JPH01117882A - Heterocyclic carboxamide derivative - Google Patents
Heterocyclic carboxamide derivativeInfo
- Publication number
- JPH01117882A JPH01117882A JP27637087A JP27637087A JPH01117882A JP H01117882 A JPH01117882 A JP H01117882A JP 27637087 A JP27637087 A JP 27637087A JP 27637087 A JP27637087 A JP 27637087A JP H01117882 A JPH01117882 A JP H01117882A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- formula
- group
- fluorobenzyl
- morpholinyl
- 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.)
- Pending
Links
- -1 Heterocyclic carboxamide Chemical class 0.000 title claims abstract description 55
- 239000002253 acid Substances 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 3
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 21
- 239000002904 solvent Substances 0.000 abstract description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 2
- 230000001079 digestive effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 8
- 150000008065 acid anhydrides Chemical class 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 150000003857 carboxamides Chemical class 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000007661 gastrointestinal function Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- JHSPPBBJOLKJDH-UHFFFAOYSA-N [4-[(4-fluorophenyl)methyl]morpholin-2-yl]methanamine Chemical compound C1COC(CN)CN1CC1=CC=C(F)C=C1 JHSPPBBJOLKJDH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- CKZVBXBEDDAEFE-UHFFFAOYSA-N (4-benzylmorpholin-2-yl)methanamine Chemical compound C1COC(CN)CN1CC1=CC=CC=C1 CKZVBXBEDDAEFE-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 229940125683 antiemetic agent Drugs 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- KMAKOBLIOCQGJP-UHFFFAOYSA-N indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VPYXATIIMHQAPR-UHFFFAOYSA-N 1,2-benzoxazole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NOC2=C1 VPYXATIIMHQAPR-UHFFFAOYSA-N 0.000 description 1
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- LSGKMZLPZFPAIN-UHFFFAOYSA-N 1h-indole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=CNC2=C1 LSGKMZLPZFPAIN-UHFFFAOYSA-N 0.000 description 1
- DUILGEYLVHGSEE-UHFFFAOYSA-N 2-(oxiran-2-ylmethyl)isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC1CO1 DUILGEYLVHGSEE-UHFFFAOYSA-N 0.000 description 1
- KWEPMOQQKUYWIN-UHFFFAOYSA-N 2-[(4-fluorophenyl)methylamino]ethanol Chemical compound OCCNCC1=CC=C(F)C=C1 KWEPMOQQKUYWIN-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N 2-hydroxy-pyridine Natural products OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- ABFYEILPZWAIBN-UHFFFAOYSA-N 3-(iminomethylideneamino)-n,n-dimethylpropan-1-amine;hydrochloride Chemical compound Cl.CN(C)CCCN=C=N ABFYEILPZWAIBN-UHFFFAOYSA-N 0.000 description 1
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 1
- ALDOZKXIKPFFOY-UHFFFAOYSA-N 4-[(4-fluorophenyl)methyl]morpholine Chemical compound C1=CC(F)=CC=C1CN1CCOCC1 ALDOZKXIKPFFOY-UHFFFAOYSA-N 0.000 description 1
- GVWRZZNYCOTWNN-UHFFFAOYSA-N 4-benzyl-2-(chloromethyl)morpholine Chemical compound C1COC(CCl)CN1CC1=CC=CC=C1 GVWRZZNYCOTWNN-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010018045 Gastroptosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical class [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 description 1
- BTVWZWFKMIUSGS-UHFFFAOYSA-N dimethylethyleneglycol Natural products CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- IYDYAXXGLUZOJN-UHFFFAOYSA-N n-[[4-[(4-fluorophenyl)methyl]morpholin-2-yl]methyl]acetamide Chemical compound C1COC(CNC(=O)C)CN1CC1=CC=C(F)C=C1 IYDYAXXGLUZOJN-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、消化管機能亢進作用を有する新規で有用な複
索環式カルボン酸アミド誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel and useful polycyclic carboxylic acid amide derivative having a gastrointestinal function enhancing effect.
従来の技術
４−アミノ−５−クロロ−Ｎ−［（２−ジエチルアミノ
）エチル］−２−メトキシベンズアミド［−数名 メト
クロプラミド；例えばＭｅｒｃｋＩｎｄｅｘ、第１θ版
、 （ｌ（１１９（１９８３）参照］が１９６０年代の
半ばに制吐剤あるいは消化管機能亢進剤として開発され
て以来、ベンゼン環を複索環に変えた種々の複素環式カ
ルボン酸アミド誘導体が合成され、その薬理学的性質が
研究されてきた（例えば特開昭５２−８３０７９号、同
ＧＯ−１２３４８５号、同００−２４８０８４号など参
照）。しかしながら、後記−数式（１）で表される、ア
ミド部分の窒素原子とモルホリン又はヘキサヒドロ−１
，４−オキサゼピン部分の２位の炭素原子がアルキレン
基を介して結合する複素環式カルボン酸アミド誘４体は
、本発明者らの知る限りにおいて文献未記載の新規化合
物である。Prior Art 4-Amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide [-several names] Metoclopramide; e.g. Merck Index, 1st Theta Edition, (see l(119 (1983))) in 1960 Since its development as an antiemetic agent or gastrointestinal function enhancer in the mid-1990s, various heterocyclic carboxylic acid amide derivatives in which the benzene ring has been changed to a multi-chord ring have been synthesized, and their pharmacological properties have been studied. (For example, see JP-A-52-83079, GO-123485, JP-A-00-248084, etc.) However, the nitrogen atom of the amide moiety and the morpholine or hexahydro-1
The heterocyclic carboxylic acid amide derivative 4, in which the carbon atom at the 2-position of the ,4-oxazepine moiety is bonded via an alkylene group, is a novel compound that has not been described in any literature to the best of the present inventors' knowledge.
本発明の目的
本発明は、優れた消化管機能亢進作用ををする複索環式
カルボン酸アミド誘４体を提供するものである。OBJECTS OF THE INVENTION The present invention provides a polycyclic carboxylic acid amide derivative which exhibits an excellent effect of enhancing gastrointestinal function.
本発明の構成及び効果
本発明によれば、−数式（Ｉ）
非置換又は置換アリール（低級）アルキル基を意味し、
Ｒ１＋ Ｒ＊及びＲ３は同−又は異なって水素原子、ハ
ロゲン原子、低級アルキル基、低級アルコキシ基、アミ
ノ基、モノ置換アミ７基又はジ置換アミ７基を意味し、
Ｒ４は水素原子又は低級アルキル基を意味し、Ｘは低級
アルキレンＬｕを意味し、ｎは１又は２を意味する。］
で表される複索環式カルボン酸アミド誘導体及び−その
酸付加塩類が提供される。Structure and effect of the present invention According to the present invention, - Formula (I) means an unsubstituted or substituted aryl (lower) alkyl group,
R1+ R* and R3 are the same or different and mean a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, a mono-substituted amine group or a di-substituted amine group,
R4 means a hydrogen atom or a lower alkyl group, X means lower alkylene Lu, and n means 1 or 2. ]
Provided are polycyclic carboxylic acid amide derivatives represented by: and acid addition salts thereof.
式（１）で表される化合物の酸付加塩としては、生理的
に許容される塩類が好ましく、例えば塩酸塩、臭化水素
酸塩、ヨウ化水素酸塩、硫酸塩、す／酸塩等の無機酸塩
、及びシュウ酸塩、マレイン酸塩、フマル酸塩、乳酸塩
、リンゴ酸塩、クエン酸塩、酒石酸塩、安息香酸塩、メ
タンスルホン酸塩等の有機酸塩が挙げられる。As the acid addition salt of the compound represented by formula (1), physiologically acceptable salts are preferable, such as hydrochloride, hydrobromide, hydroiodide, sulfate, and acid salt. and organic acid salts such as oxalates, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates, and methanesulfonates.
式（Ｉ）の化合物は、少な（とも１個の不斉炭素餡子を
打するので、数種の立体異性体が存在し得る。これらの
立体異性体、それらの混合物及びラセミ体は本発明の化
合物に包含される。Since the compound of formula (I) has a small number of asymmetric carbon atoms, several types of stereoisomers may exist. These stereoisomers, mixtures thereof and racemates are included in the present invention. It is included in the compounds of
本明細古における川１ｈを以下に説明する。The river 1h in this specification will be explained below.
「低級」とは、特にことわらない限り、１〜６個の炭素
原子を意味する。低級アルキル基、低級アルキル部分又
は低級アルキレン基は、直鎖状でも分技鎖吠でもよい。"Lower" means 1 to 6 carbon atoms unless otherwise specified. The lower alkyl group, lower alkyl moiety, or lower alkylene group may be linear or branched.
「ヘテロアリール基」とは、窒素原子、酸素原子又はイ
オウ原子を少なくとも１個含む単環性又は二環性であっ
て、その結合手かへテロ原子の存在する環から出ている
ものを意味し、例えばピロリル、フリル、チエニル、ピ
ラゾリル、イミダゾリル、オキサシリル、インオキサシ
リル、ピリジル、ピリダジニル、ピリミジニル、ピラジ
ニル、インドリル、イ７ダゾリル、ベンズイソオキサシ
リル、べ７ズインチアゾリル、キノリル、インキノリル
、キノキサリニル、ナフチリジ二ル等が挙げられる。「
非置換アリール（低級）アルキル基」の具体例としては
、べ／ジル。"Heteroaryl group" means a monocyclic or bicyclic group containing at least one nitrogen atom, oxygen atom, or sulfur atom, whose bond originates from the ring in which the heteroatom is present. Examples include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxasilyl, inoxasilyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isodazolyl, benzisoxasilyl, benzinthiazolyl, quinolyl, inquinolyl, quinoxalinyl, naphthyridinyl. Examples include Le et al. "
A specific example of "unsubstituted aryl (lower) alkyl group" is be/zyl.
１−７エールエチル、２−フェニルエチル、３−フェ二
ルプロビル、４−フェニルブチル、２−す７チルメチル
等が挙げられる。「は換アリール（低級）アルキル基」
とは、アリール部分が１〜３個のハロゲン原子、低級ア
ルキル基２ トリフルオロメチル基、低級アルコキシ基
、シアノ°基又はニトロ基で置換されているものを意味
し、例えば２−９３−もしくは４−フルオロベンジル、
２−．３−もしくは４−クロロベンジル、３−トリフル
オロメチルペンジル、２−．３−もしくは４−シアノベ
ンジル、４−クロロ−２−ニトロベンジル等が挙げられ
る。「ハロゲン原子」とは、フッ素、塩素、臭素、ヨウ
素を意味する。「低級アルキル基」の具体例としては、
メチル、エチル、プロピル、。Examples include 1-7ethyl ethyl, 2-phenylethyl, 3-phenylprobyl, 4-phenylbutyl, 2-s7thylmethyl, and the like. "Substituted aryl (lower) alkyl group"
means an aryl moiety substituted with 1 to 3 halogen atoms, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a cyano group, or a nitro group, such as 2-93- or 4 -fluorobenzyl,
2-. 3- or 4-chlorobenzyl, 3-trifluoromethylpenzyl, 2-. Examples include 3- or 4-cyanobenzyl, 4-chloro-2-nitrobenzyl, and the like. "Halogen atom" means fluorine, chlorine, bromine, and iodine. Specific examples of "lower alkyl groups" include:
Methyl, ethyl, propyl.
インプロピル、ブチル、インブチル、ペンチル。Impropyl, butyl, inbutyl, pentyl.
ヘキシル等が挙げられる。「低級アルコキシ基」の具体
例としては、メトキシ、エトキン、プロポキシ、インプ
ロポキシ、ブ、トキシ、インブトキシ等が挙げられる。Examples include hexyl. Specific examples of the "lower alkoxy group" include methoxy, ethoxy, propoxy, impropoxy, butoxy, imbutoxy, and the like.
「モノ置換アミノ基」の具体例としては、メチルアミノ
、エチルアミノ、プロピルアミノ等が挙げられる。「ジ
置換アミ７基」の具体例としては、ジメチルアミノ、ジ
エチルアミノ、メチルエチルアミノ、メチルプロピルア
ミノ。Specific examples of the "monosubstituted amino group" include methylamino, ethylamino, propylamino, and the like. Specific examples of the "di-substituted amine 7 group" include dimethylamino, diethylamino, methylethylamino, and methylpropylamino.
モルホリノ、１−ピロリジニル、ピペリジノ、４−メチ
ル−１−ピペラジニル等が挙げられる。「低級アルキレ
ン基」の具体例としては、メチレン。Examples include morpholino, 1-pyrrolidinyl, piperidino, 4-methyl-1-piperazinyl, and the like. A specific example of a "lower alkylene group" is methylene.
エヂレン、メチルメチレン、トリメチレン、プロピレン
、ジメチルメチレン、テトラメチレン、ペンクメチレン
、ヘキサメチレン等が挙げられる。Examples include ethylene, methylmethylene, trimethylene, propylene, dimethylmethylene, tetramethylene, pencumethylene, hexamethylene, and the like.
式（りで表される本発明化合物の具体例として、次のよ
うなものが挙げられる。Specific examples of the compound of the present invention represented by the formula (RI) include the following.
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−２−ピロールカルボキサミ ド。N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-2-pyrrolecarboxamide.
Ｎ−［［４−（２−クロロベンジル）−２−モルホリニ
ル］メチル］−１−メチル−３−ピロールカルボキサミ
ド。N-[[4-(2-chlorobenzyl)-2-morpholinyl]methyl]-1-methyl-3-pyrrolecarboxamide.
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−２−フランカルボキサミド。N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-2-furancarboxamide.
Ｎ−［（４−ベアジル−２−モルホリニル）メチル］−
１−エチルー３−ピラゾールカルボキサミド。N-[(4-bearyl-2-morpholinyl)methyl]-
1-Ethyl-3-pyrazole carboxamide.
２−クロロ−Ｎ−Ｃ［４−（４−フルオロベンジル）−
２−モルホリニル］メチル］−３−ピリジンカルボキサ
ミド。2-chloro-N-C[4-(4-fluorobenzyl)-
2-morpholinyl]methyl]-3-pyridinecarboxamide.
Ｎ−［１：４−（４−シアノベンジル）−２−モルホリ
ニル］メチル］−４−エトキシ−３−ピリジンカルボキ
サミド。N-[1:4-(4-cyanobenzyl)-2-morpholinyl]methyl]-4-ethoxy-3-pyridinecarboxamide.
Ｎ−［［４−（３−フルオロベンジル）−２−モルホリ
ニル］メチル］−３−メトキシ−４−ピリジンカルボキ
サミド。N-[[4-(3-fluorobenzyl)-2-morpholinyl]methyl]-3-methoxy-4-pyridinecarboxamide.
３−ブトキシ−Ｎ−［［４−（３−）リフル第１メチル
ベアジル）−２−モルホリニル］メチル］−２−ピリジ
／カルボキサミド。3-Butoxy-N-[[4-(3-)rifle-1-methylbearzyl)-2-morpholinyl]methyl]-2-pyridi/carboxamide.
４−アミノ−Ｎ−［（４−ベンジル−２−モルホリニル
）メチルゴー２−ジメチルアミノ−５−ピリミジ７カル
ポキサミド、。4-Amino-N-[(4-benzyl-2-morpholinyl)methylgo 2-dimethylamino-5-pyrimidi7carpoxamide,.
２−アミノ−Ｎ−［［４−（４−りａロベ／ジル）−２
−モルホリニル］メチル］−４−メトキシ−５−ピリミ
ジ／カルボキサミド。2-amino-N-[[4-(4-ri-a-rove/zil)-2
-morpholinyl]methyl]-4-methoxy-5-pyrimidi/carboxamide.
２−アミノ−４−エトキシ−Ｎ−［［：４−（３−フル
オロベンジル）−２−モルホリニル］メチル］−５−ピ
リミジ７カルボキサミド。2-Amino-4-ethoxy-N-[[:4-(3-fluorobenzyl)-2-morpholinyl]methyl]-5-pyrimidi7carboxamide.
５−アミノ−Ｎ−［（４−ベンジル−２−モルホリニル
）メチル］−６−クロロー３−メ）−ｔ−シー２−ピラ
ジンカルボキサミド。5-Amino-N-[(4-benzyl-2-morpholinyl)methyl]-6-chloro3-meth)-t-cy2-pyrazinecarboxamide.
５−エチルアミノ−Ｎ−［［４−（４−フルオロベンジ
ル）−２−モルホリニルコメチル］−６−りａロー３−
メトキシ−２−ビラジンカルボキサミ ド。5-ethylamino-N-[[4-(4-fluorobenzyl)-2-morpholinylcomethyl]-6-lya-3-
Methoxy-2-virazine carboxamide.
Ｎ−［（４−ベンジル−２−モルホリニル）メチル］−
３−インドールカルボキサミド。N-[(4-benzyl-2-morpholinyl)methyl]-
3-Indolecarboxamide.
Ｎ−Ｃ［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−１８−インダゾール−３−カルボキサ
ミド。N-C[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-18-indazole-3-carboxamide.
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニルコメチル］−１−メチルインダゾール−３−カルボ
キサミド。N-[[4-(4-fluorobenzyl)-2-morpholinylcomethyl]-1-methylindazole-3-carboxamide.
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−２−メチルインダゾール−３−カルボ
キサミド。N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-2-methylindazole-3-carboxamide.
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−１，２−ベンズイソオキサゾール−３
−カルボキサミド。N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-1,2-benzisoxazole-3
- Carboxamides.
２−クロロ−Ｎ−［［４−（３−クロロベンジル）−２
−モルホリニル］メチル］−４−キノリンカルボキサミ
ド。2-chloro-N-[[4-(3-chlorobenzyl)-2
-morpholinyl]methyl]-4-quinolinecarboxamide.
Ｎ−［（４−ベンジル−２−モルホリニル）メチル］−
２−メチルー３−キノリンカルボキサミ２−クロロ−Ｎ
−［［４−（４−シアノベンジル）−２−モルホリニル
］メチル］−３−キノリ／カルボキサミド。N-[(4-benzyl-2-morpholinyl)methyl]-
2-Methyl-3-quinolinecarboxami 2-chloro-N
-[[4-(4-cyanobenzyl)-2-morpholinyl]methyl]-3-quinoli/carboxamide.
２−クロロ−Ｎ−［［４−（４−フルオロベンジル）−
２−モル、ホリニル］メチル］−１，８−ナフチリジｙ
−３−°カルボキサミド。2-chloro-N-[[4-(4-fluorobenzyl)-
2-mol, holinyl]methyl]-1,8-naphthyridy
−3−°carboxamide.
２−クロロ−Ｎ−［［４−（４−フルオロベンジル）−
６−メチル−２−モルホリニル］メヂル〕−３−ピリジ
／カルボキサミド、及び
Ｎ−［（／ｌ−ベンジル−へキサヒドロ−１，４−オキ
サゼピン−２−イル）メチル］−６−クロロー３−メト
キシ−２−ピラジンカルボキサミド本発明の化合物は、
例えば以下の方法により製造することができる。2-chloro-N-[[4-(4-fluorobenzyl)-
6-Methyl-2-morpholinyl]methyl]-3-pyridi/carboxamide, and N-[(/l-benzyl-hexahydro-1,4-oxazepin-2-yl)methyl]-6-chloro3-methoxy- 2-pyrazinecarboxamide Compounds of the present invention include:
For example, it can be manufactured by the following method.
一般式（ＩＩ）
を意味する。）
で表される化合物又はその反応性誘導体と、−数式（１
）
（式中、Ｒ，Ｒ４，Ｘ及びｎは前掲に同じものを意味す
る。）
で表される化合物とを反応させることにより、式（Ｉ）
で表される化合物を得ることができる。It means general formula (II). ) or a reactive derivative thereof, and - formula (1
) (In the formula, R, R4, X and n mean the same as mentioned above.) By reacting with a compound represented by
A compound represented by can be obtained.
式（■）の化合物の反応性誘導体としては、例えば低級
アルキルエステル、活性エステル、酸無水物、酸ハライ
ド（特に酸クロリド）等を挙げることができる。活性エ
ステルの具体例としてはｐ−ニトロフェニルエステル、
２，４．ｊ−） ’） りｏ 。Examples of reactive derivatives of the compound of formula (■) include lower alkyl esters, active esters, acid anhydrides, acid halides (particularly acid chlorides), and the like. Specific examples of active esters include p-nitrophenyl ester,
2,4. j-) ') ri o.
フェニルエステル、ペンタクロロフェニルエステル、シ
アノメチルエステル、Ｎ−ヒドロキシコハク酸イミドエ
ステル、Ｎ−ヒドロキンフタルイミドエステル、Ｎ−ヒ
ドロキシ−５−ノルポルネ／−２，３−ジカルボキシイ
ミドエステル、Ｎ−ヒドロキシピペリジンエステル、８
−ヒドロキシキノリンエステル、２−ヒドロキシフェニ
ルエステル。Phenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroquine phthalimide ester, N-hydroxy-5-norporne/-2,3-dicarboximide ester, N-hydroxypiperidine ester, 8
-Hydroxyquinoline ester, 2-hydroxyphenyl ester.
２−ヒドロキシ−４，５−ジクロロフェニルエステル、
２−ヒドロキシピリジンエステル、２−ピリジルチオー
ルエステル等が挙げられる。酸無水物としては、対称酸
無水物又は混合酸無水物が用いられ、混合酸無水物の具
体例としてはクロル炭酸エチル、クロル炭酸イソブチル
のようなりロル炭酸アルキルエステルとの混合酸無水物
、クロル炭酸べ／ジルのようなりロル炭酸アラルキルエ
ステルとの混合酸無水物、クロル炭酸フェニルのような
りロル炭酸アリールエステルとの混合酸無水物、イン吉
草酸、ピバリン酸のようなアルカン酸との混合酸無水物
等が挙げられる。2-hydroxy-4,5-dichlorophenyl ester,
Examples include 2-hydroxypyridine ester and 2-pyridylthiol ester. As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides with a chloroalkyl ester such as ethyl chlorocarbonate and isobutyl chlorocarbonate; Mixed acid anhydrides with aralkyl esters of chlorocarbonate, such as benzyl carbonate; mixed acid anhydrides with aryl esters of chlorocarbonate, such as phenyl chlorocarbonate; mixed acids with alkanoic acids, such as valeric acid and pivalic acid. Examples include anhydrides.
式（ＩＩ ’）の化合物を用いる場合には、ジシクロへ
キシルカルボジイミド、１−エチル−３−（３−ジメチ
ルアミノプロピル）カルボジイミド塩酸塩、Ｎ、Ｎ’−
カルボニルジイミダゾール、１−エトキシカルボ二ルー
２−エトキシ−１，２−ジヒドロキノリンのような縮合
剤の存在下に反応させることができる。ｌＩ２！合剤と
してジシクロへキシルカルボジイミド又は１−エチル−
３−（３−ジメチルアミノプロピル）カルボジイミド塩
酸塩を用いる場合には、Ｎ−ヒドロキシコハク酸イミド
、１−ヒドロキシベンゾトリアゾール、３−ヒトａキシ
−４−ｔ＋７−３．４−ジｈ）’ｏ−１，２，３−べｙ
シトリアジン、Ｎ−ヒドロキシ−５−フルボルネン−ａ
３−ジカルボキシイミド等を添加して反応させてもよい
。When using a compound of formula (II'), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-
The reaction can be carried out in the presence of a condensing agent such as carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. lI2! Dicyclohexylcarbodiimide or 1-ethyl- as a mixture
When using 3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-human axy-4-t+7-3.4-dih)'o -1,2,3-bay
Citriazine, N-hydroxy-5-fulbornene-a
3-dicarboximide or the like may be added and reacted.
式（■）の化合物又はその反応性誘導体と式（Ｉｌｌ＞
の化合物との反応は、溶媒中又は無溶媒下に行われる。A compound of formula (■) or a reactive derivative thereof and a compound of formula (Ill>
The reaction with the compound is carried out in a solvent or without a solvent.
使用する溶媒は、原料化合物の！１類等に従って適宜選
択されるべきであるが、例えばベンゼン、トルエン、キ
シレンのような芳香族炭化水素類、ジエチルエーテル、
テトラヒドロフラン、ジオキサンのようなエーテル類、
塩化メチレン、クロロホルムのようなハロゲン化炭化水
素類、酢酸エチル、アセトニトリル、ジメチルホルムア
ミド、ジメチルスルホキシド、エチレングリコール、水
等が挙げられ、これらの溶媒はそれぞれ単独で、あるい
は２種以上混合して用いられる。本反応は必要に応じて
塩基の存在下に行われ、−塩基の具体例としては、重炭
酸ナトリウム、重炭酸カリウムのような重炭酸アルカリ
、炭酸ナトリウム、炭酸カリウムのような炭酸アルカリ
やるいはトリーエチルアミン、トリブチルアミン、ジイ
ンプロピルエチルアミン。Ｎ−メチルモルホリンのよう
な存機塩）Ｉ町が挙げられるが、式（Ｉｌｌ）の化合物
の過剰量で兼ねることもできる。反応温度は用いる原料
化合物の種類等により異なるが、通常的−３０℃ないし
約２００℃、好ましくは約−１０℃ないし約１５０℃で
ある。The solvent used depends on the raw material compound! It should be selected appropriately according to Category 1, etc., but for example, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether,
Ethers such as tetrahydrofuran and dioxane,
Examples include halogenated hydrocarbons such as methylene chloride and chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol, and water, and these solvents may be used alone or in a mixture of two or more. . This reaction is optionally carried out in the presence of a base; specific examples of the base include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate; Triethylamine, tributylamine, diimpropylethylamine. Examples include active salts such as N-methylmorpholine, but an excess amount of the compound of formula (II) can also serve as the compound. The reaction temperature varies depending on the type of raw material compound used, but is generally -30°C to about 200°C, preferably about -10°C to about 150°C.
上記製法により生成する化合物は、クロマトグラフィー
、再結晶、再沈殿等の常法により単離。The compound produced by the above production method is isolated by conventional methods such as chromatography, recrystallization, and reprecipitation.
精製される。Refined.
式（Ｉ）の化合物は、原料化合物の選定１反応・処理条
件等により、遊離塩基又は酸付加塩の形で得られる。酸
付加塩は、常法、例えば炭酸アルカリ、水酸化アルカリ
のような塩基で処理するととにより、遊離塩基に変える
ことができる。一方、遊離塩基は、常法に従って各種の
酸と処理することにより酸付加塩に導くことができる。The compound of formula (I) can be obtained in the form of a free base or an acid addition salt depending on the selection of raw material compounds, 1 reaction and treatment conditions, etc. Acid addition salts can be converted to the free base by conventional methods, eg, by treatment with a base such as an alkali carbonate or an alkali hydroxide. On the other hand, free bases can be converted into acid addition salts by treatment with various acids according to conventional methods.
式（Ｉ）の化合物及びその生理的に許容される酸付加塩
類は、制吐剤あるいは消化管機能亢進剤として、急・慢
性胃炎、胃・十二指腸潰瘍、胃神経症、胃下垂などの疾
忠における食欲不振、悪心。The compound of formula (I) and its physiologically acceptable acid addition salts can be used as antiemetics or gastrointestinal function enhancers to improve appetite in conditions such as acute and chronic gastritis, gastric and duodenal ulcers, gastric neurosis, and gastroptosis. Slump, nausea.
嘔吐、ｍ部膨溝感等の治療及び予防に、また食道・胆道
系疾忠９便秘症の治療及び予防に用いることができる。It can be used for the treatment and prevention of vomiting, a feeling of swelling in the m region, etc., and for the treatment and prevention of constipation due to diseases of the esophageal and biliary tracts.
更にまた、シスプラチンのような抗癌剤投与時の悪心、
嘔吐の治療及び予防にも用いることができる。Furthermore, nausea during administration of anticancer drugs such as cisplatin,
It can also be used to treat and prevent emesis.
本発明を更に具体的に説明するために、以下に参考例及
び実施例を挙げるが、本発明はこれら実施例に限定され
るものではない。なお、化合物の同定は元素分析値、マ
ス・スペクトル、 ＩＲスペクトル、ＮＭＲスペクト
ル等により行った。In order to explain the present invention more specifically, reference examples and examples are given below, but the present invention is not limited to these examples. The compounds were identified using elemental analysis values, mass spectra, IR spectra, NMR spectra, etc.
参考例１
２−アミノメチル−４−ベンジルモルホリンの製造：
（１１Ｓｙｎ、 Ｃｏｍｍｕｎ、、 １０．５９〜７３
（＋９８０）に１己αの方法に従って合成した、４−
ベンジル−２−クロロメチルモルホリン８０．４ｇ、
フタルイミドカリウム７８．０ｇ及びジメチルホルム
アミド７００ ｍｌから成る混合物を撹拌しながら５時
間加熱還流する。反応液を氷水中に注ぎ、析出する結晶
を４取し、水洗後インプロピルアルコールから再結晶し
てＮ−［（４−ベンジル−２−モルホリニル）メチル］
フ・タルイミド１０７ ｇを得る。Ｆ４点 １３０〜１
３９℃（２）上記フタルイミド体６７．２ｇにエタノー
ル１８０■１と８５％抱水ヒドラジ／２０．０ｇを加え
、撹拌しながら３０分加熱還流する。析出結晶を４去し
、ｄ液にクロロホルムと水を加えて振盪する。「機府を
飽和食塩水で洗浄したのち無水硫酸マグネシウムで乾燥
し、溶媒を減圧で留去して油接の目的物３３．５ｇを得
る。この遊離塩基の一部を少量のエタノールに溶解し、
フマル酸のエタノール溶液を加え、’１５Ｍしたのち冷
却すると目的物の２７マル酸塩が結晶として析出する。Reference Example 1 Production of 2-aminomethyl-4-benzylmorpholine: (11Syn, Commun, 10.59-73
(+980) synthesized according to the method of 1 self α, 4-
80.4 g of benzyl-2-chloromethylmorpholine,
A mixture of 78.0 g of potassium phthalimide and 700 ml of dimethylformamide is heated under reflux with stirring for 5 hours. The reaction solution was poured into ice water, and 4 precipitated crystals were taken, washed with water and recrystallized from inpropyl alcohol to give N-[(4-benzyl-2-morpholinyl)methyl].
107 g of phthalimide are obtained. F4 points 130-1
39° C. (2) Add 180 μl of ethanol and 20.0 g of 85% hydrazide hydrate to 67.2 g of the above phthalimide compound, and heat under reflux for 30 minutes while stirring. Remove the precipitated crystals, add chloroform and water to solution d, and shake. After washing the base with saturated saline and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 33.5 g of the target product. A portion of this free base was dissolved in a small amount of ethanol. ,
An ethanol solution of fumaric acid was added to the mixture to make it 15M, and then cooled to precipitate the target product, the 27-maric acid salt, as crystals.
融点１６０〜１７０°Ｃ参考例２
２−アセチルアミノメチル−４−（４−フルオロベンジ
ル）モルホリンの製造：
Ｎ−（４−フルオロベンジル）エタノールアミンＩＯ，
ＯｇとＮ−（２，３−エポキシプロピル）フタルイミド
１２．３ｇから成る混合物を８０℃で３時間撹拌する。Melting point 160-170°C Reference Example 2 Production of 2-acetylaminomethyl-4-(4-fluorobenzyl)morpholine: N-(4-fluorobenzyl)ethanolamine IO,
A mixture of Og and 12.3 g of N-(2,3-epoxypropyl)phthalimide is stirred at 80° C. for 3 hours.
反応液に６１酸３１．９ｇを少しずつ加え、加え終わっ
た後１５０℃で２時間撹拌する０反応液を冷却し、氷水
を加え水酸化ナトリウム水溶液でアルカリ性にした後、
クロロホルムで抽出する。Add 31.9 g of 61 acid little by little to the reaction solution, and after the addition is complete, stir at 150°C for 2 hours. Cool the reaction solution, add ice water, and make alkaline with an aqueous sodium hydroxide solution.
Extract with chloroform.
有機層を水、次いで飽和食塩水で洗浄し、無水硫酸マグ
ネシウムで乾燥したのち無水酢酸０．０ ｇを加える。The organic layer is washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and then 0.0 g of acetic anhydride is added.
この溶液を室温で２時間撹拌した後、氷水、水酸化ナト
リウム水溶液を順次加え、室温でしばらく撹拌する。ク
ロロホルム口を分取し、水。After stirring this solution at room temperature for 2 hours, ice water and an aqueous sodium hydroxide solution were sequentially added, and the mixture was stirred at room temperature for a while. Separate the chloroform solution and add water.
飽和食塩水の順で洗浄したのち無水硫酸マグネシウムで
乾燥する。クロロホルムを減圧で留去し、残渣をトルエ
ンから再結晶して目的物８．８ｇを得る。After washing with saturated saline, drying with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure, and the residue was recrystallized from toluene to obtain 8.8 g of the desired product.
参考例３
２−アミノメチル−４−（４−フルオロベンジル）モル
ホリンの装造：
２−アセチルアミノメチル−４−（４−フルオ［Ｊベン
ジル）モルホリン３．０ｇにｌθ％塩ＦＩ１５０ｍｌを
加え、４時間加熱還流する。反応液に水酸化ナトリウム
水溶液を加えてアルカリ性にし、クロロホルムで抽出す
る。有機層を水、次いで飽和食塩水で洗浄した後、無水
硫酸マグネシウムで乾燥する。Reference Example 3 Preparation of 2-aminomethyl-4-(4-fluorobenzyl)morpholine: 150 ml of lθ% salt FI was added to 3.0 g of 2-acetylaminomethyl-4-(4-fluoro[Jbenzyl)morpholine, and 4 Heat to reflux for an hour. The reaction solution is made alkaline by adding an aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer is washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate.
溶媒を減圧で留去して油状の目的物を得る。The solvent is distilled off under reduced pressure to obtain the desired product as an oil.
実施例Ｉ
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−１，２−ベンズインオキサゾール−３
−カルボキサミドの製造：１、２−ベンズイソオキサゾ
ール−３−カルボ／酸１．９ ｇと２−アミノメチル−
４−（４−フルオロベンジル）モルホリン２．７ｇを塩
化メチレン５０１に溶解し、１−エチル−３−（３−ジ
メチルアミノプロピル）カルボジイミド塩酸塩２．３ｇ
を加え、室温で４時間撹拌する。反応液を水、水酸化ナ
トリウム水溶液、水、ａ和食塩水の順で洗浄し、無水硫
酸マグネシウムで乾燥する。溶媒を留去し、賎渣をシリ
カゲルのカラムクロマトグラフィーに付し、クロロホル
ムで溶出・精製して目的物を得る。融点１２０〜１２２
℃（アセトンから再結晶）実施例２
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−２−フラノカルボキサミドの製造：
実施例１に勿ける１、２−ベンズインオキサゾール−３
−カルボン酸の代りに２−フランカルボ７酸を用い、実
施例１と同様に反応・処理して目的物を得る。これを常
法によりフマル酸で処理して目的物の３／２フマル酸塩
・ＩＥｔＯＨを得る。Example I N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-1,2-benziinoxazole-3
-Production of carboxamide: 1.9 g of 1,2-benzisoxazole-3-carbo/acid and 2-aminomethyl-
Dissolve 2.7 g of 4-(4-fluorobenzyl)morpholine in 501 methylene chloride, and dissolve 2.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
and stirred at room temperature for 4 hours. The reaction solution is washed with water, an aqueous sodium hydroxide solution, water, and Japanese brine in this order, and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography and purified by elution with chloroform to obtain the desired product. Melting point 120-122
°C (recrystallized from acetone) Example 2 Preparation of N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-2-furanocarboxamide: 1,2-benziinoxazole as in Example 1 -3
- Using 2-furancarboxylic acid instead of carboxylic acid, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. This is treated with fumaric acid in a conventional manner to obtain the target product, 3/2 fumarate/IEtOH.
融点９７〜１０１’Ｃ（エタノールから再結晶）実施例
３
Ｎ−［［４−（４−フルオロベンジル）−２−モルホリ
ニル］メチル］−１８−インダゾール−３−カルボキサ
ミドの製造：
実施例１における１、２−ベンズインオキサゾール−３
−カルボ／酸の代りにＩＨ−インダゾール−３−カルボ
ン酸を用い、実施例１と同様に反応・処理して目的物を
得る。融点１３３〜１３５°Ｃ（）ルエンから再結晶）
実施例４
２−クロロ−Ｎ−［［４−（４−フルオロベンジル）−
２−モルホリニル］メチル］−３−ピリジンカルボキサ
ミドの製造：
実施例１における１、２−ベンズイソオキサゾール−３
−カルボン酸の代りに２−クロロ−３−ピリジ／カルボ
ン酸を用い、実施例１と同様に反応・処理して目的物を
得る。融点１４８〜１４９℃（エタノールから再結晶）
実施例５
Ｎ−［（４−ベンジル−２−゛モルホリニル）メチル］
−３−インドールカルボキサミドの製造：実施例１にお
ける１、２−ベンズイソオキサゾール−３−カルボン酸
と２−アミノメチル−４−（４−フルオロベンジル）モ
ルホリンの代りにそれぞれ、３−インドールカルボン酸
と２−アミノメチル−４−ベンジルモルホリンを用い、
実施例１と同様に反応・処理して目的物を得る。これを
常法によりフマル酸で処理して目的物の１／２フマル酸
塩・１ ／２ ＥｔＯＨ・１１５水和物を得る。Melting point 97-101'C (recrystallized from ethanol) Example 3 Preparation of N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-18-indazole-3-carboxamide: 1 in Example 1 , 2-benziinoxazole-3
Using IH-indazole-3-carboxylic acid instead of -carbo/acid, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. Melting point 133-135°C (recrystallized from toluene) Example 4 2-chloro-N-[[4-(4-fluorobenzyl)-
Preparation of 2-morpholinyl]methyl]-3-pyridinecarboxamide: 1,2-benzisoxazole-3 in Example 1
- Using 2-chloro-3-pyridi/carboxylic acid instead of carboxylic acid, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. Melting point 148-149°C (recrystallized from ethanol) Example 5 N-[(4-benzyl-2-'morpholinyl)methyl]
-Production of 3-indolecarboxamide: In place of 1,2-benzisoxazole-3-carboxylic acid and 2-aminomethyl-4-(4-fluorobenzyl)morpholine in Example 1, 3-indolecarboxylic acid and Using 2-aminomethyl-4-benzylmorpholine,
The reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. This is treated with fumaric acid in a conventional manner to obtain the target product, 1/2 fumarate/1/2 EtOH/115 hydrate.
融点１（ｉ３Ｎ４（１４℃（エタノールから再結晶）実
施例６
４−アミノ−Ｎ−［： （４−ベンジル−２−モルホリ
ニル）９メチル］−２−ジメチルアミノ−５−ピリミジ
ンカルボキサミドの製造：
実施例１における１、２−ベンズイソオキサゾール−３
−カルボン酸と２−アミノメチル−４−（４−フルオロ
ベンジル）モルホリンの代りにそれぞれ、４−アミノ−
２−ジメチルアミノ−５−ピリミジ／カルボン酸と２−
アミノメチル−４−ベンジルモルホリフを用い、実施例
１と同様に反応・処理して目的物を得る。 融点 １３
５〜１３７℃（エタノールから再結晶）
特許出願人 大日本製薬株式会社Melting point 1 (i3N4 (14°C (recrystallized from ethanol)) Example 6 Preparation of 4-amino-N-[: (4-benzyl-2-morpholinyl)9methyl]-2-dimethylamino-5-pyrimidinecarboxamide: Implementation 1,2-Benzisoxazole-3 in Example 1
4-amino-carboxylic acid and 2-aminomethyl-4-(4-fluorobenzyl)morpholine, respectively.
2-dimethylamino-5-pyrimidi/carboxylic acid and 2-
Using aminomethyl-4-benzyl morpholif, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. Melting point 13
5-137℃ (recrystallized from ethanol) Patent applicant Dainippon Pharmaceutical Co., Ltd.
Claims (1)
リール基を意味し、Ｒは非置換又は置換アリール（低級
）アルキル基を意味し、Ｒ＿１、Ｒ＿２及びＲ＿３は同
一又は異なって水素原子，ハロゲン原子、低級アルキル
基、低級アルコキシ基，アミノ基，モノ置換アミノ基又
はジ置換アミノ基を意味し、Ｒ＿４は水素原子又は低級
アルキル基を意味し、Ｘは低級アルキレン基を意味し、
ｎは１又は２を意味する。］ で表される複素環式カルボン酸アミド誘導体及びその酸
付加塩類。[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, ▲ Numerical formulas, chemical formulas, tables, etc. ▼ means a heteroaryl group, R is unsubstituted or substituted aryl (lower) means an alkyl group, R_1, R_2 and R_3 are the same or different and mean a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, a mono-substituted amino group or a di-substituted amino group, and R_4 is a hydrogen atom or a lower alkyl group, X means a lower alkylene group,
n means 1 or 2. ] Heterocyclic carboxylic acid amide derivatives and acid addition salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27637087A JPH01117882A (en) | 1987-10-30 | 1987-10-30 | Heterocyclic carboxamide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27637087A JPH01117882A (en) | 1987-10-30 | 1987-10-30 | Heterocyclic carboxamide derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01117882A true JPH01117882A (en) | 1989-05-10 |
Family
ID=17568485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27637087A Pending JPH01117882A (en) | 1987-10-30 | 1987-10-30 | Heterocyclic carboxamide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01117882A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002301669A (en) * | 2001-04-05 | 2002-10-15 | Makita Corp | Power tool |
| JP2005525390A (en) * | 2002-03-28 | 2005-08-25 | グラクソ グループ リミテッド | N-{[(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- {3-[(methylsulfonyl) as a CCR3 antagonist for the treatment of inflammatory conditions ) Amino] phenyl} acetamide |
| US7101882B2 (en) | 2000-09-29 | 2006-09-05 | Glaxo Group Limited | Morpholin-acetamide derivatives for the treatment of inflammatory diseases |
| US7176310B1 (en) | 2002-04-09 | 2007-02-13 | Ucb Sa | Pyrimidinecarboxamide derivatives and their use as anti-inflammatory agents |
| US7185998B2 (en) | 2002-01-21 | 2007-03-06 | Hitachi Koki Co., Ltd. | Power tool |
| JP2007223037A (en) * | 2007-04-27 | 2007-09-06 | Hitachi Koki Co Ltd | Power tool |
| JP2008062344A (en) * | 2006-09-07 | 2008-03-21 | Hitachi Koki Co Ltd | Power tool |
| JP2011016750A (en) * | 2009-07-08 | 2011-01-27 | Tokuyama Corp | Method for purifying 2-acetylaminomethyl-4-(4-fluorobenzyl)morpholine |
| JP2011068611A (en) * | 2009-09-28 | 2011-04-07 | Tokuyama Corp | Method for purifying 4-amino-5-chloro-2-ethoxy-n-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide |
-
1987
- 1987-10-30 JP JP27637087A patent/JPH01117882A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7101882B2 (en) | 2000-09-29 | 2006-09-05 | Glaxo Group Limited | Morpholin-acetamide derivatives for the treatment of inflammatory diseases |
| US7560548B2 (en) | 2000-09-29 | 2009-07-14 | Glaxo Group Limited | Morpholin-acetamide derivatives for the treatment of inflammatory diseases |
| JP2002301669A (en) * | 2001-04-05 | 2002-10-15 | Makita Corp | Power tool |
| US7185998B2 (en) | 2002-01-21 | 2007-03-06 | Hitachi Koki Co., Ltd. | Power tool |
| US7934847B2 (en) | 2002-01-21 | 2011-05-03 | Hitachi Koki Co., Ltd. | Power tool with light unit |
| US8517558B2 (en) | 2002-01-21 | 2013-08-27 | Hitachi Koki Co., Ltd. | Power tool |
| JP2005525390A (en) * | 2002-03-28 | 2005-08-25 | グラクソ グループ リミテッド | N-{[(2S) -4- (3,4-difluorobenzyl) morpholin-2-yl] methyl} -2- {3-[(methylsulfonyl) as a CCR3 antagonist for the treatment of inflammatory conditions ) Amino] phenyl} acetamide |
| US7176310B1 (en) | 2002-04-09 | 2007-02-13 | Ucb Sa | Pyrimidinecarboxamide derivatives and their use as anti-inflammatory agents |
| JP2008062344A (en) * | 2006-09-07 | 2008-03-21 | Hitachi Koki Co Ltd | Power tool |
| JP2007223037A (en) * | 2007-04-27 | 2007-09-06 | Hitachi Koki Co Ltd | Power tool |
| JP2011016750A (en) * | 2009-07-08 | 2011-01-27 | Tokuyama Corp | Method for purifying 2-acetylaminomethyl-4-(4-fluorobenzyl)morpholine |
| JP2011068611A (en) * | 2009-09-28 | 2011-04-07 | Tokuyama Corp | Method for purifying 4-amino-5-chloro-2-ethoxy-n-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide |
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