JPH0556345B2 - - Google Patents
Info
- Publication number
- JPH0556345B2 JPH0556345B2 JP8444220A JP4422084A JPH0556345B2 JP H0556345 B2 JPH0556345 B2 JP H0556345B2 JP 8444220 A JP8444220 A JP 8444220A JP 4422084 A JP4422084 A JP 4422084A JP H0556345 B2 JPH0556345 B2 JP H0556345B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- salt
- fluorobenzoyl
- piperidinyl
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 cyano, carbamoyl Chemical group 0.000 claims description 133
- 150000001875 compounds Chemical class 0.000 claims description 117
- 150000003839 salts Chemical class 0.000 claims description 77
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- 125000004432 carbon atom Chemical group C* 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 125000003282 alkyl amino group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 125000005551 pyridylene group Chemical group 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 9
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- XMRWAAOHXNIGHP-UHFFFAOYSA-N 5-cyano-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxybenzamide Chemical compound COC1=CC=C(C#N)C=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 XMRWAAOHXNIGHP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- DGHSVXGZTBSHHD-UHFFFAOYSA-N 3-bromo-4-fluoro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]benzamide Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCNC(=O)C=2C=C(Br)C(F)=CC=2)CC1 DGHSVXGZTBSHHD-UHFFFAOYSA-N 0.000 claims description 3
- IHWSSUJVXAVJOK-UHFFFAOYSA-N 4-fluoro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]benzamide Chemical compound C1=CC(F)=CC=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 IHWSSUJVXAVJOK-UHFFFAOYSA-N 0.000 claims description 3
- COOBIGBMMSAVJT-UHFFFAOYSA-N 5-cyano-n-[2-[4-[(4-fluorophenyl)-hydroxymethylidene]piperidin-1-yl]ethyl]-2-methoxybenzamide Chemical compound COC1=CC=C(C#N)C=C1C(=O)NCCN(CC1)CCC1=C(O)C1=CC=C(F)C=C1 COOBIGBMMSAVJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- OPWUWAVBEYJLKA-UHFFFAOYSA-N 2-bromo-4-fluoro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]benzamide Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCNC(=O)C=2C(=CC(F)=CC=2)Br)CC1 OPWUWAVBEYJLKA-UHFFFAOYSA-N 0.000 claims description 2
- SQVMUOGSZMKXMJ-UHFFFAOYSA-N 3-bromo-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-4-methoxybenzamide Chemical compound C1=C(Br)C(OC)=CC=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 SQVMUOGSZMKXMJ-UHFFFAOYSA-N 0.000 claims description 2
- RWZRYNLTCOJMSO-UHFFFAOYSA-N 5-bromo-4-chloro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxybenzamide Chemical compound COC1=CC(Cl)=C(Br)C=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 RWZRYNLTCOJMSO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052705 radium Inorganic materials 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 2
- ZKKDSCWDKMGZGE-UHFFFAOYSA-N 3,5-dichloro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxy-4-methylbenzamide Chemical compound COC1=C(Cl)C(C)=C(Cl)C=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 ZKKDSCWDKMGZGE-UHFFFAOYSA-N 0.000 claims 1
- ZSIVELBPQANHFZ-UHFFFAOYSA-N 3-cyano-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-4-methoxybenzamide Chemical compound C1=C(C#N)C(OC)=CC=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 ZSIVELBPQANHFZ-UHFFFAOYSA-N 0.000 claims 1
- FRSNVCJKOCMYLN-UHFFFAOYSA-N 4-fluoro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxybenzamide Chemical compound COC1=CC(F)=CC=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 FRSNVCJKOCMYLN-UHFFFAOYSA-N 0.000 claims 1
- NGLIVDONXVSSFM-UHFFFAOYSA-N 5-bromo-4-fluoro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxybenzamide Chemical compound COC1=CC(F)=C(Br)C=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 NGLIVDONXVSSFM-UHFFFAOYSA-N 0.000 claims 1
- MHGNQCAGTSQBSS-UHFFFAOYSA-N 5-bromo-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxybenzamide Chemical compound COC1=CC=C(Br)C=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 MHGNQCAGTSQBSS-UHFFFAOYSA-N 0.000 claims 1
- JPDSQDCQRCJEDV-UHFFFAOYSA-N 5-chloro-n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxy-4-(methylaminosulfamoyl)benzamide Chemical compound C1=C(Cl)C(S(=O)(=O)NNC)=CC(OC)=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 JPDSQDCQRCJEDV-UHFFFAOYSA-N 0.000 claims 1
- 230000000561 anti-psychotic effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- AXKXBPHUXOCHSD-UHFFFAOYSA-N n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2,6-dimethoxybenzamide Chemical compound COC1=CC=CC(OC)=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 AXKXBPHUXOCHSD-UHFFFAOYSA-N 0.000 claims 1
- KATFLYVSUVZNDQ-UHFFFAOYSA-N n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxy-5-methylsulfonylbenzamide Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 KATFLYVSUVZNDQ-UHFFFAOYSA-N 0.000 claims 1
- WQXGDTHNUALJKU-UHFFFAOYSA-N n-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2-methoxy-5-sulfamoylbenzamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(=O)NCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 WQXGDTHNUALJKU-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- 239000002253 acid Substances 0.000 description 61
- 238000000034 method Methods 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 43
- 239000007858 starting material Substances 0.000 description 42
- 238000002844 melting Methods 0.000 description 41
- 230000008018 melting Effects 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 31
- 239000002585 base Substances 0.000 description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 20
- 238000011282 treatment Methods 0.000 description 19
- 150000007513 acids Chemical class 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 17
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- ABERUOJGWHYBJL-UHFFFAOYSA-N (4-fluorophenyl)-piperidin-4-ylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)C1CCNCC1 ABERUOJGWHYBJL-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 14
- 229910052794 bromium Inorganic materials 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000013543 active substance Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 235000011121 sodium hydroxide Nutrition 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical compound [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 150000004820 halides Chemical class 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 150000001718 carbodiimides Chemical class 0.000 description 9
- 229910052731 fluorine Inorganic materials 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- 239000011737 fluorine Substances 0.000 description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 235000010755 mineral Nutrition 0.000 description 8
- 239000011707 mineral Substances 0.000 description 8
- 239000000454 talc Substances 0.000 description 8
- 229910052623 talc Inorganic materials 0.000 description 8
- 235000012222 talc Nutrition 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
- 239000002841 Lewis acid Substances 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 239000011261 inert gas Substances 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 150000007517 lewis acids Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 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
- 239000000463 material Substances 0.000 description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- KLGZORFFBKAAHL-UHFFFAOYSA-N [1-(2-aminoethyl)piperidin-4-yl]-(4-fluorophenyl)methanone;hydrochloride Chemical compound Cl.C1CN(CCN)CCC1C(=O)C1=CC=C(F)C=C1 KLGZORFFBKAAHL-UHFFFAOYSA-N 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 5
- 150000001735 carboxylic acids Chemical class 0.000 description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 150000004678 hydrides Chemical class 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 4
- 239000005977 Ethylene Substances 0.000 description 4
- 238000007126 N-alkylation reaction Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Description
ãçºæã®è©³çŽ°ãªèª¬æã
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è¬ã«é¢ãããDETAILED DESCRIPTION OF THE INVENTION The present invention relates to antipsychotic drugs containing carboxamides, particularly N-(piperidinyl-alkyl)-carboxamides and salts thereof.
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åãè¡šãïŒAr1ã¯ããšãã¬ã³åºåã¯ããªãžã¬ã³åº
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ççŽ ååãæããïŒãããã¯ïŒåã®ççŽ ååã«ã
ã€ãŠïŒåã®çªçŽ ååãéãŠãŠããã¢ã«ãã¬ã³åºã
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åºãè¡šãïŒãã€ãAr2ã¯ããã²ã³ã«ãã眮æãã
ãããšãã«åºåã¯ããšãã«åºãè¡šãããäœãAr1
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CONHâã«å¯ŸããŠãªã«ãäœã«ã¯äœçœ®ããªãïŒã§
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è¬ã«é¢ããã The invention particularly relates to the following general formula: (In the formula, R represents a lower alkoxy group or a halogen atom; Ar 1 represents a phenylene group or a pyridylene group, and each of these groups is unsubstituted or lower alkyl, halo-lower alkyl, halogen,
Lower alkoxy, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbonyl, N
- mono- or polysubstituted by lower alkylamino, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl, lower alkanesulfinyl and/or lower alkanesulfonyl; alk represents an alkylene group having 2 to 7 carbon atoms and separating two nitrogen atoms by 2 or 3 carbon atoms; X represents a carbonyl group or a hydroxymethylene group; and Ar 2 represents a phenyl group or a phenyl group substituted with halogen, provided that Ar 1
N-lower alkylamino as a substituent of -
The present invention relates to an N-(piperidinyl-alkyl)-carboxamide, or a salt thereof, and a psychotropic drug containing the same.
ããšãã¬ã³åºAr1ã¯ãåºïŒ²åã³COïŒã«ã«ãã
ã«ïŒåºã«å ããŠããã«äžãããã¯å€çœ®æãããã
ãšãã¬ã³ãç¹ã«ïŒïŒïŒâããšãã¬ã³ãïŒïŒïŒâã
ãšãã¬ã³åã¯ïŒïŒïŒâããšãã¬ã³ã§ããã The phenylene radical Ar 1 is a phenylene further mono- or polysubstituted in addition to the radical R and the CO (carbonyl) group, in particular 1,2-phenylene, 1,3-phenylene or 1,4-phenylene.
ããªãžãã¬ã³åºAr1ã¯ïŒå以äžã®äœçœ®ã§ããã«
眮æãããããªãžã¬ã³ãç¹ã«ãã®ã«ã«ãã¢ã€ã«åº
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âãïŒïŒïŒâãïŒïŒïŒâãïŒïŒïŒâãïŒïŒïŒâã
ïŒïŒïŒâãããã¯ïŒïŒïŒâããªãžã¬ã³ãè¡šããã
ããšãã¬ã³åºãªããããªãžã¬ã³åºã«ãããŠã奜ãŸ
ããã¯ãã«ã«ãã¢ã€ã«åºããåºïŒ²ã«é£æ¥ããå
åã«çµåããŠããã The pyridinylene group Ar 1 is a pyridylene further substituted in one or more positions, in particular a pyridylene whose carbamoyl group is bonded to the 3-position of the pyridylene ring and the group R is bonded to its 2-position, e.g. 2,3
-, 3,2-, 2,4-, 2,5-, 2,6-,
Represents 3,4- or 3,5-pyridylene.
In the phenylene to pyridylene groups, preferably a carbamoyl group is bonded to the C atom adjacent to the group R.
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ãã¢ã¢ã€ã«ãæããããã Examples of further substituents of the aforementioned phenylene or pyridylene groups include lower alkyl, lower alkoxy, cyano, carbamoyl unsubstituted or mono- or disubstituted by lower alkyl, monosubstituted by substituted alkyl. amino, sulfamoyl or sulfinyl, unsubstituted or mono- or di-substituted by lower alkyl, halo-lower alkyl, lower alkoxycarbonyl. 1 by lower alkyl
Examples of substituted or disubstituted carbamoyl or sulfamoyl include N-lower alkyl- or N,N-dilower alkylcarbamoyl, N-lower alkyl- or N,N-dilower alkylsulfamoyl.
äž¡æ¹ã®ïŒ®ååãå°ãªããšãïŒåã®ïŒ£ååã«ãã
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ãã¢ã«ãã¬ã³ã§ããã An alkylene radical alk in which both N atoms are separated by at least 2 C atoms is an alkylene group alk in which both N atoms are separated by at least 2 C atoms, such as 2 to 7, especially 2 or 3 C atoms. It is an alkylene having a C atom.
æ¬çºæã«ãããŠçšããããçš®ã
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å®çŸ©ãããŠããªãéãã次ã®æå³ãæããã Various terms used in this invention have the following meanings unless otherwise defined.
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ååãæããããšãæå³ããã The expression "lower" means that the organic radical or compound in question preferably has no more than 7, especially no more than 4 carbon atoms.
ããã²ã³ã¯ãç¹ã«ãååçªå·35ãŸã§ã®ããã²
ã³ãäŸãã°ãããçŽ ãå¡©çŽ åã¯èçŽ ãããã¯ãšãŠ
çŽ ãæå³ããã Halogen means in particular halogens with atomic number up to 35, such as fluorine, chlorine or bromine or iodine.
äœçŽã¢ã«ã³ãã·ã¯ãäŸãã°ãã¡ããã·ããšãã
ã·ãïœâãããã«ãªãã·ãã€ãœãããã«ãªãã·ã
ïœâããã«ãªãã·ãã€ãœããã«ãªãã·ãsecâã
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ã³ãããã«ãªãã·åºããæå³ããã Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy,
n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and further,
Also meant are the corresponding pentyloxy, hexyloxy and heptyloxy groups.
äœçŽã¢ã«ãã«ã¯ãäŸãã°ãã¡ãã«ããšãã«ãïœ
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察å¿ã®ãã³ãã«åºåã³ãããã«åºãæå³ããã Lower alkyl is, for example, methyl, ethyl, n
-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and also the corresponding pentyl and heptyl groups.
ããäœçŽã¢ã«ãã«ã¯ãäŸãã°ãããªãã«ãªãã¡
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ãã«åã¯ã¯ããã¡ãã«ã§ããã Halo-lower alkyl is, for example, trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl or chloromethyl.
äœçŽã¢ã«ã³ãã·ã«ã«ããã«ã¯ãäŸãã°ãã¡ãã
ã·âããšããã·âããããã«ãªãã·âãããã¯ã
ããªã«ãªãã·âã«ã«ããã«ã§ããã Lower alkoxycarbonyl is, for example, methoxy-, ethoxy-, propyloxy- or pivalyloxy-carbonyl.
âäœçŽã¢ã«ãã«âã«ã«ãã¢ã€ã«ã¯ãäŸãã°ã
âã¡ãã«âãâãšãã«âãâïŒïœâããã
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ã§ãããïŒïŒ®âãžäœçŽã¢ã«ãã«âã«ã«ãã¢ã€ã«
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âãžãšãã«âã«ã«ãã¢ã€ã«ãæå³ããã N-lower alkyl-carbamoyl is, for example,
N-methyl-, N-ethyl-, N-(n-propyl)- or N-isopropyl-carbamoyl; N,N-dilower alkyl-carbamoyl is, for example, N,N-dimethyl- or N,N
-Means diethyl-carbamoyl.
âäœçŽã¢ã«ãã«âã¢ããã¯ãäŸãã°ãâã¡
ãã«âãâãšãã«âãâïŒïœâãããã«ïŒâå
ã¯ïŒ®âã€ãœãããã«âã¢ããã§ããã N-Lower alkyl-amino is, for example, N-methyl-, N-ethyl-, N-(n-propyl)- or N-isopropyl-amino.
âäœçŽã¢ã«ãã«âã¹ã«ãã¢ã¢ã€ã«ã¯ãäŸã
ã°ãâã¡ãã«âãããã¯ïŒ®âãšãã«ã¹ã«ãã¢ã¢
ã€ã«ããããŠãïŒïŒ®âãžäœçŽã¢ã«ãã«âã¹ã«ã
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ã¯ïŒ®ïŒïŒ®âãžãšãã«âã¹ã«ãã¢ã¢ã€ã«ã§ããã N-Lower alkyl-sulfamoyl is, for example, N-methyl- or N-ethylsulfamoyl and N,N-di-lower alkyl-sulfamoyl is, for example, N,N-dimethyl- or N,N-diethyl- It is sulfamoyl.
äœçŽã¢ã«ã«ã³ã¹ã«ãã€ãã«ãããã¯âã¹ã«ãã
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ã¯âã¹ã«ããã«ã§ããã Lower alkanesulfinyl or -sulfonyl is, for example, methane-, ethane-, n-propane- or isopropane-sulfinyl or -sulfonyl.
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ãã 2- or 3-membered alkylene having 2 to 7, especially 2 or 3 C atoms is, for example,
Ethylene, 1,3-propylene, 1,2-propylene or 2-methyl-1,2-propylene.
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ãã Salts of compounds of formula () are especially pharmaceutically acceptable salts. A compound of formula () can, for example, form an acid addition salt due to its one or more basic groups. Acid addition salts include, for example, strong inorganic acids (e.g. mineral acids such as sulfuric acid, phosphoric acid or hydrohalic acids), strong organic acids (e.g. lower alkane carboxylic acids such as acetic acid, optionally unsaturated dicarboxylic acids, For example, oxalic acid, malonic acid,
Oxycarboxylic acids such as maleic or fumaric acid, tartaric or citric acid, aryl (aromatic) carboxylic acids such as benzoic acid). Similarly, to generate acid addition salts,
Sulfonic acids such as lower alkanesulfonic acids such as methanesulfonic acid or optionally substituted benzenesulfonic acids (eg p-toluenesulfonic acid) are also suitable. Salts which are not suitable for pharmaceutical use are also included in the invention, since they can be used, for example, in the isolation or production of the corresponding free compounds of formula () and their pharmaceutically usable salts.
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ãããã The compounds according to the invention may also be in the form of structural isomers. For example, when a compound of formula () has a C atom exhibiting chirality, ie an asymmetric carbon atom, for example when X in formula () represents free hydroxymethylene, the compound according to the invention
For example, it may be in the form of a pure enantiomer or a mixture of enantiomers (e.g. a ceramicompound), or in the form of a diastereomer or a mixture of diastereomers if at least one center exhibiting chirality or asymmetric center is present. It's okay to be hot.
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ãšã¿ãã³ïŒAmphetaminïŒã«ããæ¹ãèµ·ããã
ã©ããã®åžžåçã«å¯Ÿããæ®æäœçšã瀺ãã The compounds of formula () and their pharmaceutically usable salts can be used, for example, as medicaments such as antipsychotics, or in prophylactic or therapeutic treatments of the human and animal bodies. That is, the expression ()
The compounds possess particularly useful pharmacological properties. These exhibit particularly excellent psychosis-healing effects. As an example, a compound of formula () is B.
Brain Research 123 , 89â111 by Costall et al.
(1977), about 1
When administered intraperitoneally at doses of mg/Kg or higher, it exhibits antagonizing effects on stereotypy in rats induced by amphetamine.
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ã³ã°ã®ææšãšèŠãããšãã§ããããã§ããã PC Waldmeier, Experientia 36 , 1092-4.
(1980) using the test device of about 0.1 to about 100 mg/
Experiments in which the active substance was administered intraperitoneally to rats in a dose range of Kg showed that the compound of formula () has excellent antidopamine activity. This is confirmed by the rate of production of metabolites of the neurotransmitter dopamine (DA). That is D.A.
This is because increased conversion can be seen as an indicator of dopamine receptor blocking.
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確ããããããS.Bischoffã»ããEuropean J.
Pharmacol.ïŒ68ã305â315ïŒ1980ïŒã«ããæŸå°ç·
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ããã DA-receptor blocking by the compound of formula () is shown at [ 3 H] in the rat ammonium angle.
Direct confirmation is also provided by in vivo inhibition of spiperone binding. S. Bischoff et al., European J.
The radiation receptor test by Pharmacol., 68, 305-315 (1980) revealed that the
Excellent dopamine receptor inhibiting effect was confirmed by intraperitoneal administration at a dose of about 100 mg/Kg.
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ãããšã¯ãç¹ã«å¥œéœåã§ããã Correspondingly, compounds of formula () and salts thereof, for example, due to their strong antidopamine activity,
For example, it can be used as a psychotic drug, particularly due to its action on the dopamine system. It is particularly advantageous that little or no extrapyramidal side effects are observed when using compounds of formula ().
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å«ãŸããã The uses of the compounds of formula () include, in addition to therapeutic and prophylactic uses, also the industrial adaptation of the active substances.
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è¬ãæäŸããã The present invention particularly applies to compounds of formula () (in formula (), R represents a lower alkoxy group or a halogen atom, and when Ar 1 represents a phenylene group,
It is unsubstituted or mono- or polysubstituted by halo-lower alkyl, halogen, lower alkoxy, cyano, carbamoyl, N-lower alkyl-amino, sulfamoyl and/or N,N-di-lower alkyl-sulfamoyl. and when Ar 1 represents a pyridinylene group, it is mono- or polysubstituted with lower alkoxy and/or halogen; alk represents an ethylene group or a 1,3-propylene group, and X represents a carbonyl group or represents a hydroxymethylene group,
Ar 2 represents an unsubstituted or halogen-substituted phenyl group) and salts thereof, as well as psychotropic drugs containing the same.
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ãæäŸããã The present invention particularly relates to compounds of formula () (in formula (), R represents a lower alkoxy group, and Ar 1
is unsubstituted or halo-lower alkyl,
alk represents a phenylene group mono- or polysubstituted by halogen, lower alkoxy, cyano, carbamoyl, N-lower alkyl-amino, sulfamoyl and/or N,N-di-lower alkyl-sulfamoyl; alk is ethylene or 1,3 - represents a propylene group; .
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æäŸããã The present invention particularly relates to compounds of formula () (formula ()
in which R represents lower alkoxy, in particular lower alkoxy with up to 4 C atoms (e.g. methoxy) or halogen, in particular halogen with atomic number up to 35 (e.g. fluorine), and Ar 1 is substituted. or halo-lower alkyl, especially halo-lower alkyl with an atomic number of up to 35 and a number of C atoms of up to 4 (e.g. trifluoromethyl),
Halogen, especially halogen with atomic number up to 35 (e.g. bromine), lower alkoxy, especially lower alkoxy with up to 4 C atoms (e.g. methoxy), cyano, carbamoyl, lower alkylamino, especially 4 Lower alkylamino (e.g. methylamino) having C atoms of Sulfamoyl (e.g. N,N-dimethyl-sulfamoyl)
or, on the other hand, R represents lower alkoxy, in particular lower alkoxy with up to 4 C atoms (e.g. methoxy);
Ar 1 is unsubstituted or lower alkoxy,
In particular, it represents pyridylene substituted by lower alkoxy (e.g. methoxy) having up to 4 C atoms, in particular 3,2-pyridylene, alk represents an ethylene or 1,3-propylene radical, X
represents a carbonyl group or a hydroxymethylene group, and Ar 2 represents a halogen, in particular phenyl substituted by a halogen having an atomic number of 35 or less (eg, fluorine)) and salts thereof.
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è¬ãæäŸããã The present invention particularly relates to compounds of formula () (formula ()
in which R is methoxy, for example 4
represents lower alkoxy having up to 4 C atoms, Ar 1 is unsubstituted or halo-lower alkyl, e.g. halogens with an atomic number of up to 35 such as chlorine or bromine, lower alkoxy, e.g. lower alkoxy with up to 4 C atoms such as methoxy, cyano, carbamoyl, N-lower alkylamino, e.g. methylamino N-lower alkylamino, sulfamoyl and/or N with up to 4 C atoms, such as
N-di-lower alkyl-sulfamoyl, further substituted in one or more positions (-substituted or represents a phenyl group (substituted),
alk represents an ethylene or 1,3-propylene group, X represents a carbonyl group or a hydroxymethylene group, and Af 2 represents a phenyl group substituted with a halogen, for example, a halogen having an atomic number of 35 or less such as fluorine. ) and a salt thereof.
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ã«æäŸããã The present invention relates to compounds of the formula () (in the formula (), the group R-Ar 1 is of the formula: (wherein, on the one hand, Ra is lower alkoxy (e.g. methoxy) having up to 4 carbon atoms)
Rb and Re represent hydrogen; Rc represents a lower alkylamino having up to 4 carbon atoms (e.g. methylamino), and Rd represents a halogen having an atomic number of up to 35 (e.g. chlorine ), or Rc represents hydrogen or a halogen with an atomic number below 35 (e.g. chlorine) and Rd represents cyano; or on the other hand, Ra, Rd and Re
represents hydrogen, R represents a halogen having an atomic number of up to 35 (e.g. bromine), and R represents a group R, in which R represents a lower alkoxy having up to 4 carbon atoms (e.g. methoxy); and each In the case of , alk represents an ethylene group; Provide for medicine.
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è¬ãæäŸããã The present invention particularly provides compounds of formula () in which the group R-Ar 1 is of formula b (wherein one of Ra and Rb represents hydrogen or a halogen having an atomic number of 35 or less (for example, bromine)). , the other represents a hydrogen atom,
Rc represents a group R that is a halogen (e.g., fluorine) with an atomic number of 35 or less; Rd and Re each represent hydrogen; alk represents an ethylene group; X represents a carbonyl group; and Ar 2 represents 4 - represents a fluorophenyl group)) and a salt thereof.
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ã®å¡©åã³ç°æ§äœã«é¢ããã The invention particularly relates to the compounds shown in the Examples, their salts and isomers.
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ãã€ãŠè£œé ãããã Compounds having the formula () and salts thereof are, for example, a) formula R-Ar 1 -X 1 (a) (in the above formula, X 1 is carboxy or a (reactive) carboxy mechanically converted to be reactive) ), the formula or a salt thereof, or b) Formula as well as (In the above formula, X 2 represents hydrogen, one of the groups X 3 and X 4 represents hydrogen,
The other represents a group having the formula -alk-X 5 , where X 5 represents a reactive esterified hydroxy group), or alk
To prepare compounds of formula () representing a 2- or 3-membered alkylene with 2 to 7 C atoms, X 2 , X 3 commonly represent alk', alk' being 2 to 7
represents a 2- or 3-membered alkylene having C atoms, and X 4 represents hydrogen;
b) The compound or its salt is subjected to intermolecular condensation, or the compound of formula (in the above formula, X 5 represents a reactive esterified hydroxy), or c) alk has 2 to 7 C atoms and both N-
To prepare compounds of formula () representing an alkylene group whose atoms are separated by two or three C atoms, the formula (wherein alk' represents an alkylene group having 2 to 7 C atoms and separating the C and N atoms by 2 or 3 C atoms) or d) with a compound having the formula or a salt thereof (in the above formula, X 7 represents a group that can be converted into R), converting X 7 to R and, if desired, converting the compound obtained according to the method of the present invention or another method. converting into another compound according to the invention and/or converting the salt obtained according to the process according to the invention into the free compound or another salt; and/or
By converting the compound having salt-forming ability obtained according to the method of the present invention into a salt and/or separating the isomer mixture obtained according to the method of the present invention into separate isomers, It is manufactured by a known method.
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ã«ã§ãã€ãŠãããã Examples of esterified carboxy include optionally substituted lower alkoxycarbonyl (e.g. ethoxycarbonyl), in particular reactive esterified carboxy such as optionally lower alkoxy, or to carbamoyl which may be substituted. Thus further activated vinyloxycarbonyl (e.g. 1-lower alkoxyvinyloxycarbonyl such as 1-ethoxyvinyloxycarbonyl or 2-(N-ethylcarbamoyl)-vinyloxycarbonyl)
-(N-lower alkyl-carbamoyl), phenoxycarbonyl or thiophenoxycarbonyl substituted if necessary, for example by nitro, halogen, lower alkanesulfonyl or phenylazo (for example 4-nitro-, 2,4 , 5-trichloro-, pentachloro-, 4-methanesulfonyl-, 4-phenylazo-phenoxycarbonyl,
thiophenoxy- or 4-nitrothiophenoxycarbonyl), as well as similarly activated, e.g. substituted by cyano, and substituted by carboxy, which may also be esterified.
Methoxycarbonyl, especially cyanomethoxycarbonyl. Reactive esterified carboxy is
1,1- or 1,3-disubstituted 2-isoureidocarbonyl, e.g. , 1,1-diethyl-, 1,1-diphenyl- or 1,1-dibenzyl-2-isoureidocarbonyl), 1,3-dicycloalkyl-for example 1,3-dicyclohexyl-2-isoureido-carbonyl, N-alkyleneaminooxycarbonyl, e.g. N-piperidinyl-
It can be oxycarbonyl as well as N-imido-oxycarbonyl, such as N-succinimido-oxy- or N-phthalimido-oxy-carbonyl.
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chlorocarbonyl), azidocarbonyl, halophosphoryloxycarbonyl (e.g. dichlorophosphoryloxycarbonyl), lower alkanoyloxycarbonyl which may be substituted by halogen or aryl (e.g. pivaloyloxy, trifluoroacetyloxy- or phenylacetoxycarbonyl) ). The dehydrated (anhydrized) carboxy may also be a symmetrically anhydrified carboxy having the formula R-Ar 1 -CO-O-CO-.
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ããã The condensation (N-acylation) according to the process of the invention is carried out in a manner known per se, if necessary, in particular in the presence of a basic condensing agent. Bases include, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates,
triphenyl methylide, di-lower alkylamide,
aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkyl amines,
There are basic heterocyclic compounds, ammonium hydroxide, and carbocyclic amines. Particularly preferred examples include sodium hydroxide, sodium hydride, sodium amide, potassium tertiary butyrate, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-
(aminopropyl)-amide, potassium-bis-
(trimethylsilyl)-amide, dimethylaminonaphthalene, di- or triethylamine, ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyl-trimethyl-hydroxide
Ammonium, 1,5-diazabicyclo [4.3.0]
These include nonene-5 (DBN) as well as 1,8-diaza-bicyclo[5.4.0]undecene-7 (DBU), phosphines (eg triphenylphosphine), halosilanes (eg tetrachlorosilane).
When X 1 represents carboxy, the corresponding ammonium salt is first formed, which can be treated by heating or by using a suitable dehydrating agent, such as a carbodiimide (e.g.
N,N'-dilower alkyl-, such as N,N'-diethyl-, N,N'-diisopropyl- or N,N'-dicyclohexyl-carbodiimide);
or by treatment with N,N'-dicycloalkyl-carbodiimide, advantageously N-hydroxysuccinimide, 1-hydroxy-benzotriazole (optionally substituted with halogen, lower alkoxy or lower alkyl), N-hydroxy-
5-norbornene-2,3-dicarboxamide,
Alternatively, it can be dehydrated with addition of N,N-carbonyldiimidazole. Intermediately, for example, the corresponding 1-isoureido carbonyl compounds can also be formed with carbodiimides. In addition, as a hydrophilic condensing agent, N-ethoxycarbonyl-2-
Ethoxy-1,2-dihydroquinoline, phosphoryl cyanamide or -azide (e.g. diethylphosphoryl cyanamide or diphenylphosphoryl azide), triphenylphosphine-disulfide or 1-lower alkyl-2-halo-piperidinium-halide (e.g. , 1-methyl-2-chloro-piperidinium diodide) may also be used.
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In order to prepare optionally substituted lower alkoxycarbonyl), the free acid (X 1 represents carbonyl) or an acid anhydride (X 1 represents e.g. halocarbonyl) is usually used as a starting material. This is then reacted, for example, with the corresponding alcohol, if necessary in reactive form, such as a lower alkyl halide. The preparation of compounds having the formula (a) (in which X 1 represents vinyloxycarbonyl, optionally further activated) can be produced, for example, by reaction of a lower alkyl ester with vinyl acetate (activated vinyl ester process); 1, according to the free acid of the compound of formula (a) and a lower alkoxyacetylene (e.g., ethoxyacetylene method) or, for example, the Woodward method.
This can be accomplished by reaction with 2-oxazolium salts. A compound of formula (a) containing an optionally substituted phenoxy- or thiophenoxycarbonyl is prepared by reacting it with the corresponding (thio-)phenol starting from the free acid, for example by the carbodiimide method. It can be manufactured by Similarly, starting from the free acid of formula (a), this can be reacted, for example, with a haloacetonitrile (e.g. chloroacetonitrile) (cyanomethyl ester method) or with a carbodiimide or cyanamide (carbodiimide or cyanamide method). Compounds of formula (a), in which X 1 represents activated methoxycarbonyl or 1,1- or 1,3-disubstituted 2-isoureidocarbonyl, are obtained. The N-alkyleneaminooxycarbonyl- or N-imido-oxycarbonyl compounds of formula (a) can be prepared, for example, from the corresponding N-hydroxy compound using the free acid of formula (a) by converting the activated N-hydroxy It can be carried out with carbodiimides according to the ester method. To produce a compound of formula (a) (X 1 in the formula represents lower alkoxycarbonyloxycarbonyl, halophosphoryloxycarbonyl, or optionally substituted alkanoyloxycarbonyl, which may have a branch) , for example, a free acid of formula (a) may be used as a starting material, which free acid may be, for example,
Corresponding halides (e.g. optionally substituted lower alkyl carbonate halides) (mixed o-
(anhydrous carbonic acid method) or with a phosphoryloxyhalide (e.g. phosphoroxychloride method) or with an optionally substituted lower alkanoyl halide (mixed carboxylic acid halide method). The azide compound of formula (a) can be obtained, for example, by treating the corresponding hydrazide with nitric acid (azide method). A compound of formula (a) (wherein X is optionally substituted 1-imidazolyl-carbonyl or 1
-pyrazolyl-carbonyl), the free acid of formula (a) is reacted, for example with di-(1-imidazolyl)-carbonyl (imidazolide process) or the related hydrazide, for example with , 3-diketone (pyrazolide method).
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ããšãã§ããã The starting material of formula (b) (X represents a carbonyl group) can be, for example, a compound of formula Ar2 -H(c) reacted with pyridine-4-carboxylic acid or a reactive derivative thereof in the same manner as in the Friedel-Crafts reaction. acylation in the presence of a Lewis acid. formula This obtained compound, denoted by the formula
Hal-alk-NH 2 (e) (in the formula, Hal is halogen,
(for example, bromine) in the presence of a base to convert it into the corresponding compound of formula (b). Reducing the carbonyl group X to form a hydroxymethylene group can be achieved by formula (d) or (
Starting from the compound of b), for example with a suitable metal hydride, such as lithium aluminum hydride or sodium borohydride, and the reductive conversion of the carbonyl group via the oxymethyl group to the methylene group, For example, each can be carried out by catalytic hydrogenation in the presence of a hydrogenation catalyst.
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For example, by converting methylene groups by catalytic hydrogenation, the product compound with a halonitrile, such as chloroacetonitrile, is condensed in the presence of a base, such as ethyl-diisopropylamine, and then by catalytic hydrogenation, the cyano group The compound of formula (b) (in the formula, X represents a methylene group) can also be obtained by converting into an amino group.
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ãã³ãŸã€ã«ãªãã·ãè¡šãããProcess form b) Reactive esterified hydroxy , halosulfonyloxy (e.g. fluorosulfonyloxy), lower alkanesulfonyloxy optionally substituted by halogen (e.g. methane- or trifluoromethane-sulfonyloxy), cycloalkanesulfonyloxy (e.g. cyclohexane-sulfonyloxy), ), if necessary, e.g.
Benzenesulfonyloxy substituted by lower alkyl or halogen (e.g. p-brolphenyl- or p-toluenesulfonyloxy), optionally lower alkanoyloxy substituted by e.g. halogen (e.g. acetyl- or trifluoroacetyloxy) ) or optionally represents benzoyloxy substituted, for example by lower alkyl, lower alkoxy, halogen and/or nitro.
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ã°ãããã©ã¯ããã·ã©ã³ïŒãããã Condensation (N-alkylation) according to the method of the invention
is carried out in a manner known per se, if necessary in the presence of a base. Bases include, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di-lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkyl amines. , basic heterocyclic compounds, ammonium hydroxide as well as carbocyclic amines may be used. Examples of bases include sodium hydroxide, sodium hydride, sodium amide, potassium tert-butyrate, potassium carbonate, lithium-triphenylmethylide, lithium-triphenylmethylide, lithium-diisopropylamide, potassium-3- (aminopropyl)-
Amide, potassium-bis-(trimethylsilyl)-
Amide, dimethylaminonaphthalene, diethylamine, triethylamine, ethyldiisopropylamine, N-methylpiperidine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5
-Diaza-bicyclo-[4.3.0]nonene-5
(DBN), 1,8-diaza-bicyclo[5.4.0]undecene-7 (DBU), phosphine (eg, triphenylphosphine), and halogensilane (eg, tetrachlorosilane).
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usually in its presence, at room temperature or under heat, for example at a temperature of about 0°C to about 200°C, preferably at a temperature of room temperature to about 150°C, if necessary in a closed container,
If necessary, it is also carried out under pressure and/or under an inert gas.
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Obtained by treatment with amine (e). The starting material of formula (a), in which X 2 and X 3 together represent alk', alk' represents a 2- or 3-membered alkylene having 2 to 7 C atoms, in particular ethylene, is As an example, obtained by N.acylation of the corresponding aziridine or azetidine with a compound of formula (a) or a reactive acid derivative thereof, for example in the presence of a base (eg triethylamine). The starting material of formula (a), in which X 2 and X 3 represent hydrogen, is the starting material of formula (d)
is obtained by reacting the corresponding compound of or a reactive derivative thereof with ammonia.
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can directly lead as such to the corresponding target compound of formula ().
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It can be obtained by amidation under normal conditions with an excess of the compound alk- NH2 (h). The compound of formula (i) may, by way of example, have the formula CH2 - CH2
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Di-lower alkylamides, aminoalkylamides or lower alkylsilylamides, naphthalene amines, lower alkyl amines, basic heterocyclic compounds, ammonium hydroxide or carbocyclic amines may be used. Examples of bases include sodium hydroxide,
Sodium hydride, sodium amide, potassium tert-butyrate, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium-3-(aminopropyl)-amide,
-bis-(trimethylsilyl)-amide, dimethylaminonaphthalene, diethylamine, triethylamine, ethyldiisopropylamine, N-methyl-piperidine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo[4.3.0]nonene -5 (DBN), 1,8-diaza-bicyclo[5.4.0] undecene-7 (DBU),
phosphine (e.g. triphenylphosphine),
Halogen silane (e.g. tetrachlorosilane)
There is.
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ãããããããã·ãè¡šããïŒãèªå°ãããã The substitution of the diazonium group X 7 by hydroxy in compounds of formula () can be carried out in an aqueous medium analogous to "phenol enrichment", but the diazonium salt of formula () can be replaced with an aliphatic alcohol, especially , a lower alkanol leads to a compound of formula () in which R represents hydroxy etherified with an aliphatic alcohol.
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It exists as.
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ãããšãã§ããã For this reaction, for example, Cu() ions can be used as a catalyst according to the Sandmeyer reaction, copper powder according to the Gutzterman reaction, and Cu() ions according to the Kellner-Contaldei reaction. . In order to introduce fluorine into the corresponding compound of formula (), a diazonium salt of formula () is used as a starting material according to the Seeman reaction, and this is combined with hydroborofluoric acid or its salt, in particular an alkali metal It is reacted with a salt or, according to a variant of this reaction, with the corresponding pentafluorosilicate or hexafluorophosphate. The salt having the corresponding diazonium fluorine complex produced in this case can be thermally decomposed, especially in a dry state, to form a compound of the formula (2) (wherein R represents fluorine).
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X 8 represents an amino group, if necessary advantageously protected by a readily cleavable acyl group. condensation and recleavage of any amino protecting groups that may be dependent. The expression obtained in this way In the compound represented by , the amino group can be converted into the corresponding ionic group X 7 by diazotization in the conventional manner in the presence of an acid, for example with nitric acid or nitrite, as known per se. can.
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As long as Ar 1 and Ar 2 are substituents, they are correspondingly hydrolyzed or esterified at the same time.
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In this case it is preferably operated in the presence of a base. Hydroxy groups esterified with organic carboxylic acids as substituents of aromatic groups Ar 1 and Ar 2 can be simultaneously converted into hydroxy groups etherified with aliphatic alcohols during the reaction. .
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These protecting groups include, for example, 1-aryl lower alkoxycarbonyloxy (e.g. benzyloxycarbonyloxy optionally substituted in the phenyl ring, e.g. by halogen), 1-aryl lower alkoxy (e.g. for example benzyloxy substituted in the phenyl moiety by, for example, halogen or lower alkoxy) or silyloxy (for example tri-lower alkylsilyloxy optionally substituted).
There is. Examples of corresponding preferred groups include benzyl-, 2- or 4-bromobenzyloxycarbonyloxy, benzyloxy, 3-bromo-,
2,6-dichloro- or 4-methoxybenzyloxy or trimethylsilyloxy.
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ã«ããããããã·ïŒ²ã«å€æãããããšãã§ããã These groups X 7 can be converted into hydroxy R in methods known per se, for example by hydrolysis, acidolysis or reduction.
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ãã·ã«åºã«å€æãããã®ã奜ãŸããã The 1-aryl lower alkoxycarbonyloxy or silyloxy group is preferably converted to a hydroxyl group by hydrolysis.
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åžžã䜿çšãããã For acidolysis, strong acids such as mineral acids (e.g. hydrohalic acid), perchloric acid, if necessary,
Optionally substituted lower alkane carboxylic acids or sulfonic acids (eg, optionally substituted benzenesulfonic acid) or mixtures of these acids are typically used.
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ã·åã¯ïŒâã¢ãªãŒã«äœçŽã¢ã«ã³ãã·ãããã Examples of corresponding groups convertible to hydroxy R include 1-aryl lower alkoxycarbonyloxy or 1-aryl lower alkoxy.
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çã«è»¢åãããããšãã§ããã These groups can be subjected to hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst, e.g. 1-aryl lower alkoxycarbonyloxy, in addition to reduction with a metal system consisting of a metal component and a hydrogen donating component, such as a sodium/ammonia system. Therefore, it can also be reductively converted to hydroxy.
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æ§ã¬ã¹é°å²æ°äžã§è¡ãããšãã§ããã These reactions are carried out in a manner known per se, at low or high temperatures, in the presence of solvents or diluents, if necessary, in a temperature range of about 50°C to about 150°C, in closed containers, and if necessary. For example, it can be carried out under an inert gas atmosphere.
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ãããšã«ãã€ãŠåŸãããã Starting materials of formula (), in which X 7 represents an acyloxy group or a protected hydroxy group, can be prepared by preparing a compound having the formula X 7 -Ar 1 -X 1 (d) by the method shown in process mode a). Similarly, it can be obtained by condensation with a compound having formula (a).
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ããšãã§ããã Compounds according to the invention obtained according to the process according to the invention or other processes can be converted into further compounds according to the invention by methods known per se.
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Oxymethyl groups can be esterified with organic carboxylic acids, such as lower alkane carboxylic acids. This esterification can be carried out if necessary in the presence of an acid, for example a protic acid (for example a mineral acid or a sulfonic acid) or a Lewis acid (for example the corresponding halide of an element of main group 3 or a corresponding subgroup). , by treatment with the desired carboxylic acid or reactive derivative, for example an acid anhydride or a halide, in a manner known per se.
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å解ã«ãã€ãŠéé¢ãããããšãã§ããã The esterification may be carried out in the presence of bases, such as alkali metal hydroxides or carbonates, amines or cyclic organic nitrogen-containing bases, or dehydrating agents, such as customary carbodiimides. Conversely, the hydroxy group in a group having an esterified hydroxy can also be liberated, for example, by solvolysis using a base catalyst.
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Alternatively, it can be carried out under pressure, optionally in a closed container.
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è¡ãããããšãã§ããã Compounds according to the invention containing hydroxy are
The etherification can be carried out by methods known per se. This etherification may be carried out, for example, with alcohols (eg, optionally substituted lower alkanols) or reactive esters thereof. Reactive esters of the desired alcohols include esters of strong organic or inorganic acids, such as the corresponding halides, sulfates, lower alkanesulfonates, optionally substituted benzenesulfonates (e.g. chlorides). , bromide, iodide, methanesulfonate, benzenesulfonate or p-toluenesulfonate).
Etherification may be carried out, for example, in the presence of a base, an alkali metal hydride, hydroxide or carbonate, or a basic amine. Conversely, strong acids, such as mineral acids (hydrohalic acids such as hydrobromic acid or hydroiodic acid, preferably present in the form of halogenated pyridines) or Lewis acids, such as those of the third main group or the corresponding The corresponding ethers, for example lower alkoxy compounds, can be decomposed by means of the halides of elements of the subgroups (halides of elements of the subgroups). These reactions are carried out under inert gas and/or pressure, in the absence or presence of a solvent or diluent, with cooling or heating if necessary, e.g., at temperatures from about -20°C to about 100°C. , if necessary, can be carried out in a closed container.
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ãã§ããã In compounds according to the invention having a hydroxy lower alkyl group, the hydroxy group can be converted to a halogen, for example chlorine, by treatment with a suitable halogenating agent, for example thionyl chloride.
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ã«ãããŠè¡ãããããšãã§ããã When the aryl groups Ar 1 and Ar 2 have a cyano group as a substituent, this cyano group can be removed, for example, by hydrolysis, preferably under acidic or basic conditions, for example in the presence of an alkali metal hydroxide. ,
If desired, it can also be converted to a carbamoyl group in the presence of hydrogen peroxide in a water-alcoholic solvent. These reactions are carried out in the presence or absence of a solvent or diluent, with cooling or heating if necessary, e.g., in the temperature range of about 0°C to about 150°C, sometimes even higher. This can be carried out under inert gas and/or pressure, if necessary in a closed container.
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ãããšãã§ããã In the compounds of the present invention, when Ar 1 or Ar 2 contains cyano as a substituent, these compounds can be treated with an alcohol (e.g., lower alcohol) in the presence of an acid (e.g., hydrochloric acid). For example, it can be converted to alkoxycarbonyl.
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çããããšã«ãã€ãŠãååŸãããã In addition, in the compound of formula () (in which Ar 1 or Ar 2 has a carboxy group as a substituent), a suitable esterification agent, such as an acidic reagent (such as hydrochloric acid, trifluoroacetic acid or in the presence of organic and inorganic acids such as p-toluenesulfonic acid or Lewis acids such as zinc chloride) or hydrophilic condensing agents (e.g. carbodiimides such as N,N'-dichlorohexyl-carbodiimide). For example, a carboxy group can be converted to an esterified carboxy group by treatment with an alcohol such as a lower alkanol, or alternatively by treatment with a diazo reagent (eg, a diazo lower alkane such as diazomethane).
This esterified carboxy group is present in the compound of formula () (in the formula, Ar 1 or Ar 2 is in the form of an ammonium salt or a metal salt (for example, an alkali metal salt such as a sodium salt or a potassium salt)). reactive esters of alcohols (such as methyl chloride, ethyl chloride, methyl bromide, ethyl bromide, methyl iodide or ethyl iodide) lower alkyl halides)
or by treatment with an organic sulfonic acid ester (for example methanesulfonic acid- or p-toluenesulfonic acid methyl or -ethyl ester).
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Ar 2 has an esterified carboxy group as a substituent) is a suitable esterifying agent, such as a basic reagent (sodium acetate, sodium methylate,
An alcohol (usually corresponding to that of the carboxy group to be esterified in the starting material) in the presence of an alkali metal lower alcoholate such as sodium ethylate, sodium tert-butyrate or sodium cyanide) or in the presence of a suitable acidic reagent. If necessary, the corresponding alcohol can be separated off by distillation, for example, to obtain the formula
can be converted into another ester compound. Starting material is the corresponding so-called activated ester having the formula (in which Ar 1 or Ar 2 carries an activated esterified carboxy group as a substituent as described below) (see below), and this It is also possible to convert them into other esters by treating them with alcohols, for example substituted alkanols.
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ããã·åºã眮æåºãšããŠæããïŒãçæãããã Compound of formula () (in the formula, Ar 1 or Ar 2 has an amidated carboxy group as a substituent)
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formamide, reacted with urea at elevated temperatures of 0.degree.
For example, by reacting with dimethylformamide at elevated temperature or with a suitable condensing agent, e.g. a carbodiimide such as N,N'-diethyl-carbodiimide, a phosphine (e.g. with bis-2-pyridyl-disulfide), e.g. triphenyl. By reacting with an amine in the presence of a phosphine, or a silane, e.g. trichlorosilane (e.g. together with pyridine), the corresponding amide compound of formula (), where Ar 1 or Ar 2 is an amidated carboxy group having as a substituent) can be produced. Furthermore, the corresponding ammonium salt,
For example, by treating with a dehydrating agent such as phosphorus pentoxide,
or also by reacting the corresponding alkali metal salt, e.g. the sodium salt, with an amine, preferably in the presence of a suitable condensing agent, e.g. In the formula, Ar 1 or Ar 2 has a carboxy group as a substituent which is present in the salt form).
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ãã In compounds of formula () in which the carboxy group has a carboxy group as an Ar 1 or Ar 2 substituent, the carboxy group can be removed from the mixed anhydride (e.g. by treatment with a thionyl halide such as thionyl chloride). anhydrides, including reactive derivatives such as acid halides (e.g. chlorides), or (halogen esters such as chloroformates, e.g. lower alkyl esters) salts, e.g. ammonium salts or alkali metal salts. or alternatively (by treatment with a suitable condensing agent, e.g.
activated esters (by treatment with the corresponding hydroxy compound in the presence of N,N'-dicyclohexyl-carbodiimide), e.g. cyan methyl ester, nitrophenyl ester (e.g. 4
-nitro-phenyl ester) or polyhalogen phenyl (eg pentachlorophenyl ester), respectively. This reactive derivative is then reacted with ammonia or an amine (in derivative form if necessary) to give an amide compound of formula (), where Ar 1 or Ar 2 carries an amidated carboxy group as a substituent. be able to. This compound is obtained both directly and via intermediates. That is, an activated ester of a compound of formula () having a carboxy group (e.g. 4-
A 1-imidazolyl carbonyl compound obtained by first reacting a nitrophenyl ester) with a 1-unsubstituted imidazole may be reacted with ammonia or an amine. Alternatively, other unactivated esters, such as lower alkyl esters, of the compound of formula () (in which Ar 1 or Ar 2 has as a substituent, e.g. lower alkoxycarbonyl) can be reacted with ammonia or an amine. You may let them.
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ã§ããã In compounds according to the invention in which the radicals Ar 1 or Ar 2 carry a free amino, carbamoyl or sulfamoyl group, the respective amino group can be substituted mono- or disubstituted, as described above in connection with process mode b). It can be done. Similarly, the Lutzkart-Waltzha reaction (or Eschweiler)
Clarke reaction), using formic acid as a reducing agent, convert primary or secondary carbonyl compounds into
It is also possible to reductively alkylate primary amino groups.
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åºãšããããšãã§ããã In the compound of the present invention in which X represents a carbonyl group, a suitable hydride (a complex hydride may also be used) produced from an element of the first and third main groups of the periodic table.
For example, a carbonyl group can be converted to an oxymethyl group X by treatment and reduction with sodium borohydride or sodium cyanoborohydride. The oxymethyl group X itself can be reduced with hydrogen, for example, using a hydrogenation catalyst to form a methylene group.
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å æ°Žå解ããããšãã§ããã In compounds according to the invention in which X represents a carbonyl group, this group is substituted with an alcohol such as a lower alkanol in the presence of an acid such as a mineral acid (e.g. sulfuric acid or hydrochloric acid) or a sulfonic acid (e.g. p-toluenesulfonic acid). or lower alkanediols, such as ethanol or glycols, and the acetalized carbonyl group X can be hydrolysed in turn with acids of the type mentioned above.
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žãšã®æ··åç©ã§ããã When the aromatic ring Ar 1 is substituted with lower alkylthio, this can be oxidized in a conventional manner to form the corresponding lower alkanesulfinyl or -sulfonyl. Examples of suitable oxidizing agents to oxidize to the sulfoxide stage include inorganic peracids,
For example, mineral peracids (e.g. periodic acid or persulfuric acid), organic peracids such as the corresponding percarboxylic or persulfonic acids (e.g. performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid or p-Toluene persulfonic acid or a mixture of hydrogen peroxide and an acid, such as a mixture of hydrogen peroxide and acetic acid.
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ïŒ100âã®æž©åºŠã§è¡ãã Oxidation is often carried out in the presence of a suitable catalyst;
Examples of acids suitable as catalysts in this case include optionally substituted carboxylic acids such as acetic acid or trifluoroacetic acid or oxides of transition metals such as oxides of elements of the subgroup (e.g. vanadium, molybdenum or There are various oxides of tungsten).
Oxidation is carried out under mild conditions, for example at temperatures of about -50°C to about +100°C.
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žåå€ãéåžžçšããããã The oxidation to the sulfone stage can be carried out in the presence of oxygen at correspondingly low temperatures using dinitrogen tetroxide as a catalyst, similar to the direct oxidation of lower alkylthio to lower alkanesulfonyl. However, in this case an excess amount of oxidizing agent is usually used.
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ãã When the aromatic ring Ar 1 or Ar 2 has a hydrogen atom as a substituent, this hydrogen atom can be exchanged with a halogen atom using a halogenating agent in a conventional manner, such as bromine, hypobromous acid, acyl hypobromite. acids or other organic bromine compounds such as N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridine perbromide, dioxane dibromide,
1,3-dibromer-5,5-dimethylhydantoin, brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one),
or, for example, halogenated hydrocarbons (e.g.
Chlorination is carried out with elemental chlorine in chloroform) while cooling to a temperature of, for example, about -10°C to about +10°C.
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aromatic rings, for example by exchanging a halogen atom (especially iodine or bromine) with a cyano group, by reaction under heating, in the presence or absence of a solvent or diluent, and preferably in an inert gas.
A cyano group can be introduced into Ar 1 .
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ãšãŠçŽ 䞊ã³ã«ã·ã¢ãåºã«ãã眮æãããã§ããã When the aromatic group Ar 1 or Ar 2 in the compounds of the invention has an amino group, a nitrite, e.g. By treatment with sodium nitrate, the amino group can be diazotized in a conventional manner. The abovementioned diazonium groups in the salt form thus obtained can be substituted by hydroxy groups in the presence of water, e.g. by analogous methods and analogous to phenol enrichment;
Treatment with the corresponding alcohol and substitution by an alkoxy group (with supply of energy) or substitution by a fluorine atom in analogy to the Siemann reaction for thermal decomposition of the corresponding diazonium tetrafluoroborate. Halogen elements such as chlorine, bromine, etc. can be prepared by first cooling to about 5°C and then heating from about 60°C to about 150°C, similar to the Sandmeyer reaction with the corresponding copper() salt. Alternatively, it can be substituted with iodine or a cyano group.
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ãŠã¢ããåºãšããããšãã§ããã The compounds according to the invention contain an aryl group Ar 1 or
If Ar 2 carries a nitro group, this group can be reduced to an amino group in a manner known per se, for example by catalytic hydrogenation.
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ã§ããã Further, the aromatic ring Ar 1 or Ar 2 can be alkylated with a lower alkanol, a lower alkyl halide, or a phosphoric acid lower alkyl ester in the presence of a Lewis acid (Friedel-
Crafts-alkylation reaction). In compounds of formula () in which the aromatic ring has bromine, bromine can be exchanged with lower alkyl by reacting with bromide of lower alkyl in the presence of an alkali metal.
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¥ããããšãã§ããã When the aromatic ring has a hydrogen atom as a substituent,
This atom can be exchanged for an acyl group by methods known per se. Lewis acids such as aluminum chloride, antimony chloride ()
or by reaction of reactive acyl-functional derivatives such as halides or anhydrides of organic carboxylic acids in the presence of iron chloride (2), zinc chloride (2), or boron trifluoride. Crafts-acylation reaction (GAOlah, Friedel-Crafts
and Related Reactions, vol.1, Interscience,
New York, 1963-1965).
Acyl groups can be inserted.
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ãã If the compounds of formula () contain unsaturated groups, such as lower alkenyl or lower alkadienyl groups, these groups can be converted into saturated groups, as is known per se. For example, multiple bonds can be hydrogenated by performing catalytic hydrogenation in the presence of a hydrogenation catalyst. For this purpose, noble metals or their derivatives, such as oxides, such as nickel, Raney nickel, palladium, platinum oxide, are suitable, which may, if necessary, be deposited on a support material such as carbon or calcium carbonate. Hydrogenation may particularly be carried out at a pressure of 1 to about 100 atmospheres and a temperature of about -80°C to about 200°C, especially room temperature to about 100°C. Also preferably a solvent such as water,
The reaction is suitably carried out in a lower alkanol (eg ethanol, isopropanol or n-butanol), an ether (eg dioxane) or a lower alkane carboxylic acid (eg acetic acid).
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äŸããã The present invention provides, among other things, the methods illustrated in each example.
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ã§ãååŸãåŸãã Depending on the choice of reaction conditions, the starting materials may be used in free form or as salts, and the compounds of the invention having salt-forming properties can be obtained both in free form and in salt form.
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å€æãããããšãã§ããã The acid addition salts obtained can thus be converted into the free compounds in a manner known per se, for example by treatment with a base (for example an alkali metal hydroxide) and with a suitable acid or derivative thereof. Each can be converted into another salt by treatment. The free compounds obtained which are salt-forming and basic can be converted into their salts, for example by treatment with acids or corresponding anion exchangers.
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ãã Since there is a close relationship between a salt-forming compound and a free form of a salt-forming compound, in the description of this specification, the expression free compound or salt refers to the corresponding salt. or free compounds are intended to be included according to the meaning and purpose of this invention. Salts which are unsuitable for pharmaceutical use are also encompassed by the aforementioned salts, since they can be used for the isolation or purification of the free compound and its pharmaceutically usable salt according to the invention.
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ããŠããŠãããã The compounds according to the invention, including the salts of the corresponding salt-forming compounds, can also be obtained in the form of their hydrates, the crystals of which may, for example, contain the solvent used for crystallization.
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ãšããŠååšããŠãããã Depending on the choice of the starting materials and the mode of operation, the novel compounds according to the invention can be obtained in the form of possible isomers or as mixtures thereof, and also in pure optically isomeric forms, e.g. according to the number of asymmetric carbon atoms. They may exist as isomers, such as enantiomers, or as isomeric mixtures, such as racemates, diastereomeric mixtures or racemic mixtures.
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ããã The obtained diastereomeric and racemic mixtures can be separated into pure isomers on the basis of the physicochemical differences of their components, for example by chromatography using adsorbents exhibiting chirality and/or by fractional distillation. It can be resolved by known methods into compounds, diastereomers or racemates. The racemates obtained can be further processed according to known methods, e.g. by recrystallization from optically active solvents, with the aid of microorganisms, e.g. via clathrates, using crown ethers exhibiting chirality. resolution with an insolubilizing enzyme (in this case, the enantiomers form a complex), or an optically active acid or an optically active carboxylic acid that forms a salt with a racemic base, or a reactive derivative thereof and a basic racemic target substance. reaction and separation of the diastereomeric mixture thus produced into individual diastereomers on the basis of their solubility differences, and then action of appropriate reagents to liberate the desired enantiomer. Conversion of stereomers into salts or esters resolves them into their optical antipodes. Preferably, the active enantiomer is isolated.
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æ§ãæäŸããã The invention provides for the use as starting materials of the compounds obtained as intermediates in the appropriate process steps for carrying out the subsequent steps or also for the use of derivatives or salts and/or their racemates or enantiomers, in particular producing under reaction conditions,
Embodiments of the method of the invention are also provided.
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æããã The process of the invention particularly employs starting materials that lead to the formation of the compounds listed above as particularly useful. Also included within the scope of the invention are new starting materials specifically developed for the preparation of the compounds according to the invention, for example their use as intermediates or pharmaceutically active substances, as well as processes for their preparation, in which R, AR 1 ,
Symbols such as alk, X and Ar2 have preferred meanings for each preferred group of compounds of formula ().
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100mg or approximately 0.7-70mg range.
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äŸããã The invention further provides a process for the preparation of pharmaceutical preparations containing as active substance a compound of formula () or a pharmaceutically acceptable salt of these salt-forming compounds.
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ããã The pharmaceutical preparations according to the invention are intended for enteral administration, e.g. oral or rectal administration, as well as parenteral administration to warm-blooded animals, in particular in corresponding dosage unit forms for oral administration, e.g. Dragees, tablets or capsules preferably contain from about 1 to about 100 mg of the compound of formula () or a pharmaceutically acceptable salt thereof, particularly from about 1 to about 25 mg.
mg, together with a pharmaceutically acceptable carrier material.
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For example, starch paste (corn starch, wheat starch,
(Using rice starch or potato starch)
Gelatin, tragacanth, methylcellulose and/or, if desired, disintegrants, such as the starches mentioned above, carboxymethyl starch, cross-linked polyvinyl-pyrrolidone, agar, alginic acid or its salts (eg sodium alginate). Auxiliaries are primarily lubricants and lubricants, such as silicic acid, talc, stearic acid or its salts (eg magnesium or calcium stearate), and/or polyethylene glycols. The core of the dragee can be provided with a suitable, if necessary, antigastric coating, which in particular contains a concentrated sugar solution (if necessary, gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide) or a lacquer solution in a suitable organic solvent or solvent mixture; or (in the case of anti-gastric coatings)
A solution of a suitable cellulose preparation (eg acetylcellulose phthalate or oxypropylmethylcellulose phthalate) is used. Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or identification of the various active substance doses.
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ãããã®ãã«ãã»ã«ãšããŠç¹ã«å¥œé©ã§ããã Other orally administrable pharmaceutical preparations include insert capsules made of gelatin and closed capsules made of gelatin and a softening agent, such as glycerin or sorbitol. The plug-in capsules can contain the active substances in the form of granules in a mixture consisting of a filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, if necessary, stabilizers. May be contained. In soft capsules, the active substance may be dissolved or suspended in a suitable liquid, for example fat, paraffin oil or liquid polyethylene glycol, to which stabilizers may also be added. Capsules that are not only easily chewable but also swallowable without chewing are particularly suitable.
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åæ°ŽçŽ ãããã Pharmaceutical preparations that can be used for rectal administration include suppositories, which consist of a combination of the active substance and a suppository base, which may contain, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, Polyethylene glycols or higher alkanols are suitable. Gelatin-rectal capsules containing a binder between the active substance and the base may also be used;
This base material includes, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.
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å€ãå«æããæ°Žæ§ã®æ³šå°çšæžæ¿äœãçšããããã Suitable for parenteral administration are primarily aqueous solutions of the active substances in aqueous form, for example aqueous salt forms, and also suspensions of the active substances, such as the corresponding oily injection suspensions. , in which case suitable lipophilic solvents or excipients, such as fats and oils (for example sesame oil), synthetic fatty acid esters (for example ethyl oleate) or triglycerides, and also thickeners such as sodium carboxymethylcellulose, sorbitol and/or Alternatively, aqueous injection suspensions containing dextran and, optionally, stabilizers are employed.
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ãã The pharmaceutical preparations according to the invention can be prepared in a manner known per se, for example by customary mixing, granulating,
It is produced by methods such as sugar coating, dissolution, or lipophilization. Thus, pharmaceutical preparations for oral use are prepared by combining the active substance with a solid carrier, granulating the mixture obtained if necessary, and converting the mixture or granules into tablets after adding appropriate auxiliary substances, if desired or desired. Alternatively, it is manufactured by processing the core of sugar-coated pills.
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ãã枩床ã¯ææ°ïŒâïŒã§ç€ºãããŠããã Next, the present invention will be explained using specific examples, but these examples are not intended to limit the present invention. Temperatures are given in degrees Celsius (°C).
äŸ ïŒ
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ããèç¹167ã169âã®çœè²ç²æ«ãšããŠåŸããExample 1 4-(p-fluorobenzoyl)-piperidine
Dissolve 41.4g (0.2mol) in 120ml of dioxane,
28.3 g (0.1 mol) of N-(2-bromoethyl)-5-cyano-2-methoxy-benzamide was added;
Stirred at room temperature for 60 hours. Next, potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride solution was washed neutral with water and concentrated under reduced pressure with a stream of water. 200% of the remaining pale yellow crystals
The suspension was suspended in 1 ml of ethanol and stirred for 2 hours. The solid product is then filtered and added to freezing point ethanol.
Washed with 20ml. 5-cyano-N- from the filtrate
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide was obtained as a white powder with a melting point of 167-169°C.
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ã¯ããªãïŒèç¹193ã194âïŒãåŸãã To convert to the hydrochloride salt, the free base was then dissolved in methylene chloride and reacted with an ethereal solution of hydrochloric acid until the Congo indicator showed acidity. Ether was then added until crystallization started. This results in 5-cyano-N-[2-[4
-(p-fluorobenzoyl)-piperidinyl]-
Ethyl]-2-methoxy-benzamide-hydrochloride (melting point 193-194°C) was obtained.
åºçºç©è³ªã¯æ¬¡ã®ããã«èª¿è£œããã The starting material was prepared as follows.
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é ããç²ïŒâã·ã¢ãâïŒâã¡ããã·âå®æ¯éŠé
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ããªã39.1ïœïŒ0.2ã¢ã«ïŒãšïŒâããã¢ãšãã«ã¢
ãã³âããããããã45ïœïŒ0.22ã¢ã«ïŒãšãå¡©å
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ã äžã«ãããŠä¹Ÿç¥åŸãèžçºæ¿çž®ãããååŸãã
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ãŒãã«ããïŒååçµæ¶ããããèç¹119ã120âã 39.1 g (0.2 mol) of crude 5-cyano-2-methoxy-benzoic acid chloride prepared according to French Patent No. 1525M/72CAM and 45 g (0.22 mol) of 2-bromoethylamine-hydrobromide are dissolved in 300 ml of methylene chloride. 64.6 g (0.5 mol) of ethyldiisopropylamine was added dropwise to this mixture with stirring at room temperature. The clear solution obtained was stirred for 2 hours at room temperature. The methylene chloride solution was then shaken twice with 2N hydrochloric acid and once with water, dried over magnesium sulfate and concentrated by evaporation. Obtained N
-(2-bromoethyl)-5-cyano-2-methoxy-benzamide was recrystallized once from methylene chloride-ether for purification. Melting point 119-120â.
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žå¡©ãåŸããExample 2 In the same manner as in Example 1, 41.4 g (0.2 mol) of 4-(p-fluorobenzoyl)-piperidine and N-(2
-bromoethyl)-4-chloro-5-cyano-2
- From a solution obtained by dissolving 31.8 g (0.1 mol) of methoxy-benzamide in 240 ml of dioxane, the melting point
4-chloro-5-cyano-N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide-methanesulfonate was obtained.
åºçºç©è³ªã¯æ¬¡ã®ããã«èª¿è£œããã The starting material was prepared as follows.
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ž500mlåã³æ°Ž500mlã«æº¶ãããŠåŸ
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äžã«å®€æž©ã§æ·»å ããã次ã«æŽã«ïŒæéæ¹æãç¶
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âã¯ããâïŒâã¡ããã·âå®æ¯éŠé
žãçåããç
éç©ãæ°Žã§æŽæµããã 4-chloro-2-methoxybenzoic acid 37.3g
(0.2 mol) in 500 ml of acetic acid and 500 ml of water, 10.7 ml (33.6 g; 0.21 mol) of bromine was added at room temperature with stirring. Next, stirring was continued for another hour, 500 ml of water was added, and the precipitated 5-bromo-4
-Chloro-2-methoxy-benzoic acid was filtered off, and the filtrate was washed with water.
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éŠé
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79âã81âïŒãåŸãã A solution obtained by dissolving 26.5 g (0.1 mol) of 5-bromo-4-chloro-2-methoxy-benzoic acid in 150 ml of ethanol was saturated with hydrogen chloride gas and left for 15 hours. It was then evaporated under reduced pressure with a stream of water and the residue was taken up in methylene chloride and washed with sodium bicarbonate. The methylene chloride solution was dried over magnesium sulfate and then evaporated under reduced pressure with a stream of water. 5-bromo-4-chloro- as a residue
2-Methoxy-benzoic acid-ethyl ester (melting point
79°C to 81°C).
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éŠé
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ãµã³ããåçµæ¶åŸã«ã102ã103âã§è解ããã 14.7 g (0.05 mol) of 5-bromo-4-chloro-2-methoxy-benzoic acid ethyl ester, 5.4 g (0.06 mol) of copper cyanide, and 8 ml of dimethylformamide were stirred in a nitrogen gas atmosphere for 3 hours. Heated to 190°C. After cooling, the reaction mixture was thoroughly stirred with 250 ml of methylene chloride and 250 ml of 2N hydrochloric acid. The insoluble portion was then removed and the layers were separated in a separatory funnel. The methylene chloride solution was washed with water until neutral and evaporated. The 4-chloro-5-cyano-2-methoxy-benzoic acid ethyl ester obtained as a residue melted at 102-103° C. after recrystallization from methylene chloride-hexane.
ããåããããã«ãã¡ã¿ããŒã«500mlãæ°Ž100ml
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âïŒâã¡ããã·âå®æ¯éŠé
žãåŸãã For saponification, 500ml methanol, 100ml water
and 4-chloro-5- dissolved in 1N caustic soda.
24 g (0.1 mol) of cyano-2-methoxy-benzoic acid-ethyl ester was stirred for 15 hours. The methanol is then removed by suction under reduced pressure with a water jet, and 4-chloro-5 is extracted from the residual liquid by adding dilute sulfuric acid.
-Cyano-2-methoxy-benzoic acid was precipitated. This material was filtered and recrystallized from dioxane. 4-chloro-5-cyano-2-methoxy-benzoic acid with a melting point of 191-192°C was obtained.
å®æœäŸïŒãšåæ§ã«ããŠãã¯ãããã«ã 120mlã«
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12mlïŒ19ïœïŒ0.16mlïŒããïŒâã¯ããâïŒâã·ã¢
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žã¯ããªããåŸãã In the same manner as in Example 3, 8.5 g (0.04 mol) of 4-chloro-5-cyano-2-methoxy-benzoic acid and thionyl chloride were dissolved in 120 ml of chloroform.
4-chloro-5-cyano-2-methoxy-benzoic acid chloride was obtained from 12 ml (19 g; 0.16 ml).
å®æœäŸïŒãšåæ§ã«ããŠãïŒâã¯ããâïŒâã·ã¢
ãâïŒâã¡ããã·âå®æ¯éŠé
žã¯ããªã23ïœïŒ0.1
ã¢ã«ïŒãïŒâããã¢ãšãã«ã¢ãã³âãããããã
ã20.5ïœïŒ0.1ã¢ã«ïŒåã³ãšãã«âãžã€ãœããã
ã«ã¢ãã³27.1ïœïŒ0.21ã¢ã«ïŒãããèç¹127ã129
âã®ïŒ®âïŒïŒâããã¢ãšãã«ïŒâïŒâã¯ããâïŒâ
ã·ã¢ãâïŒâã¡ããã·âãã³ãºã¢ãããåŸãã In the same manner as in Example 1, 23 g (0.1
mol), 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide and 27.1 g (0.21 mol) of ethyl-diisopropylamine, melting point 127-129
N-(2-bromoethyl)-4-chloro-5- at °C
Cyano-2-methoxy-benzamide was obtained.
äŸ ïŒ
äŸïŒãšåæ§ã«ããŠïœâãã«ãªããã³ãŸã€ã«âã
ããªãžã³43.5ïœïŒ0.21ã¢ã«ïŒãâïŒïŒâããã¢ãš
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ïŒâã¯ããââïŒâïŒâïŒïœâãã«ãªããã³
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âãã³ãºã¢ããïŒèç¹166ã168âïŒãåŸããExample 3 In the same manner as in Example 1, 43.5 g (0.21 mol) of p-fluorobenzoyl-piperidine and 37.1 g (0.1 mol) of N-(2-bromoethyl)-5-bromo-4-chloro-2-methoxy-benzamide were added. From a solution obtained by dissolving in 200 ml of dioxane, 5-bromo-
4-chloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]ethyl]-2-methoxy-benzamide (melting point 166-168°C) was obtained.
åºçºç©è³ªã¯æ¬¡ã®ããã«ããŠè£œé ããã The starting material was prepared as follows.
ã¯ãããã«ã 10mlåã³å¡©åããªãã«6.6ml
ïŒ10.7ïœïŒ0.09ã¢ã«ïŒã«æº¶ãããïŒâããã¢âïŒ
âã¯ããâïŒâã¡ããã·âå®æ¯éŠé
ž13.6ïœïŒ0.05
ã¢ã«ïŒãïŒæéå ç±æ²žéš°ãããã次ã«å転èžçºåš
äžã«ãããŠèžçºãããçœè²ç²æ«ãšããŠãïŒâãã
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žã¯ããª
ãæ®çç©ãåŸãã 10ml chloroform and 6.6ml thionyl chloride
5-bromo-4 dissolved in (10.7 g; 0.09 mol)
-Chloro-2-methoxy-benzoic acid 13.6g (0.05
mol) was heated to boiling for 2 hours. It was then evaporated in a rotary evaporator to yield 5-bromo-4-chloro-2-methoxy-benzoic acid chloride residue as a white powder.
å®æœäŸãšåæ§ã«ããŠãå¡©åã¡ãã¬ã³30mlã«æº¶ã
ããïŒâããã¢âïŒâã¯ããâïŒâã¡ããã·âå®
æ¯éŠé
žã¯ããªã5.7ïœïŒ0.02ã¢ã«ïŒãïŒâããã¢ãš
ãã«ã¢ãã³âããããããã4.1ïœïŒ0.02ã¢ã«ïŒ
åã³ãšãã«âãžã€ãœãããã«ã¢ãã³5.2ïœïŒ0.04
ã¢ã«ïŒãããèç¹99ã100âã®ïŒ®âïŒïŒâããã¢ãš
ãã«ïŒâïŒâããã¢âïŒâã¯ããâïŒâã¡ããã·
âãã³ãºã¢ãããåŸãã 5.7 g (0.02 mol) of 5-bromo-4-chloro-2-methoxy-benzoic acid chloride and 4.1 g (0.02 mol) of 2-bromoethylamine-hydrobromide were dissolved in 30 ml of methylene chloride in the same manner as in the example.
and ethyl-diisopropylamine 5.2 g (0.04
mol) to obtain N-(2-bromoethyl)-5-bromo-4-chloro-2-methoxy-benzamide with a melting point of 99-100°C.
äŸ ïŒ
äŸïŒãšåæ§ã«ããŠããžãªããµã³120mläžã«æº¶ã
ããïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³
41.4ïœïŒ0.2ã¢ã«ïŒåã³ïŒ®âïŒïŒâããã¢ãšãã«ïŒ
âïŒâãã«ãªãâïŒâã¡ããã·âãã³ãºã¢ãã
27.6ïœïŒ0.1ã¢ã«ïŒãããèç¹211âïŒå解ïŒã®ïŒ®
âïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããª
ãžãã«ïŒœâãšãã«ïŒœâïŒâãã«ãªãâïŒâã¡ããã·
âãã³ãºã¢ããâãããã¯ããªããåŸããExample 4 4-(p-fluorobenzoyl)-piperidine dissolved in 120 ml of dioxane as in Example 1.
41.4g (0.2mol) and N-(2-bromoethyl)
-4-fluoro-2-methoxy-benzamide
From 27.6 g (0.1 mol), N with a melting point of 211°C (decomposed)
-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-fluoro-2-methoxy-benzamide-hydrochloride was obtained.
äŸïŒãšåæ§ã«ããŠãïŒç±³åœç¹èš±ç¬¬3177252å·ã«åŸ
ã€ãŠè£œé ããïŒïŒâãã«ãªãâïŒâã¡ããã·âå®
æ¯éŠé
žã¯ããªã18.9ïœïŒ0.1ã¢ã«ïŒãïŒâããã¢ãš
ãã«ã¢ãã³âããããããã20.5ïœïŒ0.1ã¢ã«ïŒ
åã³ãšãã«âãžã€ãœãããã«ã¢ãã³27.1ïœïŒ0.21
ã¢ã«ïŒãããèç¹92ã94âã®ïŒ®âïŒïŒâããã¢ãš
ãã«ïŒâïŒâãã«ãªãâïŒâã¡ããã·âãã³ãºã¢
ãããåŸãã Analogously to Example 1, 18.9 g (0.1 mol) of 4-fluoro-2-methoxy-benzoic acid chloride (prepared according to U.S. Pat. No. 3,177,252), 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide.
and ethyl-diisopropylamine 27.1g (0.21
mol) to give N-(2-bromoethyl)-4-fluoro-2-methoxy-benzamide with a melting point of 92-94°C.
äŸ ïŒ
äŸïŒãšåæ§ã«ããŠããžãªããµã³200mlã«æº¶ãã
ãïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³
45.5ïœïŒ0.22ã¢ã«ïŒåã³ïŒ®âïŒïŒâããã¢ãšãã«ïŒ
âïŒâããã¢âïŒâãã«ãªãâïŒâã¡ããã·âã
ã³ãºã¢ãã35.5ïœïŒ0.1ã¢ã«ïŒãããèç¹152ã
153âã®ïŒâããã¢ââïŒâïŒâïŒïœâãã«ãª
ããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâïŒâ
ãã«ãªãâïŒâã¡ããã·âãã³ãºã¢ãããåŸããExample 5 4-(p-fluorobenzoyl)-piperidine dissolved in 200 ml of dioxane as in Example 1.
45.5g (0.22mol) and N-(2-bromoethyl)
-5-Bromo-4-fluoro-2-methoxy-benzamide from 35.5 g (0.1 mol), melting point 152 ~
5-Bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4- at 153°C
Fluoro-2-methoxy-benzamide was obtained.
åºçºç©è³ªã¯æ¬¡ã®ããã«ããŠèª¿è£œããã The starting material was prepared as follows.
äŸïŒãšåæ§ã«ããŠãé
¢é
ž90mlåã³æ°Ž140mlã«æº¶
ãããïŒâãã«ãªãâïŒâã¡ããã·âå®æ¯éŠé
ž
3.4ïœïŒ0.02ã¢ã«ïŒåã³èçŽ 1.07mlïŒ3.35ïœïŒ0.21
ã¢ã«ïŒãããèç¹176ã178âã®ïŒâããã¢âïŒâ
ãã«ãªãâïŒâã¡ããã·âå®æ¯éŠé
žãåŸãã 4-Fluoro-2-methoxy-benzoic acid dissolved in 90 ml of acetic acid and 140 ml of water as in Example 2.
3.4 g (0.02 mol) and bromine 1.07 ml (3.35 g; 0.21
mol) to 5-bromo-4- with a melting point of 176-178°C
Fluoro-2-methoxy-benzoic acid was obtained.
äŸïŒãšåæ§ã«ããŠãïŒâããã¢âïŒâãã«ãªã
âïŒâã¡ããã·âå®æ¯éŠé
ž5.0ïœïŒ0.02ã¢ã«ïŒãå¡©
åããªãã«4.3mlïŒ7.1ïœïŒ0.06ã¢ã«ïŒåã³ã¯ãã
ãã«ã 15mlããïŒâããã¢âïŒâãã«ãªãâïŒâ
ã¡ããã·âå®æ¯éŠé
žã¯ããªããçœè²ç²æ«ãšããŠåŸ
ãã Analogously to Example 3, 5-bromo-4-fluoro-benzoic acid was prepared from 5.0 g (0.02 mol) of 5-bromo-4-fluoro-2-methoxy-benzoic acid, 4.3 ml (7.1 g; 0.06 mol) of thionyl chloride and 15 ml of chloroform. -2-
Methoxy-benzoic acid chloride was obtained as a white powder.
äŸïŒãšåæ§ã«ããŠãå¡©åã¡ãã¬ã³30mlã«æº¶ãã
ãïŒâããã¢âïŒâãã«ãªãâïŒâã¡ããã·âå®
æ¯éŠé
žã¯ããªã5.4ïœïŒ0.02ã¢ã«ïŒãïŒâããã¢ãš
ãã«ã¢ãã³âããããããã4.1ïœïŒ0.02ã¢ã«ïŒ
åã³ãšãã«âãžã€ãœãããã«ã¢ãã³5.2ïœïŒ0.04
ã¢ã«ïŒãããèç¹91ã95âã®ïŒ®âïŒïŒâããã¢ãš
ãã«ïŒâïŒâããã¢âïŒâãã«ãªãâïŒâã¡ãã
ã·âãã³ãºã¢ãããåŸãã 5.4 g (0.02 mol) of 5-bromo-4-fluoro-2-methoxy-benzoic acid chloride, 4.1 g (0.02 mol) of 2-bromoethylamine-hydrobromide, dissolved in 30 ml of methylene chloride, as in Example 1.
and ethyl-diisopropylamine 5.2 g (0.04
mol) to obtain N-(2-bromoethyl)-5-bromo-4-fluoro-2-methoxy-benzamide with a melting point of 91-95°C.
äŸ ïŒ
ãžãªããµã³180mlã«æº¶ãããïŒâïŒïœâãã«ãªã
ãã³ãŸã€ã«ïŒâãããªãžã³41.4ïœïŒ0.2ã¢ã«ïŒãšïŒ®
âïŒïŒâããã¢ãšãã«ïŒâïŒâã¡ããã·âïŒâããª
ãã«ãªãã¡ãã«âãã³ãºã¢ãã32.6ïœïŒ0.1ã¢ã«ïŒ
ãããèç¹212âïŒå解ïŒã®ïŒ®âïŒâïŒâïŒïœâ
ãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœ
âïŒâã¡ããã·âïŒâããªãã«ãªãã¡ãã«âãã³
ãºã¢ããâãããã¯ããªããåŸããExample 6 41.4 g (0.2 mol) of 4-(p-fluorobenzoyl)-piperidine dissolved in 180 ml of dioxane and N
-(2-bromoethyl)-2-methoxy-5-trifluoromethyl-benzamide 32.6 g (0.1 mol)
from N-[2-[4-(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2-methoxy-5-trifluoromethyl-benzamide-hydrochloride was obtained.
åºçºç©è³ªã¯äŸïŒãšåæ§ã«ãïŒãã©ã³ã¹åœç¹èš±ç¬¬
1472025å·ã«åŸã€ãŠè£œé ããïŒâïŒâã¡ããã·âïŒ
âããªãã«ãªãã¡ãã«âå®æ¯éŠé
žã¯ããªã23.9ïœ
ïŒ0.1ã¢ã«ïŒãïŒâããã¢ãšãã«ã¢ãã³âãããã
ããã20.5ïœïŒ0.1ã¢ã«ïŒåã³ãšãã«âãžã€ãœã
ããã«ã¢ãã³27.1ïœïŒ0.21ã¢ã«ïŒãããèç¹85ã
86âã®ïŒ®âïŒïŒâããã¢ãšãã«ïŒâïŒâã¡ããã·â
ïŒâããªãã«ãªãã¡ãã«âãã³ãºã¢ãããåŸãã The starting materials were as in Example 1 (French patent no.
)-2-methoxy-5 prepared according to No. 1472025
-Trifluoromethyl-benzoic acid chloride 23.9g
(0.1 mol), 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide and 27.1 g (0.21 mol) of ethyl-diisopropylamine, melting point 85~
N-(2-bromoethyl)-2-methoxy- at 86â
5-trifluoromethyl-benzamide was obtained.
äŸ ïŒ
äŸïŒãšåæ§ã«ããŠããžã¡ãã«ãã«ã ã¢ãã250
mlã«æº¶ãããïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâã
ããªãžã³45.5ïœïŒ0.22ã¢ã«ïŒãâïŒïŒâããã¢ãš
ãã«ïŒâïŒâã¡ããã·âïŒâã¹ã«ãã¢ã¢ã€ã«âã
ã³ãºã¢ãã33.7ïœïŒ0.1ã¢ã«ïŒãããèç¹183ã
185âã®ïŒâã¡ããã·âïŒâã¹ã«ãã¢ã¢ã€ã«â
âïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããª
ãžãã«ïŒœâãšãã«ïŒœâãã³ãºã¢ãããåŸããExample 7 In the same manner as in Example 1, dimethylformamide 250
From 45.5 g (0.22 mol) of 4-(p-fluorobenzoyl)-piperidine and 33.7 g (0.1 mol) of N-(2-bromoethyl)-2-methoxy-5-sulfamoyl-benzamide dissolved in ml, melting point 183 ~
2-methoxy-5-sulfamoyl-N at 185°C
-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide was obtained.
åºçºç©è³ªã¯ãäŸïŒãšåæ§ã«ããŠã次ã®ããã«è£œ
é ããã The starting material was prepared analogously to Example 1 as follows.
ïŒâã¡ããã·âïŒâã¹ã«ãã¢ã¢ã€ã«âå®æ¯éŠé
ž
ã¯ããªãïŒãã©ã³ã¹åœç¹èš±ç¬¬1472025å·ã«åŸã€ãŠ
補é ïŒ26.5ïœïŒ0.1ã¢ã«ïŒãïŒâããã¢ãšãã«ã¢ã
ã³âããããããã20.5ïœåã³ããªãšãã«ã¢ãã³
21.2ïœïŒ0.21ã¢ã«ïŒãããèç¹179âïŒå解ïŒã®
âïŒïŒâããã¢ãšãã«ïŒâïŒâã¡ããã·âïŒâã¹
ã«ãã¢ã¢ã€ã«âãã³ãºã¢ãããåŸãã 26.5 g (0.1 mol) of 2-methoxy-5-sulfamoyl-benzoic acid chloride (prepared according to French Patent No. 1472025), 20.5 g of 2-bromoethylamine-hydrobromide and triethylamine
From 21.2 g (0.21 mol), N-(2-bromoethyl)-2-methoxy-5-sulfamoyl-benzamide having a melting point of 179 DEG C. (decomposed) was obtained.
äŸ ïŒ
ïŒâïŒïŒâã¯ããâïŒâã¡ããã·âïŒâã¡ãã«
ã¢ããããšãã«ïŒâïŒâãªããµãŸãªã³24.1ïœïŒ0.1
ã¢ã«ïŒãïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããª
ãžã³22.8ïœïŒ0.11ã¢ã«ïŒåã³ãžãªããµã³120mlã
çªçŽ é°å²æ°äžã«ãããŠ18æéå ç±æ²žéš°ããããå
åŸããæè€è²ã®æº¶æ¶²ãæ°Žæµã«ããæžå§äžã§èžçºã
ãããååŸããç²çš ãªæ²¹ç¶ç©ãã¢ã»ãã³300mlã«
溶ãããå¡©åæ°ŽçŽ ã®ãšãŒãã«æº¶æ¶²ãã³ã³ãŽãŒæ瀺
è¬ãé
žæ§ã瀺ããŸã§æ¹æäžã«æ·»å ããããã®éã«
çæç©ã®åçµæ¶ãéå§ããããæåºããïŒâã¯ã
ãââïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâ
ãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âïŒâã¡
ãã«ã¢ããâãã³ãºã¢ããâãããã¯ããªããç
åããããã®ãã®ã¯230âã§è解ïŒå解ïŒãããExample 8 24.1 g (0.1
22.8 g (0.11 mol) of 4-(p-fluorobenzoyl)-piperidine and 120 ml of dioxane were boiled for 18 hours in a nitrogen atmosphere. The dark brown solution obtained was evaporated under reduced pressure with a water jet. The viscous oil obtained was dissolved in 300 ml of acetone and an ethereal solution of hydrogen chloride was added under stirring until the Congo indicator showed acidity. At this time recrystallization of the product started. The precipitated 5-chloro-N-[2-[4-(p-fluorobenzoyl)-
Piperidinyl]-ethyl]-2-methoxy-4-methylamino-benzamide-hydrochloride was filtered off. This material melted (decomposed) at 230°C.
åºçºç©è³ªã¯æ¬¡ã®ããã«è£œé ããã The starting material was prepared as follows.
å¡©åã¡ãã¬ã³250mläžã«æº¶ãããïŒâã¯ããâ
ïŒâã¡ããã·âïŒâã¡ãã«ã¢ããâå®æ¯éŠé
ž21.6
ïœïŒ0.1ã¢ã«ïŒïŒJ.Med.Chem.1981ãïŒ24ïŒã1224ã
ãšã¹ã»ã€ã¯ããçã«ãã補é ïŒã®æº¶æ¶²ã«æ¹æãã€
ã€çªçŽ é°å²æ°äžã«ãããŠããªãšãã«ã¢ãã³11.2ïœ
ïŒ0.11ã¢ã«ïŒã滎äžãããååŸãã溶液ã«â10â
ã§ã¯ããè»é
žãšãã«ãšã¹ãã«10.9ïœïŒ0.1ã¢ã«ïŒ
ãæ·»å ããããã®æž©åºŠã§æŽã«30åéïŒâããã¢ãš
ãã«ã¢ãã³âããããããã20.5ïœïŒ0.1ã¢ã«ïŒ
åã³ããªãšãã«ã¢ãã³10.1ïœïŒ0.1ã¢ã«ïŒãšå
±ã«
æ¹æããã次ã«å·åŽæµŽãé€å»ãã宀枩ã§ïŒæéå
å¿æ··åç©ãæ¹æãããåŸåŠçã®ããã«ãå¡©åã¡ã
ã¬ã³ïŒåã³æ°ŽïŒãšåå¿ããã2Nå¡©é
žã§æ°Žçž
ãPHïŒã«èª¿ç¯ããå液ããŒããçšããŠå±€åé¢ãè¡
ã€ãã 5-chloro- dissolved in 250 ml of methylene chloride
2-Methoxy-4-methylamino-benzoic acid 21.6
g (0.1 mol) (J.Med.Chem. 1981 , (24), 1224,
11.2 g of triethylamine (manufactured by S. Iwanami et al.) in a nitrogen atmosphere with stirring.
(0.11 mol) was added dropwise. The obtained solution was heated to â10 °C.
chloroformic acid ethyl ester 10.9g (0.1 mol)
was added. 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide for a further 30 minutes at this temperature.
and 10.1 g (0.1 mol) of triethylamine. The cooling bath was then removed and the reaction mixture was stirred at room temperature for 4 hours. For work-up, it was reacted with 1 part of methylene chloride and 1 part of water, the aqueous phase was adjusted to pH 5 with 2N hydrochloric acid, and the layers were separated using a separatory funnel.
æ°Žçžãéçé
žãããªãŠã ãšæ··åããå¡©åã¡ãã¬
ã³ã§æœåºãããå¡©åã¡ãã¬ã³ãèžçºãããåŸãè
ç¹159ã161âã®ïŒâïŒïŒâã¯ããâïŒâã¡ããã·
âïŒâã¡ãã«ã¢ããâããšãã«ïŒâïŒâãªããµãŸ
ãªã³ãåŸãã The aqueous phase was mixed with sodium bicarbonate and extracted with methylene chloride. After evaporating the methylene chloride, 2-(5-chloro-2-methoxy-4-methylamino-phenyl)-2-oxazoline was obtained with a melting point of 159-161°C.
äŸ ïŒ
äŸïŒãšåæ§ã«ããŠãïŒâïŒïŒâãžã¡ãã«ã¹ã«ã
ã¢ã¢ã€ã«âïŒâã¡ããã·âããšãã«ïŒâïŒâãªã
ãµãŸãªã³28.4ïœïŒ0.1ã¢ã«ïŒãïŒâïŒïœâãã«ãªã
ãã³ãŸã€ã«ïŒâãããªãžã³20.7ïœïŒ0.1ã¢ã«ïŒåã³
ãžãªããµã³140mlãããèç¹172âïŒå解ïŒã®ïŒ®â
ïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãž
ãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âïŒâãžã¡ãã«ã¹
ã«ãã¢ã¢ã€ã«âãã³ãºã¢ããâãããã¯ããªãã
åŸããExample 9 In the same manner as in Example 8, 28.4 g (0.1 mol) of 2-(5-dimethylsulfamoyl-2-methoxy-phenyl)-2-oxazoline, 20.7 g (0.1 mol) of 4-(p-fluorobenzoyl)-piperidine mol) and 140 ml of dioxane, N- with a melting point of 172°C (decomposed)
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-dimethylsulfamoyl-benzamide-hydrochloride was obtained.
åºçºç©è³ªã¯ãäŸïŒãšåæ§ã«ã次ã®ããã«ããŠè£œ
é ããã The starting material was prepared analogously to Example 8 as follows.
ïŒâãžã¡ãã«ã¹ã«ãã¢ã¢ã€ã«âïŒâã¡ããã·â
å®æ¯éŠé
ž24.3ïœïŒ0.1ã¢ã«ïŒãããªãšãã«ã¢ãã³
21.3ïœïŒ0.21ã¢ã«ïŒãã¯ããè»é
žâãšãã«ãšã¹ã
ã«10.9ïœïŒ0.1ã¢ã«ïŒåã³ïŒâããã¢ãšãã«ã¢ã
ã³ããããããã20.5ïœïŒ0.1ã¢ã«ïŒãããèç¹
135ã138âã®ïŒâïŒïŒâãžã¡ãã«ã¹ã«ãã¢ã¢ã€ã«
âïŒâã¡ããã·âããšãã«ïŒâïŒâãªããµãŸãªã³
ãåŸãã 5-dimethylsulfamoyl-2-methoxy-
Benzoic acid 24.3g (0.1mol), triethylamine
21.3 g (0.21 mol), 10.9 g (0.1 mol) of chloroformic acid-ethyl ester and 20.5 g (0.1 mol) of 2-bromoethylamine hydrobromide, melting point
2-(5-dimethylsulfamoyl-2-methoxy-phenyl)-2-oxazoline was obtained at 135-138°C.
äŸ 10
âïŒïŒâã·ã¢ãâïŒâã¡ããã·âãã³ãŸã€ã«ïŒ
âã¢ãžãªãžã³20.2ïœïŒ0.1ã¢ã«ïŒãïŒâïŒïœâãã«
ãªããã³ãŸã€ã«ïŒâãããªãžã³22.8ïœïŒ0.11ã¢ã«ïŒ
åã³ãã«ãšã³250mlãïŒæéæ¹æãã€ã€80âã«å
ç±ãããå·åŽåŸã«æåºããïŒâã·ã¢ãââïŒ
âïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã
ã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âãã³ãºã¢ãããç
åããå°éã®ãã«ãšã³ã§æŽæµãããèç¹ã¯167ã
169âã§ãã€ããExample 10 N-(5-cyano-2-methoxy-benzoyl)
-Aziridine 20.2g (0.1mol), 4-(p-fluorobenzoyl)-piperidine 22.8g (0.11mol)
and 250 ml of toluene were heated to 80° C. with stirring for 5 hours. 5-cyano-N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide was filtered and washed with a small amount of toluene. Melting point is 167~
It was 169â.
åºçºç©è³ªã¯æ¬¡ã®ããã«ããŠè£œé ããã The starting material was prepared as follows.
ãã«ãšã³30mläžã«æº¶ããã0.5Nèæ§ãœãŒã100
mlãšã¢ãžãªãžã³2.3ïœïŒ0.53ã¢ã«ïŒãšã®æ··åç©ã«ã
å¡©åã¡ãã¬ã³50mlã«æº¶ãããïŒâã·ã¢ãâïŒâã¡
ããã·âå¡©åãã³ãŸã€ã«9.8ïœïŒ0.05ã¢ã«ïŒã®æº¶
液ãïŒãïŒâã®åå¿æž©åºŠã§ååã«æ¹æããªãã滎
äžãã次ã«åå¿æ··åç©ãæŽã«ïŒæéïŒâã§æ¹æã
ãã次ã«å液ããŒããçšããŠå±€åé¢ããææ©çžã
æ°Ž50mlãšå
±ã«æ¯ãšããç¡«é
žãã°ãã·ãŠã äžã§ä¹Ÿç¥
ãããæ°Žæµã«ããæžå§äžã§èžçºããããèç¹99ã
101âã®ïŒ®âïŒïŒâã·ã¢ãâïŒâã¡ããã·âãã³ãŸ
ã€ã«ïŒâã¢ãžãªãžã³ãæ®çç©ãšããŠåŸãããã 100ml of 0.5N caustic soda dissolved in 30ml of toluene
ml and 2.3 g (0.53 mol) of aziridine,
A solution of 9.8 g (0.05 mol) of 5-cyano-2-methoxy-benzoyl chloride in 50 ml of methylene chloride was added dropwise with good stirring at a reaction temperature of 3 to 5°C, and the reaction mixture was then stirred for a further 1 hour. Stir at â. The layers were then separated using a separatory funnel and the organic phase was shaken with 50 ml of water, dried over magnesium sulfate and evaporated under reduced pressure with a stream of water. Melting point 99~
N-(5-cyano-2-methoxy-benzoyl)-aziridine at 101°C was obtained as a residue.
äŸ 11
äŸïŒãšåæ§ã«ããŠãïŒâïŒïŒâããã¢âïŒâã¡
ããã·âããšãã«ïŒâïŒâãªããµãŸãªã³25.6ïœ
ïŒ0.1ã¢ã«ïŒåã³ïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâ
ãããªãžã³20.7ïœïŒ0.1ã¢ã«ïŒããã«ãšã³75mläž
ã«æº¶ãããŠåŸã溶液ãããèç¹125âã®ïŒâãã
ã¢ââïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâ
ãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âãã³ãº
ã¢ããâã¡ã¿ã³ã¹ã«ãããŒããåŸããExample 11 25.6 g of 2-(3-bromo-4-methoxy-phenyl)-2-oxazoline was prepared in the same manner as in Example 8.
(0.1 mol) and 4-(p-fluorobenzoyl)-
From a solution of 20.7 g (0.1 mol) of piperidine in 75 ml of toluene, 3-bromo-N-[2-[4-(p-fluorobenzoyl)-
Piperidinyl]-ethyl]-4-methoxy-benzamide-methanesulfonate was obtained.
åºçºç©è³ªã¯äŸïŒãšåæ§ã«æ¬¡ã®ããã«è£œé ããã The starting material was prepared analogously to Example 8 as follows.
ïŒâããã¢âïŒâã¡ããã·âå®æ¯éŠé
ž15.2ïœ
ïŒ0.1ã¢ã«ïŒãããªãšãã«ã¢ãã³21.3ïœïŒ0.21ã¢ã«ïŒã
ã¯ããè»é
žâãšãã«ãšã¹ãã«10.9ïœïŒ0.1ã¢ã«ïŒ
åã³ïŒâããã¢ãšãã«ã¢ãã³âããããããã
20.5ïœïŒ0.1ã¢ã«ïŒãããèç¹95âã®ïŒâïŒïŒâã
ãã¢âïŒâã¡ããã·âããšãã«ïŒâïŒâãªããµãŸ
ãªã³ãåŸåŸãã 3-Bromo-4-methoxy-benzoic acid 15.2g
(0.1 mol), triethylamine 21.3g (0.21 mol),
Chloroformic acid-ethyl ester 10.9g (0.1mol)
and 2-bromoethylamine-hydrobromide
2-(3-bromo-4-methoxy-phenyl)-2-oxazoline having a melting point of 95 DEG C. was obtained from 20.5 g (0.1 mol).
äŸ 12
äŸïŒãšåæ§ã«ããŠãïŒâïŒïŒâã¡ããã·âããš
ãã«ïŒâïŒâãªããµãŸãªã³17.7ïœïŒ0.1ã¢ã«ïŒãïŒ
âïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³10.7ïœ
ïŒ0.1ã¢ã«ïŒåã³ãžãªããµã³40mlãããèç¹205â
ïŒå解ïŒã®ïŒ®âïŒâïŒâïŒïœâãã«ãªããã³ãŸã€
ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·â
ãã³ãºã¢ããâãããã¯ããªããåŸããExample 12 In the same manner as in Example 8, 17.7 g (0.1 mol) of 2-(2-methoxy-phenyl)-2-oxazoline, 4
-(p-fluorobenzoyl)-piperidine 10.7g
(0.1 mol) and 40 ml of dioxane, melting point 205â
(Decomposition) of N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-
Benzamide-hydrochloride was obtained.
åºçºç©è³ªã¯äŸïŒãšåæ§ã«ããŠæ¬¡ã®ããã«è£œé ã
ãã The starting material was prepared analogously to Example 8 as follows.
ïŒâã¡ããã·âå®æ¯éŠé
ž15.2ïœïŒ0.1ã¢ã«ïŒãã
ãªãšãã«ã¢ãã³21.3ïœïŒ0.21ã¢ã«ïŒãã¯ããè»é
ž
âãšãã«ãšã¹ãã«10.9ïœïŒ0.1ã¢ã«ïŒåã³ïŒâã
ãã¢ãšãã«ã¢ãã³âããããããã20.5ïœïŒ0.1
ã¢ã«ïŒãããèç¹35ã38âã®ïŒâïŒïŒâã¡ããã·
âããšãã«ïŒâïŒâãªããµãŸãªã³ãåŸãã 15.2 g (0.1 mol) of 2-methoxybenzoic acid, 21.3 g (0.21 mol) of triethylamine, 10.9 g (0.1 mol) of chloroformic acid-ethyl ester and 20.5 g (0.1 mol) of 2-bromoethylamine-hydrobromide.
mol) to give 2-(2-methoxy-phenyl)-2-oxazoline with a melting point of 35-38°C.
äŸ 13
ãšã¿ããŒã«50mlã«æžæ¿ãããïŒâã·ã¢ãââ
ïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãž
ãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âãã³ãºã¢ãã
4.1ïœïŒ0.01ã¢ã«ïŒã«æ°ŽçŽ åããŠçŽ ãããªãŠã 0.38
ïœïŒ0.01ã¢ã«ïŒãæ¹æäžã«æ·»å ããïŒæé宀枩ã§
æ¹æãããååŸããææŸãªæº¶æ¶²ãã¢ã»ãã³ïŒmlãš
æ··åããåŸãæ°Žæµã«ããæžå§äžã§èžçºããããæ®
çç©ãå¡©åã¡ãã¬ã³åã³æ°Žã«åžåãããå液ããŒ
ãäžã§å±€åé¢ããææ©çžãç¡«é
žãã°ãã·ãŠã äžã«
ãããŠä¹Ÿç¥åŸãèžçºä¹Ÿåºããããæ®çç©ãšããŠè
ç¹135ã137âã®ïŒâã·ã¢ãââïŒâïŒâïŒïŒ
âãã«ãªãããšãã«ïŒâããããã·ã¡ãã¬ã³ïŒœâã
ããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âãã³ãºã¢
ãããåŸããExample 13 5-cyano-N- suspended in 50 ml of ethanol
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide
Sodium borohydride 0.38 in 4.1g (0.01mol)
g (0.01 mol) was added under stirring and stirred for 1 hour at room temperature. The clear solution obtained was mixed with 1 ml of acetone and then evaporated under reduced pressure with a water jet. The residue was taken up in methylene chloride and water, the layers were separated in a separatory funnel and the organic phase was dried over magnesium sulfate and then evaporated to dryness. 5-cyano-N-[2-[4-[(4
-fluorophenyl)-hydroxymethylene]-piperidinyl]-ethyl]-2-methoxy-benzamide was obtained.
äŸ 14
å¡©åã¡ãã¬ã³250mlã«æº¶ãããâïŒïŒâã¢ãã
ãšãã«ïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãã
ãªãžã³ãããã¯ããªã32.3ïœïŒ0.1ã¢ã«ïŒãšïŒâ
ããã¢âïŒâãã«ãªããã³ãŸã€ã«24ïœãšã®æ··åç©
ã«æ¹æãã€ã€çªçŽ é°å²æ°äžã«ãããŠâ10âãïŒâ
ã§ãžã€ãœãããã«ãšãã«ã¢ãã³45ïœïŒ0.35ã¢ã«ïŒ
ã滎äžããã次ã«åå¿æ··åç©ã宀枩ã«å ç±ããã
ã®æž©åºŠã«ïŒæéä¿æããã次ã«1Nèæ§ãœãŒã200
mlãšæ··åããå±€åé¢ããææ©çžãæ°Žã§äžæ§ã«ãªã
ãŸã§æŽæµããç¡«é
žãã°ãã·ãŠã äžã«ãããŠä¹Ÿç¥ã
ããæ°Žæµã«ããæžå§äžã§èžçºããããèç¹135â
ã®ïŒâããã¢âïŒâãã«ãªãââïŒâïŒâ
ïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãš
ãã«ïŒœâãã³ãºã¢ãããæ®çç©ãšããŠåŸããããExample 14 32.3 g (0.1 mol) of N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine hydrochloride dissolved in 250 ml of methylene chloride and 3-
A mixture of 24 g of bromo-4-fluorobenzoyl was heated to -10°C to 0°C under nitrogen atmosphere with stirring.
45 g (0.35 mol) of diisopropylethylamine
was dripped. The reaction mixture was then heated to room temperature and held at this temperature for 4 hours. Then 1N caustic soda 200
ml, the layers were separated, the organic phase was washed neutral with water, dried over magnesium sulphate and evaporated under reduced pressure with a stream of water. Melting point 135â
3-bromo-4-fluoro-N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide was obtained as a residue.
次ã«ãã®å¡©åºãå¡©é
žå¡©ïŒãããã¯ããªãïŒã«å€
æããããããå¡©åã¡ãã¬ã³ã«æº¶ãããå¡©åæ°ŽçŽ
ã®ãšãŒãã«æº¶æ¶²ãæ·»å ããããã®å¡©é
žå¡©ã®èç¹ã¯
189ã190âã§ãã€ãã The base was then converted to hydrochloride by dissolving it in methylene chloride and adding an ethereal solution of hydrogen chloride. The melting point of this hydrochloride is
The temperature was 189-190â.
åºçºç©è³ªãšããŠçšããâïŒïŒâã¢ãããšãã«ïŒ
âïŒâïŒãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³âãã
ãã¯ããªãã¯ã次ã®ããã«ããŠè£œé ããã N-(2-aminoethyl) used as starting material
-4-(fluorobenzoyl)-piperidine-hydrochloride was produced as follows.
å¡©åã¡ãã¬ã³50mlã«æžæ¿ãããïŒâïŒïœâãã«
ãªããã³ãŸã€ã«ïŒâãããªãžã³âãããã¯ããªã
24.4ïœïŒ0.1ã¢ã«ïŒåã³ã¯ããã¢ã»ããããªã«8.3
ïœïŒ0.11ã¢ã«ïŒã«ãšãã«âãžã€ãœãããã«ã¢ãã³
29.5ïœïŒ0.23ã¢ã«ïŒãæ¹æäžã«æ»Žäžãããåå¿æ··
åç©ãïŒæé宀枩ã§æ¹æããã次ã«ãšãŒãã«150
mlãæ·»å ãã2Nå¡©é
žãšå
±ã«æ¯ãšãããããã®é
ž
æœåºæ¶²ã2Nèæ§ãœãŒãã§ã¢ã«ã«ãªæ§ãšããåé¢
ããå¡©åºããšãŒãã«âå¡©åã¡ãã¬ã³ã®ïŒïŒïŒæ··å
液ãšå
±ã«æ¯ãšããããåŸãããçæç©ãäžæ§ã«ãª
ããŸã§æŽæµããç¡«é
žãã°ãã·ãŠã äžã«ãããŠä¹Ÿç¥
èžçºããããæ®çç©ãšããŠèç¹133ã134âã®ïŒ®â
ïŒã·ã¢ãâã¡ãã«ïŒâïŒâïŒïœâãã«ãªããã³ãŸã€
ã«ïŒâãããªãžã³ãåŸãããã 4-(p-fluorobenzoyl)-piperidine-hydrochloride suspended in 50 ml of methylene chloride.
24.4 g (0.1 mol) and 8.3 chloroacetonitrile
g (0.11 mol) of ethyl-diisopropylamine
29.5 g (0.23 mol) was added dropwise with stirring. The reaction mixture was stirred for 5 hours at room temperature. then ether 150
ml and shaken with 2N hydrochloric acid. The acid extract was made alkaline with 2N caustic soda and the separated base was shaken with a 3:1 mixture of ether-methylene chloride. The product obtained was washed neutral and evaporated to dryness over magnesium sulphate. N- with a melting point of 133-134â as a residue
(Cyano-methyl)-4-(p-fluorobenzoyl)-piperidine was obtained.
âïŒã·ã¢ãã¡ãã«ïŒâïŒâïŒïœâãã«ãªããã³
ãŸã€ã«ïŒâãããªãžã³14.1ïœïŒ0.05ã¢ã«ïŒãé
¢é
ž
1.51åã³æ¿å¡©é
ž30mlã«æº¶ãããé
žåçœéïŒïœãšå
±
ã«æ°ŽçŽ é°å²æ°äžã«ãããŠæ°ŽçŽ åãããïŒæéåŸã«
çè«é2.25ã®æ°ŽçŽ ãåžåãããã次ã«è§Šåªãç
éãã液ãæ°Žæµã«ããæžå§äžã§çŽ30mlãŸã§æ¿çž®
ãããçæããæ¶æ³¥ãã€ãœãããããŒã«ïŒmlåã³
ãšãŒãã«15mlãšæ··åããŠçéãããçéåã³ä¹Ÿç¥
åŸã«åŸãããâïŒïŒâã¢ãããšãã«ïŒâïŒâïŒïœ
âãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³âãããã¯
ããªãã¯ãã¡ã¿ããŒã«ããåçµæ¶åŸã«ã265âã§
è解ïŒå解ïŒããã 14.1 g (0.05 mol) of N-(cyanomethyl)-4-(p-fluorobenzoyl)-piperidine was dissolved in acetic acid.
1.51 and 30 ml of concentrated hydrochloric acid, and hydrogenated with 2 g of platinum oxide in a hydrogen atmosphere. After 6 hours, a theoretical amount of 2.25 hydrogen was absorbed. The catalyst was then filtered off and the liquid was concentrated under water jet vacuum to approximately 30 ml. The resulting crystal sludge was mixed with 5 ml of isopropanol and 15 ml of ether and filtered. N-(2-aminoethyl)-4-(p
-fluorobenzoyl)-piperidine-hydrochloride melted (decomposed) at 265°C after recrystallization from methanol.
åºçºç©è³ªãšããŠçšããïŒâããã¢âïŒâãã«ãª
ãâå¡©åãã³ãŸã€ã«ã¯ãäŸïŒãšåæ§ã«ããŠãïŒâ
ããã¢âïŒâãã«ãªãå®æ¯éŠé
ž21.9ïœïŒ0.1ã¢ã«ïŒ
ïŒJ.Indian Chem.Soc.21ã115ïŒ1944ïŒã«åŸã€ãŠè£œ
é ïŒåã³å¡©åããªãã«10mlãã補é ããã The 3-bromo-4-fluoro-benzoyl chloride used as the starting material was prepared analogously to Example 3.
Bromo-4-fluorobenzoic acid 21.9g (0.1mol)
(prepared according to J. Indian Chem. Soc. 21 , 115 (1944)) and 10 ml of thionyl chloride.
äŸ 15
äŸ14ãšåæ§ã«ããŠãå¡©åã¡ãã¬ã³25mlã«æº¶ãã
ãâïŒïŒâã¢ãããšãã«ïŒâïŒâïŒïœâãã«ãªã
ãã³ãŸã€ã«ïŒâãããªãžã³âãããã¯ããªã3.23
ïœïŒ0.01ã¢ã«ïŒãïŒâããã¢âïŒâãã«ãªãâå¡©
åãã³ãŸã€ã«2.6ïœïŒ0.01ã¢ã«ïŒåã³ãšãã«âãž
ã€ãœãããã«ã¢ãã³4.5ïœïŒ0.035ã¢ã«ïŒãããè
ç¹123ã125âã®ïŒâããã¢âïŒâãã«ãªãââ
ïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãž
ãã«ïŒœâãšãã«ïŒœâãã³ãºã¢ãããåŸããExample 15 3.23 N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine-hydrochloride dissolved in 25 ml of methylene chloride as in Example 14.
g (0.01 mol), 2-bromo-4-fluoro-benzoyl chloride 2.6 g (0.01 mol) and ethyl-diisopropylamine 4.5 g (0.035 mol), 2-bromo-4-fluoro-N having a melting point of 123-125°C. â
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide was obtained.
å¡©åã¡ãã¬ã³200mlã«æº¶ãããâïŒïŒâã¢ãã
ãšãã«ïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãã
ãªãžã³âãããã¯ããªã32.3ïœïŒ0.1ã¢ã«ïŒãïŒïŒ
ïŒâãžã¡ããã·âå¡©åãã³ãŸã€ã«20ïœåã³ãšãã«
âãžã€ãœãããã«ã¢ãã³45ïœïŒ0.35ã¢ã«ïŒããã
èç¹232ã234âïŒå解ïŒã®ïŒ®âïŒâïŒâïŒïœâ
ãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœ
âïŒïŒïŒâãžã¡ããã·âãã³ãºã¢ããâãããã¯
ããªããåŸãã 32.3 g (0.1 mol) of N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine-hydrochloride dissolved in 200 ml of methylene chloride, 2,
From 20 g of 6-dimethoxy-benzoyl chloride and 45 g (0.35 mol) of ethyl-diisopropylamine,
N-[2-[4-(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2,6-dimethoxy-benzamide-hydrochloride was obtained.
äŸ 16
äŸïŒãšåæ§ã«ããŠããžã¡ãã«ãã«ã ã¢ãã25ml
ã«æº¶ãããïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãã
ãªãžã³6.2ïœïŒ0.03ã¢ã«ïŒåã³ïŒ®âïŒïŒâããã¢ãš
ãã«ïŒâïŒâãã«ãªããã³ãºã¢ãã7.4ïœïŒ0.03ã¢
ã«ïŒãããèç¹240ã242âã®ïŒâãã«ãªãââ
ïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãž
ãã«ïŒœâãšãã«ïŒœâãã³ãºã¢ããâãããã¯ããªã
ãåŸããExample 16 In the same manner as in Example 1, add 25 ml of dimethylformamide.
From 6.2 g (0.03 mol) of 4-(p-fluorobenzoyl)-piperidine and 7.4 g (0.03 mol) of N-(2-bromoethyl)-4-fluorobenzamide dissolved in N-
[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide-hydrochloride was obtained.
äŸ 17
äŸ10ãšåæ§ã«ããŠããã«ãšã³16mlã«æº¶ããã
âïŒïŒâããã¢âïŒâã¡ããã·ãã³ãŸã€ã«ïŒâã¢ãž
ãªãžã³5.2ïœïŒ0.02ã¢ã«ïŒåã³ïŒâïŒïœâãã«ãªã
ãã³ãŸã€ã«ïŒâãããªãžã³4.4ïœïŒ0.021ã¢ã«ïŒã
ããèç¹213âïŒå解ïŒã®ïŒâããã¢ââïŒâ
ïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœ
âãšãã«ïŒœâïŒâã¡ããã·âãã³ãºã¢ããâãã
ãã¯ããªããåŸããExample 17 In the same manner as in Example 10, N dissolved in 16 ml of toluene
From 5.2 g (0.02 mol) of -(5-bromo-2-methoxybenzoyl)-aziridine and 4.4 g (0.021 mol) of 4-(p-fluorobenzoyl)-piperidine, 5-bromo-N with a melting point of 213°C (decomposed) -[2-
[4-(p-fluorobenzoyl)-piperidinyl]
-ethyl]-2-methoxy-benzamide-hydrochloride was obtained.
åºçºç©è³ªã¯äŸ10ãšåæ§ã«ããŠæ¬¡ã®ããã«è£œé ã
ãã The starting material was prepared analogously to Example 10 as follows.
ã¢ãžãªãžã³ïŒïœïŒ0.21ã¢ã«ïŒããšãã«âãžã€ãœ
ãããã«ã¢ãã³27.1ïœïŒ0.21ã¢ã«ïŒåã³ïŒâãã
ã¢âïŒâã¡ããã·âå¡©åãã³ãŸã€ã«50ïœïŒ0.02ã¢
ã«ïŒãå¡©åã¡ãã¬ã³300mlã«æº¶ãããŠåŸã溶液ã
ããâïŒïŒâããã¢âïŒâã¡ããã·âãã³ãŸã€
ã«ïŒâã¢ãžãªãžã³ãåŸãã N-(5- Bromo-2-methoxy-benzoyl)-aziridine was obtained.
å®æœäŸ10ã«èšèŒãããæ¹æ³ãšåæ§ã®æ¹æ³ã«ã
ããâïŒïŒâã·ã¢ãâïŒâã¡ããã·ãã³ãŸã€ã«ïŒ
âã¢ãžãªãžã³20.2ïœïŒ0.1ã¢ã«ïŒåã³ïŒâïŒïœâã
ã«ãªããã³ãŸã€ã«ïŒâãããªãžã³22.8ïœïŒ0.11ã¢
ã«ïŒããã«ãšã³120mlã«æº¶ãããŠåŸã溶液ããã
èç¹230âïŒå解ïŒã®ïŒâã·ã¢ãââïŒâïŒ
âïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâ
ãšãã«ïŒœâïŒâã¡ããã·âãã³ãºã¢ããâããã
ã¯ããªããåŸãããã By a method similar to that described in Example 10, N-(3-cyano-4-methoxybenzoyl)
- From a solution obtained by dissolving 20.2 g (0.1 mol) of aziridine and 22.8 g (0.11 mol) of 4-(p-fluorobenzoyl)-piperidine in 120 ml of toluene,
3-cyano-N-[2-[4
-(p-fluorobenzoyl)-piperidinyl]-
Ethyl]-4-methoxy-benzamide-hydrochloride was obtained.
ã¢ãžãªãžã³4.52ïœïŒ0.105ã¢ã«ïŒããšãã«ãžã€ãœ
ãããã«ã¢ãã³12.9ïœïŒ0.1ã¢ã«ïŒåã³ïŒâã·ã¢
ãâïŒâã¡ããã·âå¡©åãã³ãŸã€ã«19.6ïœïŒ0.1
ã¢ã«ïŒãå¡©åã¡ãã¬ã³150mlã«æº¶ãããŠåŸã溶液
ãããèç¹176ã177âã®ïŒ®âïŒïŒâã·ã¢ãâïŒâ
ã¡ããã·âãã³ãŸã€ã«ïŒâã¢ãžãªãžã³ãåŸãã 4.52 g (0.105 mol) of aziridine, 12.9 g (0.1 mol) of ethyldiisopropylamine and 19.6 g (0.1 mol) of 3-cyano-4-methoxy-benzoyl chloride.
N-(3-cyano-4-
Methoxy-benzoyl)-aziridine was obtained.
äŸ 18
äŸ14ãšåæ§ã«ããŠãå¡©åã¡ãã¬ã³25mläžã®ïŒ®â
ïŒïŒâã¢ãããšãã«ïŒâïŒâïŒïœâãã«ãªããã³ãŸ
ã€ã«ïŒâãããªãžã³âãããã¯ããªã3.23ïœ
ïŒ0.01ã¢ã«ïŒãïŒïŒïŒâãžã¯ããâïŒâã¡ããã·â
ïŒâã¡ãã«âãã³ãŸã€ã«ã¯ãã€ã2.54ïœïŒ0.01ã¢
ã«ïŒåã³ãšãã«âãžã€ãœãããã«ã¢ãã³4.5ïœ
ïŒ0.035ã¢ã«ïŒããèç¹112ã114âã®ïŒïŒïŒâãžã¯
ããââïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒ
âãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âïŒâ
ã¡ãã«âãã³ãºã¢ããâã¡ã¿ã³ã¹ã«ãããŒããåŸ
ããExample 18 Analogously to Example 14, N-
(2-Aminoethyl)-4-(p-fluorobenzoyl)-piperidine-hydrochloride 3.23g
(0.01 mol), 3,5-dichloro-2-methoxy-
2.54 g (0.01 mol) of 4-methyl-benzoylchloride and 4.5 g of ethyl-diisopropylamine
(0.035 mol) to 3,5-dichloro-N-[2-[4-(p-fluorobenzoyl), melting point 112-114°C
-piperidinyl]-ethyl]-2-methoxy-4-
Methyl-benzamide-methanesulfonate was obtained.
å¡©åã¡ãã¬ã³30mläžã®ïŒ®âïŒïŒâã¢ãããšãã«ïŒ
âïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³â
ãããã¯ããªã3.23ïœïŒ0.01ã¢ã«ïŒãïŒâã¡ãã
ã·âïŒâã¡ãã«ã¡ã«ã«ããâå¡©åãã³ãŸã€ã«2.17
ïœïŒ0.01ã¢ã«ïŒåã³ãšãã«âãžã€ãœãããã«ã¢ã
ã³4.5ïœïŒ0.035ã¢ã«ïŒãããèç¹209âïŒå解ïŒ
ã®ïŒ®âïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâã
ããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âïŒâã¡ã
ã«ã¡ã«ã«ããâãã³ãºã¢ããâãããã¯ããªãã
åŸãããã N-(2-aminoethyl) in 30 ml of methylene chloride
-4-(p-fluorobenzoyl)-piperidine-
Hydrochloride 3.23 g (0.01 mol), 2-methoxy-5-methylmercapto-benzoyl chloride 2.17
g (0.01 mol) and ethyl-diisopropylamine 4.5 g (0.035 mol), melting point 209°C (decomposition)
N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-methylmercapto-benzamide-hydrochloride was obtained.
å¡©åã¡ãã¬ã³50mläžã®ïŒ®âïŒïŒâã¢ãããšãã«ïŒ
âïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³â
ãããã¯ããªã6.5ïœïŒ0.02ã¢ã«ïŒãïŒâã¡ããã·
âïŒâã¡ã¿ã³ã¹ã«ããã«âå¡©åãã³ãŸã€ã«4.99ïœ
ïŒ0.02ã¢ã«ïŒåã³ãšãã«ãžã€ãœãããã«ã¢ãã³ïŒ
ïœïŒ0.07ã¢ã«ïŒãããèç¹163ã164âã®ïŒ®âïŒ
âïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã
ã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·âïŒâã¡ã¿ã³ã¹ã«ã
ãã«âãã³ãºã¢ããâãããã¯ããªããåŸãã N-(2-aminoethyl) in 50 ml of methylene chloride
-4-(p-fluorobenzoyl)-piperidine-
Hydrochloride 6.5g (0.02mol), 2-methoxy-5-methanesulfonyl-benzoyl chloride 4.99g
(0.02 mol) and ethyldiisopropylamine 9
g (0.07 mol) to N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-methanesulfonyl-benzamide-hydrochloride was obtained.
äŸ 19
äŸ14ãšåæ§ã«ããŠãå¡©åã¡ãã¬ã³35mläžã®ïŒ®â
ïŒïŒâã¢ãããšãã«ïŒâïŒâïŒïœâãã«ãªããã³ãŸ
ã€ã«ïŒâãããªãžã³âãžãããã¯ããªã4.6ïœ
ïŒ0.015ã¢ã«ïŒãïŒâã·ã¢ãâïŒâã¡ããã·âå¡©å
ãã³ãŸã€ã«2.93ïœïŒ0.015ã¢ã«ïŒåã³ãšãã«ãžã€
ãœãããã«ã¢ãã³6.4ïœïŒ0.05ã¢ã«ïŒãããèç¹
147ã148âã®ïŒâã·ã¢ãââïŒâïŒâïŒïœâ
ãã«ãªããã³ãžã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâ
ïŒâã¡ããã·âãã³ãºã¢ããâãããã¯ããªãã
åŸããExample 19 Similarly to Example 14, N-
(2-Aminoethyl)-4-(p-fluorobenzoyl)-piperidine-dihydrochloride 4.6g
(0.015 mol), 5-cyano-2-methoxy-benzoyl chloride 2.93 g (0.015 mol) and ethyldiisopropylamine 6.4 g (0.05 mol), melting point
5-cyano-N-[2-[4-(p-
fluorobenzyl)-piperidinyl]-ethyl]-
2-Methoxy-benzamide-hydrochloride was obtained.
åºçºç©è³ªãšããŠäœ¿çšããâïŒïŒâã¢ãããšã
ã«ïŒâïŒâïŒïœâãã«ãªããã³ãžã«ïŒâãããªãžã³
âãããã¯ããªãã¯æ¬¡ã®ããã«ããŠè£œé ããã N-(2-aminoethyl)-4-(p-fluorobenzyl)-piperidine-hydrochloride used as a starting material was produced as follows.
ïŒïœã®ãã©ãžãŠã æ
æççŽ ïŒïŒïŒ
ïŒãå«ãããª
ãã«ãªãé
¢é
ž120mläžã§ãçè«éã®æ°ŽçŽ ãåžåã
ãããŸã§70âã§ïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâ
ãããªãžã³âãããã¯ããªã24.4ïœïŒ0.10ã¢ã«ïŒ
ãæ°ŽçŽ åããã次ã«è§Šåªãå»ããæ°Žæµã«ããæž
å§åã§æ¶²ãèžçºããããæ®çç©ãæ°Ž150mlã«æº¶
解ãããæ¿èæ§ãœãŒã50mlãæ·»å åŸããšãŒãã«
250mlã§æœåºãããããããŠåŸããããšãŒãã«æº¶
液ãå¡©åæ°ŽçŽ ã¬ã¹ã§åŒ±ã³ã³ãŽãŒé
žæ§ã«èª¿ç¯ãã
ãšãèç¹166ã166.5âã®ïŒâïŒïœâãã«ãªããã³
ãŸã€ã«ïŒâãããªãžã³âãããã¯ããªããæ²æŸ±ã
ãã 4-(p-fluorobenzoyl)- in 120 ml of trifluoroacetic acid containing 5 g of palladium on carbon (5%) at 70 °C until the theoretical amount of hydrogen has been absorbed.
Piperidine-hydrochloride 24.4g (0.10mol)
was hydrogenated. The catalyst was then removed and the liquid was evaporated under reduced pressure with a water stream. Dissolve the residue in 150 ml of water, add 50 ml of concentrated caustic soda, and then dissolve in ether.
Extracted with 250ml. When the ether solution thus obtained was adjusted to be slightly Congo acidic with hydrogen chloride gas, 4-(p-fluorobenzoyl)-piperidine-hydrochloride having a melting point of 166-166.5°C was precipitated.
å¡©åã¡ãã¬ã³75mlã«æžæ¿ãããïŒâïŒïœâãã«
ãªããã³ãžã«ïŒâãããªãžã³âãããã¯ããªã23
ïœïŒ0.10ã¢ã«ïŒåã³ã¯ããã¢ã»ããããªã«8.3ïœ
ïŒ0.11ã¢ã«ïŒã«æ¹æäžã«ãšãã«âãžã€ãœãããã«
ã¢ãã³28.4ïœïŒ0.22ã¢ã«ïŒã滎äžãããåå¿æ··å
ç©ã15æé宀枩ã§æ¹æããã次ã«ãšãŒãã«150ml
ãšæ··åãã2Nå¡©é
žãšå
±ã«æ¯çªããããã®é
žæœåº
液ã2Nèæ§ãœãŒãã§ã¢ã«ã«ãªæ§ã«èª¿ç¯ããæåº
ããå¡©åºãå¡©åã¡ãã¬ã³ãšå
±ã«æ¯çªããããã®ã
ã®ãæ°Žã§äžæ§ã«ãªããŸã§æŽæµããç¡«é
žãããªãŠã
ã§ä¹Ÿç¥åŸãèžçºæ¿çž®ããããæ®çç©ãå°éã®ã€ãœ
ãããããŒã«ã«æº¶ãããå¡©åæ°ŽçŽ ã®ãšãŒãã«æº¶æ¶²
ã§åŒ±ã³ã³ãŽãŒé
žæ§ã«èª¿ç¯ããèç¹158ã160âã®ïŒ®
âïŒã·ã¢ãã¡ãã«ïŒâïŒâïŒïœâãã«ãªããã³ãžã«ïŒ
âãããªãžã³âãããã¯ããªãæåºç©ãåŸãã 4-(p-fluorobenzyl)-piperidine-hydrochloride suspended in 75 ml of methylene chloride 23
g (0.10 mol) and chloroacetonitrile 8.3 g
(0.11 mol) was added dropwise with stirring to 28.4 g (0.22 mol) of ethyl-diisopropylamine. The reaction mixture was stirred for 15 hours at room temperature. Next, 150ml of ether
and shaken with 2N hydrochloric acid. This acid extract was adjusted to alkalinity with 2N caustic soda, and the precipitated base was shaken with methylene chloride. This material was washed with water until neutral, dried over sodium sulfate, and then concentrated by evaporation. The residue was dissolved in a small amount of isopropanol, adjusted to weak Congo acidity with an ethereal solution of hydrogen chloride, and dissolved in N with a melting point of 158-160 °C.
-(cyanomethyl)-4-(p-fluorobenzyl)
-Piperidine-hydrochloride precipitate was obtained.
âïŒã·ã¢ãã¡ãã«ïŒâïŒâïŒïœâãã«ãªããã³
ãžã«ïŒâãããªãžã³âãããã¯ããªã13.44ïœ
ïŒ0.05ã¢ã«ïŒãé
¢é
ž300mlåã³æ¿å¡©é
žïŒmlã«æº¶ã
ããé
žåçœéïŒïœãšå
±ã«æ°ŽçŽ é°å²æ°äžã«ãããŠæ°Ž
çŽ åãããïŒæéåŸã«çè«é2.25ã®æ°ŽçŽ ãåžå
ãããã次ã«è§Šåªãå»ãã液ãæ°Žæµã«ããæž
å§äžã§çŽ30mlã«æ¿çž®ããããçæããæ¶æ³¥ã«ã€ãœ
ãããããŒã«ïŒmlåã³ãšãŒãã«10mlãæ·»å ãã
éãããâïŒïŒâã¢ãããšãã«ïŒâïŒâïŒïœâã
ã«ãªããã³ãžã«ïŒâãããªãžã³âãããã¯ããªã
ãååŸããããã®ãã®ã¯ãšã¿ããŒã«âãšãŒãã«ã
ãåçµæ¶ãããåŸã171ã173âã§è解ããã N-(cyanomethyl)-4-(p-fluorobenzyl)-piperidine-hydrochloride 13.44g
(0.05 mol) was dissolved in 300 ml of acetic acid and 7 ml of concentrated hydrochloric acid, and hydrogenated with 1 g of platinum oxide in a hydrogen atmosphere. After 4 hours, a theoretical amount of 2.25 hydrogen was absorbed. The catalyst was then removed and the liquid was concentrated to about 30 ml under water jet vacuum. Add 5 ml of isopropanol and 10 ml of ether to the formed crystal mud,
passed. N-(2-aminoethyl)-4-(p-fluorobenzyl)-piperidine-hydrochloride was obtained, which melted at 171-173°C after recrystallization from ethanol-ether.
äŸ 20
ïŒâã·ã¢ãââïŒâïŒâïŒïœâãã«ãªãã
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ãã·âãã³ãºã¢ããâãããã¯ããªã6.69ïœ
ïŒ0.015ã¢ã«ïŒããã¡ã¿ããŒã«50mlåã³ãã«ãšã³50
mlã«æžæ¿ããããææŸãªæº¶æ¶²ãåŸããããŸã§æ¹æ
åã³å·åŽäžã«ïŒâã§å¡©åæ°ŽçŽ ã¬ã¹ãå°å
¥ããã次
ã«æ°·æ°Ž100mlãåŸã
ã«æ³šããæŽã«ïŒæé70âã«å
ç±ãããå·åŽåŸã«ã«ãªãŠã ã§æ³šææ·±ã匱ã¢ã«ã«ãª
æ§ã«èª¿ç¯ããããããŠåŸãããæ··åç©ãå¡©åã¡ã
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æ§ã«ãªããŸã§æŽæµããç¡«é
žãã°ãã·ãŠã äžã§ä¹Ÿç¥
ãããæ°Žæµã«ããæžå§äžã§èžçºããããæ®çç©ãš
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ïŒâã¡ããã·ã«ã«ããã«âãã³ãºã¢ããããå¡©å
ã¡ãã¬ã³âãšãŒãã«ïŒïŒïŒïŒïŒã«æº¶ãããå¡©åæ°Ž
çŽ ã®ãšãŒãã«æº¶æ¶²ã«ããå¡©é
žå¡©ã«å€æããããã
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ååçµæ¶ãããïŒèç¹221âïŒå解ïŒïŒãExample 20 6.69 g of 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamino-hydrochloride
(0.015 mol), methanol 50 ml and toluene 50 ml
ml. Hydrogen chloride gas was introduced at 0° C. with stirring and cooling until a clear solution was obtained. Next, 100 ml of ice water was gradually poured into the mixture, and the mixture was further heated to 70°C for 1 hour. After cooling, the mixture was carefully made slightly alkaline with potassium and the mixture thus obtained was extracted with methylene chloride. The methylene chloride solution was washed neutral with water, dried over magnesium sulphate and evaporated under reduced pressure with a stream of water. N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy- obtained as a residue
5-Methoxycarbonyl-benzamide was dissolved in methylene chloride-ether (1:1) and converted to the hydrochloride salt with an ethereal solution of hydrogen chloride. Take this and mix it with methylene chloride-acetone.
It was recrystallized twice (melting point 221°C (decomposition)).
äŸ 21
ïŒâã·ã¢ãââïŒâïŒâïŒïœâãã«ãªãã
ã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ã
ãã·âãã³ãºã¢ããâãããã¯ããªã6.69ïœ
ïŒ0.015ã¢ã«ïŒãçªçŽ é°å²æ°äžã«ãããŠ85ïŒ
ç¡«é
ž60
mlã«æº¶è§£ãããïŒæ¥é宀枩ã«æŸçœ®ããããã®æº¶æ¶²
ãæ°·200ïœåã³æ¿ã¢ã³ã¢ãã¢130mlã®æ··åç©ã«æ¹æ
äžã«æ»Žäžããããã«ããçœè²ã®æ²æŸ±ãçæããã
ãã®ãã®ãåããå¡©åã¡ãã¬ã³âã¡ã¿ããŒã«ã
ãåçµæ¶ããããããã«ããèç¹236ã238âã®ïŒ
âã«ã«ãã¢ã€ã«ââïŒâïŒâïŒïœâãã«ãªã
ãã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡
ããã·âãã³ãºã¢ããâãåŸããããExample 21 6.69 g of 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide-hydrochloride
(0.015 mol) in 85% sulfuric acid 60 in nitrogen atmosphere
ml and left at room temperature for 7 days. This solution was added dropwise to a mixture of 200 g of ice and 130 ml of concentrated ammonia with stirring, resulting in the formation of a white precipitate.
This product was taken and recrystallized from methylene chloride-methanol. This results in a melting point of 236-238â.
-Carbamoyl-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide- was obtained.
å¡©é
žå¡©ã«å€æãããããã«éé¢å¡©åºãå¡©åã¡ã
ã¬ã³äžã«æžæ¿ããããã®ãã®ãæ¹æäžã«ã³ã³ãŽãŒ
æ瀺è¬ãé
žæ§ã瀺ããŸã§å¡©åæ°ŽçŽ ãšãŒãã«æº¶æ¶²ã
æ·»å ããææŸãªæº¶æ¶²ãçæãããã次ã«çµæ¶åã
éå§ããããŸã§ãšãŒãã«ãæ·»å ãããïŒâã«ã«ã
ã¢ã€ã«ââïŒâïŒâïŒïœâãã«ãªããã³ãŸã€
ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ããã·â
ãã³ãºã¢ããâãããã¯ããªãïŒèç¹240âïŒå
解ïŒïŒãåŸãããã For conversion to the hydrochloride salt, the free base was suspended in methylene chloride and to this was added ethereal hydrogen chloride solution with stirring until the Congo indicator showed acidity, producing a clear solution. Ether was then added until crystallization started. 5-Carbamoyl-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-
Benzamide hydrochloride (melting point 240°C (decomposition)) was obtained.
äŸ 22
ïŒâã¡ããã·âïŒâã¡ã¿ã³ã¹ã«ãã€ãã«å®æ¯éŠ
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âã¡ããã·âïŒâã¡ã¿ã³ã¹ã«ãã€ãã«âãã³ãºã¢
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ããšãŒãã«æ·»å ã«ããæ²æŸ±ããããâïŒâïŒ
âïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâ
ãšãã«ïŒœâïŒâã¡ããã·âïŒâã¡ã¿ã³ã¹ã«ãã€ã
ã«âãã³ãºã¢ããâãããã¯ããªããåŸãããã
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æ¶ãããåŸã194âã§è解ïŒå解ïŒãããExample 22 2.14 g (0.01 mol) of 2-methoxy-5-methanesulfinylbenzoic acid and 3.23 g (0.01 mol) of N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine-dihydrochloride. It was dissolved in 10 ml of dimethylformamide and 2.13 g (0.021 mol) of triethylamine was added. 3.26 g of triphenyl phosphite in a nitrogen atmosphere with stirring
(0.0105 mol) and the resulting reaction mixture
Heated to 85-90°C for 2.5 hours. After cooling, an ether solution of hydrogen chloride was added until the Congo indicator showed acidity, and the precipitated ether solution was decanted.
The residue was mixed with methylene chloride and potassium carbonate solution, and the methylene chloride solution was dried over potassium carbonate and concentrated. Residue N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2
-Methoxy-5-methanesulfinyl-benzamide was converted to the hydrochloride salt with ethereal hydrogen chloride solution in methylene chloride-methanol. This was precipitated by addition of ether. N-[2-[4
-(p-fluorobenzoyl)-piperidinyl]-
Ethyl]-2-methoxy-5-methanesulfinyl-benzamide hydrochloride was obtained which, after one recrystallization from methylene chloride-methanol, melted (decomposed) at 194°C.
äŸ 23
äŸ10ãšåæ§ã«ããŠããã«ãšã³25mläžã®ïœâãã«
ãªããã³ãŸã€ã«âã¢ãžãªãžã³4.95ïœïŒ0.03ã¢ã«ïŒ
åã³ïŒâïŒïŒâããã€ã«ïŒâãããªãžã³5.85ïœ
ïŒ0.03ã¢ã«ïŒãããèç¹204ã205âã®ïœâãã«ãª
ãââïŒâïŒâïŒïŒâããã€ã«ïŒâãããªãžã
ã«ïŒœãšãã«ïŒœâãã³ãºã¢ããâãããã¯ããªãã
åŸããããExample 23 As in Example 10, 4.95 g (0.03 mol) of p-fluorobenzoyl-aziridine in 25 ml of toluene.
and 5.85 g of 4-(2-thenoyl)-piperidine
(0.03 mol) gave p-fluoro-N-[2-[4-(2-thenoyl)-piperidinyl]ethyl]-benzamide-hydrochloride with a melting point of 204-205°C.
ãã«ãšã³20mläžã®ïŒ®âïŒïŒâã·ã¢ãâïŒâã¡ã
ãã·âãã³ãŸã€ã«ïŒâã¢ãžãªãžã³4.04ïœïŒ0.02ã¢
ã«ïŒåã³ïŒâïŒïœâã¯ãããã³ãŸã€ã«ïŒâãããªãž
ã³4.46ïœïŒ0.02ã¢ã«ïŒãããèç¹177ã178âã®ïŒ®
âïŒâïŒâïŒïœâã¯ãããã³ãŸã€ã«ïŒâãããªãž
ãã«ïŒœâãšãã«ïŒœâïŒâã·ã¢ãâïŒâã¡ããã·âã
ã³ãºã¢ããâã¡ã¿ã³ã¹ã«ãããŒããåŸãããã From 4.04 g (0.02 mol) of N-(5-cyano-2-methoxy-benzoyl)-aziridine and 4.46 g (0.02 mol) of 4-(p-chlorobenzoyl)-piperidine in 20 ml of toluene, a solution with a melting point of 177-178°C N
-[2-[4-(p-chlorobenzoyl)-piperidinyl]-ethyl]-5-cyano-2-methoxy-benzamide-methanesulfonate was obtained.
ãã«ãšã³20ïœäžã®ïœâãã«ãªããã³ãŸã€ã«âã¢
ãžãªãžã³3.3ïœïŒ0.02ã¢ã«ïŒåã³ïŒâïŒïœâã¯ãã
ãã³ãŸã€ã«ïŒâãããªãžã³4.46ïœïŒ0.02ã¢ã«ïŒã
ããèç¹149ã151âã®ïŒ®âïŒâïŒâïŒïœâã¯ã
ããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâïœâ
ãã«ãªãâãã³ãºã¢ããâã¡ã¿ã³ã¹ã«ãããŒãã
åŸãããã From 3.3 g (0.02 mol) of p-fluorobenzoyl-aziridine and 4.46 g (0.02 mol) of 4-(p-chlorobenzoyl)-piperidine in 20 ml of toluene, N-[2-[4-( p-chlorobenzoyl)-piperidinyl]-ethyl]-p-
Fluoro-benzamide-methanesulfonate was obtained.
äŸ 24
äŸ10ãšåæ§ã«ããŠããã«ãšã³10mläžã®ïŒ®âïŒïœ
âãã«ãªããã³ãŸã€ã«ïŒâïŒïŒïŒâãžã¡ãã«âã¢
ãžãªãžã³1.93ïœïŒ0.01ã¢ã«ïŒåã³ïŒâïŒïœâãã«
ãªããã³ãŸã€ã«ïŒâãããªãžã³2.07ïœïŒ0.01ã¢ã«ïŒ
ãããèç¹238ã240âã®ïœâãã«ãªãââïŒ
âïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã
ã«ïŒœâïŒâã¡ãã«ãããã«ïŒœâãã³ãºã¢ããâãã
ãã¯ããªããåŸããããExample 24 In the same manner as in Example 10, N-(p
-fluorobenzoyl)-2,2-dimethyl-aziridine 1.93 g (0.01 mol) and 4-(p-fluorobenzoyl)-piperidine 2.07 g (0.01 mol)
p-fluoro-N-[3
-[4-(p-fluorobenzoyl)-piperidinyl]-2-methylpropyl]-benzamide-hydrochloride was obtained.
åºçºç©è³ªãšããŠçšããâïŒïœâãã«ãªããã³
ãŸã€ã«ïŒâïŒïŒïŒâãžã¡ãã«ã¢ãžãªãžã³ã¯ãäŸ10
ãšåæ§ã«ããŠæ¬¡ã®ããã«è£œé ããã N-(p-fluorobenzoyl)-2,2-dimethylaziridine used as starting material was prepared from Example 10.
It was manufactured in the same manner as follows.
1Nèæ§ãœãŒã30.6mläžã®ïŒïŒïŒâãžã¡ãã«â
ã¢ãžãªãžã³2.13ïœïŒ0.03ã¢ã«ïŒåã³ïœâãã«ãªã
ãã³ãŸã€ã«ã¯ããªã4.76ïœïŒ0.03ã¢ã«ïŒããç²çš
ãªæ²¹æ§ã®ïŒ®âïŒïœâãã«ãªããã³ãŸã€ã«ïŒâïŒïŒïŒ
âãžã¡ãã«âã¢ãžãªãžã³ãåŸãããã 2,2-dimethyl- in 30.6 ml of 1N caustic soda
From 2.13 g (0.03 mol) of aziridine and 4.76 g (0.03 mol) of p-fluorobenzoyl chloride, a viscous oily N-(p-fluorobenzoyl)-2,2
-dimethyl-aziridine was obtained.
äŸ 25
ïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã³â
ãããã¯ããªã26.8ïœïŒ0.11ã¢ã«ïŒãçé
žã«ãªãŠ
ã 34.5ïœïŒ0.25ã¢ã«ïŒåã³ïŒ®âïŒïŒâã¯ãããã
ãã«ïŒâïŒâã·ã¢ãâïŒâã¡ããã·âãã³ãºã¢ã
ã25.3ïœïŒ0.1ã¢ã«ïŒããšãŠåã«ãªãŠã 0.5ïœãšå
±
ã«ãšã¿ããŒã«250mläžã«ãããŠ15æéæ¹æäžã«å
ç±æ²žéš°ãããã次ã«åå¿æ··åç©ãæ°Žæµã«ããæžå§
äžã§èžçºãããæ®çç©ããšãŒãã«ãå°éã®å¡©åã¡
ãã¬ã³åã³æ°Žã«åžåããããæ°Žçžãåé¢ããåŸã
2Nã¡ã¿ã³ã¹ã«ãã³é
žãšå
±ã«æ¯çªããããšã«ãã
å¡©åºæåãææ©çžããåé¢ãããé
žæœåºæ¶²ãèæ§
ãœãŒãã§PHïŒã«èª¿ç¯ããåŸãå¡©åã¡ãã¬ã³ã§æœåº
ãããå¡©åã¡ãã¬ã³æº¶æ¶²ãæ°Žã§äžæ§ã«ãªããŸã§æŽ
æµããç¡«é
žãã°ãã·ãŠã äžã§ä¹Ÿç¥ãããæ°Žæµã«ã
ãæžå§äžã§èžçºããããããããŠåŸãããç²çæ
ç©ããã©ãã·ãŠã¯ãããã°ã©ãã€ãŒã«ä»ããã¯ã
ããã«ã âã¡ã¿ããŒã«49ïŒïŒãã©ã¯ã·ãšã³ã«ãã€
ãŠèç¹133ã135âã®ææã®ïŒâã·ã¢ãââïŒ
âïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžã
ã«ïŒœâãããã«ïŒœâïŒâã¡ããã·âãã³ãºã¢ããã
溶é¢ããããExample 25 4-(p-fluorobenzoyl)-piperidine-
26.8 g (0.11 mol) of hydrochloride, 34.5 g (0.25 mol) of potassium carbonate and 25.3 g (0.1 mol) of N-(3-chloropropyl)-5-cyano-2-methoxy-benzamide were mixed with 0.5 g of potassium iodide in ethanol. The mixture was heated and boiled in a 250 ml solution for 15 hours with stirring. The reaction mixture was then evaporated under reduced pressure with a stream of water and the residue was taken up in ether, a little methylene chloride and water. After separating the aqueous phase,
The base component was separated from the organic phase by shaking with 2N methanesulfonic acid. The acid extract was adjusted to pH 9 with caustic soda, and then extracted with methylene chloride. The methylene chloride solution was washed with water until neutral, dried over magnesium sulphate and evaporated under reduced pressure with a stream of water. The crude product thus obtained was subjected to flash chromatography and the desired 5-cyano-N-[3
-[4-(p-fluorobenzoyl)-piperidinyl]-propyl]-2-methoxy-benzamide was eluted.
å¡©é
žå¡©ã«å€æãããããã«ãéé¢å¡©åºãå¡©åã¡
ãã¬ã³ã«æº¶è§£ããããã®æº¶æ¶²ã«å¡©åæ°ŽçŽ ã®ãšãŒã
ã«æº¶æ¶²ããã³ã³ãŽãŒæ瀺è¬ãé
žæ§ã瀺ããŸã§æ·»å
ãã次ã«çµæ¶åãéå§ããããŸã§ãšãŒãã«ãæ·»å
ãããããã«ãããèç¹171âïŒå解ïŒã®ïŒâã·
ã¢ãââïŒâïŒâïŒïœâãã«ãªããã³ãŸã€ã«ïŒ
âãããªãžãã«ïŒœâãããã«ïŒœâïŒâã¡ããã·âã
ã³ãºã¢ãããåŸãã To convert to the hydrochloride salt, the free base was dissolved in methylene chloride and to this solution an ethereal solution of hydrogen chloride was added until the Congo indicator showed acidity, then ether was added until crystallization started. . This produced 5-cyano-N-[3-[4-(p-fluorobenzoyl) with a melting point of 171°C (decomposition).
-Piperidinyl]-propyl]-2-methoxy-benzamide was obtained.
äŸ 26
ïŒâïŒïŒïŒïŒâãžã¡ããã·âããªãžãã«ïŒâïŒâ
ãªããµãŸãªã³20.8ïœïŒ0.1ã¢ã«ïŒãïŒâïŒïœâãã«
ãªããã³ãŸã€ã«ïŒâãããªãžã³22.8ïœïŒ0.11ã¢
ã«ïŒããžã€ãœãããã«âãšãã«ã¢ãã³12.9ïœïŒ0.1
ã¢ã«ïŒåã³ãžãªããµã³120mlãæ¹æäžã«16æé80
âã«å ç±ããã次ã«ãã®ãã®ã«å¡©åã¡ãã¬ã³åã³
æ°Žãæ·»å ãã飜åçé
žã«ãªãŠã 溶液ã§PHïŒã«èª¿ç¯
ãããå液ããŒãå
ã§å±€åé¢ããææ©çžãæ°Žæµã«
ããæžå§äžã§èžçºããããååŸããæ®çç©ãã¡ã¿
ããŒã«150mläžã«æº¶è§£ãããæ¹æåã«æ°Žãšæ··åãã
èç¹116ã119âã®æåºç©ãšããŠïŒ®âïŒâïŒâ
ïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãš
ãã«ïŒœâïŒïŒïŒâãžã¡ããã·âãã³ãã³é
žã¢ãã
ãåŸããExample 26 2-(2,6-dimethoxy-pyridinyl)-2-
20.8 g (0.1 mol) of oxazoline, 22.8 g (0.11 mol) of 4-(p-fluorobenzoyl)-piperidine, 12.9 g (0.1 mol) of diisopropyl-ethylamine.
80 mol) and 120 ml of dioxane for 16 hours under stirring.
heated to â. Next, methylene chloride and water were added to this, and the pH was adjusted to 9 with saturated potassium carbonate solution. The layers were separated in a separatory funnel and the organic phase was evaporated under reduced pressure with a stream of water. The obtained residue is dissolved in 150 ml of methanol and mixed with water under stirring,
N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-dimethoxy-nicotinamide was obtained.
éé¢å¡©åºãã¡ã¿ã³ã¹ã«ãã³é
žå¡©ã«å€æãããã
ãã«å°éã®å¡©åã¡ãã¬ã³ã«æº¶ããã匱ã³ã³ãŽãŒé
ž
æ§ã瀺ããŸã§æ¹æäžã«ã¡ã¿ã³ã¹ã«ãã³é
žã®ãšãŒã
ã«æº¶æ¶²ãæ·»å ããæåºç©ãšããŠãâïŒâïŒâ
ïŒïŒâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãš
ãã«ïŒœâïŒïŒïŒâãã³ãã³é
žã¢ããâã¡ã¿ã³ã¹ã«
ãããŒããåŸããç²çæç©ãã€ãœãããããŒã«ã
ãïŒååçµæ¶ãããïŒèç¹170ã172âïŒã In order to convert the free base to the methanesulfonate salt, it is dissolved in a small amount of methylene chloride and an ethereal solution of methanesulfonic acid is added under stirring until it shows weak Congo acidity, and as a precipitate, N-[2-[4-
(1-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-nicotinamide-methanesulfonate was obtained. The crude product was recrystallized once from isopropanol (mp 170-172°C).
åºçºç©è³ªã¯æ¬¡ã®ããã«è£œé ããã The starting material was prepared as follows.
çé
žã«ãªãŠã 110.6ïœïŒ0.8ã¢ã«ïŒããæ°Ž120ml
ã«æº¶ããã10âã«å·åŽããããã®æº¶æ¶²ããšãŒãã«
150mlãšå¡©åã¡ãã¬ã³100mlãšã®æ··åç©ãšæ··åã
ããåå¿æ··åç©ã«ãïŒâããã¢ãšãã«ã¢ãã³âã
ãããããã49.2ïœïŒ0.24ã¢ã«ïŒãæ·»å ããå¡©å
ã¡ãã¬ã³100mläžã®ïŒïŒïŒâãžã¡ããã·âãã³ã
ã³é
žã¯ããªã40.3ïœïŒ0.2ã¢ã«ïŒã®æº¶æ¶²ãåå¿æž©
床15ã20âã§çŽ æ©ã滎äžãããçæç©ã宀枩ã«å
ç±ããæŽã«ïŒæéãã®æž©åºŠã§æ¹æãããçæç©ã
æ°Ž50mlãšæ··åããå液ããŒãå
ã«ãããŠå±€åé¢ã
ããææ©çžãæ°Žæµã«ããæžå§äžã§èžçºãããæ·¡é»
è²ã®çµæ¶ç¶æ®çç©ãšããŠãïŒâïŒïŒïŒïŒâãžã¡ã
ãã·âããªããžã«ïŒâïŒâãªããµãŸãªã³ãåŸãã 110.6g (0.8mol) of potassium carbonate, 120ml of water
and cooled to 10°C. Transfer this solution to ether
150 ml of methylene chloride, and to the reaction mixture was added 49.2 g (0.24 mol) of 2-bromoethylamine-hydrobromide and 40.3 g (0.24 mol) of 2,6-dimethoxy-nicotinyl chloride in 100 ml of methylene chloride. A solution of 0.2 mol) was quickly added dropwise at a reaction temperature of 15-20°C. The product was heated to room temperature and stirred at this temperature for an additional hour. The product was mixed with 50 ml of water and the layers were separated in a separatory funnel. The organic phase was evaporated under reduced pressure with a stream of water to give 2-(2,6-dimethoxy-pyrimidyl)-2-oxazoline as a pale yellow crystalline residue.
äŸ 27
掻æ§æåãäŸãã°ïŒâã·ã¢ãââïŒâïŒâ
ïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãš
ãã«ïŒœâïŒâã¡ããã·âãã³ãºã¢ãã25mgãå«æ
ããé å€ã次ã®ããã«ããŠè£œé ãããExample 27 Active ingredients such as 5-cyano-N-[2-[4-
Tablets containing 25 mg of (p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide were prepared as follows.
çµæïŒ1000é åœãïŒ
掻æ§æå 25.0ïœ
ã©ã¯ããŒã¹ 100.7ïœ
å°éºŠæŸ±ç² 7.5ïœ
ããªãšãã¬ã³ã°ãªã³ãŒã«6000 5.0ïœ
ã¿ã«ã¯ 5.0ïœ
ã¹ãã¢ãªã³é
žãã°ãã·ãŠã 1.8ïœ
è±ã€ãªã³æ°Ž é©é
補 é
å
šéšã®åºåœ¢æåãã¡ãã·ãŠãµã€ãº0.6mmã®ç¯©ã«
ãããã次ã«æŽ»æ§æåãã©ã¯ããŒã¹ãã¿ã«ã¯ãã¹
ãã¢ãªã³é
žãã°ãã·ãŠã ãšåéã®æŸ±ç²ãæ··åã
ããæ®ãã®åéã®æŸ±ç²ãæ°Ž40mlã«æžæ¿ããããã®
æžæ¿äœããæ°Ž100mlã«æº¶ããã沞隰äžã®ããªãšã
ã¬ã³ã°ãªã³ãŒã«æº¶æ¶²ã«æ·»å ãããååŸãã柱ç²æ
åãå
ã®äž»èŠéšåã«æ·»å ããŠåŸãæ··åç©ããå¿
èŠ
ã«å¿ãæ°Žãæ·»å ãã€ã€é¡ç²åãããåŸãããé¡ç²
ã35âã§äžæ©ä¹Ÿç¥ãããã¡ãã·ãŠãµã€ãº1.2mmã®
篩ã«ãããã¡ãã·ãŠãµã€ãºçŽïŒmmã®äž¡å¹é¢ç¶ã®é
å€ã«ãã¬ã¹å å·¥ãããComposition (per 1000 tablets) Active ingredient 25.0g Lactose 100.7g Wheat starch 7.5g Polyethylene glycol 6000 5.0g Talc 5.0g Magnesium stearate 1.8g Deionized water Appropriate amount Manufacture All solid ingredients were passed through a sieve with a mesh size of 0.6 mm. The active ingredients, lactose, talc, magnesium stearate and half the amount of starch were then mixed. The remaining half of the starch was suspended in 40 ml of water and this suspension was added to a boiling polyethylene glycol solution in 100 ml of water. The obtained starch component was added to the main portion, and the resulting mixture was granulated, adding water as necessary. The obtained granules were dried at 35° C. overnight, passed through a sieve with a mesh size of 1.2 mm, and pressed into biconcave tablets with a mesh size of about 6 mm.
äŸ 28
ïŒâã·ã¢ãââïŒâïŒâïŒïœâãã«ãªãã
ã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãšãã«ïŒœâïŒâã¡ã
ãã·âãã³ãºã¢ããã®ã¡ã¿ã³ã¹ã«ãã³å¡©é
ž0.02ïœ
ãå«æããé å€ã次ã®ããã«ããŠè£œé ãããExample 28 0.02 g of methanesulfone hydrochloride of 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide
Tablets containing the following were manufactured as follows.
çµæïŒ10000é åœãïŒ
掻æ§æå 200.00ïœ
ã©ã¯ããŒã¹ 290.80ïœ
ã°ããããæŸ±ç² 274.70ïœ
ã¹ãã¢ãªã³é
ž 10.00ïœ
ã¿ã«ã¯ 200.00ïœ
ã¹ãã¢ãªã³é
žãã°ãã·ãŠã 2.50ïœ
ã³ãã€ãç¶äºé
žåçªçŽ 32.00ïœ
ãšã¿ããŒã« é©é
掻æ§æåãã©ã¯ããŒã¹åã³ã°ãããã柱ç²
194.70ïœã®æ··åç©ãã¹ãã¢ãªã³é
žã®ãšã¿ããŒã«æº¶
液ã§æ¹¿æœ€ããã篩ã«ããé¡ç²åããã也ç¥åŸã«æ®
ãã®ã°ãããã柱ç²ãã¿ã«ã¯ãã¹ãã¢ãªã³é
žãã°
ãã·ãŠã åã³ã³ãã€ãç¶äºé
žåçªçŽ ãæ··åããæ··
åç©ããã¬ã¹å å·¥ããå¿
èŠãªãã°çšéã«ããã现
å¯ã«é©åãããããã®éšååæ¬ ãåãåŸã0.1ïœ
ãã€ã®ééã®é å€ãšãããComposition (per 10000 tablets) Active ingredients 200.00g Lactose 290.80g Barchi 274.70g stearic acid 10.00g Tarc 200.00g of stearate 2.50g Colloid -shaped 1.50g Coroid -like silicon 32.00g Ethanole appropriate amount of active ingredients
194.70 g of the mixture was moistened with an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remaining potato starch, talc, magnesium stearate and colloidal silicon dioxide are mixed and the mixture is pressed into 0.1 g, which can be provided with part-cuts for more precise adaptation to the dosage, if necessary.
It was made into tablets of the same weight.
äŸ 29
掻æ§æåãäŸãã°ïŒâã·ã¢ãââïŒâïŒâ
ïŒïœâãã«ãªããã³ãŸã€ã«ïŒâãããªãžãã«ïŒœâãš
ãã«ïŒœâïŒâã¡ããã·âãã³ãºã¢ãã0.025ïœãå«
æããã«ãã»ã«ã次ã®ããã«ããŠè£œé ãããExample 29 Active ingredients such as 5-cyano-N-[2-[4-
Capsules containing 0.025 g of (p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide were prepared as follows.
çµæïŒ1000ã«ãã»ã«åœãïŒ
掻æ§æå 25.00ïœ
ã©ã¯ããŒã¹ 249.00ïœ
ãŒã©ãã³ 2.00ïœ
ãšãããããæŸ±ç² 10.00ïœ
ã¿ã«ã¯ 15.00ïœ
æ°Ž é©é
掻æ§æåãã©ã¯ããŒã¹ãšæ··åãããŒã©ãã³æ°Žæº¶
液ã§æ··åç©ãäžæ§ã«æ¹¿æœ€ãããã¡ãã·ãŠãµã€ãº
1.2ã1.5mmã®ç¯©ã«ããé¡ç²åãããåŸãããé¡ç²
ã也ç¥ãããšããããã柱ç²åã³ã¿ã«ã¯ãšæ··å
ãã硬質ãŒã©ãã³ã«ãã»ã«ïŒãµã€ãºïŒïŒã«300mg
ãã€å
å¡«ãããComposition (per 1000 capsules) Active ingredient 25.00g Lactose 249.00g Gelatin 2.00g Corn starch 10.00g Talc 15.00g Water Appropriate amount Mix the active ingredient with lactose, uniformly wet the mixture with an aqueous gelatin solution, and mesh size.
It was granulated through a 1.2-1.5 mm sieve. The resulting granules were mixed with dried corn starch and talc, and 300 mg was added to hard gelatin capsules (size 1).
Filled with each.
è©ŠéšäŸ
çäœå
ã§ã®ããŒããã³å容äœéšäœã®å°éããS.
BischoffããEuropean J.Pharmacol.68ã305â
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å®ãããTest example Blockade of dopamine receptor sites in vivo was performed using S.
Bischoff et al., European J. Pharmacol. 68, 305â
315 (1980), the rate of inhibition of 3 H-spiroperone binding in rat hippocampus was measured by intraperitoneal administration.
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äžã®çµæãåŸãã Results: Compound ED 50 (mg/Kg) Intraperitoneal administration (% inhibition) 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide 0.75 ( 50) N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-dimethoxynicotinamide 4.6(50) 4-chloro-5-cyano-N-[2-[4 -(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2-methoxybenzamide 1.25(50) 5-chloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-4-methylaminobenzamide 6.2(50) 3-bromo -N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-methoxybenzamide 30(71) 5-cyano-N-[2-[4-((p-fluorophenyl) -hydroxymethylene)-piperidinyl]-
ethyl]-2-methoxy-benzamide 30(80) 3-bromo-4-fluoro-N-[2-[4-(p
-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide 30 (97) 2-bromo-4-fluoro-N-[2-[4-(p
-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide 30 (74) 4-fluoro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide 0.16 (97) In addition, the present invention The toxicity of these compounds is low, and among the above compounds, acute toxicity tests in rats were conducted on compounds with high potential for development as antipsychotic drugs, and the following results were obtained.
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æäžïŒ5-Cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl-2-methoxybenzamide LD 50 >150mg/Kg (intraperitoneal administration) 4-chloro-5-cyano-N-[ 2-[4-(p-
fluorobenzoyl)-piperidinyl]-ethyl]
-2-Methoxybenzamide 500mg/oral No deaths due to administration 4-Fluoro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide LD 50 = 150mg/Kg (intraperitoneal administration)
Claims (1)
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ãå粟ç¥ç è¬ã[Claims] 1. General formula: (In the formula, R represents a lower alkoxy group or a halogen atom; Ar 1 represents a phenylene group or a pyridylene group, and each of these groups is unsubstituted or lower alkyl, halo-lower alkyl, halogen,
Lower alkoxy, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbonyl, N
- mono- or polysubstituted by lower alkylamino, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl, lower alkanesulfinyl and/or lower alkanesulfonyl; alk represents an alkylene group having 2 to 7 carbon atoms and separating two nitrogen atoms by 2 or 3 carbon atoms; X represents a carbonyl group or a hydroxymethylene group; and Ar 2 represents a phenyl group or a phenyl group substituted with halogen, provided that Ar 1
N-lower alkylamino as a substituent of -
N-(piperidinyl-alkyl)-carboxamide or a salt thereof. 2 R represents a lower alkoxy group; Ar 1 represents a phenylene group on the other hand, and this group is unsubstituted or halo-lower alkyl, halogen, lower alkoxy, cyano, carbamoyl, N-lower alkylamino, sulfamoyl, is mono- or polysubstituted by N,N-di-lower alkylsulfamoyl; or on the other hand represents a pyridylene group, which is mono- or polysubstituted by lower alkoxy and/or halogen;
Claims represented by the formula: alk represents an ethylene group or a 1,3-propylene group; X represents a carbonyl group or a hydroxymethylene group; and Ar 2 represents a phenyl group substituted with a halogen. The compound according to item 1 or a salt thereof. 3 The group R-Ar 1 has the formula: (wherein, on the one hand, Ra represents a group R in which Ra is lower alkoxy having up to 4 carbon atoms,
Rb and Re represent hydrogen, Rc represents a lower alkylamino having 4 or less carbon atoms, and Rd represents a halogen with an atomic number of 35 or less, or Rc represents hydrogen or a halogen with an atomic number of 35 or less. , Rd
represents cyano; or, on the other hand,
Ra, Rd and Re represent hydrogen, and Rb has atomic number 35
represents a group R representing the following halogen and Rc is lower alkoxy having up to 4 carbon atoms; and in each case alk represents an ethylene group; X represents a carbonyl group or a hydroxymethylene group; and Ar 2 represents a 4-fluorophenyl group), or a salt thereof according to claim 1, represented by the formula: 4 The group R-Ar 1 has the formula b (wherein one of Ra and Rb represents hydrogen or a halogen with an atomic number of 35 or less,
the other represents a hydrogen atom, Rc represents a group R that is a halogen with an atomic number of 35 or less, Rd and Re each represent a hydrogen atom; alk represents an ethylene group;
The compound according to claim 1, or a salt thereof, represented by the formula, wherein X represents a carbonyl group; and Ar2 represents a 4-fluorophenyl group. 5 5-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide or salt thereof; 4-chloro-5-cyano-N-[2-[4 â(p
-fluorobenzoyl)-piperidinyl]-ethyl]-2-benzamide or its salt; 5-bromo-4-chloro-N-[2-[4-(p
-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-fluoro-2-methoxy-benzamide or a salt thereof; 5-bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-fluoro-2-methoxy-benzamide or a salt thereof; N-[2-[4- (p-fluorobenzoyl)-piperidinyl]-ethoxy]-2-methoxy-5-trifluoromethyl-benzamide or salt thereof; 2-methoxy-5-sulfamoyl-N-[2
-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide or its salt; 5-chloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy -4-methylaminosulfamoyl-benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl-ethyl]-2-methoxy-5-dimethylsulfamoyl-benzamide or a salt thereof; 3-Bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-methoxy-benzamide or salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl] ]-ethyl]-2-methoxy-benzamide or its salt; and 5-cyano-N-[2-[4-[(4-fluorophenyl)-hydroxymethylene]-piperidinyl]
-ethyl]-2-methoxy-benzamide or a salt thereof. 6 3-Bromo-4-fluoro-N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide or a salt thereof; 2-bromo-4-fluoro-N-[2-[4-
(p-fluorobenzoyl)-piperidinyl]-ethyl]benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2,6-dimethoxy-benzamide or a salt thereof; 4 -Fluoro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-benzamide or a salt thereof; 5-bromo-N-[2-[4-(p-fluorobenzoyl)-piperidinyl] -ethyl]-2-methoxy-benzamide or a salt thereof; and 3-cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-4-methoxy-benzamide or a salt thereof; A compound according to claim 1. 7 3,5-dichloro-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-
2-methoxy-4-methyl-benzamide or a salt thereof; N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-5-methanesulfonyl-benzamide or a salt thereof; and 5 A compound according to claim 1 selected from -cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxy-benzamide or a salt thereof. 8 General formula: (In the formula, R represents a lower alkoxy group or a halogen atom; Ar 1 represents a phenylene group or a pyridylene group, and each of these groups is unsubstituted or lower alkyl, halo-lower alkyl, halogen,
Lower alkoxy, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbonyl, N
- mono- or polysubstituted by lower alkylamino, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl, lower alkanesulfinyl and/or lower alkanesulfonyl; alk represents an alkylene group having 2 to 7 carbon atoms and separating two nitrogen atoms by 2 or 3 carbon atoms; X represents a carbonyl group or a hydroxymethylene group; and Ar 2 represents a phenyl group or a phenyl group substituted with halogen, provided that Ar 1
N-lower alkylamino as a substituent of -
An antipsychotic drug containing N-(piperidinyl-alkyl)-carboxamide or a salt thereof as an active ingredient.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH125883 | 1983-03-09 | ||
CH1258/83-4 | 1983-03-09 | ||
CH3925/83-5 | 1983-07-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS59186959A JPS59186959A (en) | 1984-10-23 |
JPH0556345B2 true JPH0556345B2 (en) | 1993-08-19 |
Family
ID=4206177
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP4422084A Granted JPS59186959A (en) | 1983-03-09 | 1984-03-09 | N-(piperidinyl-alkyl)-carboxamides, manufacture, pharmaceutical blend, manufacture of same |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPS59186959A (en) |
AR (1) | AR242025A1 (en) |
ZA (1) | ZA841728B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6770659B2 (en) * | 2002-08-26 | 2004-08-03 | Sk Corporation | Benzoyl piperidine compounds |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5223080A (en) * | 1975-08-13 | 1977-02-21 | Janssen Pharmaceutica Nv | New nn**11piperidinyl*alkyl* aryl carboxysamide derivative |
US4110449A (en) * | 1977-05-23 | 1978-08-29 | E. R. Squibb & Sons, Inc. | 2-substituted benzisothiazol-3-ones |
JPS55105679A (en) * | 1979-01-08 | 1980-08-13 | Janssen Pharmaceutica Nv | Novel *piperidinylalkyl*quinazoline derivative |
JPS5890552A (en) * | 1981-10-01 | 1983-05-30 | ãžã€ã³ã»ã³ã»ãã¢âãã·ãŠâãã«ã»ãâã ãâãŒã»ããšã³ãâãã·ã€ãã | Novel n-(3-hydroxy-4-piperidinyl)benzamide derivative |
-
1984
- 1984-03-08 ZA ZA841728A patent/ZA841728B/en unknown
- 1984-03-09 JP JP4422084A patent/JPS59186959A/en active Granted
-
1986
- 1986-08-08 AR AR30484786A patent/AR242025A1/en active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5223080A (en) * | 1975-08-13 | 1977-02-21 | Janssen Pharmaceutica Nv | New nn**11piperidinyl*alkyl* aryl carboxysamide derivative |
US4110449A (en) * | 1977-05-23 | 1978-08-29 | E. R. Squibb & Sons, Inc. | 2-substituted benzisothiazol-3-ones |
JPS55105679A (en) * | 1979-01-08 | 1980-08-13 | Janssen Pharmaceutica Nv | Novel *piperidinylalkyl*quinazoline derivative |
JPS5890552A (en) * | 1981-10-01 | 1983-05-30 | ãžã€ã³ã»ã³ã»ãã¢âãã·ãŠâãã«ã»ãâã ãâãŒã»ããšã³ãâãã·ã€ãã | Novel n-(3-hydroxy-4-piperidinyl)benzamide derivative |
Also Published As
Publication number | Publication date |
---|---|
AR242025A1 (en) | 1993-02-26 |
ZA841728B (en) | 1984-11-28 |
JPS59186959A (en) | 1984-10-23 |
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