoj 61)
Ovo je spoj pripremljen od Spoja 67 na isti način kao i Spoj 28.
t.t.: 214-214°C
IC(KBr)3435, 1623, 1579, 1560, 1498, 1464, 1452, 1434, 1421, 1368, 1297, 1271, 1170, 1138, 1103, 1034, 749, 694.
Primjer 14
Pripremanje (2S,3S)-3-[5-(1,1-dimetil-2,2,2-trifluoroetil)-2-metoksibenzilamino]-2-fenilpiperidin dihidroklorida (Spoj 68)
(i) 4-(1-kloro-1-metil-2,2,2-trifluoroetil)anizol (Spoj 69)
Ovo je spoj pripremljen prema postupku opisanom u JP62234034.
(ii) 4-(1,1-dimetil-2,2,2-trifluoreoetil)anizol (Spoj 70)
Miješanoj otopim TiCl4 (57 mg, 0,30 mmo19 u bezvodnom CH2Cl2 (5 ml) dodana je otopina (1,05 mo-1) ZnMe2 (0,87 ml, 0,91 mmol) u toluolu pomoću brizgalice, a na -78°C. Poslije 15 min dodana je otopina Spoja 68 (217 mg, 0,91 mmol) u bezvodnom CH2Cl2 (2 ml) na istoj temperaturi. Reagiraj uća smjesa je miješana na -78°C tokom 1 sata i zagrijana do sobne temperature. Poslije 2 sata smjesa je razrijeđena vodom i miješana 10 min. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa CH2Cl2. Kombinirana otopina je isprana slanom otopinom, sušena (MgSO4) i koncentrirana u vakuumu pa je dobijen sirov proizvod (200 mg) (Spoja 69:70 = 1:2,4) kao blijedožuto ulje. Ono je korišteno u sljedećem stupnju bez daljnjeg pročišćavanja.
(iii) 5-(1,1-dimetil-2,2,2-trifluoroetil)-2-metoksibenzaldehid (Spoj 71)
Ovo je spoj pripremljen od smjese Spoja 69 i 70 na isti način kao i Spoj 46.
Sirov spoj je pročišćeno pripremnom TLC sa heksan-etil acetatom (6:1) da bi se dobio spoj 71 (75 mg) kao blijedožuto ulje.
1H-NMR (CDCl3) 10,47 (s, 1H), 7,95 (d, J=2,6 Hz, 1H), 7,47-7,64 (m, 1H), 6,99 (d, J = 8,8 Hz, 1H), 3,94 (s, 3H), 1,57 (s, 6H).
(iv) (2S,3S)-1-terc-butoksikarbonil-3-[5-(1,1-dimetil-2,2,2-trifluoroetil)-2-metoksibenzilamino]-2-fenilpiperidin (Spoj
72)
Ovo je spoj pripremljen od Spoja 12 i Spoja 71 na isti način kao i Spoj 26.
Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
(v) (2S,3S)-2-[S-(1,1-dimetil-2,2,2-trifluoroetil)-2-metoksibenzilamino]-2-fenil-piperidin (Spoj 73)
Ovo je spoj pripremljen od Spoja 72 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,35-7,16 (m, 6H), 7,17-7,08 (m, 1H), 6,65 (d, J=8,8 Hz, 1H), 3,91 (d, J = 2,2 Hz, 1H), 3,69 (d, J=13,9, 7H), 3,48 (s, 3H), 3,41 (d, J=13,9 Hz, 1H), 3,36-3,22 (m, 1H), 2,90-2,71 (m, 2H), 2,44 (br.s, 2H), 2,20-1,85 (m, 2H), 1,70-1,35 (m, 2H), 1,49 (s, 6H).
(vi) (2S,3S)-3-[5-(1,1-dimetil-2,2,2-trifluoroetin-2-metoksibenzilamino]-2-fenil-piperidin dihidrohlorid (Spoj 67)
Ovo je spoj pripremljen od spoja 73 na isti način kao i Spoj 28.
t.t.: 220-221°C
IC(KBr)3425, 1564, 1511, 1469, 1453, 1442, 1420, 1400, 1290, 1255, 1187, 1174, 1131, 1101, 1027, 749, 691.
Primjer 15
Pripremanje (2S,3S)-2-fenil-(5-(2,2,2-trifluoro-1-metil-1-(trifluorometil)-2-meto-ksibenzil)aminopiperidin dihidro
klorida (Spoj 78)
(i) 4-(2-2-difluoro-1-(trifluorometil)etenil)anizol (Spoj 74)
Ovo je spoj pripremljen prema procedurama opisanim u J. Am. Chem. Soc., 820 (1972).
(ii) 4-(2,2,2-trifluoro-1-metil-1-(trifluorometil)etil)anizol (Spoj 75)
Smjesa Spoja 74 (570 mg, 2,4 mmol), Mel (430 mg, 3,0 mmol) i CsF (760 mg, 5,0 mmol) u DMF (4 ml) miješana je 3 dana na 80°C. Smjesa je razrijeđena sa H2O. Organski je sloj razdvojen a vodeni je sloj ekstrahiran sa CH2Cl2. Kombinirana je otopina sušena (Na2SO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod koji je pročišćen stubnom kromatografljom na silika gelu da bi se dobio Spoj 75 (70 mg, 10%) u vidu žutog ulja.
1H-NMR (CDCl3) 7,53-6,90 (m, 4H), 4,85 (s, 3H), 3,50-3,42 (m, 3H).
(iii) 5-(2,2,2-trifluoro-1-metil-1-(trifluorometil)etil)-2-metoksibenzaldehid (Spoj 76)
Ovo je spoj pripremljen od Spoja 75 na isti način kao i Spoj 9.
1H-NMR (CDCl3) 10,49 (s, 1H), 8,09-7,08 (m, 3H), 4,02 (s, 3H), 3,51-3,45 (m, 3H).
(iv) (2S,3S)-1-terc-butoksikarbonil-2-fenil-3-(5-(2,2,2-trifluoro-1-metil-1-(triflu-orometil)etil)-2-metoksibenzil) amino
piperidin (Spoj 77)
Ovo je spoj pripremljen od Spoja 12 i Spoja 76 na isti način kao i Spoj 26.
Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
(v) (2S,3S)-2-fenil-(5-(2,2,2-trifluoro-1-metil-1-(trifluorometil)-2-metoksibenzil) aminopiperidin dihidroklorid (Spoj 78)
Ovo je spoj pripremljen od Spoja 77 na isti način kao i spoj 60.
t.t.: 267-270°C
Primjer 16
Pripremanje (2S,3S)-3-[5-[2.20difluoro-l-‘trifluorometil(etenil]-2-metoksibenzil] amino-2-fenilpiperidin dihidroklorid (Spoj 81)
(i) 5-(2.2-difluoro-1-(trifluorometil)etenin-2-metoksibenzaldehid (Spoj 79)
Ovo je spoj pripremljen od Spoja 74 na isti način kao i Spoj 9.
1H-NMR (CDCl3) 10,47 (l, 1H), 7,81 (d, J=2,4 Hz, 1H), 7,51 (dd, J = 8,6, 2,2 Hz, 1H), 7,06 (d, J=8,4, 7H), 3,98 (s, 3H).
(ii) (2S,3S)-1-terc-butoksikarbonil-3-(5-[2,2-difluoro-1-(trifluorometil)etenil]-metoksibenzil]amino-2-fenilpiperidin (Spoj 80)
Ovo je spoj pripremljen od Spoja 79 i Spoja 12 na isti način kao i Spoj 13.
1H-NMR (CDCl3) 7,63-7,55 (m, 2H), 7,37-7,15 (m, 5H), 6,85 (d, J=8,4 Hz, 1H), 5,53-5-45 (m, 1H), 4,02-3,92 (m, 1H), 3,88 (s, 2H), 3,74 (s, 3H), 3,12-2,94 (m, 2H), 1,94-1,40 (m, 4H), l,40 (s, 9H).
(iii) (2S,3S)-3-[5-[2,2-difluoro-1-(trifluorometil)etenil]-2-metoksibenzil]amino-2-fenilpiperidin dihidroklorid (Spoj 81)
Ovo je spoj pripremljen od Spoja 80 na isti način kao i Spoj 60.
t.t.: 235 -237°C.
1H-NMR (CDCl3) 7,35-7,18 (m, 5H), 7,15-7,07 (m, 1H), 6,89-6,86 (m, 1H), 6,70 (d, J = 8,4 Hz, 1H), 3,91 (d, J = 2,6 Hz, 1H), 3,69 (d, J = 14,7, 7H), 3,53 (s, 3H), 3,42 (d, J = 14,7 Hz, 1H), 3,36-3,24 (m, 1H), 2,88-2,75 (m, 2H), 2,18-1,40 (m, 4H).
Primjer 17
Pripremanje (2S,3S)-3-(2,4-dimetoksi-5-(2,2,2-trifluoroetil)benzil)amino-2-fenil-piperidin dihidroklorida (Spoj 87)
(i) 1-(2,4-dimetoksifenil)-2,2,2-trifluoretanol (spoj 82)
Ovo je spoj pripremljen od 2,4-dimetoksibenzaldehida na isti način kao i Spoj 62.
1H-NMR (CDCl3) 7,32-6,48 (m, 3H), 5,21 (kvent., J=7 Hz, 1H), 3,85 (s, 3H), 3,82 (s, 3H), 3,42 (d, J=8 Hz, 1H).
(ii) 1-(2,4-dimetoksifenil)-2,2,2-trifluoretil bromid (Spoj 83)
Ovo je spoj pripremljen od Spoja 82 na isti način kao i spoj 44.
1H-NMR (CDCl3) 7,58-6,42 (m, 3H), 5,81 (q, J=11 Hz, 1H), 3,88 (s, 3H), 3,86 (s, 3H).
(iii) 1-(2,4-dimetoksifenil)-2,2,2-trifluoretan (Spoj 64)
Ovo je spoj pripremljen od Spoja 83 na isti način kao i Spoj 45.
1H-NMR (CDCl3) 7,20-6,45 (m, 3H), 3,82 (s, 3H), 3,81 (s, 3H), 3,37 (q, J = 11 Hz, 2H).
(iv) 2,4-dimetoksi-5-(2,2,2-trifluoroetil)benzaldehid (Spoj 85)
Ovo je spoj pripremljen od Spoja 84 na isti način kao i Spoj 46.
1H-NMR (CDCl3) 10,20 (s, 1H), 7,77 (s, 1H), 6,46 (s, 3H), 3,95 (s, 3H), 3,38 (q, J = 11 Hz, 2H).
(v) (2S,3S)-1-terc-butoksikarbonil-3-(2,4-dimetoksi-5-(2,2,2-trifluoroetil)benzil) amino-2-fenilpiperidin (Spoj 86)
Ovo je spoj pripremljen od Spoja 12 i Spoja 85 na isti način kao i Spoj 13.
Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
1H-NMR (CDCl3) 7,62-7,20 (m, 5H), 7,04 (s, 1H), 6,42 (s, 1H), 4,00-2,92 (m, 8H), 3,83 (s, 3H), 3,71 (s, 3H), 1,90-1,30 (m, 4H), 1,39 (s, 9H).
(vi) (2S,3S)-3-(2,4-dimetoksi-5-(2,2,2-trifluoroetil)benzil)amino-2-fenil-piperidin dihidroklorid (Spoj 87)
Ovo je spoj pripremljen od Spoja 86 na isti način kao i Spoj 60.
1H-NMR (slobodna baza; CDCl3) 7,40-7,00 (m, 5H), 6,80 (s, 1H), 6,27 (s, 1H), 3,90-2,27 (m, 8H), 3,80 (s, 3H), 3,49 (s, 3H), 2,15-1,20 (m, 4H).
Primjer 18
Pripremanje (2S,3S)-3-((6-metoksi-1-(trifluorometil)-1,2,3,4-tetrahidronaftalin-7-il)metil)amino-2-fenilpiperidin
dihidroklorida (Spoj 94)
(i) 1-hidroksi-6-metoksi-1-(trifluorometil)-1,2,3,4-tetrahidronaftalin (Spoj 88)
Ovo je spoj pripremljen od 6-metoksi-1-tetralona na isti način kao i Spoj 62.
1H-NMR (CDCl3) 7,61 (d, J = 8,8 Hz, 1H), 6,80 (dd, J = 8,8, 2,6 Hz, 1H), 6,66 (d, J=2,6, 1H), 3,80 (s, 3H), 2,90-2,66 (m, 2H), 2,30 (s, 1H), 2,40-1,75 (m, 4H).
(ii) 6-metoksi-1-(trifluorometil)-3,4-dihidronaftalin (Spoj 89)
Ovo je spoj pripremljen od Spoja 88 na isti način kao i Spoj 63.
1H-NMR (CDCl3) 7,39-7,28 (m, 1H), 6,80-6,70 (m, 2H), 6,61-6,52 (m, 1H), 3,81 (s, 3H), 2,84-2,72 (m, 2H), 2,46-2,30 (m, 2H).
(iii) 6-metoksi-1-(trifluorometil)-1,2,3,4-tetrahidronaftalin (Spoj 90)
Ovo je spoj pripremljen od Spoja 89 na isti način kao i Spoj 64.
1H-NMR (CDCl3) 7,26 (d, J=8,4 Hz, 1H), 6,74 (dd, J = 8,4, 2,9 Hz, 1H), 6,66 (d, J=2,9, 1H), 3,79 (s, 3H), 3,57-3,36 (m, 1H), 2,90-2,62 (m, 2H), 2,20-1,60 (m, 4H).
(iv) 7-formil-6-metoksi-1-(trifluorometil)-1,2,3,4-tetrahidronaftalin (Spoj 91)
Ovo je spoj pripremljen od Spoja 90 na isti način kao i Spoj 46.
1H-NMR (CDCl3) 10,39 (1, 1H), 7,81 (s, 1H), 6,74 (s, 1H), 3,91 (s, 3H), 3,60-3,40 (m, 1H), 2,98-2,70 (m, 2H), 2,27-1,65 (m, 4H).
(v) (2S,3S)-1-terc-butoksikarbonil-3-((6-metoksi-1-(trifluorometil)-1,2,3,4-tetra-hidronaftalin-7-il)metil)amino-2-
fenilpiperidin (Spoj 92)
Ovo je spoj pripremljen od Spoja 12 i 91 na isti način kao i Spoj 26. Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
(vi) (2S,3S)-3-((6-metoksi-1-(trifluorometil)-1,2,3,4-tetrahidronaftalin-7-il)metil) amino-2-fenilpiperidin (Spoj 93)
Ovo je spoj pripremljen od Spoja 92 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,38-7,17 (m, 5H), 6,94 (s, 1H), 6,42 i 6,39 (oba s, ukupno 1H), 3,90 (d, J = 1,5 Hz, 1H), 3,73-3,58 (m, 1H), 3,50-3,23 (m, 6H), 2,90-2,60 (m, 4H), 2,39 (br.s, 2H), 2,20-1,52 (m, 7H), 1,50-1,34 (m, 1H).
(vii) (2S,3S)-3-((6-metoksi-1-(trifluorometil)-1,2,3,4-tetrahidronaftalin-7-il) me-til)amino-2-fenilpiperidin dihidroklorid (Spoj 94)
Ovo je spoj pripremljen od Spoja 93 na isti način kao i Spoj 28.
t.t.: 227-230°C
IC(KBr) 3435, 1624, 1587, 1561, 1507, 1266, 1452, 1433, 1420, 1336, 1260, 1427, 1171, 1171, 1138, 1116, 1106, 1044, 979, 834, 748, 693.
Primjer 19
Pripremanje (2S,3S)-3-((2,2-difluoro-6-metoksi-1,2,3,4-tetrahidronaftalin-7-il)metil)amino-2-fenilpiperidin
dihidroklorida (Spoj 98)
(i) 6-metoksi-2,2-difluoro-1,2,3,4-tetrahidronaftalin (Spoj 95)
Miješanoj otopini 6-metoksi-2-tetralona (352 mg, 2,00 mmol) u bezvodnom CNCl3 (5 ml) dodan je dietilaminosumpor trifluorid (366 mg, 2,27 mmol) na sobnoj temperaturi. Reagirajuća smjesa je miješana na temperaturi refluksiranja 7 sati. Smjesa je razrijeđena zasićenim NaHCO3 i ekstrahirana sa CH2Cl2. Kombinirana otopina je sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod u vidu tamno smeđeg ulja. Sirov je proizvod pročišćen stubnom kromatografijom na silika gelu sa heksan-etil acetatom 825:1) da bi se dobio spoj 95 (181 mg, 46%) u vidu žutog ulja.
1H-NMR (CDCl3) 7,00 (d, J = 8,1 Hz, 1H), 6,75 (dd, J = 8,4, 2,9 Hz, 1H), 6,68 (d, J=2,6 7H), 3,78 (s, 3H), 3,18 (t, J= 15,0 Hz, 2H), 2,98 (t, J = 7,0 Hz, 2H), 2,72-2,11 (m, 2H).
(ii) 7-formil-6-metoksi-2.2-difluoro-1,2,3,4-tetrahidronaftalin (Spoj 96)
Miješanoj otopini Spoja 95 (90 mg, 0,45 mmol) u bezvodnom CH2Cl2 (10 ml) dodan je TiCl4 (104 mg, 0,55 mmol) pomoću brizgalica, a na -78°C. Poslije 15 min dodan je diklorometil metil eter (636 mg, 0,55 mmol) na istoj temperaturi. Reagirajuća smjesa je miješana 2 sata na -78°C. Smjesa je razrijeđena vodom (10 ml) uz hlađenje ledom, pa miješana 15 min na sobnoj temperaturi. Organski je sloj izdvojen a vodeni je sloj ekstrahiran sa CH2Cl2. Kombinirana je otopina sušena (MgSO4) i koncentrirana u vakuumu da bi se dobio sirov proizvod u vidu žutog ulja. Sirov je proizvod pročišćen stubnom fotografijom na silika gelu sa heksan-etil acetatom (10:1) da bi se dobio spoj 96 (44 mg, 45%) u vidu žutog ulja.
1H-NMR (CDCl3) 10,39 (s, 1H), 7,56 (s, 1H), 6,75 (s, 1H), 3,91 (s, 3H), 3,21 (t, J=14,7, 2H), 3,05 (t, J=7,0 Hz, 1H), 2,30-2,15 (m, 2H).
(iii) (2S,3S)-1-terc-butoksikarbonil-3-((2,2-difluoro-6-metoksi-1,2,3,4-tetrahidro-naftalin-7-il)metil)amino-2-fenil
piperidin (Spoj 97)
Ovo je spoj pripremljen od Spoja 96 i Spoja 12 na isti način kao i Spoj 13.
1H-NMR (CDCl3) 7,58 (d, J=7,3 Hz, 2H), 7,34-7,25 (m, 3H), 6,90 (s, 1H), 6,56 (s, 1H), 5,49 (s, 1H), 3,97-3,71 (m, 3H), 3,68 (s, 3H), 3,14 (t, J = 15,0 Hz, 2H), 3,08-2,93 (m, 4H), 2,24-2,09 (m, 2H), 1,81-1,53 (m, 4H), 1,42 (s, 9H).
(iv) (2S,3S)-3-((2,2-difluoro-6-metoksi-1,2,3,4-tetrahidronaftalin-7-il)metil)ami-no-2-fenilpiperidin dihidroklorid (Spoj 98)
Ovo je spoj pripremljen od Spoja 97 na isti način kao i Spoj 60.
1H-NMR (CDCl3) 7,35-7,29 (m, 5H), 6,64 (s, 1H), 6,43 (s, 1H), 3,94 (s, 1H), 3,71-3,27 (m, 3H), 3,44 (s, 3H), 3,07 (t, J = 15,4 Hz, 2H), 2,93 (t, J = 6,9 Hz, 2H), 2,88-2,77 (m, 2H), 2,25-1,90 (m, 4H), 1,75-1,43 (m, 2H).
Primjer 20
Pripremanje (2S,3S)-3-(2-metoksi-5-(2,2,2-trifluoro-1-hidroksi-1-(trifluorometil) etil)benzil)amino-2-fenilpiperidin dihidroklorida (Spoj 101)
(i) 4-(2,2,2-trifluoro-1-hidroksi-1-(trifluorometil)etilanizol (spoj 99)
Ovo je spoj pripremljen prema procedurama opisanim u Izv. Akad. Nauk SSSR, Ser. Khim., (1979), 669.
(ii) 2-metoksi-5-(2,2,2-trifluoro-1-hidroksi-1-(trifluorometil)etil)benzaldehid (Spoj 100)
Ovo je spoj pripremljen od Spoja 99 na isti način kao i Spoj 9.
1H-NMR (CDCl3) 10,47 (s, 1H), 8,29-7,03 (m, 3H), 4,05 (s, 1H), 3,99 (s, 3H).
(iii) (2S,3S)-3-(2-metoksi-5-(2,2,2-trifluoro-1-hidroksi-1-(trifluorometil)etil)ben-zil)amino-2-fenilpiperidin dihidroklorid (Spoj 101)
Ovo je spoj pripremljen od Spoja 100 i od Spoja 1 na isti način kao i Spoj 2.
1H-NMR (slobodna baza; CDCl3) 7,66-6,65 (m, 8H), 4,02-2,75 (m, 6H), 3,57 (s, 3H), 3,47 (s, 1H), 2,20-1,25 (m, 4H).
1.1.: 299-302°C
Primjer 21
Pripremanje (2S,3S)-3-[5-[1-hloro-1-(trifluorometil)etil]-2-metoksibenzilami-no]-2-fenilpiperidin dihidroklorida (Spoj 105)
(i) 5-[(1-hloro-1-(trifluorometil)etil]-2-metoksibenzaldehid (Spoj 102)
Ovo je spoj pripremljen od Spoja 69 na isti način kao i Spoj 46.
1H-NMR (CDCl3) 10,47 (s, 1H), 8,06 (d, J=2,9 Hz, 1H), 7,97-7,87 (m, 1H), 7,05 (d, J = 8,8 Hz, 1H), 3,98 (s, 3H), 2,15 (s, 2H).
(ii) (2S,3S)-1-terc-butoksikarbonil-3-[5-[(1-hloro-1-(trifluormetil)etil]-2-metoksi-benzilamino]-2-fenilpiperidin (Spoj 103)
Ovo je spoj pripremljen od Spoja 12 i Spoja 102 na isti način kao i Spoj 26. Korišteno je u sljedećem stupnju bez daljnjeg pročišćavanja.
(iii) (2S,3S)-3-[5-[(1-kloro-1-(trifluorometil)etil]-2-metoksibenzilamino]-2-fenil-piperidin (Spoj 104)
Ovo je spoj pripremljen od Spoja 103 na isti način kao i Spoj 27.
1H-NMR (CDCl3) 7,50-7,15 (m, 7H), 6,72-6,62 (m, 1H), 3,89 (d, J=2,2 Hz, 1H), 3,75-3,60 (m, 1H), 3,51 (s, 3H), 3,40 (d, J=14,3 Hz, 1H), 3,35-3,21 (m, 1H), 2,90-2,71 (m, 2H), 2,20-1,80 (m, 7H), 1,70-1,35 (m, 2H).
(iv) (2S,3S)-3-[5-[(1-kloro-1-(trifluorometil)etil]-2-metoksibenzilami-no]-2-fenilpiperidin dihidroklorid (Spoi 105)
Ovo je spoj pripremljen od Spoja 104 na isti način kao i Spoj 28.
Kemijske strukture spoja pripremljenih u Primjerima 1 do 21 prikazane su u Tabeli 1.
[image]
Spojevi navedeni u tabelama 2 i 3 pripremljeni su koristeći odgovarajuće polazne materijale postupcima opisanim u primjerima 10, 13, 14, 17, 18 ili 19
[image]
[image]
Claims (20)
1. Spoj formule (I):
[image]
i njegove farmaceutski prihvatljive soli, naznačen time, što
R je halo C1-C8 alkil, halo C2-C8 alkenil, halo C2-C8 alkinil ili halo C1-C8 alkil supstituiran s hidroksi ili C1-C8 alkoksi; R1 je vodik, halo ili C1-C8 alkoksi, ili
R i R1, zajedno s dva ugljikova atoma koje zajednički koriste benzolski prsten i T i R1, upotpunjuju jedan kondenziran C4-C6 cikloalkil, pri čemu je jedan ugljikov atom eventualno zamijenjen kisikom i pri čemu su jedan ili dva ugljikova atoma eventualno supstituirana s do pet supstituenata biranih od halo, C1-C6 alkila i halo C1-C6 alkila;
X je C1-C6 alkoksi, halo C1-C6 alkoksi, fenoksi ili halo; a
Ar je fenil, eventualno supstituiran s halo.
2. Spoj prema zahtjevu 1, naznačen time, što H je halo, metoksi, difluorometoksi, trifluorometoksi ili fenoksi, i nalazi se na položaju 2 na fenilnom prstenu, dok je Ar fenil.
3. Spoj prema zahtjevu 2, naznačen time, što X je metoksi, difluorometoksi ili trifluorometoksi.
4. Spoj prema zahtjevu 2 ili 3, naznačen time, što R je C1-C6 alkil, hidroksi C1-C6 alkil, C2-C6 alkenil, C2-C6 alkinil, pri čemu su alkilna, alkenilna i alkinilna jezgra supstituirane s dva do sedam atoma halogena, a R1 je vodik ili metoksi.
5. Spoj prema zahtjevu 2 ili 3, naznačen time, što R i R1 zajedno s dva ugljikova atoma, zajednička s benzolskim prstenom i R i R1, upotpunjuju kondenziran C4-C6 cikloalkil pri čemu je jedan ugljikov atom eventualno zamijenjen kisikom i što po jedan ili dva ugljikova atoma eventualno supstituiran s do četiri supstituenta birana od atoma fluora i trifluormetila.
6. Spoj prema zahtjevu 1, predstavljen općom formulom (la):
[image]
naznačen time, stoje R1 vodik, halo ili metoksi; R2 i R3 se neovisno biraju od halo, C1-C6 alkila, C2-C6 alkenila i C2-C6 alkinila, ili R2 i R3 zajedno tvore C2-C6 alkiliden, pri čemu su jezgre alkila, alkenila, alkinila i alkilidena eventualno supstituirane s do sedam halogenih atoma;
ili R1 R2 su uzeti zajedno da tvore jedan kondenziran C4-C6 cikloalkil, pri čemu je jedan ugljikov atom eventualno zamijenjen kisikom, a C4-C6 cikloalkil je eventualno supstituiran s do četiri supstituenata biranih od halo, C1-C4 alkila i halo C1-C4 alkila.
7. Spoj prema zahtjevu 4, naznačen time, što R je C1-C6 alkil, hidroksi C1-C6 alkil, C2-C6 alkenil ili C2-C6 alkinil, pri čemu su te jezgre supstituirane sa dva do tri atoma fluora.
8. Spoj prema zahtjevu 7, naznačen time, što R je C1-C6 alkil, supstituiran s dva do tri atoma fluora.
9. Spoj prema zahtjevu 4, naznačen time, što R je C1-C6 alkil, hidroksi C1-C6 alkil, C2-C6 alkenil ili C2-C6 alkinil, pri čemu su te jezgre supstituirane s dva do sedam atoma fluora.
10. Spoj prema zahtjevu 7, naznačen time, što R je trifluorometil, difluoroetil, trifluoroetil, trifluoroizopropil, trifluoro-terc-butil, trifluoro-1,1-dimetilmetil-3-butinil i 2-hlorotrifluoroizopropil.
11. Spoj prema zahtjevu 9, naznačen time, što R je pentafluoroetil, pentafluoropropil, pentafluoroizopropenil, heksafluoroizopropil, heksafluoro-2-hidroksiizopropil i heksafluoro-terc-butil.
12. Spoj prema zahtjevu 5, naznačen time, što R i R1 zajedno s dva atoma ugljika, zajednička za benzolski prsten i R i R1, mogu upotpunjuju trifluorometilciklopentil, trifluorometilcikloheksil, difluorocikloheksil ili difluoro dimetil cikloheksil.
13. Spoj prema zahtjevu 7, naznačen time, što se bira iz grupe koju čine:
(2S, 3S)-3-(2-fluoro-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-kloro-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-metoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-fenoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(5-(1,1-difluoroetil)-2-(trifluorometoksi)benzil)amino-2-fenil-piperidin ili njegove soli;
(2S, 3S)-3-(5-(1,1-difluoroetil)-2-metoksibenzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2-metoksi-5-(2,2,2-trifluoroetil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S ,3S)-3-(2-metoksi-5-(1-(trifluorometil)etil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-[5-(1,1-dimetil-4,4,4-trifluoro-2-butinil)-2-metoksibenzil]amino-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-[5-(1,1-dimetil-2,2,2-trifluoroetil)-2-metoksibenzilamino]-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-(2,4-dimetoksi-5-(2,2,2-trifluoroetil)benzil)amino-2-fenilpiperidin ili njegove soli; i
(2S, 3S)-3-[5-[(1-kloro-1-(trifluorometil)etil]-2-metoksibenzilamino]-2-fenilpiperidin ili njegove soli;
14. Spoj prema zahtjevu 9, naznačen time, što se bira iz grupe koju čine:
(2S, 3S)-fenil-3-(5-(2,2,2-trifluoro-1-(trifluorometil)etil)-2-metoksiben-zil)aminopiperidin ili njegove soli;
(2S, 3S)-fenil-3-(5-(2,2,2-trifluoro-1-(trifluorometil)etil)-2-metoksiben-zil)aminopiperidin ili njegove soli;
(2S, 3S)-fenil-3-(5-(2,2,2-tetrafluoro-1-(trifluorometil)etil)-2-metoksiben-zil)aminopiperidin ili njegove soli;
(2S, 3S)-3-(2-metoksi-5-(1,1,2,2,2-pentafluoroetil)benzil)amino)-2-fenilpiperidin ili njegove soli;
(2S, 3S)-fenil-3-(5-(2,2,2-trifluoro-1-(metil)-1-(trifluorometil)etil)-2-metoksibenzil)aminopiperidin ili njegove soli;
(2S,3S)-3-[5-[2,2-difluoro-1-(trifluorometil)etenil)-2-metoksibenzil]aminopiperidinili njegove soli; i
(2S, 3S)-3-(2-metoksi-5-(2,2,2-trifluoro-1-hidroksi-1-(trifluorometil)etil) benzil)amino-2-piperidin ili njegove soli.
15. Spoj prema zahtjevu 12, naznačen time, što se bira iz grupe koju čine:
(2S, 3S)-3-[5-metoksi-1-(trifluorometil)indan-6-il)metilamino]-2-fenilpiperidin ili njegove soli;
(2S, 3S)-3-((6-metoksi-1-(trifluorometil)-1,2,3,4-tetrahidronaftalin-7-il)metil)amino)-2-fenilpiperidin ili njegove soli; i
(2S,3S)-3-((2,2-difluoro-6-metoksi-1-1,2,3,4-tetrahidronaftalin-7-il)me-til)amino)-2-fenilpiperidin ili njegove soli.
16. Spoj prema zahtjevu 10, naznačen time, što se bira iz grupe koju čine:
(2S,3S)-3-(2-metoksi-5-(trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S,3S)-3-(2-metoksi-5-(2,2,2-trifluorometil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S,3S)-3-(2-metoksi-5-(1-(trifluorometil)etil)benzil)amino-2-fenilpiperidin ili njegove soli;
(2S,3S)-3-(5-(1,1-difluoroetil)-2-(trifluorometoksi)benzil)amino-2-fenilpiperidin ili njegove soli; i
(2S,3S)-3-[5-(1,1-dimetil-2,2,2-trifluoroetil)-2-metoksibenzil)amino]-2-fenilpiperidin ili njegove soli.
17. Spoj prema zahtjevu 12, naznačen time, što je to (2S,3S)-2-fenil-3-(5-(2,2,2-trifluoro-1-(trifluorometil)etil)-2-metoksibenzil)aminopiperidin ili njegova sol.
18. Spoj prema zahtjevu 16, naznačen time, što je to (2S,3S)-3-[5-metoksi-1-trifluorometilindan-6-il)metilamino]-2-fenilpiperidin ili njegove soli.
19. Postupak za liječenje ili sprečavanje gaostrointestinalnih poremećaja, poremećaja centralnog živčanog sustava, upalnih oboljenja, povraćanja, nezadržavanja mokrenja, bola, migrene, opekotina od sunca, oboljenja angiogeneza a, poremećaja i nepovoljnih stanja izazvanih bakterijom Helicobacter pylori ili angiogeneze kod sisavaca, naznačen time, što obuhvaća davanje tom sisavcu terapeutski djelotvorne količine spoja prema zahtjevu 1.
20. Farmaceutska kompozicija za liječenje ili sprečavanje poremećaja gastrointestinalnog trakta, poremećaja centralnog živčanog sustava (CNS), inflamatornih oboljenja, povraćanja, nezadržavanja mokrenja, bola, migrene, opekotina od sunca, oboljenja angiogeneza a, poremećaja i nepovoljnih stanja izazvanih bakterijom Helico bacterpylori, ili angiogeneze kod sisavaca, naznačena time, što sadrži terapeutski djelotvornu količinu jednog spoja prema zahtjevu 1 zajedno s farmaceutski prihvatljivim nosačem.
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EP0653208A3 (en) * | 1993-11-17 | 1995-10-11 | Pfizer | Substance P antagonists for the treatment or prevention of sunburn. |
EP0655246A1 (en) * | 1993-11-30 | 1995-05-31 | Pfizer Inc. | Substance P antagonists for the treatment of disorders caused by helicobacter pylori or other spiral urease-positive gram-negative bacteria |
PT780375E (pt) * | 1995-12-21 | 2002-12-31 | Pfizer | 3-¬(benzilo substituido em 5)amino|-2-phenilpiperidinas como antagonistas da substancia p |
US5990125A (en) | 1996-01-19 | 1999-11-23 | Pfizer Inc. | NK-1 receptor antagonists for the treatment of cancer |
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1996
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1997
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