CN102712626A - 具有pgds抑制作用的哌嗪化合物 - Google Patents
具有pgds抑制作用的哌嗪化合物 Download PDFInfo
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- CN102712626A CN102712626A CN2011800067256A CN201180006725A CN102712626A CN 102712626 A CN102712626 A CN 102712626A CN 2011800067256 A CN2011800067256 A CN 2011800067256A CN 201180006725 A CN201180006725 A CN 201180006725A CN 102712626 A CN102712626 A CN 102712626A
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- China
- Prior art keywords
- expression
- carbonyl
- alkyl
- substituent
- phenyl
- Prior art date
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Links
- -1 Piperazine compound Chemical class 0.000 title claims abstract description 162
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 title claims description 45
- 230000002401 inhibitory effect Effects 0.000 title description 5
- 101710145576 Prostaglandin-H2 D-isomerase Proteins 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 28
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 129
- 125000001424 substituent group Chemical group 0.000 claims description 58
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 claims description 44
- 238000000034 method Methods 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 44
- 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
- 201000010099 disease Diseases 0.000 claims description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000003795 chemical substances by application Substances 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 239000002207 metabolite Substances 0.000 claims description 18
- 125000002757 morpholinyl group Chemical group 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 108030003866 Prostaglandin-D synthases Proteins 0.000 claims description 12
- 102000048176 Prostaglandin-D synthases Human genes 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 239000002512 suppressor factor Substances 0.000 claims description 11
- VPUAYOJTHRDUTK-UHFFFAOYSA-N 1-ethylpyrrole Chemical compound CCN1C=CC=C1 VPUAYOJTHRDUTK-UHFFFAOYSA-N 0.000 claims description 10
- 230000002052 anaphylactic effect Effects 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 206010061218 Inflammation Diseases 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 8
- 125000004193 piperazinyl group Chemical group 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- BKCYGCVPVHPQPK-UHFFFAOYSA-N 4-(1-methylpyrrole-2-carbonyl)-n-[1-[4-(morpholine-4-carbonyl)phenyl]piperidin-4-yl]piperazine-1-carboxamide Chemical class CN1C=CC=C1C(=O)N1CCN(C(=O)NC2CCN(CC2)C=2C=CC(=CC=2)C(=O)N2CCOCC2)CC1 BKCYGCVPVHPQPK-UHFFFAOYSA-N 0.000 claims description 6
- NMCRPUILYKBXFW-UHFFFAOYSA-N 4-(1-methylpyrrole-2-carbonyl)-n-[1-[4-(pyrrolidine-1-carbonyl)phenyl]piperidin-4-yl]piperazine-1-carboxamide Chemical class CN1C=CC=C1C(=O)N1CCN(C(=O)NC2CCN(CC2)C=2C=CC(=CC=2)C(=O)N2CCCC2)CC1 NMCRPUILYKBXFW-UHFFFAOYSA-N 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 230000003449 preventive effect Effects 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 125000001399 1,2,3-triazolyl group Chemical class N1N=NC(=C1)* 0.000 claims description 5
- 229960003512 nicotinic acid Drugs 0.000 claims description 5
- 239000011664 nicotinic acid Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- AZBZOJAYUBOUPG-UHFFFAOYSA-N 4-(1-methylpyrrole-2-carbonyl)-n-[1-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperidin-4-yl]piperazine-1-carboxamide Chemical class CN1C=CC=C1C(=O)N1CCN(C(=O)NC2CCN(CC2)C=2C=CC(CCC(=O)N3CCOCC3)=CC=2)CC1 AZBZOJAYUBOUPG-UHFFFAOYSA-N 0.000 claims description 4
- UWPGEGCBGCSVHF-UHFFFAOYSA-N 4-(1-methylpyrrole-2-carbonyl)-n-[1-[4-(piperidine-1-carbonyl)phenyl]piperidin-4-yl]piperazine-1-carboxamide Chemical class CN1C=CC=C1C(=O)N1CCN(C(=O)NC2CCN(CC2)C=2C=CC(=CC=2)C(=O)N2CCCCC2)CC1 UWPGEGCBGCSVHF-UHFFFAOYSA-N 0.000 claims description 4
- SBXOKSPFXRYQFN-UHFFFAOYSA-N 4-(1-methylpyrrole-2-carbonyl)-n-[1-[5-(morpholine-4-carbonyl)pyridin-2-yl]piperidin-4-yl]piperazine-1-carboxamide Chemical class CN1C=CC=C1C(=O)N1CCN(C(=O)NC2CCN(CC2)C=2N=CC(=CC=2)C(=O)N2CCOCC2)CC1 SBXOKSPFXRYQFN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 239000002585 base Substances 0.000 description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- 239000007787 solid Substances 0.000 description 54
- 235000002639 sodium chloride Nutrition 0.000 description 47
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
- 239000002904 solvent Substances 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 229910052760 oxygen Inorganic materials 0.000 description 26
- 239000001301 oxygen Substances 0.000 description 26
- 239000003513 alkali Substances 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 23
- 239000003153 chemical reaction reagent Substances 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 238000004821 distillation Methods 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 238000005406 washing Methods 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 125000004185 ester group Chemical group 0.000 description 14
- 150000002170 ethers Chemical class 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 210000003928 nasal cavity Anatomy 0.000 description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 229910052500 inorganic mineral Inorganic materials 0.000 description 11
- 235000010755 mineral Nutrition 0.000 description 11
- 239000011707 mineral Substances 0.000 description 11
- 230000000452 restraining effect Effects 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 235000015320 potassium carbonate Nutrition 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 150000001298 alcohols Chemical class 0.000 description 9
- 238000010511 deprotection reaction Methods 0.000 description 9
- 125000000524 functional group Chemical group 0.000 description 9
- 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 9
- 238000012360 testing method Methods 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 239000007788 liquid Substances 0.000 description 8
- 239000006210 lotion Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 150000008282 halocarbons Chemical class 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- 235000017550 sodium carbonate Nutrition 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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000000217 alkyl group Chemical group 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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 206010039083 rhinitis Diseases 0.000 description 6
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- HNWKCASAOOFITC-UHFFFAOYSA-N 4-(3-fluorobenzoyl)piperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1C(=O)C1=CC=CC(F)=C1 HNWKCASAOOFITC-UHFFFAOYSA-N 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 206010070834 Sensitisation Diseases 0.000 description 5
- 125000003368 amide group Chemical group 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 5
- 229910000105 potassium hydride Inorganic materials 0.000 description 5
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 5
- 230000008313 sensitization Effects 0.000 description 5
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 4
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000005840 aryl radicals Chemical class 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- YQUKSNZCALCQHY-UHFFFAOYSA-N benzyl n-[1-[4-(2-hydroxyethyl)phenyl]piperidin-4-yl]carbamate Chemical compound C1=CC(CCO)=CC=C1N1CCC(NC(=O)OCC=2C=CC=CC=2)CC1 YQUKSNZCALCQHY-UHFFFAOYSA-N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 4
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- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
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- 244000223760 Cinnamomum zeylanicum Species 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 3
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- 230000002378 acidificating effect Effects 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
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- 238000009833 condensation Methods 0.000 description 3
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- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
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- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
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Classifications
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- 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
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Abstract
Description
技术领域
本发明涉及哌嗪化合物或其盐,以及含有所述哌嗪化合物或其盐作为活性成分的药物组合物,并具体地涉及由于其造血型前列腺素D合酶抑制作用而用于预防和/或治疗过敏性疾病、炎症性疾病等的试剂。
背景技术
前列腺素D2(PGD2)为炎性介质,其由抗原和免疫球蛋白E的复合体结合而激活的肥大细胞大量产生和释放(非专利文献1),并认为其在解释引起过敏性反应中发挥重要作用。在哮喘患者的支气管肺泡灌洗液中检测到高浓度的PGD2(非专利文献2),并有报道称与健康人相比哮喘患者因吸入PGD2而确认有气道收缩(非专利文献3)。
另一方面,产生PGD2的合酶被称为前列腺素D合酶(PGDS)。已知前列腺素D合酶存在造血型酶和脂质运载蛋白型(lipocalin-type)酶这两种。PGD2作为以过敏症为代表的各种疾病的发病和恶化因子而发挥作用、与生物体内调节机制相关,因此被认为改善其产生异常作为针对各种疾病的药品极为有效。
人造血型前列腺素D合酶(H-PGDS)主要分布于胎盘、肺、胎儿肝脏、淋巴结、脑、心脏、胸腺、骨髓和脾。此外,有报道称它们在脑内的小胶质细胞、骨髓巨核细胞、皮肤的朗格汉氏细胞、肝脏中的库普弗细胞、巨噬细胞、树突状细胞等很多抗原呈递细胞、肥大细胞和Th2细胞中以细胞水平表达。
鉴于H-PGDS在过敏性鼻炎患者的鼻粘膜下或慢性鼻窦炎患者的鼻息肉中、肥大细胞或炎性细胞中高度表达等,认为由H-PGDS产生的PGD2在诸如哮喘、鼻窦炎、皮炎和慢性阻塞性肺病等的过敏性疾病的发病和恶化中发挥重要作用(非专利文献4)。此外,在通常不发生H-PGDS表达的骨骼肌的坏死部分中证实H-PGDS表达(非专利文献5)。由于该原因,表明由造血型酶产生的PGD2也与伴随组织损伤的疾病相关,例如肌营养不良症、肌萎缩性侧索硬化症、多发性硬化症、溃疡性结肠炎、类风湿关节炎和慢性阻塞性动脉疾病等。
因此,能够期望H-PGDS抑制剂成为作为对预防和/或治疗诸如与由造血型酶产生的PGD2或其代谢物相关的过敏性疾病或炎症性疾病、进而肌肉坏死、外伤性脑损伤等疾病的试剂有用的药物。
有一些报道是关于H-PGDS抑制剂的提供(例如,专利文献1和2),并且也公开了具有与本发明化合物相似结构的H-PGDS抑制剂(专利文献3)。此外,关于哌嗪化合物,已经广泛研究其作为H-PGDS抑制剂之外的对药物等有用的化合物。
专利文献4中,作为刺猬信号(hedgehog signaling)抑制剂,公开了具有呋喃基羰基哌嗪结构的哌嗪化合物。
专利文献5(国际公开WO99/007672号公报)中,作为与钾通道相互作用的化合物公开了宽范围的哌嗪化合物。
现有技术文献
专利文献
专利文献1:国际公开WO2007-007778号公报
专利文献2:国际公开WO2007-041634号公报
专利文献3:国际公开WO2008-122787号公报
专利文献4:国际公开WO2007-054623号公报
专利文献5:国际公开WO99/007672号公报
非专利文献
非专利文献1:J.Immumol.,129,1627-1631(1982)
非专利文献2:N.Eng.J.Med.,315,800-804(1986)
非专利文献3:N.Eng.J.Med.,311,209-213(1984)
非专利文献4:Arch.Otolaryngol Head Neck Surg.,133,693-700(2007)
非专利文献5:Acta Neuropathol,104,377-384(2002)
发明内容
发明所要解决的课题
本发明的主要课题在于提供在低剂量下对前列腺素D合酶、特别是H-PGDS表现出高抑制效果的新型化合物。
此外,本发明的另一从属课题,基于H-PGDS抑制作用,提供对预防和/或治疗来自该酶的PGD2或其代谢物介导的疾病有效、且副作用少、安全性高的药物。
解决问题的手段
本发明人等对具有H-PGDS抑制作用的化合物进行深入研究,结果发现由下述通式(I)表示的新型哌嗪化合物对H-PGDS具有极其优异的抑制作用,经过进一步地研究,最终完成本发明。
本发明提供以下的哌嗪化合物、药物组合物、前列腺素D合酶抑制剂、以及用于预防或治疗与前列腺素D2或其代谢物相关的疾病的试剂。
项1.哌嗪化合物或其盐,其由下述通式(I)表示,
[式中,X表示CH或N原子;R1表示C1~6烷基;R2表示可具有取代基的C1~6烷基、可具有取代基的C2~6烯基、-(C=O)-N(R3)(R4)或-(C=O)-OR5;R3和R4相同或不同,且各自表示氢或可具有取代基的C1~6烷基,或者R3和R4可和与其结合的氮原子一起形成饱和杂环基;并且,R5表示氢、或者可具有取代基的C1~6烷基、或者芳烷基。]
项2.根据项1所述的哌嗪化合物或其盐,其中,
X表示CH或N原子;R1表示甲基或乙基;R2表示可具有氨基甲酰基或不饱和杂环基作为取代基的C1~3烷基、可具有氨基甲酰基作为取代基的丙烯基、-(C=O)-N(R3)(R4)或-(C=O)-OR5;R3和R4中的一个表示氢,另一个表示可具有饱和或不饱和杂环基作为取代基的C1~6烷基,或者R3和R4可和与其结合的氮原子一起形成吡咯烷基、哌啶基、哌嗪基和吗啉基;并且,R5表示氢、甲基、乙基、叔丁基或苄基。
项3.根据项1或2所述的哌嗪化合物或其盐,其中
X表示CH或N原子;R1表示甲基;R2表示可具有吗啉基氨基甲酰基和三唑基中的任何一个作为取代基的C1~3烷基、-(C=O)-N(R3)(R4)或-(C=O)-OR5,所述三唑基可具有1~2个C1~6烷基作为取代基;R3和R4中的一个表示氢,另一个表示可具有吗啉基或吡啶基作为取代基的C1-3烷基,或者R3和R4可和与其结合的氮原子一起形成吗啉基;并且,R5表示氢。
项4.根据项目1-3中任一项所述的哌嗪化合物或其盐,其中,
X表示CH;R1表示甲基;R2表示具有1,2,3-三唑基、1,2,4-三唑基和3,5-二甲基-1,2,4-三唑基中的任何一个作为取代基的直链C1-3烷基,或者表示-(C=O)-N(R3)(R4)或-(C=O)-OR5;R3和R4可和与其结合的氮原子一起形成吗啉基;并且,R5表示氢。
项5.根据项目1所述的哌嗪化合物或其盐,其选自:
4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(吡啶-3-基甲基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(4-吗啉基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
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-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-吡咯烷基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
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-哌嗪甲酰胺、
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-哌嗪甲酰胺、
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-哌嗪甲酰胺、
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-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙烯-1-基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)-哌啶-1-基)-烟酸、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(5-(4-吗啉基羰基)吡啶-2-基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺和
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-哌嗪甲酰胺。
项6.药物组合物,其包含有效量的至少一种项目1~5所述的化合物或其药物可接受的盐,以及药物可接受的载体。
项7.前列腺素D合酶抑制剂,其包含有效量的项目1~5中任一权利要求所述的化合物或其药物可接受的盐,以及药物可接受的载体。
项8.用于预防或治疗与前列腺素D2或其代谢物相关的疾病的预防剂或治疗剂,所述预防剂或治疗剂包含有效量的项目1~5中任一项所述的化合物或其药物可接受的盐,以及药物可接受的载体。
项9.根据项目8所述的预防剂或治疗剂,其中所述与前列腺素D2或其代谢物相关的疾病为过敏性疾病或炎症性疾病。
项10.用于治疗与前列腺素D2或其代谢物相关的疾病的方法,包括向有必要进行所述治疗的患者给予有效量的通式(I)表示的哌嗪化合物或其盐,
[式中,X表示CH或N原子;R1表示C1~6烷基;R2表示可具有取代基的C1~6烷基、可具有取代基的C2~6烯基、-(C=O)-N(R3)(R4)或-(C=O)-OR5;R3和R4相同或不同,且各自表示氢或可具有取代基的C1~6烷基,或者R3和R4可和与其结合的氮原子一起形成饱和杂环基;并且,R5表示氢、或者可具有取代基的C1~6烷基、或者芳烷基。]
项11.项目10所述的方法,其中所述与前列腺素D2或其代谢物相关的疾病为过敏性疾病或炎症性疾病。
项12.由通式(I)表示的哌嗪化合物或其盐,用于治疗与前列腺素D2或其代谢物相关的疾病,
[其中,X表示CH或N原子;R1表示C1~6烷基;R2表示可具有取代基的C1~6烷基、可具有取代基的C2~6烯基、-(C=O)-N(R3)(R4)或-(C=O)-OR5;R3和R4相同或不同,且各自表示氢或可具有取代基的C1~6烷基,或者R3和R4可和与其结合的氮原子一起形成饱和杂环基;并且,R5表示氢、或者可具有取代基的C1~6烷基、或者芳烷基。]
项13.由通式(I)表示的哌嗪化合物或其盐在治疗与前列腺素D2或其代谢物相关的疾病中的用途,
[式中,X表示CH或N原子;R1表示C1~6烷基;R2表示可具有取代基的C1~6烷基、可具有取代基的C2~6烯基、-(C=O)-N(R3)(R4)或-(C=O)-OR5;R3和R4相同或不同,且各自表示氢或可具有取代基的C1~6烷基,或者R3和R4可和与其结合的氮原子一起形成饱和杂环基;并且,R5表示氢、或者可具有取代基的C1~6烷基、或者芳烷基。]
发明效果
根据本发明,提供由上述通式(I)表示的新型哌嗪化合物或其盐,其作为前列腺素D合酶抑制剂且特别是H-PGDS抑制剂是有用的。
本发明的哌嗪化合物或其盐,具有优异的体外H-PGDS抑制活性。此外可知,在抗原-诱导的鼻炎的豚鼠中,在鼻腔洗液中具有对PGD2产生的抑制作用,且显示优异的鼻塞改善作用。
因此,本发明的该哌嗪化合物或其盐,基于其优异的H-PGDS抑制活性,作为预防和/或治疗与PGD 2或其代谢物相关的疾病、例如过敏性疾病或炎症性疾病等的试剂是有用的,可以期待其他有用的药效。
具体实施方式
本发明的哌嗪化合物,是由下述通式(I)表示的哌嗪化合物或其盐,
[式中,X表示CH或N原子;R1表示C1~6烷基;R2表示可具有取代基的C1~6烷基、可具有取代基的C2~6烯基、-(C=O)-N(R3)(R4)或-(C=O)-OR5;R3和R4相同或不同,且各自表示氢或可具有取代基的C1~6烷基,或者R3和R4可和与其结合的氮原子一起形成饱和杂环基;并且,R5表示、氢或者可具有取代基的C1~6烷基、或者芳烷基。]
本发明的由上述通式(I)表示的哌嗪化合物是以兼具有(N-烷基吡咯-2-基)羰基和(哌啶-4-基)氨基羰基为特征的化合物,也是未在上述现有专利文献等中具体公开的新型化合物。
例如,专利文献3(国际公开WO 2008/122787号公报)公开了多种抑制H-PGDS的哌嗪化合物。然而,专利文献3与本发明不同的是本发明化合物具有(哌啶-4-基)氨基羰基,而且本发明的化合物所具有的具有(N-烷基吡咯-2-基)羰基的哌嗪化合物,并未完全被公开。此外,如下文描述的试验例所示,专利文献3中作为实施例公开的化合物(参考例12~17)没有显示出在抗原-诱导的鼻炎的豚鼠中鼻腔洗液中的对PGD2产生的抑制作用。
专利文献4(国际公开WO 2007/054623号公报)中公开了作为刺猬信号抑制剂的具有呋喃基羰基哌嗪结构的哌嗪化合物。然而,专利文献4与本发明不同的是本发明化合物的(N-烷基吡咯-2-基)羰基局限于呋喃基羰基,专利文献4对于H-PGDS抑制作用完全没有记载。
专利文献5(国际公开WO 99/007672号公报)中,作为与钾通道相互作用的化合物,公开了呋喃基羰基哌嗪化合物、苯甲酰哌嗪化合物等。然而,专利文献5完全没有公开如本发明化合物那样具有(N-烷基吡咯-2-基)羰基的化合物,并且对于H-PGDS抑制作用完全没有记载。
如下面的试验例所示,不具有(N-烷基吡咯-2-基)羰基的哌嗪化合物几乎未表现出H-PGDS抑制作用。
本说明书中的“取代基”,可以举出例如卤素、羟基、氰基、硝基、烷基、卤代烷基、环烷基、环烷基-烷基、芳烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷氧基、环烷基-烷氧基、芳烷氧基、烷硫基、环烷基-烷硫基、氨基、单烷氨基或二烷氨基、环烷基-烷氨基、酰基、酰氧基、氧基、羧基、烷氧羰基、芳烷氧羰基、氨基甲酰基、饱和或不饱和杂环基、芳香烃基、饱和杂环氧基等,当存在上述取代基时,其数量典型地是1个、2个或3个。
在所述取代基中,作为卤素,可以列举氯、溴、氟、碘。
在所述取代基中,作为烷基、卤代烷基,优选为直链或支链C1-6或链C1-4烷基或者烷基的一个至所有氢由上述卤素取代的基团,可以列举甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基和己基等的烷基、三氟甲基等的卤代烷基。
在所述取代基中,环烷基优选为C3-7环烷基,可以列举环丙基、环丁基、环戊基、环己基和环庚基。
在所述取代基中,环烷基-烷基优选为由C3-7环烷基取代的C1-6烷基,可以举出环丙甲基、环丙乙基、环丁甲基、环戊甲基和环己甲基等。
在所述取代基中,芳烷基优选为由C6-14芳香烃基取代的直链或支链C1-6烷基,可以举出苄基、苯乙基、苯丙基、萘甲基和萘乙基等。
在所述取代基中,烯基表示含有碳碳双键的、优选C2-6烯基,可以举出乙烯基、烯丙基、甲基乙烯基、丙烯基、丁烯基、戊烯基和己烯基等。
在所述取代基中,炔基表示含有碳碳三键的、优选是C2-6炔基,可以举出乙炔基和丙炔基等。
在所述取代基中,烷氧基或卤代烷氧基优选为直链或支链C1-6烷氧基或在这些烷氧基中取代的上述卤素的基,可以举出甲氧基、乙氧基、正丙氧基、异丙氧基、1-甲基丙氧基、正丁氧基、异丁氧基、叔丁氧基、2-甲基丁氧基、新戊氧基、戊烷-2-基氧基、氟代甲氧基、二氟甲氧基、三氟甲氧基、1,1-二氟代乙氧基、2,2-二氟代乙氧基、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-基氧基和2,2,3,3,3-五氟-1-丙氧基等。
在所述取代基中,环烷氧基优选为C3-7环烷氧基,可以举出环丙氧基、环丁氧基、环戊氧基、环己氧基和环庚氧基。
在所述取代基中,环烷基-烷氧基优选为由C3-7环烷基取代的C1-6烷氧基,可以举出环丙基甲氧基、环丙基乙氧基、环丁基甲氧基、环戊基甲氧基和环己基甲氧基等。
在所述取代基中,芳烷基优选表示具有上述芳烷基的氧基,可以举出苄氧基、苯乙基氧基、苯丙基氧基、萘甲基氧基、萘乙基等。
在所述取代基中,烷硫基优选表示直链或支链C1-6烷硫基,可以举出甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基、戊硫基和己硫基等。
在所述取代基中,环烷基-烷硫基优选为由C3-7环烷基取代的C1-6烷硫基,可以举出环丙基甲硫基、环丙基乙硫基、环丁基甲硫基、环戊基甲硫基和环己基甲硫基等。
在所述取代基中,单烷氨基或二烷氨基表示由上述直链或支链C1-6烷基单取代或二取代的氨基,可以举出甲氨基、二甲氨基、乙氨基、二乙氨基和甲基乙氨基等。
在所述取代基中,环烷基-烷氨基表示由上述环烷基取代的烷氨基,可以举出环丙甲氨基、环丁甲氨基和环戊甲氨基等。
在所述取代基中,酰基可以举出甲酰基、乙酰基、丙酰基、正丁酰基、异丁酰基、戊酰基、异戊酰基和新戊酰基等具有直链或支链的C1-6酰基或苯甲酰基等。
在所述取代基中,酰氧基可以举出甲酰氧基、乙酰氧基、丙酰氧基、正丁酰氧基、异丁酰氧基、戊酰氧基、异戊酰氧基和新戊酰氧基等具有直链或支链的C1-6烷酰基氧基或苯甲酰氧基等。
在所述取代基中,烷氧羰基表示由上述烷氧基取代的羰基,可以举出甲氧羰基、乙氧羰基、正丙氧羰基、异丙氧羰基、1-甲基丙氧羰基、正丁氧羰基、异丁氧羰基、叔丁氧羰基、2-甲基-丁氧羰基、新戊氧羰基和戊烷-2-基氧基羰基。
在所述取代基中,芳烷氧羰基优选表示由上述芳烷氧基取代的羰基,可以举出苄氧羰基、苯乙氧羰基、苯丙氧羰基、萘甲氧羰基和萘乙氧羰基等。
在所述取代基中,氨基甲酰基可以举出-CONH2、(单烷基或二烷基)氨基甲酰基、(单芳基或二芳基)氨基甲酰基、(N-烷基-N-芳基)氨基甲酰基、吡咯烷基氨基甲酰基、哌啶基氨基甲酰基、哌嗪基氨基甲酰基和吗啉基氨基甲酰基等。
在所述取代基中,饱和或不饱和杂环基优选为单环或双环饱和或不饱和杂环基,其具有氧原子、氮原子或硫原子中的任何一个原子、优选为1至4个。可以举出例如吡咯烷基、哌啶基、哌嗪基、六亚甲基亚胺基、吗啉基、硫代吗啉基、高哌嗪基(homopiperazinyl)、四氢呋喃基、四氢吡喃基、咪唑基、噻吩基、呋喃基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、三唑基、四唑基、吡啶基、吡嗪基(pyrazyl)、嘧啶基、哒嗪基、吲哚基、异吲哚基、吲唑基、亚甲基二氧基苯基、亚乙基二氧基苯基、苯并呋喃基、二氢苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并噻唑基、嘌呤基(purinyl)、喹啉基、异喹啉基、喹唑啉基和喹喔啉基等。
在所述取代基中,芳香烃基优选表示C6-14芳香烃基,可以举出苯基和萘基等。在所述取代基中,饱和杂环氧基为具有一个或两个氧原子、氮原子和硫原子中的任何一个原子的单环饱和杂环基,例如表示具有吡咯烷基、哌啶基、哌嗪基、六亚甲基亚胺基、吗啉基、硫代吗啉基、高哌嗪基(homopiperazinyl)、四氢呋喃基、四氢吡喃基等的氧基,可以举出四氢呋喃基氧基和四氢吡喃基氧基。
通式(I)中,由R1表示的“C1-6烷基”表示直链或支链的C1-6烷基,可例示甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基和正己基等,优选甲基、乙基,更优选甲基。
通式(I)中,由R2表示的“可具有取代基的C1-6烷基”的“C1-6烷基”,可例示R1表示的C1-6烷基,优选C1-3烷基,更优选直链C1-3烷基,即甲基、乙基和正丙基。
由R2表示的“可具有取代基的C1-6烷基”中的“取代基”可例示上述取代基,优选氨基甲酰基、或不饱和杂环基,更优选吗啉代氨基甲酰基、三唑基,特别优选吗啉代氨基甲酰基、1,2,3-三唑基、1,2,4-三唑基。该不饱和杂环基可以具有取代基,优选取代基为甲基,其个数为1~2个。
由R2表示的“可具有取代基的C1-6烷基”特别优选吗啉基氨基甲酰基-乙基、1,2,3-三唑-乙基、1,2,3-三唑-丙基、1,2,4-三唑-丙基、3,5-二甲基-1,2,4-三唑-乙基、3,5-二甲基-1,2,4-三唑-丙基。
由R2表示的“可具有取代基的C2~6烯基”中的“C2~6烯基”可例示上述的C2~6烯基,优选乙烯基。
由R2表示的“可具有取代基的C2~6烯基”中的“取代基”,可例示上述的取代基,优选可具有取代基的氨基甲酰基,更优选吗啉代氨基甲酰基。
通式(I)中,由R3和R4表示的“可具有取代基的C1-6烷基”中的“C1-6烷基”,可例示由R1表示的C1-6烷基,优选C1-3烷基,更优选甲基或乙基。
由R3和R4表示的“可具有取代基的C1-6烷基”的“取代基”可例示上述取代基,优选饱和杂环基或不饱和杂环基,更优选吗啉基、或吡啶基。
R3和R4优选一个是氢,另一个是可具有取代基的C1~6烷基,特别优选一个是氢,另一个是具有吗啉基或吡啶基的C1-3烷基。
通式(I)中,R3和R4与其结合的氮原子一起形成的“饱和杂环基”,可例示吡咯烷基、哌啶基、哌嗪基、吗啉基等,优选吡咯烷基、哌啶基、吗啉基。
通式(I)中,由R5表示的“可具有取代基的C1-6烷基”优选甲基、乙基、叔丁基和苄基,但R5优选氢。
本发明的哌嗪化合物,可以按照下述反应方案1~7来制备。
本发明化合物的制备法
对通式(I)表示的化合物的代表性制备法进行说明。
方法1
在上述反应方案1中,X、R1和R2与上述相同,R表示氨基的保护基或氢。
第一步骤
通过常规方法将式(1a)表示的哌嗪化合物或其盐与式(1b)表示的吡咯羧酸化合物或其活性种(active species)进行缩合,由此形成通式(2)表示的酰胺化合物。
化合物(1b)的活性种可以举出甲基酯等一般的酯,酰氯等的酰卤,和具有N-羟基苯并三唑等的活性酯,对称型酸酐、具有烷基碳酸等的混合酸酐。
此外,当化合物(1b)与游离酸反应时、或当活性酯或酰卤反应而未分离时,适宜地使用1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐和4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉氯化物等的缩合剂。
当相对于1摩尔的式(1a)表示的哌嗪化合物或其盐使用0.5摩尔~10摩尔、优选为0.8摩尔~2摩尔的式(1b)表示的羧酸化合物或其活性种时,缩合剂的使用量相对于1摩尔的由式(1a)表示的哌嗪化合物或其盐,为0.5摩尔~20摩尔、优选为0.8摩尔~3摩尔。
尽管反应溶剂取决于所使用的活性种或缩合剂,但通常在-20°C~150°C、优选在0°C~100°C下在对反应惰性的溶剂中进行反应。这样的溶剂可以举出二氯甲烷和氯仿等的卤代烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;乙酸乙酯等的酯类;甲醇和乙醇等的醇类;水;乙腈;N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;二甲基亚砜;和吡啶等。反应时间是1~24小时左右。
在反应时,通过在相对于1摩尔的式(1a)表示的哌嗪化合物或其盐为0.5摩尔~20摩尔、优选为0.8摩尔~5摩尔的三乙胺、二异丙基乙基胺、N-甲基吗啉、N,N-二甲基苯胺、4-(N,N-二甲氨基)吡啶和吡啶等的碱存在下,反应则其能顺利进行。
第二步骤
在第二步骤中,将式(2)表示的酰胺化合物的氨基的保护基R利用通常的公知方法脱保护,利用常规方法使其产物与式(1c)表示的胺化合物或其活性种缩合,由此可以得到通式(I)表示的化合物。
例如,在保护基R为甲酰基、叔丁氧基羰基等的情况下,在酸性条件下可以进行脱保护,在R为苄基、苄氧基羰基等的情况下,可以用接触还原法等进行脱保护。
在缩合时,在存在或不存在三乙胺或吡啶等有机碱的情况下,在二氯甲烷、氯仿、四氢呋喃、乙腈、乙酸乙酯、N,N-二甲基乙酰胺等对反应为惰性的溶剂中,在-50°C~150°C、优选-20°C~100°C下使三光气、1,1’-羰基二咪唑(CDI)、氯甲酸苯酯、4-硝基氯甲酸苯酯、氯甲酸乙酯等与式(1c)表示的胺化合物或其盐作用而制备的具有离去基团的活性种,优选使用上述活性种。反应时间是1~24小时左右。
作为式(1c)活性种,例如可以举出具有离去基团的活性种,可在分离后用于反应、或可在反应体系中制备并且不分离而用于反应。离去基团可以举出氯、咪唑基、苯氧基、硝基苯氧基或乙氧基。
式(2)表示的胺化合物的盐,例如可以举出与盐酸、氢溴酸、硫酸等的无机酸,碳酸、甲磺酸等的有机酸形成的酸加成盐。
此外,相对于1摩尔的式(1c)表示的胺化合物或其活性种,使用0.5摩尔~10摩尔、优选为0.8摩尔~2摩尔的式(2)表示的胺化合物或其盐,在使用上述缩合剂时,其使用量相对于1摩尔的式(1c)表示的胺化合物或其盐,为0.5摩尔~20摩尔、优选为0.8摩尔~3摩尔。
尽管反应溶剂取决于所使用的活性种或缩合剂,但其通常在-50°C~150°C、优选-20°C~100°C下在对反应惰性的溶剂中进行,上述溶剂为二氯甲烷、氯仿等的卤代烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;乙酸乙酯等的酯类;甲醇、乙醇等的醇类;水;乙腈;N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;二甲基亚砜;和吡啶等。
在反应时,通过在相对于1摩尔的式(1c)表示的胺化合物或其活性种,在0.5摩尔~20摩尔、优选为0.8摩尔~5摩尔的三乙胺、二异丙基乙基胺、N-甲基吗啉、N,N-二甲基苯胺、4-(N,N-二甲氨基)吡啶、吡啶等的碱存在下,反应能顺利地进行。
需要说明的是,本发明化合物也可以通过交换上述第一步骤和第二步骤来制备,R2可以根据需要按照通常公知的方法来变化。此外,上述式(1a)表示的哌嗪化合物或其盐、式(1b)表示的吡咯羧酸化合物或其活性种、以及式(1c)表示的胺化合物或其盐可以容易地获取,或者可以按照公知方法来制备。
接下来,在反应方案2、3、4及5中表示上述反应方案的化合物(1c)的制备方法。
在上述反应方案2中,X、R与上述相同,R6可以举出与上述R5同义或叔丁基甲基甲硅烷基等的甲硅烷基保护基,R7、R8与由R2表示的“可具有取代基的C1-6烷基”的“取代基”同义,特别表示饱和杂环基或不饱和杂环基,Y1、Y2、Y3表示离去性官能团。
第一步骤
第一步骤的化合物(2b)的Y1只要是离去性官能团即可,例如可以举出氟、氯等的卤素、甲磺酰氧基、对甲苯磺酰氧基等。
在适当的溶剂中,相对于式(2b)表示的化合物1摩尔,使用0.5摩尔~10摩尔、优选0.8摩尔~2摩尔的式(2a)表示的哌啶化合物或其盐,在0.5摩尔~10摩尔、优选0.8摩尔~3摩尔碱的存在下,在-20°C~180°C、优选0°C~150°C下与1摩尔式(2b)表示的化合物反应1~24小时左右,从而可以获得由式(2c)表示的具有酯基的化合物。
反应溶剂若是不影响反应则没有特别限制,例如可以举出二氯甲烷、氯仿等的卤代烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;乙酸乙酯等的酯类;甲醇、乙醇等的醇类;水;乙腈;N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;N-甲基吡咯烷酮、二甲基亚砜、吡啶等,可以将它们单独使用,或者可以将它们混合后加以使用。
碱可以使用例如氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、碳酸锂、碳酸钠、碳酸钾、氢化钠、氢化钾等无机碱以及例如吡啶、4-(N,N-二甲基氨基)吡啶、三乙胺、二异丙基乙基胺、1,5-二氮杂二环[4.3.0]壬-5-烯、1,8-二氮杂二环[5.4.0]十一-7-烯、叔丁醇钾等有机碱。
在R为氢时,在适当的溶剂中,相对于式(2c)所示的化合物1摩尔,在0.5摩尔~10摩尔、优选0.8摩尔~3摩尔的碱存在下,在相对于式(2c)所示的化合物1摩尔,使用0.5摩尔~10摩尔、优选0.8摩尔~2摩尔的氨基保护试剂,在-20°C~180°C、优选0°C~150°C使它们反应1~24小时左右,由此可以获得在式(2c)所示的氨基上具有保护基的化合物。
反应溶剂若是不影响反应则没有特别限制,例如可以举出二氯甲烷、氯仿等的卤代烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;乙酸乙酯等的酯类;甲醇、乙醇等的醇类;水;乙腈;N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;N-甲基吡咯烷酮、二甲基亚砜、吡啶等,可以将它们单独使用,或者可以将它们混合后加以使用。
氨基保护试剂可以使用例如氯甲酸乙酯、9-芴基甲基羰酰氯(9-fluorenylmethylcarbonyl chloride)、二碳酸二叔丁酯、苄氧基羰基氯、苄基氯等。
碱可以使用例如氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、碳酸锂、碳酸钠、碳酸钾、氢化钠、氢化钾等无机碱以及例如吡啶、4-(N,N-二甲基氨基)吡啶、三乙胺、二异丙基乙基胺、1,5-二氮杂二环[4.3.0]壬-5-烯、1,8-二氮杂二环[5.4.0]十一-7-烯、叔丁醇钾等有机碱。
第二步骤
在本步骤中,将式(2c)所示的具有酯基的化合物在适当的溶剂中,相对于1摩尔式(2c)所示的化合物,在0.2摩尔~10摩尔、优选0.5~5摩尔的还原剂存在下,在-80°C~100°C、优选-50°C~30°C使其反应1~24小时左右,由此可以获得式(2d)所示的具有羟基的化合物。
反应溶剂若是不影响反应则没有特别限制,可以举出正己烷等的脂肪烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;甲醇、乙醇等的醇类;水等,可以将它们单独使用,或者可以将它们混合后加以使用。
还原剂可以举出氢化铝锂、硼氢化钠、硼烷试剂(例如二硼烷)和氢化二异丁基铝等。
第三步骤
在适当的溶剂中,相对于1摩尔式(2d)所示的具有羟基的化合物,使用0.5摩尔~10摩尔、优选0.8摩尔~2摩尔的式(2e)所示的具有离去性官能团的化合物,相对于式(2d)所示的化合物1摩尔,在存在或者不存在0.5摩尔~10摩尔、优选0.8摩尔~3摩尔的碱的条件下,在-20~180°C、优选0~150°C下使它们反应1~24小时左右,从而可以获得式(2f)所示的化合物。
适当的溶剂若是不影响反应则没有特别限制,例如可以举出二氯甲烷、氯仿等的卤代烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;乙酸乙酯等的酯类;甲醇、乙醇等的醇类;水;乙腈;N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;N-甲基吡咯烷酮、二甲基亚砜、吡啶等,可以将它们单独使用,或者可以将它们混合后加以使用。
式(2e)所示的具有离去性官能团的化合物可以使用例如甲基磺酰氯、三氟甲烷磺酰氯、对甲苯磺酰氯、苯磺酰氯等。
碱可以使用例如氢氧化钠、氢氧化钙、碳酸钠、碳酸钾、氢化钠、氢化钾等无机碱以及例如吡啶、4-(N,N-二甲基氨基)吡啶、三乙胺、二异丙基乙基胺、1,5-二氮杂二环[4.3.0]壬-5-烯、1,8-二氮杂二环[5.4.0]十一-7-烯、叔丁醇钾等有机碱。
第四步骤
接着,在适当的溶剂中,在相对于1摩尔式(2f)所示的化合物,存在或不存在0.5摩尔~10摩尔、优选0.8摩尔~3摩尔的碱的情况下,在-20°C~180°C、优选0°C~150°C下,使相对于1摩尔式(2f)所示的化合物为0.5摩尔~10摩尔、优选0.8摩尔~3摩尔式(2g)所示的胺化合物或其盐反应1~24小时左右,由此得到式(2h)所示的化合物。
适当的溶剂若是不影响反应则没有特别限制,例如可以举出二氯甲烷、氯仿等的卤代烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;乙酸乙酯等的酯类;乙腈;N,N-二甲基甲酰胺;N,N-二甲基乙酰胺;N-甲基吡咯烷酮、二甲基亚砜、吡啶等,可以将它们单独使用,或者可以将它们混合后加以使用。
碱可以使用例如氢氧化钠、氢氧化钙、碳酸钠、碳酸钾、氢化钠等无机碱以及例如吡啶、4-(N,N-二甲基氨基)吡啶、三乙胺、二异丙基乙基胺、1,8-二氮杂二环[5.4.0]十一-7-烯、叔丁醇钾等有机碱。碱也可以使用过剩量的式(2g)所示的胺化合物。
第五步骤
在第五步骤中,将式(2h)所示的化合物的氨基的保护基R通过通常公知的方法来脱保护,由此可以得到式(2i)所示的化合物。
例如,在保护基R为甲酰基、叔丁氧基羰基等的情况下,在酸性条件下可以脱保护,在R为苄基、苄氧基羰基等的情况下,可以用接触还原法等进行脱保护。
需要说明的是,在反应方案2中使用的化合物(2a)、(2b)、(2e)和(2g)可以容易地获得,或者按照公知方法来制造。
在上述反应方案3中,W是羟基的保护基,R、R6、R7、R8、X和Y1、Y2、Y3与上述同义。
第一步骤
本步骤与反应方案2的第一步骤同样,可以获得式(3c)所示的具有酯基的化合物。
第二步骤
本步骤与反应方案2的第二步骤同样,可以获得式(3d)所示的具有羟基的化合物。
第三步骤
本步骤中,将式(3d)所示的具有羟基的化合物利用通常公知的方法氧化,从而可以获得具有醛基的化合物(3e)。
在适当的溶剂中,相对于式(3d)所示的化合物1摩尔,在0.8摩尔~100摩尔、优选1摩尔~30摩尔的氧化剂存在下,在-80°C~180°C、优选-50°C~150°C下反应1~3天左右,从而可以获得式(3e)表示的具有醛基的化合物。
适当的溶剂若是不影响反应则没有特别限制,例如可以举出二氯甲烷、氯仿、二氯乙烷等的卤代烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;二甲基亚砜等,可以将它们单独使用,或者可以将它们混合后加以使用。
氧化剂可以举出氯铬酸吡啶盐(PCC)、二氯吡啶酯(PDC)、二氧化锰、三氧化硫吡啶络合物、Swern氧化试剂、Dess-Martin试剂等。
第四步骤
接着,在适当的溶剂中,相对于式(3e)所示的醛化合物1摩尔,使用0.8摩尔~10摩尔、优选1~8摩尔的式(3f)所示的Wittig试剂,相对于式(3e)所示的化合物1摩尔,在0.5摩尔~10摩尔、优选0.8摩尔~5摩尔碱存在下,在-20°C~150°C、优选0°C~80°C下使它们反应1~24小时左右,由此可以获得式(3g)所示的化合物。
适当的溶剂若是不影响反应则没有特别限制,例如可以举出正己烷等的脂肪烃类;甲苯等的芳香烃类;四氢呋喃等的醚类,可以将它们单独使用,或者可以将它们混合后加以使用。
式(3f)所示的Wittig试剂的羟基的保护基W,可以举出甲基、甲氧基甲基、四氢吡喃基、叔丁基二甲基甲硅烷基等。
碱可以使用例如正丁基锂、二异丙基氨基锂、六甲基二硅基胺基锂(リチウムヘキサメチルジシラザミド)、甲醇钠、乙醇钠、叔丁醇钾、氢化钠等。
第五步骤
接着,在适当的溶剂中,将式(3g)所示的化合物的羟基的保护基利用酸性条件来脱保护,然后在适当的溶剂中,相对于式(3g)所示的化合物1摩尔,在0.2摩尔~10摩尔、优选0.5摩尔~5摩尔的还原剂存在下,在-80°C~100°C、优选-50°C~30°C下,将具有醛基的化合物反应1~24小时左右,由此可以获得式(3h)所示的具有羟基的化合物。
反应溶剂若是不影响反应则没有特别限制,可以举出正己烷等的脂肪烃类;甲苯等的芳香烃类;四氢呋喃等的醚类;甲醇、乙醇等的醇类;水等,可以将它们单独使用,或者可以将它们混合后加以使用。
还原剂可以举出氢化铝锂、硼氢化钠、氰基硼氢化钠等。
第六步骤
本步骤与反应方案2的第三步骤同样,可以获得式(3j)所示具有离去基团的化合物。
第七步骤
本步骤与反应方案2的第四步骤同样,可以获得式(3l)所示具有氨基的化合物。
第八步骤
本步骤与反应方案2的第五步骤同样,可以获得式(3m)所示具有氨基的化合物。
需要说明的是,在反应方案3中使用的化合物(3a)、(3b)、(3f)、(3i)及(3k)可以容易地获得,或者可以按照公知方法来制备。
在上述反应方案4中,R9是酯基的保护基,R、R6、R7、R8、X及Y1、Y2、Y3与上述同义。Z是CH2P+R10 3Y4-、CH=PR11 3或CH2P(O)(OR12)2。R10、R11、R12是甲基、乙基、丁基等低级烷基,或者苯基等的芳香烃基,Y4是氯、溴等的卤素。
第一步骤
本步骤与反应方案2的第一步骤同样,可以获得式(4c)所示的具有酯基的化合物。
第二步骤
本步骤与反应方案2的第二步骤同样,可以获得式(4d)所示的具有羟基的化合物。
第三步骤
本步骤与反应方案3的第三步骤同样,可以获得式(4e)所示的具有醛基的化合物。
第四步骤
接下来,在适当的溶剂中,相对于式(4e)所示的醛化合物1摩尔,使用0.8摩尔~10摩尔、优选1摩尔~8摩尔的式(4f)表示的Wittig试剂或Horner-Emmons试剂,相对于式(4e)所示的化合物1摩尔,在存在或者不存在0.5摩尔~10摩尔、优选0.8摩尔~5摩尔的碱的情况下,在-20°C~150°C、优选0°C~120°C下使其反应1~24小时左右,由此可以获得具有α,β-不饱和酯基的化合物。
适当的溶剂若是不影响反应则没有特别限制,例如可以举出正己烷等的脂肪烃类;甲苯等的芳香烃类;四氢呋喃等的醚类,可以将它们单独使用,或者可以将它们混合后加以使用。
(4f)所示的Wittig试剂或Horner-Emmons试剂的酯基的保护基(R9),可以举出甲基、乙基、叔丁基、叔丁基二甲基甲硅烷基、苄基等。
碱可以使用例如氢氧化钠、氢氧化钙、碳酸钠、碳酸钾、氢化钠、氢化钾等无机碱以及例如正丁基锂、二异丙基氨基锂、六甲基二硅基胺基锂、甲醇钠、乙醇钠、叔丁醇钾、二异丙基乙基胺、1,8-二氮杂二环[5.4.0]十一-7-烯等有机碱。
接着,在四氢呋喃等的醚类、乙酸乙酯等的酯类;甲醇、乙醇等的醇类;甲酸、乙酸等的有机酸或它们的混合溶剂中,相对于式(4e)所示的化合物1摩尔,在存在0.001摩尔~1摩尔、优选0.01摩尔~0.3摩尔的碳支持的钯、氧化铂和雷尼镍等的还原催化剂的情况下,在0°C~120°C、优选20°C~100°C下将氢气在常压甚至在加压下使其作用,或者相对于式(4e)所示的化合物1摩尔,将0.5摩尔~20摩尔、优选1摩尔~10摩尔的甲酸、甲酸铵、环己烯等作为氢源使用代替氢气,反应1~3天左右,由此可以获得由式(4g)表示具有酯基的化合物。
第五步骤
本步骤与反应方案1的第二步骤同样,可以获得式(4h)所示的具有羟基的化合物。
第六步骤
本步骤与反应方案2的第三步骤同样,可以获得式(4j)所示的具有离去基团的化合物。
第七步骤
本步骤与反应方案2的第四步骤同样,可以获得式(4l)所示的具有氨基的化合物。
第八步骤
本步骤与反应方案2的第五步骤同样,可以获得式(4m)所示的具有氨基的化合物。
需要说明的是,在反应方案4中使用的化合物(4a)、(4b)、(4f)、(4i)及(4k)可以容易地获得,或者可以按照公知方法来制备。
在上述反应方案5中,V1是-CH=CH-或-CH2CH2-,R、R6、R7、R8、R9、X、Y1及Z与上述同义。
第一步骤
本步骤与反应方案2的第一步骤同样,可以获得式(5c)所示的具有酯基的化合物。
第二步骤
本步骤与反应方案2的第二步骤同样,可以获得式(5d)所示的具有羟基的化合物。
第三步骤
本步骤与反应方案3的第三步骤同样,可以获得式(5e)所示的具有醛基的化合物。
第四步骤
接着,在适当的溶剂中,相对于式(5e)所示的醛类化合物1摩尔,使用0.8摩尔~10摩尔、优选1~8摩尔的式(5f)所示的Wittig试剂或Horner-Emmons试剂,相对于式(5e)所示的化合物1摩尔,在存在或不存在0.5摩尔~10摩尔、优选0.8摩尔~5摩尔碱的情况下,在-20°C~150°C、优选0°C~120°C下使它们反应1~24小时左右,可以获得式(5g)所示的具有α,β-不饱和酯基的化合物。
适当的溶剂若是不影响反应则没有特别限制,可以举出例如正己烷等的脂肪烃类;甲苯等的芳香烃类;四氢呋喃等的醚类,可以将它们单独使用,或者可以将它们混合后加以使用。
(5f)所示的Wittig试剂或Horner-Emmons试剂的酯基的保护基(R9),可以举出甲基、乙基、叔丁基、叔丁基二甲基甲硅烷基、苄基等。
碱可以使用例如氢氧化钠、氢氧化钙、碳酸钠、碳酸钾、氢化钠、氢化钾等无机碱以及例如正丁基锂、二异丙基氨基锂、六甲基二硅基胺基锂、甲醇钠、乙醇钠、叔丁醇钾、二异丙基乙基胺、1,8-二氮杂二环[5.4.0]十一-7-烯等。
第五步骤
在本步骤中,将式(5g)所示的具有酯基的化合物中的酯基利用通常公知的方法进行脱保护,由此可以获得式(5h)所示的羧酸化合物。
第六步骤
在本步骤中,与反应方案1的第一步骤同样,与式(5i)所示的胺化合物或其盐缩合反应,由此可以获得式(5j)所示的酰胺化合物。
第七步骤
在本步骤中,当式(5k)所示的化合物的V1为-CH=CH-的情况下,与反应方案2的第五步骤同样,可以获得由式(5k)所示的具有氨基的化合物。
在本步骤中,当式(5k)所示的化合物的V1为-CH=CH-的情况下,在四氢呋喃等的醚类;乙酸乙酯等的酯类;甲醇、乙醇等的醇类;甲酸、乙酸等的有机酸或它们的混合溶剂中,相对于式(5j)所示的化合物1摩尔,在存在0.001摩尔~1摩尔、优选0.01摩尔~0.3摩尔的碳支持的钯、氧化铂和雷尼镍等的还原催化剂的情况下,在0℃~120℃、优选20℃~100℃下将氢气在常压甚至在加压下使其作用,或者相对于式(5j)所示的化合物1摩尔,将0.5摩尔~20摩尔、优选1摩尔~10摩尔的甲酸、甲酸铵、环己烯等作为氢源代替氢气使用,反应1~3天左右,与反应方案2的第五步骤同样,可以获得由式(5k)表示的具有氨基的化合物。
需要说明的是,在反应方案5中使用的化合物(5a)、(5b)、(5f)及(5i)可以容易地获得,或者可以按照公知方法来制备。
此外,在反应方案3~5中使用的化合物(3e)、(4e)及(5e),也可以如下述反应方案6所示制备出来。
在上述反应方案6中,R是氨基的保护基,X及Y1与上述同义。
本步骤与反应方案2的第一步骤同样,代替式(2b)所示的具有酯基的化合物,使用由式(6b)所示的具有醛基的化合物,可以获得由式(6c)表示的具有醛基的化合物。
此外,本发明的化合物中,具有这种官能团,如下述反应方案7所示,将该官能团进行化学修饰,由此可以变换成其他的本发明化合物。
在上述反应方案7中,V2是C0~3的亚烷基或-CH=CH-,R1、R6、R7、R8及X与上述同义。C0的亚烷基意味着单键。
在本步骤中,将式(7a)所示的具有酯基的化合物中的酯基利用通常公知方法进行脱保护而得到的羧酸化合物或其活性种,与反应方案1的第一步骤同样,与式(7b)所示的胺化合物或其盐缩合反应,由此可以获得式(7c)所示的酰胺化合物。
此外,在用于本发明的药品的活性成分的化合物(I)中存在1个或多个手性碳的情况下,在存在源于手性碳的光学异构体(对映体,非对映异构体)、其他的异构体时,这些分离的异构体物质或它们的混合物也全部包含在本发明中。
此外,可用作本发明药物活性成分的化合物(I)也包括药物可接受的前药。药物可接受的前药为具有在溶剂分解等的化学条件下或生理条件下能转化为可用作本发明药物活性成分的化合物(I)中的氨基、羟基、羧基、羰基等官能团的官能团的化合物。形成前药的代表性官能团可以举出在《药品的开发》(广川书店,1990年)第7卷,163-198页中公开的基团等。
进而,可用作本发明药物活性成分的化合物(I)有时也形成酸加成盐或包含碱的盐,该盐只要是在药物可接受的范围内可包含在本发明中。其具体可以举出无机酸的酸加成盐,所述无机酸例如盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等;或有机酸的酸加成盐,所述有机酸例如甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、酒石酸、碳酸、苦味酸、甲磺酸、对甲苯磺酸、谷氨酸等;或无机碱的盐,所述无机碱例如钠、钾、镁、钙、铝等;或有机碱的盐,所述有机碱例如甲胺、乙胺、葡甲胺(meglumine)、乙醇胺等;或者碱性氨基酸的盐,所述碱性氨基酸例如赖氨酸、精氨酸、鸟氨酸等;以及铵盐。
进而,本发明还包括可用作本发明药物活性成分的化合物(I)及其药物可接受的盐的各种水合物、溶剂化物和晶体多晶型物。
当药物组合物包含本发明的哌嗪化合物或其盐时,根据需要与药物载体配合,可以采用根据预防或治疗目的的各种给药剂型,作为该剂型,例如可以举出口服制剂、注射剂、栓剂、软膏剂、贴剂等,优选口服制剂。通过本领域技术人员已知的常规方法可以制备这些给药剂型。
对于药物载体,可以使用作为制剂材料常用的各种有机或无机载体材料,配合作为固体制剂中的赋形剂、粘合剂、崩解剂、润滑剂或着色剂;或作为液体制剂中的溶剂、增溶剂、悬浮剂、等渗剂、缓冲剂或舒缓剂等。此外,根据需要还可使用防腐剂、抗氧化剂、着色剂、矫味剂和稳定剂等的药物制剂添加剂。
如下制备口服固体制剂。使用常规方法将赋形剂、根据需要的粘合剂、崩解剂、润滑剂、着色剂、矫味剂/调味剂等加入至本发明的化合物后,制备片剂、包衣片剂、颗粒剂、粉末剂、胶囊剂等。
赋形剂可以举出乳糖、蔗糖、D-甘露糖、葡萄糖、淀粉、碳酸钙、高岭土、微晶纤维素和二氧化硅(silicic acid anhydride)等。
粘合剂可以举出水、乙醇、1-丙醇、2-丙醇、单糖浆、液体葡萄糖、液体α-淀粉、液体明胶、D-甘露糖、羧甲基纤维素、羟丙基纤维素、羟丙基淀粉、甲基纤维素、乙基纤维素、虫胶、磷酸钙和聚乙烯基吡咯烷酮等。
崩解剂可以举出干淀粉、海藻酸钠、琼脂粉、碳酸氢钠、碳酸钙、十二烷基硫酸钠、硬脂酸单甘油酯和乳糖等。
润滑剂可以举出精制滑石、硬脂酸钠、硬脂酸镁、硼砂和聚乙二醇等。
着色剂可以举出氧化钛和氧化铁等。
矫味剂/调味剂可以举出蔗糖、橙皮、柠檬酸和酒石酸等。
口服液体制剂的制备如下。可以使用常规方法将矫味剂、缓冲剂、稳定剂、矫臭剂等加入至本发明化合物来制备内服液体制剂、糖浆剂、酏剂(elixir)等。在这种情况下,矫味剂/矫臭剂也可以是上述举出的制剂。缓冲剂可以举出柠檬酸钠等。稳定剂可以举出黄芪胶、阿拉伯胶和明胶等。根据需要,出于肠溶包衣或药效持续的目的,也可以利用公知方法对口服制剂施以包衣。这种包衣剂中,可以举出羟丙甲基纤维素、乙基纤维素、羟甲基纤维素、羟丙基纤维素、聚氧乙二醇和吐温80(注册商标)等。
注射剂的制备如下。使用常规方法将pH调节剂、缓冲剂、稳定剂、等渗剂、局部麻醉剂等加入至本发明的化合物以制备皮下注射剂、肌内注射剂和静脉注射剂。在该情况下,pH调节剂和缓冲剂可以举出柠檬酸钠、醋酸钠和磷酸钠等。稳定剂可以举出焦亚硫酸钠、EDTA、巯基乙酸和硫代乳酸等。局部麻醉剂可以举出盐酸普鲁卡因和盐酸利多卡因等。等渗剂可以举出氯化钠、葡萄糖、D-甘露糖和甘油等。
栓剂的制备如下。将本领域公知的制剂用载体诸如聚乙二醇、羊毛脂、可可脂和脂肪酸甘油三酸酯等,进一步根据需要将吐温80(注册商标)这样的表面活性剂等加入本发明的化合物,随后使用常规方法制备。
软膏剂的制备如下。在本发明化合物中根据需要配合通常使用的基剂、稳定剂、湿润剂、防腐剂等,按照常规方法混合,使其制剂化。基剂可以举出液体石蜡、白凡士林、白蜂蜡、辛基十二烷醇和石蜡等。防腐剂可以举出对羟基苯甲酸甲酯、对羟基苯甲酸乙酯和对羟基苯甲酸丙酯等。
在制备贴剂时,在通常的支持物上使用常规方法涂覆上述软膏剂、乳剂、凝胶剂、糊剂等即可。支持物优选由棉花、人造短纤维和化学纤维制成的织布或无纺布、软氯乙烯、聚乙烯和聚氨酯等的膜或泡沫片。
在上述各单位剂型中应配合的本发明化合物的量取决于适用的患者症状或者因该剂型等不是恒定的,通常每给药单位剂型,对于口服制剂为约0.05mg~1,000mg,对于注射剂为约0.01mg~500mg,对于栓剂为约1mg~1,000mg左右。
此外,具有上述给药剂型的药剂的每日给药量,取决于患者的症状、体重、年龄、性别等而不同,不能一概而定,但成年人(体重:50kg)的每日剂量通常为约0.05mg~约5,000mg,优选为0.1mg~1,000mg,且优选每天分一次或两至三次给药。
由于通过给予含有本发明化合物的药剂,例如对于哺乳动物特别是人类具有H-PGDS抑制作用,因此本发明的化合物对于治疗、预防或改善由因本合酶产生的PGD2或其代谢物导致的疾病是有效的。能用含有本发明化合物的药剂治疗、预防或改善的疾病可以举出支气管哮喘、花粉症、过敏性鼻炎、鼻窦炎、中耳炎、过敏性结膜炎、春季结膜炎、特应性皮炎、接触性皮炎和食物过敏等过敏性疾病。
此外,含有本发明的化合物的药物在治疗、预防或改善下述疾病上是有用的,如慢性阻塞性肺病、间质性肺炎、过敏性肺炎、嗜酸粒细胞性肺炎、类风湿关节炎、退行性关节炎、多发性硬化症、肌萎缩性侧索硬化症、炎症性肠病、皮肤病(干癣、湿疹、红斑、瘙痒症、及粉刺等)、肌肉痛、肌营养不良症、PTCA后再狭窄、慢性阻塞性动脉疾病、再灌注损伤、移植排斥反应等炎症性疾病;粘液分泌障碍;生殖障碍;血液凝固障碍;睡眠障碍;疼痛;视力问题;肥胖;以及免疫性疾病和自身免疫性疾病。
含有本发明化合物的药剂还可以期待预防阿尔茨海默症或脑损伤的恶化的作用、和/或改善脑损伤的预后的作用,由于其能够抑制细胞瘤转化和转移性肿瘤生长,因此它在癌症治疗中也是有效的。
此外,其在治疗和/或预防纤维原细胞增殖、糖尿病视网膜病变和肿瘤血管生成等的由PGD2或其代谢物存在性的增殖性疾病中是有效的,由于其也能抑制PGD2诱导的平滑肌收缩,因此它也能用于治疗和/或预防不孕症、痛经、早产和嗜酸性白细胞相关疾病。
实施例
下面示出参考例、实施例和试验例对本发明进行更为详尽地描述,本发明并不受它们的限制。
需要说明的是,1H-NMR光谱是将TMS(四甲基硅烷)作为内标来进行检测,并由δ值(ppm)表示化学位移。对于化学位移,在括号中表示吸收模式、耦合常数(J值)和质子数。
此外,关于吸收模式,使用下列符号。s=单峰,d=二重峰,t=三重峰,q=四重峰,dd=双二重峰,m=多重峰,br=宽峰以及brs=宽单峰。
此外,关于化合物的结构式,使用下列符号。Me=甲基,Et=乙基。
实施例1(1)
4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯
将4-氟苯甲酸叔丁基酯(19.6g,100mmol)溶解在二甲基亚砜(以下称为DMSO)(50ml)中,加入碳酸钾(20.7g,150mmol)、4-氨基哌啶(11.0g,110mmol),在120℃下搅拌17小时。将反应液冷却至室温后,加入水后过滤收集析出的固体,由此得到乳白色固体,即4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯(23.3g,84%)。
1H-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=9.2Hz,2H),7.85(d,J=9.2Hz,2H)
实施例1(2)
4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸叔丁基酯
将氯甲酸4-硝基苯酯(2.42g,12mmol)溶解在四氢呋喃(以下称为THF)(50ml)中,在-30℃下,滴加由实施例1(1)得到的4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯(2.76g,10mmol)的THF(30ml)溶液。在同一温度下搅拌30分钟后,加入1-[(1-甲基-1H-吡咯-2-基)羰基]哌嗪盐酸盐(2.53g,11mmol)、三乙胺(5.6ml,40mmol),在室温下搅拌15小时。在反应液中加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取。将有机层用水、饱和食盐水洗涤后,用无水硫酸钠干燥。滤除干燥剂后,在减压下将溶剂蒸馏除去而得到残留物,将该残留物用中压硅胶快速柱层析(甲醇:氯仿=0:1~1:30)纯化,由此得到乳白色固体,即4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸叔丁基酯(3.73g,75%)。
1H-NMR(CDCl3):δ(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(m4H),3.79(s,3H),3.68-4.00(m,7H),4.33(d,J=7.1Hz,1H),6.06-6.18(m,1H),6.30-6.41(m,1H),6.68-6.78(m,1H),6.85(d,J=9.1Hz,2H),7.86(d,J=9.1Hz,2H)
实施例1
4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸(化合物1)
将实施例1(2)中得到的4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸叔丁基酯(2.48g,5.0mmol)溶解在甲酸(10ml)中,在60℃下搅拌5小时。在减压下浓缩而得到的残留物中加入水,过滤收集析出的固体,由此得到乳白色固体,即4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸(2.12g,97%)。
1H-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=9.0Hz,2H),7.76(d,J=9.0Hz,2H),12.21(br,1H)
实施例2
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(吡啶-3-基甲基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物2)
将实施例1中得到的4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸(440mg,1.0mmol)溶解在N,N-二甲基甲酰胺(以下称为DMF)(3.0ml),加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(以下称为WSCD)(230mg,1.2mmol)、1-羟基苯并三唑一水合物(以下称为HOBt)(168mg,1.1mmol)、3-氨基甲基吡啶(0.12ml,1.2mmol),在60℃下加热搅拌3小时。冷却至室温后,加入饱和碳酸氢钠水溶液后,过滤收集析出的固体,在减压下加热干燥,由此得到乳白色固体,即4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(吡啶-3-基甲基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(223mg,42%)。
1H-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(m4H),3.78(s,3H),3.65-4.00(m,7H),4.37-4.50(m,1H),4.64(d,J=5.8Hz,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=9.1Hz,2H),7.20-7.35(m,1H),7.59-7.78(m,3H),8.47-8.65(m,2H)
实施例3
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物3)
根据实施例2,使用氨基乙基吗啉代替3-氨基甲基吡啶,由此得到乳白色固体,即4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(62%)。
1H-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=7.3Hz,1H),6.05-6.14(m,1H),6.29-6.40(m,1H),6.55-6.78(m,2H),6.90(d,J=8.9Hz,2H),7.68(d,J=8.9Hz,2H)
实施例4
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(4-吗啉基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物4)
根据实施例2,使用吗啉代替3-氨基甲基吡啶,由此得到乳白色固体,即4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(4-吗啉基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(52%)。
1H-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=8.9Hz,2H),7.34(d,J=8.9Hz,2H)
实施例5
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-哌嗪甲酰胺(化合物5)
根据实施例2,使用哌啶代替3-氨基甲基吡啶,由此得到乳白色固体,即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-哌嗪甲酰胺(68%)。
1H-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=8.9Hz,2H),7.32(d,J=8.9Hz,2H)
实施例6
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-吡咯烷基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物6)
根据实施例2,使用吡咯烷代替3-氨基甲基吡啶,由此可以得到乳白色固体,即4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-吡咯烷基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(72%)。
1H-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=8.9Hz,2H),7.48(d,J=8.9Hz,2H)
实施例7(1)
4-(4-氨基哌啶-1-基)-苯甲酸乙酯
根据实施例1(1),使用4-氟苯甲酸乙酯代替4-氟苯甲酸叔丁基酯,由此得到黄色固体,即4-(4-氨基哌啶-1-基)-苯甲酸乙酯(98%)。
1H-NMR(CDCl3):δ(ppm)1.33-1.40(m,2H),1.36(t,J=7.0Hz,3H),1.93(d,J=5.4Hz,2H),2.85-2.96(m,4H),3.83(d,J=13.2Hz,2H),4.32(q,J=7.0Hz,2H),4.74(br,1H),6.90(d,J=9.2Hz,2H),7.91(d,J=9.2Hz,2H)
实施例7(2)
4-(4-苄氧基羰基氨基哌啶-1-基)-苯甲酸乙酯
将实施例7(1)中得到的4-(4-氨基哌啶-1-基)-苯甲酸乙酯(15.7g,63.2mmol)溶解在THF(200ml)中,加入2M碳酸钠水溶液(63ml),接着加入苄氧基碳酰氯(11.7ml,82.2mmol),在室温下搅拌2小时。在反应液中加入水,用乙酸乙酯萃取。将有机层用水、饱和食盐水洗涤后,用无水硫酸钠进行干燥。滤除干燥剂后,在减压下将溶剂蒸馏除去得到固体,过滤收集该固体,在减压下进行干燥,由此得到白色固体,即4-(4-苄氧基羰基氨基哌啶-1-基)-苯甲酸乙酯(18.0g,74%)。
1H-NMR(CDCl3):δ(ppm)1.36(t,J=7.0Hz,3H),1.38-1.62(m,2H),2.04-2.10(m,2H),2.98(t,J=11.1Hz,2H),3.75-3.85(m,3H),4.32(q,J=7.0Hz,2H),4.71(br,1H),5.11(s,2H),6.85(d,J=9.2Hz,2H),7.26-7.36(m,5H),7.91(d,J=9.2Hz,2H)
实施例7(3)
4-(4-苄氧基羰基氨基哌啶-1-基)-苯甲醛
将实施例7(2)中得到的4-(4-苄氧基羰基氨基哌啶-1-基)-苯甲酸乙酯(13.6g,35.6mmol)溶解在二氯甲烷(150ml)中,加入二异丁基氢化铝-己烷溶液(91ml,89.0mmol),在-78℃下搅拌1小时。在反应液中加入甲醇后,加入饱和食盐水搅拌。用硅藻土(celite)过滤收集不溶物后,将滤液在减压下蒸馏除去溶剂而获得残留物,将该残留物溶解在二氯乙烷(180ml)中,加入二氧化锰(38.0g),在60℃下搅拌21小时。用硅藻土滤出不溶物后,将滤液在减压下蒸馏除去溶剂,由此得到白色固体,即4-(4-苄氧基羰基氨基哌啶-1-基)-苯甲醛(7.0g,58%)。
1H-NMR(CDCl3):δ(ppm)1.43-1.56(m,2H),2.08(d,J=9.7Hz,2H),3.10(t,J=11.1Hz,2H),3.80-3.90(m,3H),4.70(br,1H),5.11(s,2H),6.91(d,J=8.9Hz,2H),7.26-7.36(m,5H),7.74(d,J=8.9Hz,2H),9.77(s,1H)
实施例7(4)
N-(4-(2-羟乙基)苯基)-4-苄氧基羰基氨基哌啶
将甲氧基甲基三苯基氯化鏻(16.2g,47.3mmol)溶解在THF(300ml)中,在0℃下,滴加正丁基锂-己烷溶液(29.0ml,45.4mmol),搅拌30分钟。接下来,加入实施例7(3)中得到的4-(4-苄氧基羰基氨基哌啶-1-基)-苯甲醛(3.2g,9.46mmol),在室温下搅拌17小时。在反应液中加入饱和碳酸氢钠水溶液,用氯仿萃取。将有机层在减压下将溶剂蒸馏除去而得到残留物,将该残留物用中压硅胶快速柱层析(NH二氧化硅凝胶,乙酸乙酯:己烷=1:4)纯化,由此得到获得混合物形式的粗烯醇醚体。将得到的混合物在乙酸乙酯(30ml)中形成溶液,加入6N盐酸水溶液(6.0ml),搅拌1小时。在反应液中加入饱和碳酸氢钠水溶液进行中和,用氯仿萃取。将有机层在减压下将溶剂蒸馏除去而得到残留物,将该残留物在THF(15ml)、甲醇(15ml)中形成溶液,加入硼氢化钠(155mg,4.09mmol),在0℃下搅拌1小时。在反应液中加入饱和氯化铵水溶液后,向在减压下浓缩而得的残留物中加入水,过滤收集析出的固体,由此获得白色固体,即N-(4-(2-羟乙基)苯基)-4-苄氧基羰基氨基哌啶(960mg,29%)。
1H-NMR(CDCl3):δ(ppm)1.43-1.59(m,2H),2.06(d,J=10.3Hz,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=8.6Hz,2H),7.11(d,J=8.6Hz,2H),7.26-7.36(m,5H)
实施例7(5)
N-(4-(2-对甲苯磺酰基氧基乙基)苯基)-4-苄氧基羰基氨基哌啶
将实施例7(4)得到的N-(4-(2-羟乙基)苯基)-4-苄氧基羰基氨基哌啶(1.38g,3.89mmol)溶解在吡啶(7.5ml)中,在冰浴冷却下,加入对甲苯磺酰氯(960mg,5.04mmol)搅拌4小时。在反应液中加入水,过滤收集析出的固体,由此得到黄色固体,即N-(4-(2-对甲苯磺酰基氧基乙基)苯基)-4-苄氧基羰基氨基哌啶(1.35g,68%)。
1H-NMR(CDCl3):δ(ppm)1.48-1.62(m,2H),2.06(d,J=9.2Hz,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=8.6Hz,2H),6.99(d,J=8.6Hz,2H),7.29(d,J=8.4Hz,2H),7.30-7.38(m,5H),7.71(d,J=8.4Hz,2H)
实施例7(6)
N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-苄氧基羰基氨基哌啶
在实施例7(5)中得到的N-(4-(2-对甲苯磺酰基氧基乙基)苯基)-4-苄氧基羰基氨基哌啶(3.0g,5.90mmol)中加入1,2,3-三唑(3.4ml,58.6mmol),在90℃下搅拌2小时。在反应液中加入甲醇,加热回流1小时后,放冷至室温,过滤收集析出的固体,由此得到白色固体,即N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-苄氧基羰基氨基哌啶(1.3g,54%)。
1H-NMR(CDCl3):δ(ppm)1.50-1.65(m,2H),2.07(d,J=11.3Hz,2H),2.84(t,J=12.7Hz,2H),3.12(t,J=7.3Hz,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=8.4Hz,2H),6.96(d,J=8.4Hz,2H),7.30-7.38(m,6H),7.61(s,1H)
实施例7(7)
N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-氨基哌啶
将实施例7(6)中得到的N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-苄氧基羰基氨基哌啶(1.3g,50mmol)溶解于甲醇(13ml)、THF(13ml)中,加入10%钯-碳(以下称为Pd-C)(130mg),在氢气气氛下,于室温搅拌24小时。用硅藻土滤出不溶物后,将滤液在减压下蒸馏除去溶剂,从而得到白色固体,即N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-氨基哌啶(870mg,99%)。
1H-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=8.4Hz,2H),7.01(d,J=8.4Hz,2H),7.65(s,1H),8.02(s,1H)
实施例7
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-哌嗪甲酰胺(化合物7)
根据实施例1(2),使用N-(4-(2-(1,2,3-三唑-1-基)-乙基)-苯基)-4-氨基哌啶代替4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯,得到乳白色固体,即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-哌嗪甲酰胺(46%)。
1H-NMR(CDCl3):δ(ppm)1.48-1.65(m,2H),2.09(d,J=12.0Hz,2H),2.86(d,J=11.0Hz,2H),3.12(t,J=7.0Hz,2H),3.41-3.45(m,4H),3.61(d,J=13.0Hz,2H),3.76-3.90(m,8H),4.32(d,J=7.3,1H),4.58(t,J=7.3Hz,2H),6.09(dd,J=3.8,2.7,1H),6.34(dd,J=3.8,1.4Hz,1H),6.72(dd,J=2.7,1.4Hz,1H),6.85(d,J=8.9Hz,2H),6.97(d,J=8.9Hz,2H),7.27(s,1H),7.62(s,1H)
实施例8(1)
4-(4-叔丁氧基羰基氨基哌啶-1-基)-肉桂酸乙酯
将4-氟苯甲醛(37g,0.30mol)溶解于DMSO(300ml),加入碳酸钾(124g,0.89mol)、4-叔丁氧基羰基氨基哌啶(66g,0.33mol),在120°C下加热搅拌12小时。在反应液中加入磷酰基乙酸三乙酯(134g,0.60mol),进而加热搅拌2.5小时。在反应液中加入水(900ml),冷却至室温后,过滤收集析出的固体,用水(300ml)和己烷(300ml)洗涤,由此得到白色固体,即4-(4-叔丁氧基羰基氨基哌啶-1-基)-肉桂酸乙酯(110g,99%)。
1H-NMR(CDCl3):δ(ppm)1.32(t,J=7.1Hz,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=7.1Hz,2H),4.45(brs,1H),6.26(d,J=16Hz,1H),6.87(d,J=9.0Hz,2H),7.41(d,J=9.0Hz,2H),7.60(d,J=16Hz,1H)
实施例8(2)
4-(4-叔丁氧基羰基氨基哌啶-1-基)-二氢肉桂酸乙酯
将实施例8(1)中得到的4-(4-叔丁氧基羰基氨基哌啶-1-基)-肉桂酸乙酯(126g,0.33mol)溶解于乙醇(1L)中,加入10%Pd-C(48.5g),在氢气氛下,搅拌18小时。用硅藻土过滤不溶物,将滤液减压蒸馏,由此得到白色固体,即4-(4-叔丁氧基羰基氨基哌啶-1-基)-二氢肉桂酸乙酯(107g,85%)。
1H-NMR(CDCl3):δ(ppm)1.23(t,J=7.1Hz,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=7.1Hz,2H),4.47(brs,1H),6.86(d,J=8.5Hz,2H),7.08(d,J=8.5Hz,2H)
实施例8(3)
N-(4-(3-羟丙基)苯基)-4-叔丁氧基羰基氨基哌啶
将实施例8(2)中得到的4-(4-叔丁氧基羰基氨基哌啶-1-基)-二氢肉桂酸乙酯(68g,0.18mol)溶解于甲苯(1L)中,冷却至-78℃,滴加二异丁基氢化铝-己烷溶液(607ml,0.6mol)。搅拌1.5小时后,加入甲醇(10ml)、饱和氯化钠水溶液(550ml)搅拌3小时,用硅藻土过滤不溶物。将滤液的溶剂蒸馏除去而得到残留物,将该残留物溶解于甲醇(500ml)和THF(250ml)中,在0℃下加入硼氢化钠(6.9g,0.18mol)。搅拌1小时后,加入饱和氯化铵水溶液,用氯仿萃取,用硫酸镁进行干燥。滤除干燥剂后,蒸馏除去溶剂,由此得到N-(4-(3-羟丙基)苯基)-4-叔丁氧基羰基氨基哌啶(60g,98%)。
1H-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=8.5Hz,2H),7.08(d,J=8.5Hz,2H)
实施例8(4)
N-(4-(3-对甲苯磺酰基氧基丙基)苯基)-4-叔丁氧基羰基氨基哌啶
根据实施例7(5),使用N-(4-(3-羟丙基)苯基)-4-叔丁氧基羰基氨基哌啶代替N-(4-(2-羟乙基)苯基)-4-苄氧基羰基氨基哌啶,得到N-(4-(3-对甲苯磺酰基氧基丙基)苯基)-4-叔丁氧基羰基氨基哌啶(59%)。
1H-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=7.6Hz,2H),2.76-2.82(m,2H),3.50-3.55(m,3H),4.02(t,J=6.3Hz,2H),4.47(brs,1H),6.81(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),7.34(d,J=8.2Hz,2H),7.79(d,J=8.2Hz,2H)
实施例8(5)
N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶
将实施例8(4)中得到的N-(4-(3-对甲苯磺酰基氧基丙基)苯基)-4-叔丁氧基羰基氨基哌啶(330mg,0.68mmol)溶解于乙腈(5ml)和DMF(5ml)的混合溶媒中,加入1,2,4-三唑(54mg,0.81mmol)和碳酸钾(187mg,1.35mmol),在60℃下搅拌1小时。将反应液冷却至室温后,加入水后过滤收集析出的固体,由此得到N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶(192mg,74%)。
1H-NMR(CDCl3):δ(ppm)1.45(s,9H),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=7.0Hz,2H),4.94(brs,1H),6.87(d,J=8.5Hz,2H),7.04(d,J=8.5Hz,2H),7.93(s,1H),8.04(s,1H)
实施例8(6)
N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-氨基哌啶
将实施例8(5)中得到的N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶(180mg,0.47mmol)在0℃下溶解于三氟乙酸(5ml)中,在室温下搅拌1小时。将反应液减压蒸馏除去得到残留物,将该残留物用中压硅胶快速柱层析(NH二氧化硅凝胶,甲醇:氯仿=1:9)纯化,由此得到N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-氨基哌啶(127mg,95%)。
1H-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=7.0Hz,2H),6.84(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),7.96(s,1H),8.51(s,1H)
实施例8
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-哌嗪甲酰胺(化合物8)
根据实施例1(2),使用N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-氨基哌啶代替4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯,得到白色固体,即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-哌嗪甲酰胺(45%)。
1H-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=3.0Hz,1H),6.35(s,1H),6.72(s,1H),6.88(d,J=8.4Hz,2H),7.04(d,J=8.4Hz,2H),7.95(s,1H),7.97(s,1H)
实施例9(1)
N-(4-(3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-4-氨基哌啶
根据实施例8(5)和实施例8(6),使用3,5-二甲基-1,2,4-三唑代替1,2,4-三唑,由此得到白色固体,即N-(4-(3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-4-氨基哌啶(52%)。
1H-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=7.5Hz,2H),2.71-2.85(m,3H),3.58-3.61(m,2H),3.95(t,J=7.2Hz,2H),6.87(d,J=8.7Hz,2H),7.04(d,J=8.7Hz,2H)
实施例9
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-哌嗪甲酰胺(化合物9)
根据实施例1(2),使用N-(4-(3-(3,5-二甲基-1,2,4-三唑-1-基)-丙基)-苯基)-4-氨基哌啶代替4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯,由此得到无定形状固体,即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-哌嗪甲酰胺(45%)。
1H-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=7.4Hz,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=7.0Hz,2H),4.35(d,J=7.3Hz,1H),6.09-6.10(m,1H),6.34(d,J=3.9Hz,1H),6.72(s,1H),6.87(d,J=8.5Hz,2H),7.05(d,J=8.5Hz,2H)
实施例10(1)
N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶
根据实施例8(5),使用1,2,3-三唑代替1,2,4-三唑,由此得到白色固体,即N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶(33%)。
1H-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=7.4Hz,2H),2.79-2.84(m,2H),4.36(t,J=7.1Hz,2H),4.48(brs,1H),6.88(d,J=8.3Hz,2H),7.06(d,J=8.3Hz,2H),7.50(s,1H),7.71(s,1H)
实施例10(2)
N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-氨基哌啶
根据实施例8(6),使用N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶代替N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶,由此得到油状物,即N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-氨基哌啶(83%)。
1H-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=7.5Hz,2H),2.72-2.84(m,3H),3.59-3.63(m,2H),4.37(t,J=7.2Hz,2H),6.88(d,J=8.4Hz,2H),7.05(d,J=8.4Hz,2H),7.50(s,1H),7.70(s,1H)
实施例10
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-(12,3-三唑-1-基)-丙基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物10)
根据实施例1(2),使用N-(4-(3-(1,2,3-三唑-1-基)-丙基)-苯基)-4-氨基哌啶代替4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯,由此得到白色固体,即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-哌嗪甲酰胺(42%)。
1H-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=7.1Hz,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=8.5Hz,2H),7.06(d,J=8.5Hz,2H),7.51(s,1H),7.71(s,1H)
实施例11(1)
4-(4-叔丁氧基羰基氨基哌啶-1-基)-肉桂酸
将实施例8(1)中得到的4-(4-叔丁氧基羰基氨基哌啶-1-基)-肉桂酸乙酯(2.7g,7.2mmol)溶解在乙醇(40ml)中,加入4M氢氧化钠水溶液(3.6ml),加热回流12小时。将反应液冷却至室温,加入水(40ml),用10%柠檬酸水溶液中和,过滤收集析出的固体,由此得到白色固体,即4-(4-叔丁氧基羰基氨基哌啶-1-基)-肉桂酸(1.9g,77%)。
1H-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=15.8Hz,1H),6.83(brs,1H),6.90(d,J=8.8Hz,2H),7.42-7.63(m,3H)
实施例11(2)
(3-(4-(4-叔丁氧基羰基氨基哌啶-1-基)-苯基)-1-氧代-2-丙烯-1-基)-吗啉
将实施例11(1)中得到的4-(4-叔丁氧基羰基氨基哌啶-1-基)-肉桂酸(870mg,2.5mmol)溶解于N,N-二甲基乙酰胺(以下称为DMA)(15ml),加入HOBt(423mg,2.8mmol)、WSCD(530mg,2.8mmol)、吗啉(241mg,2.8mmol),在80℃搅拌16小时。冷却至室温后,加入水过滤收集析出的固体,由此得到白色固体,即(3-(4-(4-叔丁氧基羰基氨基哌啶-1-基)-苯基)-1-氧代-2-丙烯-1-基)-吗啉(836mg,80%)。
1H-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=15.4Hz,1H),6.87(d,J=8.8Hz,2H),7.41(d,J=8.8Hz,2H),7.64(d,J=15.4Hz,1H)
实施例11(3)
(3-(4-(4-氨基哌啶-1-基)-苯基)-1-氧代-2-丙烯-1-基)-吗啉
根据实施例8(6),使用(3-(4-(4-叔丁氧基羰基氨基哌啶-1-基)-苯基)-1-氧代-2-丙烯-1-基)-吗啉代替N-(4-(3-(1,2,4-三唑-1-基)-丙基)-苯基)-4-叔丁氧基羰基氨基哌啶,由此得到油状物,即(3-(4-(4-氨基哌啶-1-基)-苯基)-1-氧代-2-丙烯-1-基)-吗啉(68%)。
1H-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=15.3Hz,1H),6.87(d,J=8.7Hz,2H),7.42(d,J=8.7Hz,2H),7.64(d,J=15.3Hz,1H)
实施例11
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙烯-1-基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物11)
根据实施例1(2),使用(3-(4-(4-氨基哌啶-1-基)-苯基)-1-氧代-2-丙烯-1-基)-吗啉代替4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯,由此得到白色固体,即4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙烯-1-基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(64%)。
1H-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=8.8Hz,2H),7.42(d,J=8.8Hz,2H),7.64(d,J=15.2Hz,1H)
实施例12
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物12)
将实施例11中得到的4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙烯-1-基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(100mg,0.19mmol)溶解于THF(20ml)、甲醇(5ml)中,加入10%Pd-C(39mg),在氢气氛下搅拌12小时。用硅藻土滤出不溶物后,减压蒸馏除去滤液,由此得到白色固体,即4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(84mg,84%)。
1H-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,8H),3.59-3.62(m,6H),3.77-3.86(m,8H),4.33(d,J=7.3Hz,1H),6.09(dd,J=2.5,3.7Hz,1H),6.34(dd,J=1.7,3.7Hz,1H),6.71-6.72(m,1H),6.87(d,J=8.8Hz,2H),7.10(d,J=8.8Hz,2H)
实施例13(1)
6-(4-氨基哌啶-1-基)烟酸乙酯
将6-氯烟酸乙酯(4.27g,23mmol)溶解于DMF(30ml),加入碳酸钾(4.77g,35mmol)、4-氨基哌啶(2.76g,28mmol),在80℃下搅拌3小时,在100℃下搅拌1小时。将反应液冷却至室温后,加入水用乙酸乙酯萃取,将有机层用水、饱和食盐水洗涤后,用无水硫酸钠进行干燥。滤除干燥剂后,在减压下将溶剂蒸馏除去,由此得到淡褐色油状物,即6-(4-氨基哌啶-1-基)烟酸乙酯(4.17g,73%)。
1H-NMR(CDCl3):δ(ppm)1.20-1.65(m,4H),1.36(t,J=7.1Hz,3H),1.83-2.00(m,2H),2.84-3.15(m,3H),4.33(q,J=7.1Hz,2H),4.23-4.47(m,2H),6.60(dd,J=9.1,0.6Hz,1H),7.99(dd,J=9.1,2.4Hz,1H),8.79(dd,J=2.4,0.6Hz,1H)
实施例13(2)
6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-烟酸乙酯
根据实施例1(2),使用6-(4-氨基哌啶-1-基)烟酸乙酯代替4-(4-氨基哌啶-1-基)苯甲酸叔丁基酯,由此得到乳白色固体,即6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-烟酸乙酯(61%)。
1H-NMR(CDCl3):δ(ppm)1.27-1.50(m,2H),1.36(t,J=7.1Hz,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=7.1Hz,2H),4.28-4.52(m,2H),6.06-6.15(m,1H),6.29-6.40(m,1H),6.61(d,J=9.0Hz,1H),6.67-6.77(m,1H),8.01(dd,J=9.0,2.1Hz,1H),8.79(d,J=2.1Hz,1H)
实施例13
6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)-哌啶-1-基)-烟酸(化合物13)
将实施例13(2)中得到的6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-烟酸乙酯(234mg,0.5mmol)溶解于乙醇(1.5ml)、THF(1.5ml),加入2M氢氧化钠水溶液(1.4ml,2.8mmol),在室温下搅拌5小时。将反应液用2M盐酸水中和,用甲醇:氯仿(1:9)萃取。将有机层用水、饱和食盐水洗涤后,用无水硫酸钠进行干燥。滤除干燥剂后,在减压下将溶剂蒸馏除去,由此得到乳白色固体,即6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)-哌啶-1-基)-烟酸(90%)。
1H-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=9.2Hz,1H),6.68-6.76(m,1H),8.04(dd,J=9.2,2.4Hz,1H),8.85(d,J=2.4Hz,1H)
实施例14
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(5-(4-吗啉基羰基)吡啶-2-基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物14)
将实施例13(3)中得到的6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)-哌啶-1-基)-烟酸(132mg,0.3mmol)溶解于DMF(2.0ml),加入WSCD(69mg,0.36mmol)、HOBt(51mg,0.33mmol)、吗啉(0.04ml,0.45mmol),在60℃下加热搅拌16小时。冷却至室温后,在反应液中加入水,用乙酸乙酯萃取。将有机层用水、饱和食盐水洗涤后,用无水硫酸钠进行干燥。滤除干燥剂后,在减压下将溶剂蒸馏除去而得到残留物,将该残留物用中压硅胶快速柱层析(甲醇:氯仿=1:50~1:15)纯化,由此得到乳白色固体,即4-((1-甲基吡咯-2-基)-羰基)-N-(1-(5-(4-吗啉基羰基)吡啶-2-基)-哌啶-4-基)-1-哌嗪甲酰胺(24%)。
1H-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=8.9Hz,1H),6.68-6.79(m,1H),7.60(dd,J=8.9,2.1Hz,1H),8.26(d,J=2.1Hz,1H)
实施例15(1)
4-(4-苯氧基羰基氨基哌啶-1-基)-苯甲酸叔丁基酯
将氯甲酸苯酯(7.83g,50.0mmol)溶解于乙腈(100ml),在冰浴冷却下滴加实施例1(1)中得到的4-(4-氨基哌啶-1-基)-苯甲酸叔丁基酯(13.82g,50.0mmol)的乙腈(50ml)、DMA(50ml)溶液。加入三乙胺(7.0ml,50.0mmol),在相同温度下搅拌2小时后,加入水,过滤收集析出的固体,由此得到乳白色固体,即4-(4-苯氧基羰基氨基哌啶-1-基)-苯甲酸叔丁基酯(15.5g,78%),直接用于下面的反应。
实施例15(2)
4-(4-((4-苄氧基羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸叔丁基酯
将实施例15(1)中得到的4-(4-苯氧基羰基氨基哌啶-1-基)-苯甲酸叔丁基酯(13.88g,35.0mmol)溶解于乙腈(150ml),在冰浴冷却下,加入N-苄氧基羰基哌嗪(7.71g,35.0mmol)、1,8-二氮杂二环[5.4.0]十一-7-烯(6.6ml,42mmol),在室温下搅拌19小时后,加入水过滤收集析出的固体,由此得到乳白色固体,即4-(4-((4-苄氧基羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸叔丁基酯(16.1g,88%)。
1H-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=7.4Hz,1H),5.15(s,2H),6.84(dd,J=2.0,7.1Hz,2H),7.31-7.38(m,5H),7.85(dd,J=2.0,7.1Hz,2H)
实施例15(3)
4-(4-((4-苄氧基羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸
将实施例15(2)中得到的4-(4-((4-苄氧基羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸叔丁基酯(5.23g,10.0mmol)溶解于甲酸(20ml),在60℃下,搅拌3小时。在减压下将溶剂蒸馏除去而得到残留物,在该残留物中加入水,过滤收集析出的固体,由此得到乳白色固体,即4-(4-(4-苄氧基羰基)哌啶-1-甲酰氨基)哌啶-1-基)-苯甲酸(4.75g,quant.)。
1H-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=7.6Hz,1H),6.95(d,J=8.9Hz,2H),7.28-7.37(m,5H),7.75(d,J=8.9Hz,2H),12.15(brs,1H)
实施例15(4)
4-苄氧基羰基-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
将实施例15(3)中得到的4-(4-(4-苄氧基羰基)哌啶-1-甲酰氨基)哌啶-1-基)-苯甲酸(23.3g,50mmol)溶解于DMF(100ml),加入WSCD(10.5g,55mmol)、HOBt(8.04g,52.5mmol)、2-氨基乙基吗啉(7.9ml,60mmol),在60℃加热搅拌3小时。冷却至室温后,加入饱和碳酸氢钠水溶液,用乙酸乙酯萃取。将有机层用水、饱和食盐水洗涤后,用无水硫酸钠进行干燥。滤除干燥剂后,在减压下将溶剂蒸馏除去,由此得到乳白色固体,即4-苄氧基羰基-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(20.7g,72%)。
1H-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=6.0Hz,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=7.3Hz,1H),5.14(s,2H),6.63-6.66(m,1H),6.89(d,J=8.9Hz,2H),7.31-7.38(m,5H),7.67(d,J=8.9Hz,2H)
实施例15(5)
N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺
将实施例15(4)中得到的4-苄氧基羰基-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺(14.5g,25.0mmol)溶解于甲醇(80ml)、THF(80ml),加入10%Pd-C(3.0g),在氢气氛下于室温下搅拌17小时。在反应液中加入氯仿,用硅藻土滤出不溶物后,将滤液减压蒸馏除去,由此得到乳白色固体,即N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(11.2g,quant.)。
1H-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=7.4Hz,1H),6.85-6.86(m,1H),6.90(d,J=8.9Hz,2H),7.69(d,J=8.9Hz,2H)
实施例15
4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(化合物15)
将1-乙基吡咯-2-羧酸(139mg,1.0mmol)溶解于DMF(3.0ml),加入WSCD(230mg,1.2mmol)、HOBt(168mg,1.2mmol)、实施例15(5)中得到的N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(400mg,0.9mmol),在80℃下加热搅拌14小时。将反应液放冷至室温后,在反应液中加入饱和碳酸氢钠水溶液,用氯仿萃取,用水、饱和食盐水洗涤后,用无水硫酸钠进行干燥。滤除干燥剂后,在减压下降溶剂蒸馏除去而得到残留物,将该残留物用中压硅胶快速柱层析(甲醇:氯仿=1:30~1:10)纯化,由此得到乳白色固体,即4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺(213mg,42%)。
1H-NMR(CDCl3):δ(ppm)1.36(t,J=7.3Hz,3H),1.46-1.57(m,2H),2.04-2.08(m,2H),2.48-2.51(m,4H),2.58(t,J=6.0Hz,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=7.3Hz,2H),4.56(brs,1H),6.10(dd,J=2.6,3.8Hz,1H),6.30(dd,J=1.7,3.8Hz,1H),6.79(dd,J=1.7,2.6Hz,1H),6.90(d,J=8.9Hz,2H),7.67(d,J=8.9Hz,2H)
实施例16
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-哌嗪甲酰胺(化合物16)
根据实施例7(8),使用1-((1-乙基-1H-吡咯-2-基)羰基)哌嗪盐酸盐代替1-((1-甲基-1H-吡咯-2-基)羰基)哌嗪盐酸盐,由此得到白色固体,即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-哌嗪甲酰胺(75%)。
1H-NMR(CDCl3):δ(ppm)1.38(t,J=7.3Hz,3H),1.51-1.57(m,2H),2.06-2.09(m,2H),2.80-2.90(m,2H),3.12(t,J=7.1Hz,2H),3.40-3.44(m,4H),3.58-3.63(m,2H),3.76-3.90(m,5H),4.18(q,J=7.3Hz,2H),4.38(d,J=7.3Hz,1H),7.58(t,J=7.1Hz,2H),6.10(dd,J=2.6,3.8Hz,1H),6.32(dd,J=1.7,3.8Hz,1H),6.79(dd,J=1.7,2.6Hz,1H),6.85(d,J=8.7Hz,2H),6.97(d,J=8.7Hz,2H),7.28(d,J=0.9Hz,1H),7.62(d,J=0.9Hz,1H)
参考例
方法A
根据实施例15,使用对应的羧酸代替1-乙基吡咯-2-羧酸,得到标题化合物。
方法B
使实施例15(5)中得到的N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺悬浮于THF和氯仿中,加入三乙胺、对应的酸卤化物,在室温下搅拌。在反应液中加入饱和碳酸氢钠水溶液,用氯仿萃取,用水、饱和食盐水洗涤后,用无水硫酸钠进行干燥。滤除干燥剂后,在减压下将溶剂蒸馏除去而得到残留物,将该残留物用中压硅胶快速柱层析纯化,由此得到标题化合物。
参考例1
4-((吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法A 收率:39%
1H-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=6.9Hz,1H),6.27(s,1H),6.53(s,1H),6.65(brs,1H),6.80-7.05(m,3H),7.67(d,J=7.4Hz,2H),9.55(brs,1H)
参考例2
4-((3,5-二甲基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法A 收率:22%
1H-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=8.9Hz,2H),7.69(d,J=8.9Hz,2H),8.07(brs,1H),10.73(s,1H)
参考例3
4-((1-甲基吡咯-3-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法A 收率:38%
1H-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=7.4Hz,1H),6.22-6.30(m,1H),6.50-6.73(m,2H),6.90(d,J=8.9Hz,2H),6.95-7.03(m,1H),7.67(d,J=8.9Hz,2H)
参考例4
4-((噻吩-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法A 收率:58%
1H-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=7.1Hz,1H),6.64(brs,1H),6.90(d,J=8.9Hz,2H),7.00-7.11(m,1H),7.25-7.33(m,1H),7.41-7.52(m,1H),7.67(d,J=8.9Hz,2H)
参考例5
4-((噻吩-3-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法B 收率:55%
1H-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=6.9Hz,1H),6.55-6.70(m,1H),6.90(d,J=8.9Hz,2H),7.13-7.24(m,1H),7.33-7.42(m,1H),7.49-7.60(m,1H),7.67(d,J=8.9Hz,2H)
参考例6
4-((呋喃-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法B 收率:71%
1H-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=7.4Hz,1H),6.50(dd,J=3.5,1.7Hz,1H),6.60-6.77(m,1H),6.89(d,J=8.9Hz,2H),7.03(dd,J=3.5,0.5Hz,1H),7.43-7.56(m,1H),7.67(d,J=8.9Hz,2H)
参考例7
4-((呋喃-3-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法A收率:47%
1H-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=7.4Hz,1H),6.54(dd,J=2.0,0.8Hz,1H),6.58-6.75(m,1H),6.89(d,J=9.1Hz,2H),7.39-7.51(m,1H),7.60-7.78(m,3H)
参考例8
4-((异噁唑-5-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法B 收率:43%
1H-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=7.4Hz,1H),6.58-6.75(m,1H),6.81(d,J=1.8Hz,1H),6.89(d,J=8.9Hz,2H),7.66(d,J=8.9Hz,2H),8.33(d,J=1.8Hz,1H)
参考例9
4-((1-甲基咪唑-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法A 收率:46%
1H-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=7.4Hz,1H),6.69(brs,1H),6.90(d,J=8.9Hz,2H),6.96(d,J=1.0Hz,1H),7.04(d,J=1.0Hz,1H),7.68(d,J=8.9Hz,2H)
参考例10
4-环戊基羰基-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法B 收率:65%
1H-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=7.4Hz,1H),6.58-6.75(m,1H),6.90(d,J=8.9Hz,2H),7.68(d,J=8.9Hz,2H)
参考例11
4-苯甲酰基-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺
方法A 收率:13%
1H-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=7.4Hz,1H),6.55-6.72(m,1H),6.90(d,J=8.9Hz,2H),7.30-7.53(m,5H),7.67(d,J=8.9Hz,2H)
参考例12
4-(3-氟苯甲酰基)-哌嗪-1-羧酸-(6-溴苯并噻唑-2-基)-酰胺
参考例13
4-(3-氟苯甲酰基)-哌嗪-1-羧酸-(5,6-二甲基苯并噻唑-2-基)-酰胺
参考例14
4-(3-氟苯甲酰基)-哌嗪-1-羧酸-(6-甲基苯并噻唑-2-基)-酰胺
参考例15
4-(3-氟苯甲酰基)-哌嗪-1-羧酸-(6-甲氧基苯并噻唑-2-基)-酰胺
参考例16
4-(3-氟苯甲酰基)-哌嗪-1-羧酸-(6-氯苯并噻唑-2-基)-酰胺
参考例17
4-(6-氟吡啶-2-羰基)-哌嗪-1-羧酸-(4-三氟甲基苯基)-酰胺
参考例12~17按照国际公开WO2008-122787号公报中的方法来合成。
参考例18
N-甲氧基-N-甲基-4-(5-苯甲酰基苯并咪唑-2-基-3,5-二甲基吡咯-2-甲酰氨基
按照国际公开WO2007-007778号公报中的方法来合成。
试验例
试验例1造血型前列腺素D合酶(H-PGDS)抑制作用
按照Urade、Y.等的方法(J.Biol.Chem.262,3820-3825(1987))进行实验。即,将反应液(49μL);100mM Tris-HCl(pH8.0)、1mM还原型谷胱甘肽、0.1mg/mLγ-球蛋白、人H-PGDS(适量)及化合物(终浓度:0.01~100μM)在25℃下预培养5分钟。需要说明的是,在溶剂对照组(对照组)中,添加终浓度为1%的DMSO溶液。接着,添加[14C]前列腺素H2(终浓度:10μM)1μL由此引发反应。反应开始1分钟后,在-20°C下,添加反应终止液(二乙醚/甲醇/1M柠檬酸(30/4/1)250μL,由此终止反应。反应终止后的上层部(有机溶剂层)的50μL涂覆于TLC板并在-20°C下展开45分钟(展开溶剂:二乙醚/甲醇/醋酸(90/2/1))。在TLC板干燥后,将TLC板暴露于成像板1小时至一昼夜,使用图像分析仪(由Fujifilm Corporation制造)来解析相应于前列腺素D2(PGD2)的放射性。计算由PGD2的带在每道所占的比例(%),由此确定在实验中设置的相对于对照组的0.1μM各实施例化合物的抑制率(%)、及相对于H-PGDS的50%抑制浓度(IC50值、nM),将其结果示于表1及表2。
[表1]
[表2]
第1表(续)
参考例1~11,本发明化合物的特征,即(N-烷基吡咯-2-基)羰基被其他杂环等的取代基所取代的化合物。如第1表所示,如本发明化合物那样具有(N-烷基吡咯-2-基)-羰基的哌嗪化合物表现出强烈的H-PGDS抑制效果,而参考例1~11几乎没有抑制效果。
此外,参考例12至16的化合物具有与本发明化合物相似的结构,即兼具有氟苯甲酰基和氨基羰基,并且具有高的GST2抑制活性(等级A)的结构。参考例17的化合物兼具有氟吡啶羰基和氨基羰基,并对小鼠的代谢综合症有效,所有这些化合物均为在专利文献3中公开的化合物。
显然本发明化合物比这些参考例12~17表现出更强的H-PGDS抑制效果。
试验例2在具有抗原-诱导的鼻炎的豚鼠的鼻腔中的对PGD2产生的抑制作用
以1ml/只的量将1mg/mL的卵清蛋白的生理盐水溶液皮下注射至五周龄的雄性Std:Hartley豚鼠的背部,激活致敏(初始致敏)。在初始致敏一周后和两周之后,使用微量移液管将10mg/mL的卵清蛋白的生理盐水溶液滴入两侧的鼻腔中各20μL(通过鼻腔给药致敏)。在初始致敏三周后,使用微量移液管将10mg/mL的卵清蛋白的生理盐水溶液滴入两侧的鼻腔中各20μL以诱导鼻炎反应。
在诱导鼻炎反应30分钟后,在戊巴比妥钠麻醉下洗涤鼻腔。使用蠕动泵(Gilson,Inc.)以1ml/分钟的流速将鼻腔洗净用液(含有3mM的EDTA和10μM的吲哚美辛的磷酸盐缓冲盐水)在从气管至上呼吸道的方向上冲洗,并在1分钟内收集从鼻腔中流出的液体。将收集的液体离心分离,将其上清液作为鼻腔洗液。使用EIA试剂盒(前列腺素D2-MOX EIA试剂盒,Cayman Chemical)测定鼻腔洗液中的PGD2的浓度。
在诱导鼻炎反应之前的1小时口服给予供试化合物(30mg/kg)。以下所示为计算鼻腔洗液中PGD2减少比例的计算式。
鼻腔洗液中PGD2减少的比例(%)=
{(对照组的PGD2浓度–给予化合物组的PGD2浓度)÷(对照组的PGD2浓度-正常组的PGD2浓度)}×100
从各组获得8例或更多病例来确定是否发生对PGD2产生的抑制作用的表达,并将对照组的鼻腔洗液中的PGD2浓度和各给予化合物组的鼻腔洗液中的PGD2浓度进行比较,将比较结果示于第2表。需要说明的是,在显著性水平(significance level)低于0.05时,存在该作用并在表中由(*)表示,使用被认为是H-PGDS抑制剂的参考例18作为阳性对照物。
[表3]
第2表
由第2表的结果可知,本发明化合物表现出与属于阳性对照物质的参考例18同等的PGD2浓度的减少比例(均具有显著性差异)。另一方面,专利文献3公开的参考例12~17没有表现出PGD2浓度的显著降低。
Claims (13)
2.根据权利要求1所述的哌嗪化合物或其盐,其中,
X表示CH或N原子;
R1表示甲基或乙基;
R2表示可具有氨基甲酰基或不饱和杂环基作为取代基的C1~3烷基、可具有氨基甲酰基作为取代基的丙烯基、-(C=O)-N(R3)(R4)或-(C=O)-OR5;
R3和R4中的一个表示氢,另一个表示可具有饱和或不饱和杂环基作为取代基的C1~6烷基,或者R3和R4可和与其结合的氮原子一起形成吡咯烷基、哌啶基、哌嗪基和吗啉基;
R5表示氢、甲基、乙基、叔丁基或苄基。
3.根据权利要求1或2所述的哌嗪化合物或其盐,其中,
X表示CH或N原子;
R1表示甲基;
R2表示可具有吗啉基氨基甲酰基和三唑基中的任何一个作为取代基的C1~3烷基、-(C=O)-N(R3)(R4)或-(C=O)-OR5,所述三唑基可具有1~2个C1~6烷基作为取代基;
R3和R4中的一个表示氢,另一个表示可具有吗啉基或吡啶基作为取代基的C1-3烷基,或者R3和R4和与其结合的氮原子一起形成吗啉基;并且
R5表示氢。
4.根据权利要求1~3所述的哌嗪化合物或其盐,其中,
X表示CH;
R1表示甲基;
R2表示具有1,2,3-三唑基、1,2,4-三唑基和3,5-二甲基-1,2,4-三唑基中的任何一个作为取代基的直链C1-3烷基,或者表示-(C=O)-N(R3)(R4)或-(C=O)-OR5;
R3和R4和与其结合的氮原子一起形成吗啉基;
R5表示氢。
5.根据权利要求1所述的哌嗪化合物或其盐,其选自:
4-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)哌啶-1-基)-苯甲酸、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(吡啶-3-基甲基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(4-吗啉基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
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-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(1-吡咯烷基羰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
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-哌嗪甲酰胺、
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-哌嗪甲酰胺、
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-哌嗪甲酰胺、
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-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙烯-1-基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(4-(3-吗啉基-3-氧代丙基)-苯基)-哌啶-4-基)-1-哌嗪甲酰胺、
6-(4-(4-((1-甲基吡咯-2-基)-羰基)-1-哌嗪氨基甲酰基)-哌啶-1-基)-烟酸、
4-((1-甲基吡咯-2-基)-羰基)-N-(1-(5-(4-吗啉基羰基)吡啶-2-基)-哌啶-4-基)-1-哌嗪甲酰胺、
4-((1-乙基吡咯-2-基)-羰基)-N-(1-(4-(2-吗啉基乙基氨基甲酰基)苯基)-哌啶-4-基)-1-哌嗪甲酰胺和
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-哌嗪甲酰胺。
6.药物组合物,其包含有效量的至少一种权利要求1~5中的任一项权利要求所述的化合物或其药物可接受的盐,以及药物可接受的载体。
7.前列腺素D合酶抑制剂,其包含有效量的权利要求1~5中任一权利要求所述的化合物或其药物可接受的盐,以及药物可接受的载体。
8.与前列腺素D2或其代谢物相关的疾病的预防剂或治疗剂,其特征在于,所述预防剂或治疗剂包含有效量的权利要求1~5中任一权利要求所述的化合物或其药物可接受的盐,以及药物可接受的载体。
9.根据权利要求8所述的预防剂或治疗剂,其中所述与前列腺素D2或其代谢物相关的疾病为过敏性疾病或炎症性疾病。
11.根据权利要求10所述的方法,其中所述与前列腺素D2或其代谢物相关的疾病为过敏性疾病或炎症性疾病。
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CN111989119A (zh) * | 2018-04-19 | 2020-11-24 | 国立大学法人东京农工大学 | 用于肌肉减少症的预防和治疗剂 |
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