TWI465443B - Piper with PGDS inhibitory effect Compounds - Google Patents
Piper with PGDS inhibitory effect Compounds Download PDFInfo
- Publication number
- TWI465443B TWI465443B TW100102129A TW100102129A TWI465443B TW I465443 B TWI465443 B TW I465443B TW 100102129 A TW100102129 A TW 100102129A TW 100102129 A TW100102129 A TW 100102129A TW I465443 B TWI465443 B TW I465443B
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- phenyl
- compound
- carbonyl
- piperidin
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 178
- 241000009298 Trigla lyra Species 0.000 title claims description 14
- 230000002401 inhibitory effect Effects 0.000 title description 15
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 title 1
- 101710145576 Prostaglandin-H2 D-isomerase Proteins 0.000 title 1
- -1 aralkoxy Chemical group 0.000 claims description 169
- 125000001424 substituent group Chemical group 0.000 claims description 89
- 125000004432 carbon atom Chemical group C* 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 47
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 claims description 44
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000003277 amino group Chemical group 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 208000026935 allergic disease Diseases 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 8
- 102000003960 Ligases Human genes 0.000 claims description 8
- 108090000364 Ligases Proteins 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 208000027866 inflammatory disease Diseases 0.000 claims description 8
- 150000003180 prostaglandins Chemical class 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000011664 nicotinic acid Substances 0.000 claims description 6
- 229960003512 nicotinic acid Drugs 0.000 claims description 6
- 230000000069 prophylactic effect Effects 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 3
- 125000006612 decyloxy group Chemical group 0.000 claims description 3
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- 150000003852 triazoles Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- 239000007787 solid Substances 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 40
- 238000000034 method Methods 0.000 description 40
- 235000002639 sodium chloride Nutrition 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 25
- 238000001914 filtration Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- 239000003795 chemical substances by application Substances 0.000 description 19
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 13
- 125000004185 ester group Chemical group 0.000 description 13
- 239000002207 metabolite Substances 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000002274 desiccant Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 9
- 229910000105 potassium hydride Inorganic materials 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 150000007530 organic bases Chemical class 0.000 description 8
- 239000011591 potassium Substances 0.000 description 8
- 229910052700 potassium Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 125000003172 aldehyde group Chemical group 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 150000008282 halocarbons Chemical class 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 150000007529 inorganic bases Chemical class 0.000 description 7
- 206010039083 rhinitis Diseases 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- BVEJZHHXGQCGMY-UHFFFAOYSA-N tert-butyl 4-(4-aminopiperidin-1-yl)benzoate Chemical compound C1=CC(C(=O)OC(C)(C)C)=CC=C1N1CCC(N)CC1 BVEJZHHXGQCGMY-UHFFFAOYSA-N 0.000 description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 6
- 239000000920 calcium hydroxide Substances 0.000 description 6
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 230000003394 haemopoietic effect Effects 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 5
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 5
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
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- 150000001298 alcohols Chemical class 0.000 description 4
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- 239000003086 colorant Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
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- 230000002265 prevention Effects 0.000 description 4
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 229910052715 tantalum Inorganic materials 0.000 description 4
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 4
- RCPVVSKAQIFBTC-UHFFFAOYSA-N 1-[4-[3-(triazol-1-yl)propyl]phenyl]piperidin-4-amine Chemical compound C1CC(N)CCN1C(C=C1)=CC=C1CCCN1N=NC=C1 RCPVVSKAQIFBTC-UHFFFAOYSA-N 0.000 description 3
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 3
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 208000030961 allergic reaction Diseases 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000006172 buffering agent Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- SADPINFEWFPMEA-UHFFFAOYSA-N furan-2-yl(piperazin-1-yl)methanone Chemical compound C=1C=COC=1C(=O)N1CCNCC1 SADPINFEWFPMEA-UHFFFAOYSA-N 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
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- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000009284 tracheal contraction Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical group FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
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Description
本發明係有關於一種將哌化合物或其鹽、和將該等設為有效成分之醫藥組成物,特別是有關於一種藉由造血器官(hematopoietic organ)型前列腺素(prostaglandin)D合成酵素阻礙作用之過敏疾病、炎症性疾病等的預防及/或治療劑。
前列腺素D2(PGD2)係在抗原與免疫球蛋白E的複合體鍵結而被活性化而成之肥胖細胞,被最大量地產生、排出之炎症性媒介(非專利文獻1),被認為是引起過敏症狀之重要角色者。PGD2係在氣喘病人的氣管支肺泡洗淨液中被高濃度地檢出(非專利文獻2),有報告揭示相較於健康人,由於吸入PGD2而能夠觀察到氣管收縮(非專利文獻3)。
另一方面,產生PGD2之合成酵素係被稱為前列腺素D合成酵素(PGDS),已知有造血器官型酵素及脂質運載蛋白(lipocalin)型酵素之2種類存在。因為PGD2係作為以過敏疾病為首之各式各樣的疾病之發症和病情惡化因素的機能、及參與活體內調節機構,認為改善其產生異常,對於作為各種疾病的醫藥品係非常有效的。
在人體的造血器官前列腺素D合成酵素(H-PGDS),係主要分布在胎盤、肺、胎生期肝臟、淋巴節、腦、心臟、胸腺、骨髓及脾臟。又,有報告揭示細胞等級係在腦內的小神經膠質(microglia)細胞、骨髓巨核球、皮膚的蘭格罕細胞(Langerhans cell)、肝臟的庫氏細胞(Kuffer cell)、巨噬細胞(macrophage)、樹狀細胞等許多的抗原提示細胞、肥胖細胞及Th2細胞出現。
因為在過敏性鼻炎病人的鼻黏膜下、或在慢性副鼻腔炎病人的鼻竇炎中,在肥胖細胞和炎症性細胞之H-PGDS的出現較多等,所以認為氣喘、鼻副鼻腔炎、皮膚炎、慢性閉塞性肺疾病等的過敏疾病之發症、病情惡化,來自H-PGDS之PGD2係扮演著重要的角色(非專利文獻4)。而且,在通常未觀察到出現之骨骼肌,在其壞死部亦確認有H-PGDS出現(非專利文獻5)。因此,暗示來自造血器官型酵素之PGD2係亦參與伴隨著肌肉失養症(muscular dystrophy)、肌肉萎縮性側索硬化症、多發性硬化症、刺激性大腸炎、關節風濕症、慢性閉塞性肺疾病等的組織損傷之疾病。
因此,作為由造血器官酵素所產生的PGD2或其代謝物所參與之過敏疾病或炎症性疾病、進而肌肉壞死和外傷性腦損傷等的疾病等之預防及/或治療劑,H-PGDS的阻礙劑係能夠期待的。
有若干報告揭示有關H-PGDS阻礙劑的提供(例如專利文獻1及2),亦揭示具有與本發明化合物類似構造之H-PGDS阻礙劑(專利文獻3)。又,哌化合物係除了作為H-PGDS阻礙劑以外,亦作為醫藥等有用的化合物而被廣泛地研究。
在專利文獻4,作為刺猬信號(Hedgehog Signaling)的阻礙劑,有記載一種具有呋喃基羰基哌構成之哌化合物。
在專利文獻5(國際公開WO99/007672號公報),作為與鉀離子通道(K+channel)相互作用之化合物,有記載一種廣闊範圍的哌化合物。
專利文獻1:國際公開WO2007-007778號
專利文獻2:國際公開WO2007-041634號
專利文獻3:國際公開WO2008-122787號
專利文獻4:國際公開WO2007-054623號
專利文獻5:國際公開WO99/007672號
非專利文獻1:J. Immumol(免疫期刊).,129,1627-1631(1982年)
非專利文獻2:N. Eng. J. Med(新英格蘭醫藥期刊).,315,800-804(1986年)
非專利文獻3:N. Eng. J. Med.,311,209-213(1984年)
非專利文獻4:Arch. Otolaryngol Head Neck Surg(耳鼻喉科學-頭頸外科檔案).,133,693-700(2007年)
非專利文獻5:Acta Neuropathol(神經病理解剖學),104,377-384(2002年)
本發明的主要課題,係提供一種使用低用量阻礙前列腺素D合成酵素、特別是H-PGDS的效果高之新穎化合物。
又,本發明的附加性課題,係提供一種醫藥,該醫藥係基於H-PGDS阻礙作用,對於來自該酵素之PGD2或其代謝物介在性的疾病之預防、治療,係有效、副作用少且安全性高。
關於具有H-PGDS阻礙作用之化合物,本發明者等進行專心研究時,發現下述通式(I)所表示的新穎哌化合物對於H-PGDS係具有非常優良的阻礙作用,進而重複研討而完成了本發明。
本發明係提供以下的哌化合物、醫藥組成物、前列腺素D合成酵素阻礙劑、前列腺素D2或其代謝物參與的疾病之預防劑或治療劑。
第1項. 一種哌化合物或其鹽,該哌化合物係由下述通式(I)表示,
[式中,X係表示CH、或N原子,R1
係表示碳數1~6的烷基,R2
係表示亦可具有取代基之碳數1~6的烷基、亦可具有取代基之碳數2~6的烯基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基之任一者,R3
、R4
係表示相同或相異且係氫原子、或亦可具有取代基之碳數1~6的烷基,R3
及R4
係表示亦可以與各自所鍵結的氮原子一起形成飽和雜環基,R5
係表示氫原子、或亦可具有取代基之碳數1~6的烷基或芳烷基]。
第2項. 如第1項之哌化合物或其鹽,其中,X係表示CH、或N原子,R1
係表示甲基、或乙基,R2
係表示亦可具有胺基甲醯基或不飽和雜環基作為取代基之碳數1~3的烷基、亦可具有胺基甲醯基作為取代基之丙烯基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基,R3
、R4
係表示一方為氫原子,另外一方為亦可具有飽和雜環基、或不飽和雜環基作為取代基之碳數1~6的烷基,R3
及R4
係表示亦可以與各自所鍵結的氮原子一起形成吡咯啶基、哌啶基、哌基、啉基,R5
係表示氫原子、甲基、乙基、第三丁基或苄基。
第3項. 如第1或2項之哌化合物或其鹽,其中,X係表示CH、或N原子,R1
係表示甲基,R2
係表示亦可具有啉胺基甲醯基、或三唑基的任一者作為取代基之碳數1~3的烷基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基,該三唑基係亦可具有1~2個碳數1~6的烷基作為取代基,R3
、R4
係表示一方為氫原子,另外一方為亦可具有具有啉基、或吡啶基作為取代基之碳數1~3的烷基,R3
及R4
係表示亦可以與各自所鍵結的氮原子一起形成啉基,R5
係表示氫原子。
第4項. 如第1至3項中任一項之哌化合物或其鹽,其中,X係表示CH,R1
係表示甲基,R2
係表示亦可具有1,2,3-三唑基、1,2,4-三唑基、或3,5-二甲基-1,2,4-三唑基的任一者作為取代基之直鏈狀碳數1~3的烷基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基,R3
、R4
係表示亦可以與各自所鍵結的氮原子一起形成啉基,R5
係表示氫原子。
第5項. 如第1至4項中任一項之哌化合物或其鹽,其係選自下列所組成群組:
‧ 4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(吡啶-3-基-甲基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-啉乙基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(4-啉基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-哌啶基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-吡咯啶基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-啉-3-側氧丙烯-1-基)-苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-啉-3-側氧丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 6-(4-(4-((1-甲基吡咯-2-基)-羰基)1-哌胺基甲醯基)-哌啶-1-基)-菸鹼酸
‧ 4-((1-甲基吡咯-2-基)-羰基)-N-(1-(5-(4-啉基羰基)吡啶-2-基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4(2-啉乙基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺
‧ 4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4(2-(1,2,3-三唑-1-基)-乙基)-苯基)-哌啶-4-基)-1-哌羧醯胺
第6項. 一種醫藥組成物,其係含有如第1至5項中任一項之化合物的至少1種或其藥學上被容許的鹽之有效量、及藥學性載體。
第7項. 一種前列腺素D合成酵素阻礙劑,其特徵為含有如第1至5項中任一項之化合物或其藥學上被容許的鹽之有效量、及藥學性載體。
第8項. 一種前列腺素D2或其代謝物參與的疾病之預防劑或治療劑,其特徵為含有如第1至5項中任一項之化合物或其藥學上被容許的鹽之有效量、及藥學性載體。
第9項. 如第8項之預防劑或治療劑,其中前列腺素D2或其代謝物參與之疾病係過敏疾病、或炎症性疾病。
第10項. 一種前列腺素D2或其代謝物參與的疾病之治療方法,其係治療前列腺素D2或其代謝物參與的疾病之方法,其中包含對將此種治療設為必要之病人,投給哌化合物或其鹽之有效量,該哌化合物係由下述通式(I)表示,
[式中,X係表示CH、或N原子,R1
係表示碳數1~6的烷基,R2
係表示亦可具有取代基之碳數1~6的烷基、亦可具有取代基之碳數2~6的烯基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基之任一者,R3
、R4
係表示相同或相異且係氫原子、或亦可具有取代基之碳數1~6的烷基,R3
及R4
係表示亦可以與各自所鍵結的氮原子一起形成飽和雜環基,R5
係表示氫原子、或亦可具有取代基之碳數1~6的烷基或芳烷基]。
第11項. 如第10項之方法,其中前列腺素D2或其代謝物參與之疾病係過敏疾病、或炎症性疾病。
第12項. 一種哌化合物或其鹽,其係用以治療前列腺素D2或其代謝物參與之疾病而使用,該哌化合物係由下述通式(I)表示,
[式中,X係表示CH、或N原子,R1
係表示碳數1~6的烷基,R2
係表示亦可具有取代基之碳數1~6的烷基、亦可具有取代基之碳數2~6的烯基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基之任一者,R3
、R4
係表示相同或相異且係氫原子、或亦可具有取代基之碳數1~6的烷基,R3
及R4
係表示亦可以與各自所鍵結的氮原子一起形成飽和雜環基,R5
係表示氫原子、或亦可具有取代基之碳數1~6的烷基或芳烷基]。
第13項. 一種哌化合物或其鹽之使用,其係用以治療前列腺素D2或其代謝物參與之疾病,該哌化合物係由下述通式(I)表示,
[式中,X係表示CH、或N原子,R1
係表示碳數1~6的烷基,R2
係表示亦可具有取代基之碳數1~6的烷基、亦可具有取代基之碳數2~6的烯基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基之任一者,R3
、R4
係表示相同或相異且係氫原子、或亦可具有取代基之碳數1~6的烷基,R3
及R4
係表示亦可以與各自所鍵結的氮原子一起形成飽和雜環基,R5
係表示氫原子、或亦可具有取代基之碳數1~6的烷基或芳烷基]。
依照本發明,係提供一種作為前列腺素D合成酵素阻礙劑、特別是作為H-PGDS阻礙劑有用之上述通式(1)所表示的新穎哌化合物或其鹽。
本發明的哌化合物或其鹽係在體外(in vitro)具有優良的H-PGDS阻礙活性。而且清楚明白在抗原引起鼻炎之土撥鼠,具有抑制鼻腔洗淨液中產生PGD2之作用,並且顯示優良的鼻塞改善作用。
因此,本發明的該哌化合物或其鹽,係基於其優良的H-PGDS阻礙活性,作為PGD2或其代謝物參與之疾病、例如過敏疾病或炎症性疾病等的預防及/或治療劑係有用的,且能夠期待其他有用的藥效。
本發明係一種哌化合物或其鹽,其中該哌化合物係一由下述通式(I)表示,
[式中,X係表示CH、或N原子,R1
係表示碳數1~6的烷基,R2
係表示亦可具有取代基之碳數1~6的烷基、亦可具有取代基之碳數2~6的烯基、-(C=O)-N(R3
)(R4
)基或-(C=O)-OR5
基之任一者,R3
、R4
係表示相同或相異且係氫原子、或亦可具有取代基之碳數1~6的烷基,R3
及R4
係表示亦可以與各自所鍵結的氮原子一起形成飽和雜環基,R5
係表示氫原子、或亦可具有取代基之碳數1~6的烷基或芳烷基]。
在本發明之上述通式(I)所表示的哌化合物,其特徵為兼具(N-烷基吡咯-2-基)羰基、及(哌啶-4-基)胺基羰基之化合物,且在前述先前技術文獻等亦無具體地記載之新穎化合物。
例如,在專利文獻3(國際公開WO2008-122787號公報),係廣泛地記載一種阻礙H-PGDS之哌化合物。但是,在本發明化合物係具有(哌啶-4-基)胺基羰基之點為不同,又,關於本發明所含有之具有(N-烷基吡咯-2-基)羰基之哌化合物,係完全未揭示。而且,如後述的試驗例所表示,在專利文獻3作為實驗例而揭示之化合物(參考例12~17),係在抗原引起鼻炎土撥鼠未顯示抑制鼻腔洗淨液中產生PGD2之作用。
在專利文獻4(國際公開WO2007-054623號公報),作為刺猬信號(Hedgehog Signaling)的阻礙劑,係揭示一種具有呋喃基羰基哌構造之哌化合物。但是,在本發明化合物之(N-烷基吡咯-2-基)羰基係不被呋喃基羰基限定之點為不同,且關於H-PGDS阻礙作用亦完全未記載。
在專利文獻5(國際公開WO99/007672號公報),作為與鉀通道相互作用之化合物,係記載呋喃基羰基哌化合物和苯甲醯基哌化合物等。但是未揭示如本發明之具有(N-烷基呋咯-2-基)羰基之哌化合物,且關於H-PGDS阻礙作用亦完全未記載。
如後述的試驗例所表示,未具有(N-烷基吡咯-2-基)羰基之哌化合物,係幾乎未顯示H-PGDS阻礙作用。
在本說明書,所謂「取代基」,可舉出鹵素原子、羥基、氰基、硝基、烷基、鹵烷基、環烷基、環烷基-烷基、芳烷基、烯基、炔基、烷氧基、鹵烷氧基、環烷氧基、環烷基-烷氧基、芳烷氧基、烷硫基、環烷基-烷硫基、胺基、一或二烷胺基、環烷基-烷胺基、醯基、醯氧基、側氧基、羧基、烷氧基羰基、芳烷氧基羰基、胺基甲醯基、飽和或不飽和雜環基、芳香族烴基、飽和雜環氧基等,前述取代基存在時,其個數係典型地為1個、2個或3個。
在前述的取代基,作為鹵素原子,可舉出氯原子、溴原子、氟原子、碘原子。
在前述的取代基,作為烷基、鹵烷基,較佳是碳數1~6或1~4的直鏈狀或分枝狀的烷基或表示該等烷基的1個~全部氫原子係使用前述鹵素原子取代而成之基,可舉出甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基、己基等的烷基、三氟甲基等的鹵烷基。
在前述取代基,作為環烷基,較佳是碳數3~7的環烷基,可舉出環丙基、環丁基、環戊基、環己基、環庚基。
在前述的取代基,作為環烷基-烷基,較佳是被碳數3~7的環烷基取代而成之碳數1~6的烷基,可舉出環丙基甲基、環丙基乙基、環丁基甲基、環戊基甲基、環己基甲基等。
在前述取代基,作為芳烷基,較佳是被碳數6~14的芳香族烴基取代而成之碳數1~6的直鏈狀或分枝狀的烷基,可舉出苄基、苯乙基、苯丙基、萘甲基、萘乙基等。
在前述的取代基,作為烯基係含有碳-碳雙鍵,較佳是表示碳數2~6的烯基,可舉出乙烯基、烯丙基、甲基乙烯基、丙烯基、丁烯基、戊烯基、己烯基等。
在前述的取代基,作為炔基係含有碳-碳參鍵,較佳是表示碳數2~6的炔基,可舉出乙炔基、丙炔基等。
在前述的取代基,作為烷氧基、鹵烷氧基,較佳是表示碳數1~6的直鏈狀或分枝狀的烷氧基、或前述的鹵素原子在該等的烷氧基取代而成之基,可舉出甲氧基、乙氧基、正丙氧基、異丙氧基、1-甲基丙氧基、正丁氧基、異丁氧基、第三丁氧基、2-甲基-丁氧基、新戊氧基、戊烷-2-基-氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、1,1-二氟乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基、1,1,2,2-四氟乙氧基、全氟乙氧基、3-氟-2-(氟甲基)-丙氧基、1,3-二氟丙烷-2-基-氧基、2,2,3,3,3-五氟-1-丙氧基等。
在前述的取代基,作為環烷氧基,較佳是碳數3~7的環烷氧基,可舉出環丙氧基、環丁氧基、環戊氧基、環己氧基、環庚氧基。
在前述的取代基,作為環烷基-烷胺基,較佳是使用碳數3~7的環烷基取代而成之碳數1~6的烷氧基,可舉出環丙基甲氧基、環丙基乙氧基、環丁基甲氧基、環戊基甲氧基、環己基甲氧基等。
在前述的取代基,作為芳烷氧基,較佳是表示具有前述芳烷基之氧基,可舉出苄氧基、苯乙基氧基、苯基丙氧基、萘基甲氧基、萘基乙氧基等。
在前述的取代基,作為烷硫基,較佳是表示碳數1~6的直鏈狀或分枝狀的烷硫基,可舉出甲硫基、乙硫基、正丙硫基、異丙硫基、正丁硫基、異丁硫基、第二丁硫基、第三丁硫基、戊硫基、己硫基等。
在前述的取代基,作為環烷基-烷硫基,較佳是被碳數3~7的環烷基取代而成之碳數1~6的烷硫基,可舉出環丙基甲硫基、環丙基乙硫基、環丁基甲硫基、環戊基甲硫基、環己基甲硫基等。
在前述的取代基,作為一或二烷胺基,係表示被前述之具有碳數1~6的直鏈或分枝的烷基一取代或二取代而成之胺基,可舉出甲胺基、二甲胺基、乙胺基、二乙胺基、甲基乙胺基等。
在前述的取代基,作為環烷基-烷胺基,係表示被前述之環烷基取代而成之烷胺基,可舉出環丙基甲胺基、環丁基甲胺基、環戊基甲胺基等。
在前述的取代基,作為醯基,可舉出甲醯基、乙醯基、丙醯基、正丁醯基、異丁醯基、戊醯基、異戊醯基、三甲基乙醯基等具有直鏈或分枝之碳數1~6的醯基、苯甲醯基等。
在前述的取代基,作為醯氧基,可舉出甲醯氧基、乙醯氧基、丙醯氧基、正丁醯氧基、異丁醯氧基、戊醯氧基、異戊醯氧基、三甲基乙醯氧基等的具有直鏈或分枝之碳數1~6的烷醯氧基、苯甲醯氧基等。
在前述的取代基,作為烷氧基羰基,係表示被前述的烷氧基取代而成之羰基,可舉出甲氧基羰基、乙氧基羰基、正丙氧基羰基、異丙氧基羰基、1-甲基丙氧基羰基、正丁氧基羰基、異丁氧基羰基、第三丁氧基羰基、2-甲基-丁氧基羰基、新戊氧基羰基、戊烷-2-基-氧基羰基等。
在前述的取代基,作為芳烷氧基羰基,較佳是表示被前芳烷氧基取代而成之羰基,可舉出苄氧基羰基、苯乙氧基羰基、苯基丙氧基羰基、萘基甲氧基羰基、萘基乙氧基羰基等。
在前述的取代基,作為胺基甲醯基,可舉出-CONH2
基、(一或二烷基)胺基甲醯基、(一或二芳香基)胺基甲醯基、(N-烷基-N-芳香基)胺基甲醯基、吡咯啶基胺基甲醯基、N-六氫吡啶基(piperidino)胺基甲醯基、哌基胺基甲醯基、啉胺基甲醯基等。
在前述的取代基,作為飽和或不飽和雜環基,較佳是表示具有以1~4個氧原子、氮原子、硫原子之任一原子為佳之二環性的飽和或不飽和雜環基,可舉出例如吡咯啶基、哌啶基、哌基、六亞甲基亞胺基、啉基、硫啉基、高哌基、四氫呋喃基、四氫吡喃基、咪唑基、噻吩基、呋喃基、吡咯基、唑基、異唑基、噻唑基、異噻唑基、吡唑基、三唑基、四唑基、吡啶基、吡基、嘧啶基、嗒基、吲哚基、異吲哚基、吲唑基、亞甲基二氧基苯基、伸乙基二氧基苯基、苯并呋喃基、二氫苯并呋喃基、苯并咪唑基、苯并唑基、苯并噻唑基、嘌呤基、喹啉基、異喹啉基、喹唑啉基、喹啉基等。
在前述的取代基,作為芳香族烴基,較佳是表示碳數6~14的芳香族烴基,可舉出苯基、萘基等。
在前述的取代基,作為飽和雜環氧基,係表示具有1個或2個氧原子、氮原子、硫原子之任一原子之單環性的飽和雜環基,例如具有吡咯啶基、哌啶基、哌基、六亞甲基亞胺基、啉基、硫啉基、高哌基、四氫呋喃基、四氫吡喃基之氧基,可舉出四氫呋喃基氧基、四氫吡喃基氧基。
通式(I)中,作為R1
所表示之「碳數1~6的烷基」,係表示碳數1~6的直鏈狀或分枝狀烷基,可例示甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、正戊基、正己基等,以甲基、乙基為佳,以甲基為更佳。
通式(I)中,作為R2
所表示之「亦可具有取代基之碳數1~6的烷基」之「碳數1~6的烷基」,可例示在R1
所表示之碳數1~6的烷基,以碳數1~3的烷基為佳,以直鏈狀或分枝狀之碳數1~3的烷基,亦即甲基、乙基、正丙基。
作為R2
所表示之「亦可具有取代基之碳數1~6的的烷基」之「取代基」,係前述所例示之取代基,以胺基甲醯基、或不飽和雜環基為佳,以啉胺基甲醯基、三唑基為更佳,以啉胺基甲醯基、1,2,3-三唑基、1,2,4-三唑基為特佳。該不飽和雜環基係亦可具有取代基,較佳取代基係甲基,其個數為1~2個。
作為R2
所表示之「亦可具有取代基之碳數1~6的烷基」,係以啉胺基甲醯基-乙基、1,2,3-三唑基-乙基、1,2,3-三唑基-丙基、1,2,4-三唑基-丙基、3,5-二甲基-1,2,4-三唑基-乙基、3,5-二甲基-1,2,4-三唑基-丙基為特佳。
作為R2
所表示之「亦可具有取代基之碳數2~6的烯基」的「碳數2~6的烯基」,可例示前述之碳數2~6的烯基,以乙烯基為佳。
作為R2
所表示之「亦可具有取代基之碳數2~6的烯基」的「取代基」,可例示前述的取代基,以亦可具有取代基之胺基甲醯基為佳,以啉胺基甲醯基為更佳。
通式(I)中,作為R3
、R4
所表示之「亦可具有取代基之碳數1~6的烷基」之「碳數1~6的烷基」,可例示在R1
所表示之碳數1~6的烷基,以碳數1~3的烷基為佳,以甲基、或乙基為更佳。
作為R3
、R4
所表示之「亦可具有取代基之碳數1~6的烷基」的「取代基」,可例示前述的取代基,以飽和雜環基、或不飽和雜環基為佳,以啉基、或吡啶基為更佳。
作為R3
、R4
,係以一方為氫原子、另一方為亦可具有取代基之碳數1~6的烷基為佳,以一方為氫原子、另一方為具有啉基、或吡啶基之碳數1~3的烷基為特佳。
通式(I)中,作為R3
、R4
亦可以與該等所鍵結的氮原子一起形成的「飽和雜環基」,可例示吡咯啶基、哌啶基、哌基、啉基等,以吡咯啶基、哌啶基、啉基為佳。
通式(I)中,作為R5
所表示之「亦可具有取代基之碳數1~6的烷基」,以甲基、乙基、第三丁基、苄基為佳,作為R5
係以氫原子為佳。
本發明的哌化合物係能夠依照下述反應步驟式1~7來製造。
說明通式(I)所表示的化合物之代表性製造方法。
在上述反應步驟式1,X、R1
及R2
係與前述相同,R係表示胺基的保護基或氫原子。
藉由將式(1a)所表示的哌化合物或其鹽、及式(1b)所表示的吡咯羧酸化合物或其活性種依照常用方法使其縮合,能夠得到通式(2)所表示之醯胺化合物。
作為(1b)的活性種,可舉出甲酯等通常的酯、醯氯等的醯鹵、N-羥基苯并三唑等之活性酯、對稱型酸酐、烷基碳酸等之混合酸酐。
又,使用游離酸使化合物(1b)反應時,或是使活性酯或醯鹵不離析而反應時,以使用1-乙基-3-(3-二甲胺基丙基)碳化二亞胺鹽酸鹽、氯化4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉氮鎓等的縮合劑為佳。
相對於1莫耳之式(1a)所表示的哌化合物或其鹽,以使用0.5~10莫耳、較佳是0.8~2莫耳之式(1b)所表示的羧酸化合物或其活性種為佳,使用縮合劑時,其使用量係相對於1莫耳之式(1a)所表示的哌化合物或其鹽,為0.5~20莫耳,以0.8~3莫耳為佳。
反應溶劑係依照所使用的活性種或縮合劑而異,通常能夠在二氯甲烷、氯仿等的鹵化烴類、甲苯等的芳香族烴類、四氫呋喃等的醚類、乙酸乙酯等的酯類、甲醇、乙醇等的醇類、水、乙腈、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二甲基亞碸、吡啶等對反應為惰性之溶劑中,於-20℃至150℃、較佳是0℃至100℃進行。反應時間係1~24小時左右。
在反應時,藉由在相對於1莫耳之式(1a)所表示的哌化合物或其鹽,0.5~20莫耳、較佳是0.8~5莫耳的三乙胺、二異丙基乙胺、N-甲基啉、N,N-二甲基苯胺、4-(N,N-二甲胺基)吡啶、吡啶等的鹼存在下進行反應,有反應順利地進行之情形。
在第二步驟,係能夠藉由將式(2)所表示的醯胺化合物的胺基之保護基R使用通常眾所周知的方法進行脫保護,並且與式(1c)所表示的胺化合物或其活性種使用通常的方法使其縮合,來得到通式(1)所表示的化合物。
例如,在保護基R為甲醯基、第三丁氧基羰基等的情況,能夠在酸性條件下進行脫保護,R為苄基、苄氧基羰基等的情況,能夠使用接觸還原法等進行脫保護。
在縮合時,以使用具有脫離基的活性種為佳,該活性種係在三乙胺、吡啶等有機鹼的存在下或非存在下,於二氯甲烷、氯仿、四氫呋喃、乙腈、乙酸乙酯、N,N-二甲基乙醯胺等對反應為惰性之溶劑中,於-50℃至150℃、較佳是20℃~100℃,使三光氣、1,1’-羰基二咪唑(CDI)、氯甲酸苯酯、氯甲酸-4-硝基苯酯、氯甲酸乙酯等對式(1c)所表示的胺化合物或其鹽進行作用來調製。反應時間係1~24小時左右。
作為式(1c)活性種,可舉出例如具有脫離基者,有離析而使用於反應的情況,亦有在反應系統中調製並且不離析而使用於反應的情況,作為脫離基,可舉出氯原子、咪唑基、苯氧基、硝基苯氧基、或乙氧基。
作為式(2)所表示的胺化合物之鹽,可舉出例如與鹽酸、溴化氫酸、硫酸等的無機酸和碳酸、甲磺酸有機酸之酸加成鹽。
又,相對於1莫耳之式(1c)所表示的胺化合物或其活性種,係使用0.5~10莫耳、較佳是0.8~2莫耳之式(2)所表示的胺化合物或其鹽,使用上述縮合劑時,其使用量係相對於1莫耳式(1c)所表示的胺化合物或其鹽,為0.5~20莫耳,以0.8~3莫耳為佳。
反應溶劑係因所使用的活性種和縮合劑而異,通常能夠在二氯甲烷、氯仿等的鹵化烴類、甲苯等芳香族烴類、四氫呋喃等的醚類、乙酸乙酯等的酯類、甲醇、乙醇等的醇類、水、乙腈、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二甲基亞碸、吡啶等對反應為惰性的溶劑中,於-50℃至150℃、較佳是-20℃至100℃進行。
在反應時,藉由相對於1莫耳之式(1c)所表示的胺化合物或其活性種,在0.5~20莫耳、較佳是0.8~5莫耳的三乙胺、二異丙基乙胺、N-甲基啉、N,N-二甲基苯胺、4-(N,N-二甲胺基)吡啶、吡啶等的鹼存在下進行反應,有反應順利地進行之情形。
而且,本發明化合物亦能夠將上述第一步驟與第二步驟更換而製造,且R2
係按照必要能夠依照通常眾所周知的方法而變換。又,式(1a)所表示的哌化合物或其鹽、及式(1b)所表示的吡咯羧酸化合物或其活性種、和式(1c)所表示的胺化合物或其鹽係能夠容易地取得、或是能夠依照眾所周知的方法製造。
隨後,將上述反應步驟式的化合物(1c)之製造方法顯示在反應步驟式2、3、4及5。
在上述反應步驟式2,X、R係與前述相同,R6
係與前述R5
同義或是可舉出第三丁基甲基矽烷基等的矽烷基保護基,R7
、R8
係與R2
所表示之「亦可具有取代基之碳數1~6的烷基」之「取代基」同義,特別是表示飽和雜環基、或不飽和雜環基,Y1
、Y2
、Y3
係表示脫離性官能基。
第一步驟的化合物(2b)之Y1係只要是脫離性官能基,任一者均可,可舉出例如氟原子、氯原子等的鹵素原子、甲磺醯氧基、對甲苯磺醯氧基等。
能夠藉由在適當的溶劑中,相對於1莫耳式(2b)所表示的化合物,使用0.5~10莫耳、較佳是0.8~2莫耳之式(2a)所表示的哌啶化合物或其鹽,相對於1莫耳之式(2b)所表示的化合物,在0.5~10莫耳、較佳是0.8~3莫耳的鹼存在下,於-20℃至180℃、較佳是0℃至150℃使其反應1~24小時左右,來得到式(2c)所表示之具有酯基的化合物。
作為反應溶劑,只要不影響反應係沒有特別限制,可舉出例如二氯甲烷、氯仿等的鹵化烴類、甲苯等的芳香族烴類、四氫呋喃等的醚類、乙酸乙酯等的酯類、甲醇、乙醇等的醇類、水、乙腈、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、二甲基亞碸、吡啶等,能夠單獨或混合而使用該等。
作為鹼,能夠使用無機鹼、例如氫氧化鋰、氫氧化鈉、氫氧化鉀、氫氧化鈣、碳酸鋰、碳酸鈉、碳酸鉀、氫化鈉、氫化鉀等、以及有機鹼、例如吡啶、4-(N,N-二甲胺基)吡啶、三乙胺、二異丙基乙胺、1,5-二氧雜雙環[4.3.0]酮-5-烯、1,8-二氧雜雙環[5.4.0]十一-7-烯、第三丁氧基鉀等。
R係氫原子時,能夠藉由在適當的溶劑中,相對於1莫耳式(2c)所表示的化合物,使用0.5~10莫耳、較佳是0.8~2莫耳之胺基保護試藥,相對於1莫耳之式(2c)所表示的化合物,在0.5~10莫耳、較佳是0.8~3莫耳的鹼存在下,於-20℃至180℃、較佳是0℃至150℃使其反應1~24小時左右,來得到式(2c)所表示之在胺基具有保護基的化合物。
作為反應溶劑,只要不影響反應係沒有特別限制,可舉出例如二氯甲烷、氯仿等的鹵化烴類、甲苯等的芳香族烴類、四氫呋喃等的醚類、乙酸乙酯等的酯類、甲醇、乙醇等的醇類、水、乙腈、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、二甲基亞碸、吡啶等,能夠單獨或混合而使用該等。
作為胺基保護試藥,能夠使用例如氯碳酸乙酯、9-茀基甲基碳醯氯、二碳酸二-第三丁酯、苄氧基碳醯氯、苄基氯等。
作為鹼,能夠使用無機鹼、例如氫氧化鋰、氫氧化鈉、氫氧化鉀、氫氧化鈣、碳酸鋰、碳酸鈉、碳酸鉀、氫化鈉、氫化鉀等、以及有機鹼、例如吡啶-4-(N,N-二甲胺基)吡啶、三乙胺、二異丙基乙胺、1,5-二氧雜雙環[4.3.0]酮-5-烯、1,8-二氧雜雙環[5.4.0]十一-7-烯、第三丁氧基鉀等。
在本步驟,係能夠藉由將式(2c)所表示之具有酯基的化合物,在適當的溶劑中,在相對於1莫耳式(2c)所表示的化合物,0.2~10莫耳、較佳是0.5~5莫耳的還原劑存在下,於-80℃至100℃、較佳是-50℃至30℃使其反應1~24小時左右,來得到式(2d)所表示之具有羥基的化合物。
作為反應溶劑,只要不影響反應係沒有特別限制,可舉出例如正己烷等的脂肪族烴類、甲苯等的芳香族烴類、四氫呋喃等的醚類、甲醇、乙醇等的醇類、水等,能夠單獨或混合而使用該等。
作為還原劑,可舉出氫化鋁鋰、氫化硼鈉、硼烷(borane)試藥(例如二硼烷)及氫化二異丁基鋁等。
能夠藉由在適當的溶劑中,相對於1莫耳式(2d)所表示的化合物,使用0.5~10莫耳、較佳是0.8~2莫耳之式(2e)所表示之具有脫離性官能基的化合物,相對於1莫耳之式(2d)所表示的化合物,在0.5~10莫耳、較佳是0.8~3莫耳的鹼存在下,於-20℃至180℃、較佳是0℃至150℃使其反應1~24小時左右,來得到式(2f)所表示之化合物。
作為適當的溶劑,只要不影響反應係沒有特別限制,可舉出例如二氯甲烷、氯仿等的鹵化烴類、甲苯等的芳香族烴類、四氫呋喃等的醚類、乙酸乙酯等的酯類、甲醇、乙醇等的醇類、水、乙腈、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、二甲基亞碸、吡啶等,能夠單獨或混合而使用該等。
作為式(2e)所表示之具有脫離性官能基的化合物,可舉出例如氯化甲磺醯基、氯化三氟甲磺醯基、氯化對甲苯磺醯基、氯化苯磺醯基。
作為鹼,能夠使用無機鹼、例如氫氧化鈉、氫氧化鈣、碳酸鈉、碳酸鉀、氫化鈉、氫化鉀等、以及有機鹼、例如吡啶、4-(N,N-二甲胺基)吡啶、三乙胺、二異丙基乙胺、1,5-二氧雜雙環[4.3.0]酮-5-烯、1,8-二氧雜雙環[5.4.0]十一-7-烯、第三丁氧基鉀等。
隨後,能夠藉由在適當的溶劑中,相對於1莫耳式(2f)所表示的化合物,使用0.5~10莫耳、較佳是0.8~3莫耳之式(2g)所表示之胺化合物或其鹽,和相對於1莫耳之式(2f)所表示的化合物,在0.5~10莫耳、較佳是0.8~3莫耳的鹼存在下,於-20℃至180℃、較佳是0℃至150℃使其反應1~24小時左右,來得到式(2h)所表示之化合物。
作為適當的溶劑,只要不影響反應係沒有特別限制,可舉出例如二氯甲烷、氯仿等的鹵化烴類、甲苯等的芳香族烴類、四氫呋喃等的醚類、乙酸乙酯等的酯類、乙腈、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、二甲基亞碸、吡啶等,能夠單獨或混合而使用該等。
作為鹼,能夠使用無機鹼、例如氫氧化鈉、氫氧化鈣、碳酸鈉、碳酸鉀、氫化鈉等、以及有機鹼、例如吡啶、4-(N,N-二甲胺基)吡啶、三乙胺、二異丙基乙胺、1,8-二氧雜雙環[5.4.0]十一-7-烯、第三丁氧基鉀等。作為鹼,亦能夠將式(2g)所表示的胺化合物使用過剩量。
在第五步驟,係將式(2h)所表示的化合物之胺基的保護基R,使用通常眾所周知的方法進行脫保護,來得到式(2i)所表示的化合物。
例如保護基R係甲醯基、第三丁氧基羰基等時,能夠在酸的條件下進行脫保護,R係苄基、苄氧基羰基等時,能夠使用接觸還原法等進行脫保護。
又,在反應步驟式2所使用的化合物(2a)、(2b)、(2e)及(2g)係能夠容易地取得、或是能夠依照眾所周知的方法製造。
在上述反應步驟式3,W係羥基的保護基,R、R6
、R7
、R8
、X及Y1
、Y2
、Y3
係與前述同義。
本步驟係與反應步驟式2<第一步驟>同樣地進行,能夠得到(3c)所表示之具有酯基的化合物。
本步驟係與反應步驟式2<第二步驟>同樣地進行,能夠得到式(3d)所表示之具有羥基的化合物。
在本步驟係將式(3d)所表示之具有羥基的化合物,使用通常眾所周知的方法進行氧化,來得到具有醛基的化合物(3e)。
能夠藉由在適當的溶劑中,相對於1莫耳式(3d)所表示的化合物,0.8~100莫耳、較佳是1~30莫耳的氧化劑存在下,於-80℃至180℃、較佳是-50℃至150℃使其反應1~3天左右,來得到式(3e)所表示之具有醛基的化合物。
作為適當的溶劑,只要不影響反應係沒有特別限制,可舉出例如二氯甲烷、氯仿、二氯乙烷等的鹵化烴類、甲苯等的芳香族烴類、四氫呋喃等的醚類、二甲基亞碸等,能夠單獨或混合而使用該等。
作為氧化劑,可舉出氯鉻酸吡啶鎓(PCC)、重鉻酸吡啶鎓(PDC)、二氧化錳、三氧化硫吡啶複合物、Swern氧化試藥、Dess-Martin試藥等。
隨後,能夠藉由在適當的溶劑中,相對於1莫耳式(3e)所表示的醛化合物,使用0.8~10莫耳、較佳是1~8莫耳之式(3f)所表示的Wittig試藥,相對於1莫耳之式(3e)所表示的化合物,在0.5~10莫耳、較佳是0.8~5莫耳的鹼存在下,於-20℃至150℃、較佳是0℃至80℃使其反應1~24小時左右,來得到式(3g)所表示之化合物。
作為適當的溶劑,只要不影響反應係沒有特別限制,可舉出例如正己烷等的脂肪族烴、甲苯等的芳香族烴類、四氫呋喃等的醚類,能夠單獨或混合而使用該等。
作為式(3f)所表示之Wittig試藥之羥基的保護基W,可舉出甲基、甲氧基甲基、四氫吡喃基、第三丁基二甲基矽烷基等。
作為鹼,能夠使用例如正丁基鋰、二異丙基醯胺鋰、六甲基二矽基氮烷鉀、甲醇鈉、乙醇鈉、第三丁氧基鉀、氫化鈉等。
隨後,在適當的溶劑中將式(3g)所表示之化合物之羥基的保護基藉由酸性條件進行脫保護後,能夠藉由將具有醛基的化合物,在適當的溶劑中,相對於1莫耳式(3g)所表示的化合物,使用0.2~10莫耳、較佳是0.5~5莫耳的還原劑存在下,於-80℃至100℃、較佳是-50℃至30℃使其反應1~24小時左右,來得到式(3h)所表示之具有羥基的化合物。
作為適當的溶劑,只要不影響反應係沒有特別限制,可舉出例如正己烷等的脂肪族烴、甲苯等的芳香族烴類、四氫呋喃等的醚類,甲醇、乙醇等的醇類、水等,能夠單獨或混合而使用該等。
作為還原劑,可舉出氫化鋁鋰、氫化硼鈉、氰基氫化硼鈉等。
本步驟係與反應步驟式2<第三步驟>同樣地進行,能夠得到式(3j)所表示之具有脫離基之化合物。
本步驟係與反應步驟式2<第四步驟>同樣地進行,能夠得到式(31)所表示之具有胺基之化合物。
本步驟係與反應步驟式2<第五步驟>同樣地進行,能夠得到式(3m)所表示之具有胺基之化合物。
又,在反應步驟式3所使用的化合物(3a)、(3b)、(3f)、(3i)及(3k)係能夠容易地取得、或是能夠依照眾所周知的方法製造。
在上述反應步驟式4,R9
係酯基的保護基,R、R6
、R7
、R8
、X及Y1
、Y2
、Y3
係與前述同義。Z係CH2
P+
R10 3
Y4-
、CH=PR11 3
或CH2
P(O)(OR12
)2
。R10
、R11
、R12
係甲基、乙基、丁基等的低級烷基或苯基等的芳香族烴基,Y4
係氯原子、溴原子等的鹵素原子。
本步驟係與反應步驟式2<第一步驟>同樣地進行,能夠得到(4c)所表示之具有酯基的化合物。
本步驟係與反應步驟式2<第二步驟>同樣地進行,能夠得到式(4d)所表示之具有羥基的化合物。
本步驟係與反應步驟式3<第二步驟>同樣地進行,能夠得到式(4e)所表示之具有醛基的化合物。
隨後,能夠藉由在適當的溶劑中,相對於1莫耳式(4e)所表示的醛化合物,使用0.8~10莫耳、較佳是1~8莫耳之式(4f)所表示的Wittig試藥或horner-Emmons試藥,相對於1莫耳之式(4e)所表示的化合物,在0.5~10莫耳、較佳是0.8~5莫耳的鹼存在下或非存在下,於-20℃至150℃、較佳是0℃至120℃使其反應1~24小時左右,來得到具有α、β-不飽和酯基之化合物。
作為適當的溶劑,只要不影響反應係沒有特別限制,可舉出例如正己烷等的脂肪族烴、甲苯等的芳香族烴類、四氫呋喃等的醚類,能夠單獨或混合而使用該等。
作為式(4f)所表示之Wittig試藥或horner-Emmons試藥之羥基的保護基(R9
),可舉出甲基、乙基、第三丁基、第三丁基二甲基矽烷基、苄基等。
作為鹼,能夠使用無機鹼、例如氫氧化鈉、氫氧化鈣、碳酸鈉、碳酸鉀、氫化鈉、氫化鉀等、以及有機鹼、例如正丁基鋰、二異丙基醯胺鋰、六甲基二矽基氮烷鉀、甲醇鈉、乙醇鈉、第三丁氧基鉀、二異丙基乙胺、1,8-二氧雜雙環[5.4.0]十一-7-烯等。
隨後,藉由在四氫呋喃等的醚類、乙酸乙酯等的酯類、甲醇、乙醇等的醇類、甲酸、乙酸等的有機酸或該等的混合溶劑中,相對於1莫耳式(4e)所表示的化合物,使用0.001~1莫耳、較佳是0.01~0.3莫耳碳負載鈀、氧化鉑、雷氏鎳(Raney nickel)等還原劑存在下,於0℃~120℃、較佳是20℃~100℃在將氫氣設為常壓或加壓下使其作用、或是相對於1莫耳之式(4e)所表示的化合物,使用0.5~20莫耳、較佳是1~10莫耳的甲酸或甲酸銨、環己烯等作為氫起源來代替氫氣並使其反應1~3天左右,能夠得到式(4g)所表示之具有酯基的化合物。
本步驟係與反應步驟式1<第三步驟>同樣地進行,能夠得到式(4h)所表示之具有羥基之化合物。
本步驟係與反應步驟式2<第三步驟>同樣地進行,能夠得到式(4j)所表示之具有脫離基之化合物。
本步驟係與反應步驟式2<第四步驟>同樣地進行,能夠得到式(41)所表示之具有胺基之化合物。
本步驟係與反應步驟式2<第五步驟>同樣地進行,能夠得到式(4m)所表示之具有胺基之化合物。
而且,在反應步驟式4所使用的化合物(4a)、(4b)、(4f)、(4i)及(4k)係能夠容易地取得、或是能夠依照眾所周知的方法製造。
在上述反應步驟式5,V1係-CH=CH-或-CH2
CH2
-,R、R、R6
、R7
、R8
、R9
、X、Y1
及Z係與前述同義。
本步驟係與反應步驟式2<第一步驟>同樣地進行,能夠得到(5c)所表示之具有酯基的化合物。
本步驟係與反應步驟式2<第二步驟>同樣地進行,能夠得到式(5d)所表示之具有羥基的化合物。
本步驟係與反應步驟式3<第三步驟>同樣地進行,能夠得到式(5e)所表示之具有醛基的化合物。
隨後,能夠藉由在適當的溶劑中,相對於1莫耳式(5e)所表示的醛化合物,使用0.8~10莫耳、較佳是1~8莫耳之式(5f)所表示的Wittig試藥或horner-Emmons試藥,相對於1莫耳之式(5e)所表示的化合物,在0.5~10莫耳、較佳是0.8~5莫耳的鹼存在下或非存在下,於-20℃至150℃、較佳是0℃至120℃使其反應1~24小時左右,來得到具有α、β-不飽和酯基之化合物。
作為適當的溶劑,只要不影響反應係沒有特別限制,可舉出例如正己烷等的脂肪族烴、甲苯等的芳香族烴類、四氫呋喃等的醚類,能夠單獨或混合而使用該等。
作為式(5f)所表示之Wittig試藥或horner-Emmons試藥之羥基的保護基(R9
),可舉出甲基、乙基、第三丁基、第三丁基二甲基矽烷基、苄基等。
作為鹼,能夠使用無機鹼、例如氫氧化鈉、氫氧化鈣、碳酸鈉、碳酸鉀、氫化鈉、氫化鉀等、以及有機鹼、例如正丁基鋰、二異丙基醯胺鋰、六甲基二矽基氮烷鉀、甲醇鈉、乙醇鈉、第三丁氧基鉀、二異丙基乙胺、1,8-二氧雜雙環[5.4.0]十一-7-烯等。
本步驟係將具有式(5g)所表示之具有酯基的化合物之酯基,藉由使用通常眾所周知的方法進行脫保護,能夠得到式(5h)所表示的羧酸化合物。
本步驟係與反應步驟式1<第一步驟>同樣地進行,藉由與式(5i)所表示之胺化合物或其鹽進行縮合反應,能夠得到式(5j)所表示之醯胺化合物。
在本步驟,式(5k)所表示的化合物的V1為-CH=CH-時,與反應步驟式2<第五步驟>同樣地進行,能夠得到具有式(5k)所表示之具有胺基的化合物。
在本步驟,式(5k)所表示的化合物的V1為-CH2
-CH2
-時,藉由在四氫呋喃等的醚類、乙酸乙酯等的酯類、甲醇、乙醇等的醇類、甲酸、乙酸等的有機酸或該等的混合溶劑中,相對於1莫耳式(5j)所表示的化合物,使用0.001~1莫耳、較佳是0.01~0.3莫耳碳負載鈀、氧化鉑、雷氏鎳(Raney nickel)等還原劑存在下,於0℃~120℃、較佳是20℃~100℃在將氫氣設為常壓或加壓下使其作用、或是相對於1莫耳之式(5j)所表示的化合物,使用0.5~20莫耳、較佳是1~10莫耳的甲酸或甲酸銨、環己烯等作為氫起源來代替氫氣並使其反應1~3天左右之後,與反應步驟式2<第五步驟>同樣地進行,能夠得到式(5k)所表示之具有胺基的化合物。
而且,在反應步驟式5所使用的化合物(5a)、(5b)、(5f)及(5i)係能夠容易地取得、或是能夠依照眾所周知的方法製造。
又,在反應步驟式3~5所使用的化合物(3e)、(4e)及(5e),亦能夠以如下述反應步驟式6所表示的方式製造。
在上述反應步驟式6,R係胺基的保護基,X及Y1係與前述同義。
本步驟係與反應步驟式2<第一步驟>同樣地進行,藉由使用式(6b)所表示之具有醛基的化合物代替式(2b)所表示之具有酯基的化合物,能夠得到式(6c)所表示之具有醛基的化合物。
又,本發明的化合物之中,具有某種官能基者,係能夠如下述反應步驟式7所表示,藉由化學修改其官能基,來變換為其他本發明的化合物。
在上反應步驟式7,V2
係碳數0~3的伸烷基或-CH=CH-,R1
、R6
、R7
、R8
及X係與前述同義。碳數為0之伸烷基係意味著單鍵。
在本步驟,係將式(7a)所表示之具有酯基的化合物之酯基,藉由使用通常眾所周知的方法進行脫保護而得到羧酸化合物或其活性種,將該羧酸化合物或其活性種與反應步驟式1<第一步驟>同樣地進行,藉由與式(7b)所表示的胺化合物或其鹽進行縮合反應,能夠得到式(7c)所表的醯胺化合物。
又,在作為本發明的醫藥的有效成分之有用的化合物(I),不對稱碳原子(asymmetric carbon)係存在1個或複數個時,有來自不對稱碳原子光學異構物(鏡像異構物(enantiomer)、非鏡像異構物(diastereomer))、及其他異構物之情形,本發明係包含將該等異構物分割而成者或是該等的混合物之全部。
又,在作為本發明的醫藥的有效成分之有用的化合物(I),亦包含在藥理學上被容許的先驅藥(prodrug),所謂在藥理學上被容許的先驅藥,係指一種化合物,其所具有的官能基在加溶劑分解等的化學條件下或生理學條件下,能夠變換成為本發明的醫藥之有效成分亦即化合物(I)的胺基、羥基、羧基、羰基等的官能基。作為形成先驅藥之代表性的官能基,可舉出在「醫藥品的開發」(廣川書店、1990年)第7卷163-198所記載之基等。
而且,作為本發明的醫藥的有效成分之有用的化合物(I),亦有形成酸附加鹽或與鹼形成鹽之情形,只要如此的鹽係在製藥學上被容許的鹽,亦被本發明所包含。具體上,可舉出例如與鹽酸、溴化氫酸、碘化氫酸、硫酸、硝酸、磷酸等的無機酸、和甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、反丁烯二酸、順丁烯二酸、乳酸、蘋果酸、檸檬酸、酒石酸、碳酸、苦味酸、甲磺酸、對甲苯磺酸、麩胺酸等的有機酸之酸加成鹽、與鈉、鉀、鎂、鈣、鋁等的無機鹼、和甲胺、乙胺、美洛明(meglumine)、乙醇胺等的有機鹼或離胺酸、精胺酸(arginine)、鳥胺酸(ornithine)等的鹼性胺基酸之鹽和銨鹽。
而且,本發明係亦包含作為本發明的醫藥的有效成分之有用的化合物(I)和其製藥學上被容許之鹽的各種水合物和溶劑合物及結晶多晶型的物質。
使在醫藥組成物含有本發明的哌化合物或其鹽時,能夠按照必要與藥學上的載體調配,並按照必要預防或治療的目的而採用各種投給的形態,作為該形態可舉出例如口服劑、注射劑、栓劑、軟膏劑、貼劑等,以口服劑為佳。該等的投給形態,係能夠使用各自該業者眾所周知的常用的製藥方法來製造。
藥學上的載體係能夠使用常用的各種有機或無機載體物質作為製劑原料,能夠在固體製劑調配賦形劑、結合劑、崩塌劑、潤滑劑、著色劑;在液狀製劑調配溶劑、溶解輔助劑、懸浮劑、等滲透壓劑、緩衝劑、無痛化劑等。又,亦可按照必要使用防腐劑、抗氧化劑、著色劑、甜味劑、安定化劑等的製劑添加物。
調製口服用固體製劑時,能夠在本發明化合物添加賦形劑且按照必要之結合劑、崩塌劑、潤滑劑、著色劑、矯味-矯臭劑等之後,使用常用方法來製造錠劑、被覆錠劑、顆粒劑、散劑、膠囊劑等。
作為賦形劑,可舉出乳糖、白糖、D-甘露糖醇、葡萄糖、澱粉、碳酸鈣、高嶺土、微結晶纖維素、矽酸酐等。
作為結合劑,可舉出水、乙醇、1-丙醇、2-丙醇、單糖漿劑、葡萄糖液、α-澱粉液、明膠液、D-甘露糖醇、羧甲基纖維素、羥丙基纖維素、羥丙基澱粉、甲基纖維素、乙基纖維素、蟲膠(shellac)、磷酸鈣、聚乙烯基吡咯啶酮等。
作為崩塌劑,可舉出乾燥澱粉、海藻酸鈉、瓊脂粉末、碳酸氫鈉、碳酸鈣、月桂基硫酸鈉、硬脂酸一甘油、乳糖等。
作為潤滑劑,可舉出精製滑石粉、硬脂酸鈉、硬脂酸鎂、硼砂、聚乙二醇等。
作為著色劑,可舉出氧化鈦、氧化鐵等。
作為矯味-矯臭劑,可舉出白糖、橙皮、檸檬酸、酒石酸等。
調製口服用液體製劑時,係藉由在本發明化合物添加矯味劑、緩衝劑、安定化劑、矯臭劑等,來製造內服液劑、糖漿劑、酏劑(elixir)等。此時,作為矯味-矯臭劑,可以是前述所舉出者,作為緩衝劑,可舉出檸檬酸鈉等,作為安定劑,可舉出黃耆膠(tragacanth)、阿拉伯樹膠、明膠等。按照必要亦能夠將腸溶性被覆或保持效果設作目的,使用眾所周知的方法在口服製劑施加被覆。作為此種被覆劑,可舉出羥丙基甲基纖維素、乙基纖維素、羥甲基纖維素、羥丙基纖維素、聚氧乙二醇、Tween80(註冊商標)等。
調製注射劑時,係在本發明化合物添加pH調節劑、緩衝劑、安定化劑、等滲透壓劑、局部麻醉劑等,並依照通常的方法來製造皮下、肌肉內及靜脈內用注射劑。此時,作為pH調節劑及緩衝劑,可舉出檸檬酸鈉、乙酸鈉、磷酸鈉等。作為安定化劑,可舉出焦亞硫酸鈉、EDTA、巰乙酸、硫乳酸等。作為局部麻醉劑,可舉出鹽酸普卡因(Procaine hydrochloride)、鹽酸利多卡因(Lidocaine hydrochloride)等。作為等滲透壓劑,可舉出氯化鈉、葡萄糖、D-甘露糖醇、甘油等。
調製栓劑時,能夠在本發明化合物添加在該業界眾所周知的製劑用載體、例如聚乙二醇、羊脂膏(lanolin)、可可脂(cacao butter)、脂肪酸三甘油酯等,進而按照必要添加如Tween80(註冊商標)之界面活性劑等之後,依照常用方法來製造。
調製軟膏劑時,係在本發明化合物按照必要調配通常使用的基劑、安定劑、濕潤劑、保存劑等,且使用常用方法混合、製劑化。作為基劑,可舉出流動石蠟、白色凡士林、白蠟(bleached bees wax)、辛基十二烷基醇、石蠟等。作為保存劑,可舉出對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯等。
調劑貼劑時,係在通常的支撐體使用常用方法塗布前述軟膏、乳油、凝膠、糊等即可。作為支撐體,係以由棉、短纖維(staple fiber)、化學纖維所構成的織布、不織布和軟質氯乙烯、聚乙烯、聚胺甲酸酯等的薄膜或發泡體薄片為適當。
在前述的各投給單位形態中所適合配調之本發明化合物的量,係依照可能應用它之病人的症狀,或是依照該劑的劑形等而不一定,通常係平均投給單位形態,口服劑時約0.05~1000mg,注射劑時約為0.01~500mg,栓劑時約1~1000mg左右。
又,具有前述投給形態的藥劑之平均1天的投給量,係依照病人的症狀、體重、年齡、性別而異,無法一概地決定,通常成人(體重50kg)係平均1天為約0.05~5000mg左右,以0.1~1000mg為佳,且將其分成1天1次或2~3次左右而投給為佳。
藉由投給含有本發明化合物之藥劑,例如在哺乳動物、特別是人體,因為具有H-PGDS阻礙作用,在治療、預防或改善由源自該酵素的PGD2或其代謝物所引起的疾病係有用的。作為使用含有本發明化合物的藥劑能夠治療、預防或改善的疾病,可舉出支氣管氣喘、花粉症、過敏性鼻炎、副鼻腔炎、中耳炎、過敏性結膜炎、春季黏膜炎、特異體質性(atopie)皮膚炎、接觸性皮膚炎、食物過敏等的過敏性疾病。
在治療、預防或改善慢性閉塞性肺疾病、間質性肺炎、過敏性肺炎、好酸球性肺炎、關節風濕症、變形性關節症、多發性硬化症、肌肉萎縮性側索硬化症、炎症性腸疾病、皮膚的障礙(乾癬、濕疹、紅斑、發癢症、及青春痘等)、肌肉炎、肌肉失養症、PTCA(冠狀動脈氣球擴張術)後再狹窄、慢性閉塞性動脈性疾病、再灌流傷害、移植片拒絕反應等的炎症性疾病、黏液分泌障礙、生殖障礙、血液凝固障礙、睡眠障礙、疼痛、視覺問題、肥胖和免疫疾病、及自免疫疾病上係有用的。
含有本發明化合物的藥劑,係在老人癡呆症或腦損傷的病情惡化之預防作用、及/或腦損傷的病癒後狀況的改善用作用亦能夠期待的,而且因為能夠阻礙細胞惡性形質轉換及腫瘤轉移成長,而能夠使用在癌治療上。
進而在纖維芽細胞增殖、糖尿病性網膜症及因腫瘤血管新生而生長之物等PGD2或其代謝物介在性的增殖障礙之治療及/或預防亦是有用的,而且,因為亦能夠抑制PGD2引起平滑肌收縮,而亦能夠使用於不孕症、月經困難症、早產及好酸球關聯障礙之治療及/或預防。
以下,出示參考例、實施例及試驗例,來更詳細地說明本發明,但是本發明不被該等限制。
又,1
H-NMR光譜係將TMS(四甲基矽烷)設為內部標準來測定,並以δ值(ppm)表示化學位移。化學位移係在括弧內表示吸收圖型(absorption pattern)、偶合常數(J值)、質子數。
而且,關於吸收圖型,係使用以下的記號。s=單峰(singlet)、d=二重峰(doublet)、t=三重峰(triplet)、q=四重峰(quartet)、dd=雙二重峰、m=多重峰、br=寬、brs=寬單蜂。
又,關於化合物的構造式,係使用以下的記號。Me=甲基、Et=乙基。
將19.6g(100mmol)4-氟苯甲酸第三丁酯溶解於50ml的二甲基亞碸(以下、DMSO),添加20.7g(150mmol)碳酸鉀、11.0g(110mmol)4-胺基哌啶,並且在120℃攪拌17小時。將反應液冷卻至室溫後,添加水且藉由過濾取得所析出的固體,而以乳白色固體的形式得到4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯(23.3g、84%)。
1
H-NMR(CDCl3
):δ(ppm) 1.15-1.75(m,4H),1.57(s,9H),1.83-2.04(m,2H),2.81-3.02(m,3H),3.72-3.94(m,2H),6.85(d,J=9.2 Hz,2H),7.85(d,J=9.2 Hz,2H)
將2.42g(12mmol)氯甲酸4-硝基苯酯溶解於50ml四氫呋喃(以下、THF),並在-30℃下,將2.76g(10mmol)在實施例1(1)所得到之4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯的30ml THF溶液滴下。在同溫攪拌30分鐘後,添加2.53g(11mmol) 1-[(1-甲基-1H-吡咯-2-基)羰基]哌鹽酸鹽、5.6ml(40mmol)三乙胺,並在室溫攪拌15小時。在反應液添加飽和碳酸氫鈉水溶液,並使用乙酸乙酯萃取。使用水、飽和食鹽水洗淨有機層後,使用無水硫酸鈉乾燥。過濾除去乾燥劑後,在減壓下蒸餾除去溶劑而得到殘留物,將殘留物藉由中壓矽膠快速管柱層析法(甲醇:氯仿=0:1~1:30)進行純化,而以乳白色固體的形式得到4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸第三丁酯(3.73g、75%)。
1
H-NMR(CDCl3
):6(ppm) 1.40-1.68(m,2H),1.57(s,9H),1.98-2.17(m,2H),2.91-3.08(m,2H),3.35-3.53(m 4H),3.79(s,3H),3.68-4.00(m,7H),4.33(d,J=7.1 Hz,1H),6.06-6.18(m,1H),6.30-6.41(m,1H),6.68-6.78(m,1H),6.85(d,J=9.1 Hz,2H),7.86(d,J=9.1 Hz,2H)
將2.48g(5.0mmol)在實施例1(2)所得到的4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸第三丁酯溶解於10ml甲酸,並在60℃攪拌5小時。在進行減壓濃縮而得到的殘留物添加水,藉由過濾取得所析出的固體,而以乳白色固體的形式得到4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸(2.12g、97%)。
1
H-NMR(DMSO-d6
):δ(ppm) 1.32-1.60(m,2H),1.75-1.95(m,2H),2.82-3.10(m,2H),3.66(s,3H),3.15-4.06(m,11H),6.00-6.12(m,1H),6.30-6.48(m,2H),6.85-6.97(m,1H),6.95(d,J=9.0 Hz,2H),7.76(d,J=9.0 Hz,2H),12.21(br,1H)
將440mg(1.0mmol)實施例1所得到的4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸溶解於3.0ml的N,N-二甲基甲醯胺(以下、DMF),並添加230mg(1.2mmol)1-乙基-3-(3-二甲胺基丙基)碳化二亞胺鹽酸鹽(以下、WSCD)、168mg(1.1mmol)一水合1-羥基苯并三唑(以下、HOBt)、0.12ml(1.2mmol)3-胺甲基,啶,並在60℃加熱攪拌3小時。冷卻至室溫後,添加飽和碳酸氫鈉水溶液並過濾取得所析出的固體,並且藉由在減壓下加熱乾燥,而以乳白色固體的形式得到4-((1-甲基,咯-2-基)-羰基)-N-(1-4-(,啶-3-基-甲基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺(223mg、42%)。
1
H-NMR(CDCl3
):δ(ppm) 1.36-1.60(m,2H),1.98-2.18(m,2H),2.85-3.08(m,2H),3.30-3.48(m 4H),3.78(s,3H),3.65-4.00(m,7H),4.37-4.50(m,1H),4.64(d,J=5.8 Hz,2H),6.06-6.14(m,1H),6.31-6.39(m,1H),6.41-6.56(m,1H),6.67-6.76(m,1H),6.88(d,J=9.1 Hz,2H),7.20-7.35(m,1H),7.59-7.78(m,3H),8.47-8.65(m,2H)
依照實施例2,並且藉由使用胺乙基啉代替3-胺甲基吡啶,而以乳白色固體的形式得到4-((1-甲基,咯-2-基)-羰基)-N-(1-4-(2-啉乙基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺(62%)。
1
H-NMR(CDCl3
):δ(ppm) 1.41-1.63(m,2H),1.99-2.17(m,2H),2.38-2.69(m,6H),2.87-3.09(m,2H),3.33-3.60(m,6H),3.79(s,3H),3.62-4.00(m,11H),4.45(d,J=7.3 Hz,1H),6.05-6.14(m,1H),6.29-6.40(m,1H),6.55-6.78(m,2H),6.90(d,J=8.9 Hz,2H),7.68(d,J=8.9 Hz,2H)
依照實施例2,並且藉由使用啉代替3-胺甲基吡啶,而以乳白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-4-(4-啉基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺(52%)。
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.67(m,2H),2.01-2.24(m,2H),2.87-3.03(m,2H),3.34-3.57(m4H),3.79(s,3H),3.59-4.00(m,15H),4.32-4.45(m,1H),6.05-6.14(m,1H),6.30-6.39(m,1H),6.68-6.77(m,1H),6.89(d,J=8.9 Hz,2H),7.34(d,J=8.9 Hz,2H)
依照實施例2,並且藉由使用哌啶代替3-胺甲基吡啶,而以乳白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-4-(1-哌啶基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺(68%)。
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.74(m,8H),2.00-2.19(m,2H),2.79-3.03(m,2H),3.38-4.05(m,15H),3.79(s,3H),4.33-4.44(m,1H),6.02-6.11(m,1H),6.31-6.38(m,1H),6.72(brs,1H),6.89(d,J=8.9 Hz,2H),7.32(d,J=8.9 Hz,2H)
依照實施例2,並且藉由使用吡咯啶(pyrrolidine)代替3-胺甲基吡啶,而以乳白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-4-(1-吡咯啶基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺(72%)。
1
H-NMR(CDCl3
):δ(ppm) 1.38-1.72(m,2H),1.82-2.21(m,6H),2.82-3.05(m,2H),3.40-4.02(m,15H),3.78(s,3H),4.34-4.48(m,1H),6.05-6.12(m,1H),6.31-6.36(m,1H),6.68-6.64(m,1H),6.88(d,J=8.9 Hz,2H),7.48(d,J=8.9 Hz,2H)
依照實施例1(1),並且藉由使用4-氟苯甲酸乙酯代替4-氟苯甲酸第三丁酯,而以黃色固體的形式得到4-(4-胺基哌啶-1-基)-苯甲酸乙酯(98%)。
1
H-NMR(CDCl3
):δ(ppm) 1.33-1.40(m,2H),1.36(t,J=7.0 Hz,3H),1.93(d,J=5.4 Hz,2H),2.85-2.96(m,4H),3.83(d,J=13.2 Hz,2H),4.32(q,J=7.0 Hz,2H),4.74(br,1H),6.90(d,J=9.2 Hz,2H),7.91(d,J=9.2 Hz,2H)
將15.7g(63.2mmol)實施例7(1)所得到的4-(4-胺基哌啶-1-基)-苯甲酸乙酯溶解於200ml THF,並添加63ml 2M碳酸鈉水溶液,隨後,添加11.7ml(82.2mmol)苄氧基碳醯氯且於室溫攪拌2小時。在反應液添加水並使用乙酸乙酯進行萃取。使用水、飽和食鹽水洗淨有機層後,使用無水硫酸鈉乾燥。過濾除去乾燥劑後,將在減壓下蒸餾除去溶劑而得到的固體過濾,藉由在減壓下乾燥,而以白色固體的形式得到4-(4-苄氧基羰基胺基哌啶-1-基)-苯甲酸乙酯(18.0g、74%)。
1
H-NMR(CDCl3
):δ(ppm) 1.36(t,J=7.0 Hz,3H),1.38-1.62(m,2H),2.04-2.10(m,2H),2.98(t,J=11.1 Hz,2H),3.75-3.85(m,3H),4.32(q,J=7.0 Hz,2H),4.71(br,1H),5.11(s,2H),6.85(d,J=9.2 Hz,2H),7.26-7.36(m,5H),7.91(d,J=9.2 Hz,2H)
將13.6g(35.6mmol)實施例7(2)所得到的4-(4-苄氧基羰基胺基哌啶-1-基)-苯甲酸乙酯溶解於150ml二氯甲烷,並添加91ml(89.0mmol)氫化二異丁基鋁-己烷溶液且於-78℃攪拌1小時。在反應液添加甲醇後,添加飽和食鹽水並攪拌。使用矽藻土將不溶物過濾分開後,將濾液在減壓下蒸餾除去溶劑而得到的殘留物溶解於180ml二氯乙烷,並添加38.0g二氧化錳且於60℃攪拌21小時。使用矽藻土將不溶物過濾分開後,藉由將濾液在減壓下蒸餾除去溶劑,而以白色固體的形式得到4-(4-苄氧基羰基胺基哌啶-1-基)-苯甲醛(7.0g、58%)。
1
H-NMR(CDCl3
):δ(ppm) 1.43-1.56(m,2H),2.08(d,J=9.7 Hz,2H),3.10(t,J=11.1 Hz,2H),3.80-3.90(m,3H),4.70(br,1H),5.11(s,2H),6.91(d,J=8.9 Hz,2H),7.26-7.36(m,5H),7.74(d,J=8.9 Hz,2H),9.77(s,1H)
將16.2g(47.3mmol)氯化甲氧基甲基三苯基鏻溶解於300ml THF,並在O℃下將29.0ml(45.4mmol)正丁基鋰-己烷溶液滴下且攪拌30分鐘。隨後,添加3.2g(9.46mmol)在實施例7(3)所得到的4-(4-苄氧基羰基胺基哌啶-1-基)-苯甲醛,並在室溫攪拌17小時。在反應液添加飽和碳酸氫鈉水溶液,並使用氯仿萃取。將有機層在減壓下蒸餾除去溶劑而得到殘留物,將殘留物藉由中壓矽膠快速管柱層析法(NH矽膠,乙酸乙酯:己烷=1:4)進行純化,而以混合物的形式得到粗烯醇基醚體。在所得到的混合物溶解於30ml乙酸乙酯,添加6.0ml 6N鹽酸水溶液且攪拌1小時。在反應液添加飽和碳酸氫鈉水溶液而中和,並使用氯仿萃取。將有機層在減壓下蒸餾除去溶劑而得到殘留物,將該殘留物溶解於15ml THF、15ml甲醇並添加155mg(4.09mmol)氫化硼鈉,且於0℃攪拌1小時。在反應液添加飽和氯化銨水溶液後,將在減壓下濃縮而得到的殘留物添加水,藉由過濾所析出的固體,而以白色固體的形式得到N-(4-(2-羥乙基)苯基)-4-苄氧基羰基胺基哌啶(960mg、29%)。
1
H-NMR(CDCl3
):δ(ppm) 1.43-1.59(m,2H),2.06(d,J=10.3 Hz,2H),2.76-2.85(m,4H),3.53-3.80(m,5H),4.70-4.80(m,2H),5.11(s,2H),6.88(d,J=8.6 Hz,2H),7.11(d,J=8.6 Hz,2H),7.26-7.36(m,5H)
將1.38g(3.89mmol)實施例7(4)所得到的N-(4-(2-羥乙基)苯基)-4-苄氧基羰基胺基哌啶溶解於7.5ml吡啶,在冰冷下添加960mg(5.04mmol)氯化對甲苯磺醯且攪拌4小時。藉由將在反應液添加水所析出的固體過濾取得,而以黃色固體的形式得到N-(4-(2-甲苯磺醯氧基乙基)苯基)-4-苄氧基羰基胺基哌啶(1.35g、68%)。
1
H-NMR(CDCl3
):δ(ppm) 1.48-1.62(m,2H),2.06(d,J=9.2 Hz,2H),2.43(s,3H),2.78-2.89(m,4H),3.52-3.65(m,3H),4.15(t,J=7.3,2H),4.82(br,1H),5.11(s,2H),6.81(d,J=8.6 Hz,2H),6.99(d,J=8.6 Hz,2H),7.29(d,J=8.4 Hz,2H),7.30-7.38(m,5H),7.71(d,J=8.4 Hz,2H)
在3.0g(5.90mmol)實施例7(5)所得到的N-(4-(2-甲苯磺醯氧基乙基)苯基)-4-苄氧基羰基胺基哌啶添加3.4ml(58.6mmol)1,2,3-三唑,並在90℃攪拌2小時。在反應液添加甲醇且加熱回流1小時後,藉由將放冷至室溫而析出的固體過濾取得,而以白色固體的形式得到N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-苄氧基羰基胺基哌啶(1.3g、54%)。
1
H-NMR(CDCl3
):δ(ppm) 1.50-1.65(m,2H),2.07(d,J=11.3 Hz,2H),2.84(t,J=12.7 Hz,2H),3.12(t,J=7.3 Hz,2H),3.54-3.67(m,3H),4.57(t,J=7.3,2H),4.69(br,1H),5.11(s,2H),6.84(d,J=8.4 Hz,2H),6.96(d,J=8.4 Hz,2H),7.30-7.38(m,6H),7.61(s,1H)
將1.3g(50mmol)實施例7(6)所得到的N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-苄氧基羰基胺基哌啶溶解於13ml甲醇、13ml THF,並添加130mg 10%鈀-碳(以下、Pd-C)且在氫氣環境下、於室溫攪拌24小時。使用矽藻土將不溶物過濾分開後,藉由將濾液在減壓下蒸餾除去溶劑,而以白色固體的形式得到N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-胺基哌啶(870g、99%)。
1
H-NMR(DMSO):δ(ppm) 1.60-1.65(m,2H),1.90-1.95(m,2H),2.66-2.75(m,2H),3.00-3.20(m,5H),3.60-3.70(m,2H),4.50-4.60(m,2H),6.84(d,J=8.4 Hz,2H),7.01(d,J=8.4 Hz,2H),7.65(s,1H),8.02(s,1H)
依照實施例1(2),並且藉由使用N-(1-4-(2-(1,2,3-三唑-1-基)-乙基-苯基)-4-胺基哌啶代替4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯,而以乳白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-4-(2-(1,2,3-三唑-1-基)-乙基-苯基)-哌啶-4-基)-1-哌羧醯胺(46%)。
1
H-NMR(CDCl3
):δ(ppm) 1.48-1.65(m,2H),2.09(d,J=12.0 Hz,2H),2.86(d,J=11.0 Hz,2H),3.12(t,J=7.0 Hz,2H),3.41-3.45(m,4H),3.61(d,J=13.0 Hz,2H),3.76-3.90(m,8H),4.32(d,J=7.3,1H),4.58(t,J=7.3 Hz,2H),6.09(dd,J=3.8,2.7,1H),6.34(dd,J=3.8,1.4 Hz,1H),6.72(dd,J=2.7,1.4 Hz,1H),6.85(d,J=8.9 Hz,2H),6.97(d,J=8.9 Hz,2H),7.27(s,1H),7.62(s,1H)
將37g(0.30mol)4-氟苯甲醛溶解於DMSO(300ml),並添加124g(0.89mol)碳酸鈣、66g(0.33mol)4-第三丁氧基羰基胺基哌啶,且於120℃加熱攪拌12小時。在反應液添加134g(0.60mol)膦酸基乙酸三乙酯而且更加熱攪拌2.5小時。在反應液添加水(900ml)且冷卻至室溫後,藉由過濾取得所析出的固體且使用300ml水及300ml己烷洗淨,而以白色固體的形式得到4-(4-第三丁氧基羰基胺基哌啶-1-基)-桂皮酸乙酯(110g、99%)。
1
H-NMR(CDCl3
):δ(ppm) 1.32(t,J=7.1 Hz,3H),1.43-1.54(m,11H),2.03-2.05(m,2H),2.90-2.96(m,2H),3.71-3.75(m,3H),4.24(q,J=7.1 Hz,2H),4.45(brs,1H),6.26(d,J=16 Hz,1H),6.87(d,J=9.0 Hz,2H),7.41(d,J=9.0 Hz,2H),7.60(d,J=16 Hz,1H)
將126g(0.33mol)在實施例8(1)所到得的4-(4-第三丁氧基羰基胺基哌啶-1-基)-桂皮酸乙酯溶解於1L乙醇,並添加48.5g 10%Pd-C且在氫氣環境下攪拌18小時。使用矽藻土將不溶物過濾分開並藉由將濾液減壓蒸餾,而以白色固體的形式得到4-(4-第三丁氧基羰基胺基哌啶-1-基)-二氫桂皮酸乙酯(107g、85%)。
1
H-NMR(CDCl3
):δ(ppm) 1.23(t,J=7.1 Hz,3H),1.29-1.58(m,11H),2.02-2.05(m,2H),2.55-2.59(m,2H),2.77-2.88(m,4H),3.53-3.57(m,3H),4.12(q,J=7.1 Hz,2H),4.47(brs,1H),6.86(d,J=8.5 Hz,2H),7.08(d,J=8.5 Hz,2H)
將68g(0.18mol)在實施例8(2)所到得的4-(4-第三丁氧基羰基胺基哌啶-1-基)-二氫桂皮酸乙酯溶解於1L甲苯,冷卻至-78℃並滴下607ml(0.6mol)氫化二異丁基鋁-己烷溶液。攪拌1.5小時後,添加10ml甲醇、550ml飽和食鹽化鈉水溶液並攪拌3小時。使用矽藻土將不溶物過濾分開,將濾液蒸餾除去溶劑而得到的殘留物溶解於550ml甲醇及250ml THF,且在0℃下添加6.9g(0.18mol)氫化硼鈉。攪拌1小時後,添加飽和氯化銨水溶液,並使用氯仿萃取且使用硫酸鎂乾燥,將乾燥劑過濾後,藉由蒸餾除去溶劑而得到N-(4-(3-羥丙基)苯基)-4-第三丁氧基羰基胺基哌啶(60g、98%)。
1
H-NMR(CDCl3
):δ(ppm) 1.45(s,9H),1.50-1.61(m,2H),1.82-1.89(m,2H),2.02-2.05(m,2H),2.60-2.64(m,2H),2.77-2.83(m,2H),3.48-3.66(m,5H),4.48(brs,1H),6.87(d,J=8.5 Hz,2H),7.08(d,J=8.5 Hz,2H)
依照實施例7(5),並且藉由使用N-(4-(3-羥丙基)苯基)-4-第三丁氧基羰基胺基吡啶代替N-(4-(2-甲苯磺醯氧基乙基)苯基)-4-苄氧基羰基胺基哌啶,而得到N-(4-(3-對甲苯磺醯基丙基)苯基)-4-第三丁氧基羰基胺基哌啶(59%)。
1
H-NMR(CDCl3
):δ(ppm) 1.46(s,9H),1.49-1.52(m,2H),1.87-1.94(m,2H),2.02-2.05(m,2H),2.45(s,3H),2.56(t,J=7.6 Hz,2H),2.76-2.82(m,2H),3.50-3.55(m,3H),4.02(t,J=6.3 Hz,2H),4.47(brs,1H),6.81(d,J=8.4 Hz,2H),6.95(d,J=8.4 Hz,2H),7.34(d,J=8.2 Hz,2H),7.79(d,J=8.2 Hz,2H)
將330mg(0.68mmol)在實施例8(4)所到得的N-(4-(3-對甲苯磺醯基丙基)苯基)-4-第三丁氧基羰基胺基哌啶溶解於5ml乙腈與5ml DMF的混合溶劑,並添加54mg(0.81mmol)1,2,4-三唑及187mg(1.35mmol)碳酸鉀,且於60℃攪拌1小時。將反應液冷卻至室溫後,添加水且藉由過濾取得所析出的固體,而得到N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-第三丁氧基羰基胺基哌啶(192mg、74%)。
1
H-NMR(CDCl3
):δ(ppm)1.45(s,9 H),1.51-1.61(m,2H),2.01-2.04(m,2H),2.15-2.23(m,2H),2.52-2.57(m,2H),2.77-2.82(m,2H),3.56-3.59(m,3H),4.15(t,J=7.0 Hz,2H),4.94(brs,1H),6.87(d,J=8.5 Hz,2H),7.04(d,J=8.5 Hz,2H),7.93(s,1H),8.04(s,1H)
將180mg(0.47mmol)在實施例8(5)所到得的N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-第三丁氧基羰基胺基哌啶溶解於0℃下5ml三氟乙酸,並在室溫下攪拌1小時。將反應液減壓下蒸餾除去而得到殘留物,將殘留物藉由中壓矽膠快速管柱層析法(NH矽膠、甲醇:氯仿=1:9)進行純化,而得到N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-胺基哌啶(127mg、95%)。
1
H-NMR(DMSO-d6
):δ(ppm) 1.26-1.35(m,2H),1.68-1.76(m,4H),1.99-2.06(m,2H),2.41-2.45(m,2H),2.50-2.70(m,3H),3.53-3.56(m,2H),4.15(t,J=7.0 Hz,2H),6.84(d,J=8.8 Hz,2H),7.01(d,J=8.8 Hz,2H),7.96(s,1H),8.51(s,1H)
依照實施例1(2),並且藉由使用N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-胺基哌啶代替4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯,而以白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-4-(3-(1,2,4-三唑-1-基)-丙基-苯基)-哌啶-4-基)-1-哌羧醯胺(45%)。
1
H-NMR(CDCl3
):δ(ppm) 1.53-1.57(m,2H),2.06-2.10(m,2H),2.18-2.22(m,2H),2.54-2.57(m,2H),2.84-2.87(m,2H),3.43-3.45(m,4H),3.60-3.63(m,2H),3.75-3.90(m,8H),4.12-4.16(m,2H),4.38(brs,1H),6.10(d,J=3.0 Hz,1H),6.35(s,1H),6.72(s,1H),6.88(d,J=8.4 Hz,2H),7.04(d,J=8.4 Hz,2H),7.95(s,1H),7.97(s,1H)
依照實施例8(5)及實施例8(6),並且藉由使用3,5-二甲基-1,2,4-三唑代替1,2,4-三唑,而以白色固體的形式得到N-(4-3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-4-胺基吡啶(52%)。
1
H-NMR(CDCl3
):δ(ppm)1.45-1.57(m,4H),1.91-1.94(m,2H),2.09-2.16(m,2H),2.30(s,3H),2.33(s,3H),2.56(t,J=7.5 Hz,2H),2.71-2.85(m,3H),3.58-3.61(m,2H),3.95(t,J=7.2 Hz,2H),6.87(d,J=8.7 Hz,2H),7.04(d,J=8.7 Hz,2H)
依照實施例1(2),並且藉由使用N-(4-(3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-4-胺基哌啶代替4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯,而以非晶狀固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺(45%)。
1
H-NMR(CDCl3
):δ(ppm) 1.56-1.65(m,2H),2.09-2.17(m,4H),2.30(s,3H),2.32(s,3H),2.56(t,J=7.4 Hz,2H),2.82-2.88(m,2H),3.42-3.45(m,4H),3.58-3.62(m,2H),3.77-3.90(m,8H),3.95(t,J=7.0 Hz,2H),4.35(d,J=7.3 Hz,1H),6.09-6.10(m,1H),6.34(d,J=3.9 Hz,1H),6.72(s,1H),6.87(d,J=8.5 Hz,2H),7.05(d,J=8.5 Hz,2H)
依照實施例8(5),並且藉由使用1,2,3-三唑代替1,2,4-三唑,而以白色固體的形式得到N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-第三丁氧基羰基胺基哌啶(33%)。
1
H-NMR(CDCl3
):δ(ppm) 1.46(s,9H),1.51-1.57(m,2H),2.03-2.06(m,2H),2.18-2.26(m,2H),2.57(t,J=7.4 Hz,2H),2.79-2.84(m,2H),4.36(t,J=7.1 Hz,2H),4.48(brs,1H),6.88(d,J=8.3 Hz,2H),7.06(d,J=8.3 Hz,2H),7.50(s,1H),7.71(s,1H)
依照實施例8(6),並且藉由使用N-(4-3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-第三丁氧基羰基胺基哌啶代替N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-第三丁氧基羰基胺基哌啶,而以油狀物的形式得到N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-胺基哌啶(83%)。
1
H-NMR(CDCl3
):δ(ppm) 1.45-1.61(m,4H),1.90-1.94(m,2H),2.18-2.26(m,2H),2.57(t,J=7.5 Hz,2H),2.72-2.84(m,3H),3.59-3.63(m,2H),4.37(t,J=7.2 Hz,2H),6.88(d,J=8.4 Hz,2H),7.05(d,J=8.4 Hz,2H),7.50(s,1H),7.70(s,1H)
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺(化合物10)。
依照實施例1(2),並且藉由使用N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-胺基哌啶代替4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯,而以白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺(42%)。
1
H-NMR(CDCl3
): δ(ppm) 1.56-1.60(m,2H),2.07-2.10(m,2H),2.20-2.24(m,2H),2.58(t,J=7.1 Hz,2H),2.83-2.89(m,2H),3.42-3.45(m,4H),3.59-3.62(m,2H),3.77-3.80(m,8H),4.34-4.39(m,3H),6.09-6.10(m,1H),6.34-6.35(m,1H),6.72(s,1H),6.88(d,J=8.5 Hz,2H),7.06(d,J=8.5 Hz,2H),7.51(s,1H),7.71(s,1H)
將2.7g(7.2mmol)在實施例8(1)所得到的4-(4-第三丁氧基羰基胺基哌啶-1-基)-桂皮酸乙酯溶解於40ml乙醇,並添加3.6ml 4M氫氧化鈉水溶液且加熱回流12小時。將反應液冷卻至室溫,添加40ml水,並且藉由過濾取得使用10%檸檬酸水溶液中和而析出的固體,而以白色固體的形式得到4-(4-第三丁氧基羰基胺基哌啶-1-基)-桂皮酸(1.9g、77%)。
1
H-NMR(DMSO-d6
):δ(ppm) 1.34-1.43(m,11H),1.75-1.78(m,2H),2.80-2.86(m,2H),3.32-3.48(m,1H),3.76-3.79(m,2H),6.24(d,J=15.8 Hz,1H),6.83(brs,1H),6.90(d,J=8.8 Hz,2H),7.42-7.63(m,3H)
將870mg(2.5mmol)在實施例11(1)所得到的4-(4-第三丁氧基羰基胺基哌啶-1-基)-桂皮酸溶解於15ml N,N-二甲基乙醯胺(以下、DMA),並添加423mg(2.8mmol)HOBt、530mg(2.8mmol) WSCD、241mg(2.8mmol)啉,且於80℃攪拌16小時。冷卻至室溫後,藉由過濾取得添加水而析出的固體,而以白色固體的形式得到(3-(4-(4-第三丁氧基羰基胺基哌啶-1-基)-苯基)-1-側氧基-2-丙烷-1-基)-啉(836mg、80%)。
1
H-NMR(CDCl3
):δ(ppm) 1.45(s,9H),1.49-1.55(m,2H),2.03-2.06(m,2H),2.88-2.95(m,2H),3.72(brs,11H),4.47(brs,1H),6.66(d,J=15.4 Hz,1H),6.87(d,J=8.8 Hz,2H),7.41(d,J=8.8 Hz,2H),7.64(d,J=15.4 Hz,1H)
依照實施例8(6),並且藉由使用(3-(4-(4-第三丁氧基羰基胺基哌啶-1-基)-苯基)-1-側氧基-2-丙烷-1-基)-啉代替N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-第三丁氧基羰基胺基哌啶,而以油狀物的形式得到(3-(4-(4-胺基哌啶-1-基)-苯基)-1-側氧基-2-丙烷-1-基)-啉(68%)。
1
H-NMR(CDCl3
):δ(ppm) 1.43-1.53(m,2H),1.69(brs,2H),1.92-1.95(m,2H),2.83-2.92(m,3H),3.71-3.77(m,10H),6.66(d,J=15.3 Hz,1H),6.87(d,J=8.7 Hz,2H),7.42(d,J=8.7 Hz,2H),7.64(d,J=15.3 Hz,1H)
依照實施例1(2),並且藉由使用(3-4-(4-胺基哌啶-1-基)-苯基)-1-側氧基-2-丙烷-1-基)-啉代替4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯,而以白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-啉-3-側氧基丙烷-1-基)苯基)-哌啶-4-基)-1-哌羧醯胺(64%)。
1
H-NMR(CDCl3
):δ(ppm)1.47-1.57(m,2H),2.07-2.10(m,2H),2.93-2.98(m,2H),3.42-3.44(m,4H),3.72-3.90(m,18H),4.30-4.32(m,1H),6.09-6.10(m,1H),6.33-6.35(m,1H),6.66(d,J=15.2Hz,1H),6.71-6.72(m,1H),6.88(d,J=8.8 Hz,2H),7.42(d,J=8.8 Hz,2H),7.64(d,J=15.2 Hz,1H)
將100mg(0.19mmol)實施例11所得到的4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-啉-3-側氧基丙烷-1-基)苯基)-哌啶-4-基)-1-哌羧醯胺溶解於20ml THF、5ml甲醇,並添加39mg Pd-C且在氫氣環境下攪拌12小時。使用矽藻土將不溶物過濾分開並藉由將濾液減壓蒸餾,而以白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-啉-3-側氧基丙烷)-苯基)-哌啶-4-基)-1-哌羧醯胺(84mg、84%)。
1
H-NMR(CDCl3
):δ(ppm)1.53-1.59(m,2H),2.05-2.07(m,2H),2.55-2.59(m,2H),2.83-2.92(m,4H),3.33-3.51(m,8 H),3.59-3.62(m,6H),3.77-3.86(m,8 H),4.33(d,J=7.3 Hz,1H),6.09(dd,J=2.5,3.7 Hz,1H),6.34(dd,J=1.7,3.7 Hz,1H),6.71-6.72(m,1H),6.87(d,J=8.8 Hz,2H),7.10(d,J=8.8 Hz,2H)
將4.27g(23mmol)6-氯菸鹼酸乙酯溶解於30ml DMF,並添加4.77g(35mmol)碳酸鉀、2.76g(28mmol)4-胺基哌啶,並且在80℃攪拌3小時、在100℃攪拌1小時。將反應液冷卻至室溫後,添加水且使用乙酸乙酯萃取,並使用水、飽和食鹽水洗淨有機層之後,使用無水硫酸鈉乾燥。過濾除去乾燥劑後,藉由減壓下蒸餾除去溶劑,而以薄褐色油狀物的形式得到6-(4-胺基哌啶-1-基)菸鹼酸乙酯(4.17g、73%)。
1
H-NMR(CDCl3
):δ(ppm)1.20-1.65(m,4H),1.36(t,J=7.1 Hz,3H),1.83-2.00(m,2H),2.84-3.15(m,3H),4.33(q,J=7.1 Hz,2H),4.23-4.47(m,2H),6.60(dd,J=9.1,0.6 Hz,1H),7.99(dd,J=9.1,2.4 Hz,1H),8.79(dd,J=2.4,0.6 Hz,1H)
依照實施例1(2),並且藉由使用6-(4-胺基哌啶-1-基)菸鹼酸乙酯代替4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯,而以乳白色固體的形式得到6-(4-4-(1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)-哌啶-1-基)菸鹼酸乙酯(641%)。
1
H-NMR(CDCl3
):δ(ppm) 1.27-1.50(m,2H),1.36(t,J=7.1 Hz,3H),1.97-2.18(m,2H),3.00-3.17(m,2H),3.31-3.48(m,4H),3.65-3.85(m,4H),3.79(s,3H),3.87-4.06(m,1H),4.33(q,J=7.1 Hz,2H),4.28-4.52(m,2H),6.06-6.15(m,1H),6.29-6.40(m,1H),6.61(d,J=9.0 Hz,1H),6.67-6.77(m,1H),8.01(dd,J=9.0,2.1 Hz,1H),8.79(d,J=2.1 Hz,1H)
將234mg(0.5mmol)在實施例13(2)所得到的6-(4-4-(1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)-哌啶-1-基)-菸鹼酸乙酯溶解於1.5ml乙醇、1.5ml THF,並添加1.4ml(2.8mmol)2M氫氧化鈉水溶液,且在室溫攪拌5小時。使用2M鹽酸水中和反應液,並使用甲醇:氯仿(1:9)萃取。使用水、飽和食鹽水洗淨有機層之後,使用無水硫酸鈉乾燥。過濾除去乾燥劑後,藉由減壓下蒸餾除去溶劑,而以乳白色固體的形式得到6-(4-4-(1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)-哌啶-1-基)-菸鹼酸(90%)。
1
H-NMR(CDCl3
):δ(ppm) 1.30-1.52(m,2H),2.01-2.21(m,2H),3.00-3.22(m,2H),3.32-3.53(m,4H),3.65-3.87(m,4H),3.79(s,3H),3.90-4.11(m,1H),4.30-4.55(m,3H),6.06-6.15(m,1H),6.30-6.39(m,1H),6.63(d,J=9.2 Hz,1H),6.68-6.76(m,1H),8.04(dd,J=9.2,2.4 Hz,1H),8.85(d,J=2.4 Hz,1H)
將132mg(0.3mmol)實施例13(3)所得到的6-(4-4-(1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)-哌啶-1-基)-菸鹼酸溶解於2.0ml DMF,並添加69mg(0.36mmol) WSCD、51mg(0.33mmol)HOBt、0.04ml(0.45mmol)啉,且於60℃加熱攪拌16小時。冷卻至室溫後,在反應液添加水,並使用乙酸乙酯萃取。使用水、飽和食鹽水洗淨有機層之後,使用無水硫酸鈉乾燥。將乾燥劑過濾除去後,在減壓下蒸餾除去溶劑而得到殘留物,將殘留物藉由中壓矽膠快速管柱層析法(甲醇:氯仿=1:50~1:15)進行純化,而以乳白色固體的形式得到4-((1-甲基吡咯-2-基)-羰基)-N-(1-(5-(4-啉基羰基)吡啶-2-基)-哌啶-4-基)-1-哌羧醯胺(24%)。
1
H-NMR(CDCl3
):δ(ppm) 1.32-1.54(m,2H),2.00-2.19(m,2H),2.96-3.15(m,2H),3.34-3.50(m,4H),3.55-4.07(m,13H),3.79(s,3H),4.26-4.48(m,3H),6.04-6.15(m,1H),6.30-6.42(m,1H),6.66(d,J=8.9 Hz,1H),6.68-6.79(m,1H),7.60(dd,J=8.9,2.1 Hz,1H),8.26(d,J=2.1 Hz,1H)
7.83g(50.0mmol)氯甲酸苯酯溶解於100ml乙腈,在冰冷下滴下13.82g(50.0mmol)在實施例1(1)所得到的4-(4-胺基哌啶-1-基)-苯甲酸第三丁酯的50ml乙腈、50ml DMA溶液。添加7.0ml(50.0mmol)三乙胺,並在同溫攪拌2小時後,藉由過濾取得添加水而析出的固體,而以乳白色固體的形式得到4-(4-苯氧基羰基胺基哌啶-1-基)-苯甲酸第三丁酯(15.5g、78%)。
將13.88g(35.0mmol)實施例15(1)所得到的4-(4-苯氧基羰基胺基哌啶-1-基)-苯甲酸第三丁酯溶解於150ml乙腈,在冰冷下添加71g(35.0mmol)N-苄氧基羰基哌、6.6ml(42mmol)1,8-二氧雜雙環[5.4.0]十一-7-烯,在室溫下攪拌19小時後,藉由過濾取得添加水而析出的固體,而以乳白色固體的形式得到4-(4-((4-苄氧基羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸第三丁酯(16.1g、88%)。
1
H-NMR(CDCl3
):δ(ppm) 1.44-1.57(m,11H),2.03-2.7(m,2H),2.92-3.02(m,2H),3.34-3.38(m,4H),3.50-3.51(m,4H),.78-3.92(m,3H),4.31(d,J=7.4 Hz,1H),5.15(s,2H),6.84(dd,J=2.0,7.1 Hz,2H),7.31-7.38(m,5H),7.85(dd,J=2.0,7.1 Hz,2H)
將5.23g(10.0mmol)實施例15(2)所得到的4-(4-((4-苄氧基羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸第三丁酯溶解於20ml甲酸,且於60℃加熱攪拌3小時。在減壓下蒸餾除去溶劑而得到殘留物,藉由過濾取得在殘留物添加水而析出的固體,而以乳白色固體的形式得到4-(4-((4-苄氧基羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸(4.75g、quant.)。
1
H-NMR(DMSO-d6
):δ(ppm) 1.39-1.51(m,2H),1.76-1.80(m,2H),2.87-2.96(m,2H),3.29-3.34(m,8H),3.68-3.73(m,1H),3.86-8.91(m,2H),5.09(s,2H),6.35(d,J=7.6 Hz,1H),6.95(d,J=8.9 Hz,2H),7.28-7.37(m,5H),7.75(d,J=8.9 Hz,2H),12.15(brs,1H)
將23.3g(50mmol)實施例15(3)所得到的4-(4-((4-苄氧基羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸溶解於100ml DMF,並添加10.5g(55mmol)WSCD、8.04g(52.5mmol)HOBt、7.9ml(60mmol)2-胺乙基啉,且於60℃加熱攪拌3小時。冷卻至室溫後,添加飽和碳酸氫鈉水溶液並使用乙酸乙酯萃取。使用水、飽和食鹽水洗淨有機層之後,使用無水硫酸鈉乾燥。將乾燥劑過濾除去後,藉由在減壓下蒸餾除去溶劑,而以乳白色固體的形式得到4-苄氧基羰基-N-(1-(4-(2-啉乙基胺基甲醯基)-苯基)-哌啶-4-基)-1-哌羧醯胺(20.7g、72%)。
1
H-NMR(CDCl3
):δ(ppm) 1.46-1.57(m,2H),2.04-2.07(m,2H),2.48-2.51(m,4H),2.58(t,J=6.0 Hz,2H),2.90-3.00(m,2H),3.34-3.38(m,4H),3.50-3.55(m,6H),3.70-3.80(m,7H),4.43(d,J=7.3 Hz,1H),5.14(s,2H),6.63-6.66(m,1H),6.89(d,J=8.9 Hz,2H),7.31-7.38(m,5H),7.67(d,J=8.9 Hz,2H)
將14.5g(25mmol)實施例15(4)所得到的4-苄氧基羰基-N-(1-(4-(2-啉乙基胺基甲醯基)-苯基)-哌啶-4-基)-1-哌羧醯胺溶解於80ml甲醇、80ml THF,並添加3.0g 10% Pd-C且在氫氣環境下、於室溫攪拌17小時。在反應液添加氯仿並使用矽藻土將不溶物過濾分開後,藉由將濾液在減壓下蒸餾除去,而以乳白色固體的形式得到N-(1-(4-2-啉乙基胺基甲醯基)-苯基)-哌啶-4-基)-1-哌羧醯胺(11.2g、quant.)。
1
H-NMR(CDCl3
):δ(ppm) 1.50-1.60(m,2H),2.02-2.05(m,2H) 2.45-2.61(m,7H),2.82-3.00(m,6H),3.31-3.35(m,4H),3.49-3.56(m,2H),3.70-3.90(m,7H),4.88(d,J=7.4 Hz,1H),6.85-6.86(m,1H),6.90(d,J=8.9 Hz,2H),7.69(d,J=8.9 Hz,2H)
將139mg(1.0mmol)1-乙基吡咯-2-羧酸溶解於3.0ml DMF,並添加230mg(1.2mmol)WSCD、168mg(1.2mmol)HOBt、400mg(0.9mmol)實施例15(5)所得到的N-(1-(4-2-啉乙基胺基甲醯基)-苯基)-哌啶-4-基)-1-哌羧醯胺,且於80℃加熱攪拌14小時。將反應液放冷至室溫後,在反應液添加飽和碳酸氫鈉水溶液,並使用氯仿萃取。使用水、飽和食鹽水洗淨有機層之後,使用無水硫酸鈉乾燥。將乾燥劑過濾除去後,在減壓下蒸餾除去溶劑而得到殘留物,將殘留物藉由中壓矽膠快速管柱層析法(甲醇:氯仿=1:30~1:10)進行純化,而以乳白色固體的形式得到4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4-(2-啉乙基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺(213mg、42%)。
1
H-NMR(CDCl3
):δ(ppm) 1.36(t,J=7.3 Hz,3H),1.46-1.57(m,2H),2.04-2.08(m,2H),2.48-2.51(m,4H),2.58(t,J=6.0 Hz,2H),2.93-3.01(m,2H),3.39-3.42(m,2H),3.49-3.55(m,2H),3.70-3.93(m,10H),4.16(q,J=7.3 Hz,2H),4.56(brs,1H),6.10(dd,J=2.6,3.8 Hz,1H),6.30(dd,J=1.7,3.8 Hz,1H),6.79(dd,J=1.7,2.6 Hz,1H),6.90(d,J=8.9 Hz,2H),7.67(d,J=8.9 Hz,2H)
依照實施例7(8),並且藉由使用1-[(1-乙基-1H-吡咯-2-基)羰基]哌鹽酸鹽代替1-[(1-甲基-1H-吡咯-2-基)羰基]哌鹽酸鹽,而以白色固體的形式得到4-((1-乙基吡咯-2-基)-羰基)-N-(1-4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-哌啶-4-基)-1-哌羧醯胺(75%)
1
H-NMR(CDCl3
):δ(ppm) 1.38(t,J=7.3 Hz,3H),1.51-1.57(m,2H),2.06-2.09(m,2H),2.80-2.90(m,2H),3.12(t,J=7.1 Hz,2H),3.40-3.44(m,4H),3.58-3.63(m,2H),3.76-3.90(m,5H),4.18(q,J=7.3 Hz,2H),4.38(d,J=7.3 Hz,1H),7.58(t,J=7.1 Hz,2H),6.10(dd,J=2.6,3.8 Hz,1H),6.32(dd,J=1.7,3.8 Hz,1H),6.79(dd,J=1.7,2.6 Hz,1H),6.85(d,J=8.7 Hz,2H),6.97(d,J=8.7 Hz,2H),7.28(d,J=0.9 Hz,1H),7.62(d,J=0.9 Hz,1H)
依照實施例15,藉由使用對應代替1-乙基吡咯-2-羧酸之羧酸,來得到標記化合物。
將實施例15(5)所得到的N-(1-(4-2-啉乙基胺基甲醯基)-苯基)-哌啶-4-基)-1-哌羧醯胺懸浮在THF及氯仿,並添加三乙胺、對應的醯氯、且在室溫攪拌。在反應液添加飽和碳酸氫鈉水溶液,並使用氯仿萃取且使用水、飽和食鹽水洗淨後,使用無水硫酸鈉乾燥。將乾燥劑過濾除去後,將減壓下蒸餾除去溶劑而得到的殘留物使用中壓矽膠快速管柱層析法進行純化,而得到標記化合物。
Method A 產率:39%
1
H-NMR(CDCl3
):δ(ppm) 1.42-1.60(m,2H),2.00-2.15(m,2H),2.45-2.70(m,6H),2.88-3.05(m,2H),3.40-4.02(m,17H),4.43(d,J=6.9 Hz,1H),6.27(s,1H),6.53(s,1H),6.65(brs,1H),6.80-7.05(m,3H),7.67(d,J=7.4 Hz,2H),9.55(brs,1H)
Method A 產率:22%
1
H-NMR(DMSO-d6):δ(ppm) 1.37-1.63(m,2H),1.70-1.87(m,2H),2.00(s,3H),2.12(s,3H),2.30-2.67(m,7H),2.73-2.98(m,2H),3.15-4.00(m,16H),5.62(s,1H),6.3(m,1H),6.94(d,J=8.9 Hz,2H),7.69(d,J=8.9 Hz,2H),8.07(brs,1H),10.73(s,1H)
MethodA 產率:38%
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.62(m,2H),1.98-2.15(m,2H),2.42-2.67(m,6H),2.88-3.07(m,2H),3.33-4.05(m,17H),3.66(s,3H),4.53(d,J=7.4 Hz,1H),6.22-6.30(m,1H),6.50-6.73(m,2H),6.90(d,J=8.9 Hz,2H),6.95-7.03(m,1H),7.67(d,J=8.9 Hz,2H)
MethodA 產率:58%
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.62(m,2H),1.97-2.15(m,2H),2.38-2.65(m,6H),2.88-3.05(m,2H),3.35-4.04(m,17H),4.56(d,J=7.1 Hz,1H),6.64(brs,1H),6.90(d,J=8.9 Hz,2H),7.00-7.11(m,1H),7.25-7.33(m,1H),7.41-7.52(m,1H),7.67(d,J=8.9 Hz,2H)
MethodB 產率:55%
1
H-NMR(CDCl3
):δ(ppm) 1.42-1.62(m,2H),1.97-2.18(m,2H),2.40-2.68(m,6H),2.88-3.05(m,2H),3.30-4.02(m,17H),4.61(d,J=6.9 Hz,1H),6.55-6.70(m,1H),6.90(d,J=8.9 Hz,2H),7.13-7.24(m,1H),7.33-7.42(m,1H),7.49-7.60(m,1H),7.67(d,J=8.9 Hz,2H)
Method B 產率:71%
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.63(m,2H),1.97-2.15(m,2H),2.37-2.67(m,6H),2.86-3.08(m,2H),3.35-4.00(m,17H),4.68(d,J=7.4 Hz,1H),6.50(dd,J=3.5,1.7 Hz,1H),6.60-6.77(m,1H),6.89(d,J=8.9 Hz,2H),7.03(dd,J=3.5,0.5 Hz,1H),7.43-7.56(m,1H),7.67(d,J=8.9 Hz,2H)
Method A 產率:47%
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.65(m,2H),1.97-2.13(m,2H),2.38-2.66(m,6H),2.88-3.07(m,2H),3.33-4.00(m,17H),4.63(d,J=7.4 Hz,1H),6.54(dd,J=2.0,0.8 Hz,1H),6.58-6.75(m,1H),6.89(d,J=9.1 Hz,2H),7.39-7.51(m,1H),7.60-7.78(m,3H)
Method B 產率:43%
1
H-NMR(CDCl3
):δ(ppm) 1.38-1.63(m,2H),1.92-2.13(m,2H),2.39-2.68(m,6H),2.85-3.08(m,2H),3.38-4.03(m,17H),4.77(d,J=7.4 Hz,1H),6.58-6.75(m,1H),6.81(d,J=1.8 Hz,1H),6.89(d,J=8.9 Hz,2H),7.66(d,J=8.9 Hz,2H),8.33(d,J=1.8 Hz,1H)
Method A 產率:46%
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.63(m,2H),1.95-2.18(m,2H),2.40-2.70(m,6H),2.85-3.10(m,2H),3.35-4.28(m,17H),3.89(s,3H),4.50(d,J=7.4 Hz,1H),6.69(brs,1H),6.90(d,J=8.9 Hz,2H),6.96(d,J=1.0 Hz,1H),7.04(d,J=1.0 Hz,1H),7.68(d,J=8.9 Hz,2H)
Method B 產率:65%
1
H-NMR(CDCl3
):δ(ppm) 1.40-1.92(m,11H),1.99-2.15(m,2H),2.42-2.68(m,6H),2.88-3.10(m,2H),3.25-3.98(m,17H),4.40(d,J=7.4 Hz,1H),6.58-6.75(m,1H),6.90(d,J=8.9 Hz,2H),7.68(d,J=8.9 Hz,2H)
4-苯甲醯基-N-(1-(4-(2-啉乙基胺基甲醯基)-苯基)-哌啶-4-基)-1-哌羧醯胺
Method A 產率:13%
1
H-NMR(CDCl3
):δ(ppm) 1.39-1.63(m,2H),2.00-2.15(m,2H),2.42-2.67(m,6H),2.87-3.06(m,2H),3.28-4.05(m,17H),4.51(d,J=7.4 Hz,1H),6.55-6.72(m,1H),6.90(d,J=8.9 Hz,2H),7.30-7.53(m,5H),7.67(d,J=8.9 Hz,2H)
依照國際公開WO2007-007778號公報的方法合成。
依照Urade、Y.等人的方法(J. Biol. Chem. 262. 3820-3825(1987年)實施。亦即,將49μL反應液、100mM Tris-HCl(pH8.0)、1mM還原型麩胱甘肽(glutathione)、0.1mg/mLγ-球蛋白(γ-globulin)、人體H-PGDS(適量)及化合物(最後濃度:0.01~100μM),在25℃預保溫5分鐘。又,在溶劑對照群(control群)係添加最後濃度為1%DMSO溶液。隨後,藉由添加1μL[14C]前列腺素H2(最後濃度:10μM)而開始反應。反應開始1分鐘後,藉由添加250μL之-20℃的反應停止液(二乙醚/甲醇/1M檸檬酸(30/4/1)來使反應停止。將50μL反應停止後的上層部(有機溶劑層)塗布在TLC plate(薄層板),並在-20℃展開45分鐘(展開劑:二乙醚/甲醇/乙酸(90/2/1)。將TLC plate乾燥後,在成像板曝光1小時至一晝夜,並使用影像解析器(富士FILM)解析相當於prostaglandinD2(前列腺素D2;PGD2)之放射活性。算出PGD2的條帶(band)在平均1泳道(lane)佔有比率(%),並算出相對於在各實驗所設置的對照群之0.1μM實施例化合物的抑制率(%)、及對H-PGDS之50%阻礙濃度(IC50值、nM),將該結果顯示在表1及表2。
參考例1~11係本發明化合物的特徵亦即(N-烷基吡咯-2-基)羰基變換成為其他的雜環等的取代基之化合物。如第1表所表示,相對於如本發明化合物之具有(N-烷基吡咯-2-基)羰基之哌化合物係顯示強的H-PGDS阻礙效果,參考例1~11係幾乎未顯示阻礙效果。
又,參考例12~16係兼具與本發明化合物類似的結構、亦即氟苯甲醯基及胺基羰基,且具有高GST2阻礙活性(Range A)之化合物,參考例17係兼具氟吡啶羰基及胺基羰基,在小鼠,係具有對於代謝症候群(metabolic syndrome)有用性之化合物,任一者均是在專利文獻3所揭示之化合物。
清楚明白本發明化合物係顯示比該等參考例12~17更強的H-PGDS阻礙效果。
在5週齡雄性Std:Hartley系土撥鼠,背部皮下注射1mg/mL的蛋白白蛋白(albumin)生理食鹽溶液來進行主動過敏反應(初次過敏反應)。初次過敏反應1星期後及2星期後,使用微吸量管將10mg/mL蛋白白蛋白生理食鹽溶液各20μL投給兩側的鼻腔內(點鼻過敏反應)。初次過敏反應3星期後,使用微吸量管將將10mg/mL蛋白白蛋白生理食鹽溶液各20μL投給兩側的鼻腔內而引起鼻炎反應。
引起鼻炎反應30分鐘後,在戊巴比妥鈉(pentobarbital sodium)麻醉下進行鼻腔洗淨。使用蠕動泵(peristaltic pump)(GILSON公司)並以1mL/min流速、從氣管往上氣道方向流動鼻腔洗淨用液(含有3mM EDTA及10uM吲哚美酒辛(indomethacin)的磷酸鹽緩衝鹽水(phosphate buffered saline),並回收從鼻腔流出的液體1分鐘。將所回收的液體離心分離,並將其上部澄清液作為鼻腔洗淨液。使用酵素免疫偵側試劑盒(EIA kit)(Prostaglandin D2-MOX EIA kit、Cayman Chemical)測定鼻腔洗淨液中的PGD2濃度。
供試化合物(30mg/kg)係在鼻炎反應引起1小時前口服投給。算出鼻腔洗淨液中PGD2降低率之計算式係如以下所表示。
鼻腔洗淨液中PGD2降低率(%)={(對照群的PGD2濃度-化合物投給群的PGD2濃度)÷(對照群的PGD2濃度-正常群的PGD2濃度)}×100
關於有無顯現PGD2產生之抑制作用,係確保各群8例以上,且將比較群的鼻腔洗淨液中的PGD2濃度與各化合物群中的PGD2濃度之結果顯示在第2表。又,有意義的水準為小於0.05時,係在表中以(*)表示有作用,作為陽性對照物質,係使用眾所周知的參考例18作為H-PGDS阻礙劑。
從第2表之結果,本發明化合物係顯示與陽性對照物質亦即參考例18同等的PGD2濃度降低率(都是具有意義的差異)。另一方面,在專利文獻3所揭示之參考例12~17,係未顯示具有意義的PGD2濃度降低。
Claims (11)
- 一種哌化合物或其鹽,該哌化合物係由下述通式(I)表示,
- 如申請專利範圍第1項之哌化合物或其鹽,其中X係表示CH、或N原子,R1 係表示甲基、或乙基,R2 係表示亦可具有胺基甲醯基或不飽和雜環基作為取代基之碳數1~3的烷基、亦可具有胺基甲醯基作為取代基之丙烯基、-(C=O)-N(R3 )(R4 )基或-(C=O)-OR5 基,R3 、R4 係表示一方為氫原子,另外一方為亦可具有飽和雜環基、或不飽和雜環基作為取代基之碳數1~6的烷基,亦或R3 及R4 係表示亦可以與其等所鍵結的氮原子一起形成吡咯啶基、哌啶基、哌基、啉基,R5 係表示氫原子、甲基、乙基、第三丁基或苄基。
- 如申請專利範圍第1或2項之哌化合物或其鹽,其中X係表示CH、或N原子,R1 係表示甲基,R2 係表示亦可具有啉胺基甲醯基、或三唑基的任一者作為取代基之碳數1~3的烷基、-(C=O)-N(R3 )(R4 )基或-(C=O)-OR5 基,該三唑基係亦可具有1~2個碳數1~6的烷基作為取代基,R3 、R4 係表示一方為氫原子,另外一方為亦可具有具有啉基、或吡啶基作為取代基之碳數1~3的烷基,亦或R3 及R4 係表示亦可以與其等所鍵結的氮原子一起形成啉基,R5 係表示氫原子。
- 如申請專利範圍第1或2項之哌化合物或其鹽,其中X係表示CH,R1 係表示甲基,R2 係表示亦可具有1,2,3-三唑基、1,2,4-三唑基、或3,5-二甲基-1,2,4-三唑基的任一者作為取代基之直鏈狀碳數1~3的烷基、亦或是-(C=O)-N(R3 )(R4 )基或-(C=O)-OR5 基,R3 、R4 係表示亦可 以與其等所鍵結的氮原子一起形成啉基,R5 係表示氫原子。
- 如申請專利範圍第1項之哌化合物或其鹽,其係選自下述群組:‧4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌胺基甲醯基)哌啶-1-基)-苯甲酸‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(吡啶-3-基-甲基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-啉乙基胺基甲醯基)-苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(4-啉基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-哌啶基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-吡咯啶基羰基)苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(1,2,3-三唑 -1-基)-丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-啉-3-側氧丙烯-1-基)-苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-啉-3-側氧丙基)-苯基)-哌啶-4-基)-1-哌羧醯胺‧6-(4-(4-((1-甲基吡咯-2-基)-羰基)1-哌胺基甲醯基)-哌啶-1-基)-菸鹼酸‧4-((1-甲基吡咯-2-基)-羰基)-N-(1-(5-(4-啉基羰基)吡啶-2-基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4-(2-啉乙基胺基甲醯基)苯基)-哌啶-4-基)-1-哌羧醯胺‧4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-哌啶-4-基)-1-哌羧醯胺。
- 一種醫藥組成物,其係含有如申請專利範圍第1至5項中任一項之化合物的至少1種或其藥學上被容許的鹽之有效量、及藥學性載體。
- 一種前列腺素D(prostaglandin D)合成酵素阻礙劑,其特徵為含有如申請專利範圍第1至5項中任一項之化合物或其藥學上被容許的鹽之有效量、及藥學性載體。
- 一種與前列腺素D2相關的疾病之預防劑或治療劑,其特徵為含有如申請專利範圍第1至5項中任一項之化合物或其藥學上被容許的鹽之有效量、及藥學性載體。
- 如申請專利範圍第8項之預防劑或治療劑,其中,與前列腺素D2相關之疾病係過敏疾病、或炎症性疾病。
- 一種哌化合物或其鹽用於製造一藥物之用途,該藥物係用以治療與前列腺素D2相關之疾病,且該哌化合物係由下述通式(I)表示,
- 如申請專利範圍第10項之用途,其中,與前列腺素D2相關之疾病係過敏疾病、或炎症性疾病。
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TW201321353A (zh) | 2011-10-08 | 2013-06-01 | Novartis Ag | 胺基甲酸酯/尿素衍生物 |
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TWI707851B (zh) * | 2015-09-17 | 2020-10-21 | 日商大鵬藥品工業股份有限公司 | 哌嗪化合物的新穎結晶 |
EP3390384B1 (en) | 2015-12-17 | 2021-09-15 | Astex Therapeutics Limited | Quinoline-3-carboxamides as h-pgds inhibitors |
JOP20190072A1 (ar) | 2016-10-13 | 2019-04-07 | Glaxosmithkline Ip Dev Ltd | مشتقات 1، 3 سيكلوبوتان ثنائي الاستبدال أو آزيتيدين كمثبطات للإنزيم المخلق للبروستاجلاندين d المكون للدم |
CA3066979A1 (en) | 2017-06-13 | 2018-12-20 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds as h-pgds inhibitors |
WO2019116256A1 (en) | 2017-12-13 | 2019-06-20 | Glaxosmithkline Intellectual Property Development Limited | Fused pyridines which act as inhibitors of h-pgds |
WO2020095215A1 (en) | 2018-11-08 | 2020-05-14 | Glaxosmithkline Intellectual Property Development Limited | Chemical compounds |
CN110105286B (zh) * | 2019-05-21 | 2022-08-09 | 中国药科大学 | 一种含有脲素骨架的取代杂环类化合物及其制备方法和用途 |
CN115667259A (zh) | 2020-06-19 | 2023-01-31 | 佐藤制药株式会社 | 抑制h-pgds的稠环化合物 |
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