JPH02138161A - Substituted cinnamamide derivative - Google Patents
Substituted cinnamamide derivativeInfo
- Publication number
- JPH02138161A JPH02138161A JP29311288A JP29311288A JPH02138161A JP H02138161 A JPH02138161 A JP H02138161A JP 29311288 A JP29311288 A JP 29311288A JP 29311288 A JP29311288 A JP 29311288A JP H02138161 A JPH02138161 A JP H02138161A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- compound
- expressed
- alkyl
- 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
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical class NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 title claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000005156 substituted alkylene group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 46
- 239000003795 chemical substances by application Substances 0.000 abstract description 8
- 150000001851 cinnamic acid derivatives Chemical class 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 150000004985 diamines Chemical class 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 229940127088 antihypertensive drug Drugs 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- QBIAZVPERXOGAL-OWOJBTEDSA-N (e)-prop-1-ene-1,3-diamine Chemical compound NC\C=C\N QBIAZVPERXOGAL-OWOJBTEDSA-N 0.000 abstract 1
- 206010002383 Angina Pectoris Diseases 0.000 abstract 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000013985 cinnamic acid Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- -1 inpropoxy group Chemical group 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 229930016911 cinnamic acid Natural products 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229960002748 norepinephrine Drugs 0.000 description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 241000700198 Cavia Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 2
- 238000011047 acute toxicity test Methods 0.000 description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000000059 bradycardiac effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000002837 heart atrium Anatomy 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- HGQSKTQYEWJJRZ-SNAWJCMRSA-N (e)-3-[3-(trifluoromethyl)phenyl]prop-2-enoyl chloride Chemical compound FC(F)(F)C1=CC=CC(\C=C\C(Cl)=O)=C1 HGQSKTQYEWJJRZ-SNAWJCMRSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 1
- JZINNAKNHHQBOS-AATRIKPKSA-N 3-methylcinnamic acid Chemical compound CC1=CC=CC(\C=C\C(O)=O)=C1 JZINNAKNHHQBOS-AATRIKPKSA-N 0.000 description 1
- WOGITNXCNOTRLK-UHFFFAOYSA-N 3-phenylprop-2-enoyl chloride Chemical class ClC(=O)C=CC1=CC=CC=C1 WOGITNXCNOTRLK-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 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 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 150000003950 cyclic amides Chemical class 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000005247 right atrial appendage Anatomy 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は抗頻脈作用や血管拡張作用を有し、循環系の医
薬として有用である新規な置換ケイ皮酸アミド誘導体ま
たはそれらの薬学的に許容される酸付加塩に関する。Detailed Description of the Invention [Industrial Application Field] The present invention relates to novel substituted cinnamic acid amide derivatives having antitachycardia and vasodilatory effects and useful as medicines for the circulatory system, or their pharmaceutical properties. Concerning acid addition salts acceptable to.
〔従来の技術及び発明が解決しようとする問題点〕特開
昭37−//3gAA号公報には2−(N−メチル=N
−(3,tx−ジメトキシフェネチル)アミノプロピ
ル) −S、t、−ジメトキシフタリミジンー/−オン
(AQA−,7q )が徐脈作用を示すことが記載され
ている。[Problems to be solved by the prior art and the invention] JP-A-37-/3gAA discloses that 2-(N-methyl=N
It has been described that -(3,tx-dimethoxyphenethyl)aminopropyl) -S,t,-dimethoxyphthalimidin-/-one (AQA-, 7q) exhibits a bradycardic effect.
OR’
また特開昭!;3−、3/1,7コ号公報、特開昭&?
−/93ダ6コ号公報、特開昭1.2−/3ge9/号
公報にAQA−、,7?と同様の構造、すなわちN−ア
ルキル置換のベンゼン環と縮合した環状アミドを有する
化合物が徐脈作用を示すことが記載されている。OR' Tokukai Akira again! ;3-, 3/1, 7th publication, JP-A-Sho&?
AQA-, 7? It has been described that a compound having a structure similar to that, that is, a cyclic amide fused to an N-alkyl-substituted benzene ring, exhibits bradycardic effects.
さらに、西ドイツ公開特許32112.3’l’l
には次式で示される化合物
トリフルオロメチル基、炭素数/〜SのアルキZは炭素
数2〜ダの置換されていてもよいアルキレン基を表わし
、R+は水素原子、炭素数/〜gのアルキル基またはベ
ンジル基を表わしR2は炭素数/〜gのアルキル基また
はベンジル基を表わす。またR1とZは互いに連結して
次式が徐脈作用を示すことが述べられている。Additionally, West German Published Patent No. 32112.3'l'l
is a trifluoromethyl group represented by the following formula, alkyl having carbon number/~S, Z represents an optionally substituted alkylene group having 2 to 2 carbon atoms, R+ is a hydrogen atom, and carbon number/~S is an optionally substituted alkylene group; It represents an alkyl group or a benzyl group, and R2 represents an alkyl group or a benzyl group having carbon number/~g. It is also stated that when R1 and Z are connected to each other, the following formula shows a bradycardia effect.
そこでさらに新規で循環系の医薬として有用な化合物を
見い出すべく、鋭意検討した結果、本発明に到達した。Therefore, in order to find a new compound that is useful as a medicine for the circulatory system, the present invention was achieved as a result of intensive studies.
すなわち本発明の要旨は下記一般式(I)R2は前記と
同意義)で示される環状ジアミノ基を表わしてもよ<
R2とZは互いに連結して次式R+は前記と同意義)で
示される環状ジアミノ基を表わしてもよい。〕で示され
る置換ケイ皮酸アミド誘導体またはそれらの薬学的に許
容される酸付加塩に存する。That is, the gist of the present invention is that R2 may represent a cyclic diamino group represented by the following general formula (I) (with the same meaning as above).
R2 and Z may be connected to each other to represent a cyclic diamino group represented by the following formula (R+ has the same meaning as above). ] or their pharmaceutically acceptable acid addition salts.
以下、具体例を示し本発明の詳細な説明する。Hereinafter, the present invention will be explained in detail with reference to specific examples.
前記式(1)中、X及びYの定義において表わされる炭
素数/〜Sのアルキル基としては、例えばメチル基、エ
チル基、n−プロピル基、イソプロピル基、n−ブチル
基、5ec−ブチル基、インペンチル基、n−ペンチル
基が挙げられる。In the formula (1), the alkyl group having carbon number/~S expressed in the definition of , impentyl group, and n-pentyl group.
X及びYの定義において表わされる炭素数7〜Sのアル
コキシ基としては、例えばメトキシ基、エトキシ基、n
−プロポキシ基、インプロポキシ基、n−ブトキシ基、
n−ペントキシ基が挙げられる。X及びYの定義におい
て表わされるハロゲン原子としては、例えばフッ素原子
、塩素原子、臭素原子、ヨウ素原子が挙げられる。Examples of the alkoxy group having 7 to S carbon atoms represented in the definitions of X and Y include methoxy group, ethoxy group, n
-propoxy group, inpropoxy group, n-butoxy group,
An n-pentoxy group is mentioned. Examples of the halogen atom represented in the definitions of X and Y include fluorine atom, chlorine atom, bromine atom, and iodine atom.
R1及びR2の定義において表わされる炭素数/〜gの
アルキル基としては、例えばメチル基、エチル基、n−
プロピル基、n−ブチル基、5ec−ブチル基、シクロ
プロピルメチル基、n−ペンチル基、n−ヘキシル基、
シクロペンチルメチル基、シクロヘキシルメチル基、n
−オクチル基が挙げられる。Examples of the alkyl group having carbon number/~g expressed in the definition of R1 and R2 include methyl group, ethyl group, n-
Propyl group, n-butyl group, 5ec-butyl group, cyclopropylmethyl group, n-pentyl group, n-hexyl group,
cyclopentylmethyl group, cyclohexylmethyl group, n
-octyl group.
X及びYは、それぞれモノ置換、ジ置換、トリ置換でも
よく、XまたはYがジ置換またはトリ置換の場合、置換
基は互いに同一でも異なっていてもよい。X and Y may be mono-substituted, di-substituted, or tri-substituted, respectively; when X or Y is di-substituted or tri-substituted, the substituents may be the same or different from each other.
置換ケイ皮酸の二重結合の立体配置はトランス配置でも
シス配置でもよいが、安定性の面からトランス配置が好
ましい。The configuration of the double bond in the substituted cinnamic acid may be trans configuration or cis configuration, but trans configuration is preferable from the viewpoint of stability.
また、薬学的に許容される酸付加塩としては、塩基性化
合物の毒性を実質的に増大しない酸の付加塩を意味する
。これらは、例えば塩酸、硫酸、リン酸等の鉱酸、また
は酢酸、マロン酸、フマル酸、マレイン酸、コハク酸、
酒石酸、メタンスルホン酸、ハラトルエンスルホン酸等
の有機酸の塩が挙げられる。このような酸付加塩は本発
明化合物を適当な溶媒に溶かし、酸をそのまま、あるい
は適当な溶媒に溶解して加えることにより得られる。適
当な溶媒としては、例えばエーテル、エタノール等が挙
げられる。Moreover, the pharmaceutically acceptable acid addition salt means an acid addition salt that does not substantially increase the toxicity of the basic compound. These are, for example, mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid, malonic acid, fumaric acid, maleic acid, succinic acid,
Examples include salts of organic acids such as tartaric acid, methanesulfonic acid, and halatoluenesulfonic acid. Such acid addition salts can be obtained by dissolving the compound of the present invention in a suitable solvent and adding the acid as it is or dissolved in a suitable solvent. Suitable solvents include, for example, ether, ethanol, and the like.
本発明の化合物は、常法によりヒトに経口又は非経口で
適用される。経口的に用いる場合は7回0./〜100
H7を787〜3回投与するのが好ましく、静脈注射の
場合は/1日0.θ/〜iomgを787〜5回投与す
るのが好ましく、また、直腸内投与の場合は/回θ、/
〜100■を787〜3回投与するのが好ましい。その
際、本発明の化合物(1)あるいはその塩は、通常用い
られる製薬用担体、賦形剤その他の添加物を含む組成物
で利用するのが一般的である。医薬担体は固体でも液体
でもよく、固体担体の例としては、乳糖、白陶土、ショ
糖、結晶セルロース、コーンスターチ、メルク、寒天、
ヘクチン、アカシア、ステアリン酸、ステアリン酸マグ
ネシウム、レシチン、塩化ナトリウムなどが挙げられる
。液状担体の例としては、シロップ、グリセリン、落花
生油、ポリビニルピロリドン1、tlJ−プ油、エタノ
ール、ベンジルアルコール、プロピレングリコール、水
などが挙げられる。The compounds of the invention are administered orally or parenterally to humans in a conventional manner. When used orally, 7 times 0. /~100
Preferably H7 is administered 787 to 3 times, 0.787/day if administered intravenously. It is preferable to administer θ/~iomg 787 to 5 times, and in the case of rectal administration, /times θ, /
Preferably, ~100 μ is administered 787 ~3 times. In this case, the compound (1) of the present invention or a salt thereof is generally used in a composition containing commonly used pharmaceutical carriers, excipients, and other additives. Pharmaceutical carriers may be solid or liquid; examples of solid carriers include lactose, china clay, sucrose, crystalline cellulose, cornstarch, Merck, agar,
Examples include hectin, acacia, stearic acid, magnesium stearate, lecithin, and sodium chloride. Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone 1, tlJ-propylene oil, ethanol, benzyl alcohol, propylene glycol, water, and the like.
本発明の化合物を含んだ医薬は、種々の剤形をとること
ができ、固体担体を用いる場合は、錠剤、粉末、顆粒、
硬ゼラチンカプセル入り粉末もしくは顆粒、坐剤、又は
トローチとすることができる。Pharmaceuticals containing the compound of the present invention can take various dosage forms, and when a solid carrier is used, tablets, powders, granules,
It can be presented as a powder or granules in hard gelatin capsules, suppositories, or troches.
固体担体の量は広範に変えることができるが、好ましく
は約l■〜/9とする。液状担体な用いる場合は、シロ
ップ、乳液、軟ゼラチンカプセル、さらにアンプル入り
のような滅菌注射剤又は水性もしくは非水性の懸濁液と
することができる。The amount of solid carrier can vary widely, but is preferably about 1/2 to 1/9. When a liquid carrier is used, it can be a syrup, emulsion, soft gelatin capsule, sterile injectable preparation such as an ampoule, or an aqueous or non-aqueous suspension.
また、本発明の化合物(1)あるいはその塩をシクロデ
キストリン抱接化合物、あるいはリポソーム中に入れる
操作をして用いることもできるO
次に、本発明の化合物の製造方法について述べる。上記
−形成(1)で示される本発明の化合物は、例えば次の
合成経路A−Eに従い製造することができる。Furthermore, the compound (1) of the present invention or a salt thereof can be used by incorporating it into a cyclodextrin conjugate compound or into a liposome. Next, a method for producing the compound of the present invention will be described. The compound of the present invention represented by Formation (1) above can be produced, for example, according to the following synthetic routes A to E.
〈合成経路A〉
(ただし、式中、X、Y、Z、R’、R2,a 、b及
びmは既に定義したとおりであり、R3は水酸基、ハロ
ゲン原子、炭素数/〜Sのアルコキシ基、炭素数/〜夕
のアルキルカルボニルオキシ基を表わす。)
本経路は置換ケイ皮酸誘導体(U)とジアミン(■)を
縮合することにより本発明の化合物(I)を得る製造法
である。上記化合物(n)と上記化合物(■)からアミ
ド結合を形成し化合物(1)へ導く方法としては種々の
方法を用いることができるが、
例えば(1)置換ケイ皮酸(n;R3が水酸基)とジア
ミン(■)を縮合剤たとえばジシクロへキシルカルボジ
イミド(DCC)、ジフェニルリン酸アジド(DPPA
)などを用いて縮合する方法
(2)置換ケイ皮酸の反応性誘導体、例えば酸・・ライ
ト”(If;R3がハロゲン原子)、混合酸無水物(n
;R3がアルキルカルボニルオキシ基)、エステル(l
l:R”がアルコキシ基)とジアミン(■)を縮合する
方法
等の方法により化合物(I)を得る。<Synthetic route A> (wherein, , represents an alkylcarbonyloxy group with carbon number/~.) This route is a production method for obtaining the compound (I) of the present invention by condensing a substituted cinnamic acid derivative (U) and a diamine (■). Various methods can be used to form an amide bond from the above compound (n) and the above compound (■) and lead to compound (1). For example, (1) substituted cinnamic acid (n; R3 is a hydroxyl group). ) and diamine (■) using a condensing agent such as dicyclohexylcarbodiimide (DCC), diphenylphosphoric azide (DPPA),
), etc. (2) Reactive derivatives of substituted cinnamic acids, such as acid...light''(If; R3 is a halogen atom), mixed acid anhydrides (n
;R3 is an alkylcarbonyloxy group), ester (l
Compound (I) is obtained by a method such as a method of condensing l:R" is an alkoxy group) and a diamine (■).
上記(1)の製造法では、置換ケイ皮酸(n)を化合物
(■)に対して0.!; −2当量用いる。縮合剤は置
換ケイ皮酸に対して0.5〜.2当量、好ましくはo、
g〜八−当量用いる。反応溶媒は、反応に関与しなけれ
ば特に限定されないが、例えばジクロロエタン、クロロ
ホルム等のハロゲン化炭化水素;ジエチルエーテル、テ
トラヒドロフラン等のエーテルが挙げられる。反応温度
は−ダ0〜ダθ℃で、反応時間はθ、!;−eg時間で
ある。In the production method (1) above, the substituted cinnamic acid (n) is added at 0.00% relative to the compound (■). ! ; -2 equivalents are used. The condensing agent is 0.5-. 2 equivalents, preferably o,
g to 8-equivalents are used. The reaction solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include halogenated hydrocarbons such as dichloroethane and chloroform; and ethers such as diethyl ether and tetrahydrofuran. The reaction temperature was -da0~daθ℃, and the reaction time was θ,! ;-eg time.
上記(2)の合成法では置換ケイ皮酸の反応性誘導体を
化合物(■)に対し0.3−2当量用いる。In the synthesis method (2) above, the reactive derivative of substituted cinnamic acid is used in an amount of 0.3 to 2 equivalents based on compound (■).
必要に応じ脱酸剤を用いると反応が円滑に進行する。脱
酸剤としては、化合物(II)と反応しなければ特に限
定はないが、例えばトリエチルアミン、ピリジン等の有
機塩基類、炭酸カリウム、酢酸ナトリウム等のアルカリ
金属塩、水酸化ナトリウム、水酸化カリウム等の無機塩
基が挙げられる。溶媒は反応に関与しなければ特に限定
はないが例えばアセトン、メチルエチルケトン等のケト
ン類;テトラヒドロフラン、ジオキサン等のエーテル類
、ベンゼン、トルエン等の芳香族炭化水素、水等が挙げ
られる。反応温度は一り0℃〜/θ0℃で、反応温度は
O,S〜tIg時間である。The reaction proceeds smoothly by using a deoxidizing agent if necessary. The deoxidizing agent is not particularly limited as long as it does not react with compound (II), but examples include organic bases such as triethylamine and pyridine, alkali metal salts such as potassium carbonate and sodium acetate, sodium hydroxide, potassium hydroxide, etc. Examples include inorganic bases. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; and water. The reaction temperature is 0° C. to /θ0° C., and the reaction temperature is O, S to tIg time.
く合成経路B〉
(ただし式中、X、Y、Z、R’、R2,a、b、及び
mは既に定義したとおりであり、R4は、)・ロゲン原
子、メシルオキシ基またはトシルオキシ基を表わす。)
本経路は、置換ケイ皮酸アミド誘導体(1)とフェニル
アルカン誘導体(VllDとの反応により化合物(1)
を得る製造法である。化合物(旧は、化合物(III)
に対して0.2〜5当量用いる。反応溶媒は反応に関与
しなければ特に限定はされなイカ、例工ばベンゼン、ト
ルエン、キシレン等の芳香族炭化水素:メタノール、エ
タノール、イングロパノール等のアルコール類;テトラ
ヒドロフラン、ジオキサン、エチレングリコールジエチ
ルエーテル等のエーテル類;アセトン、メチルエチルケ
トン等のケトン類;ジメチルホルムアミド、酢酸エチル
、ジメチルスルホキノド等が挙げられる。反応温度は0
−200℃、好ましくはSO〜/SO℃で、反応時間ば
O,S〜qg時間、好ましくは7〜29時間である。Synthetic route B> (wherein, . ) This route produces compound (1) through the reaction of a substituted cinnamic acid amide derivative (1) with a phenylalkane derivative (VllD).
This is a manufacturing method that obtains Compound (formerly compound (III)
0.2 to 5 equivalents are used. Reaction solvents are not particularly limited as long as they are not involved in the reaction; examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, and ingropanol; tetrahydrofuran, dioxane, and ethylene glycol diethyl. Ethers such as ether; ketones such as acetone and methyl ethyl ketone; dimethyl formamide, ethyl acetate, dimethyl sulfoquinide, and the like. The reaction temperature is 0
-200°C, preferably SO to /SO°C, and reaction time is O,S to qg hours, preferably 7 to 29 hours.
反応に際し、脱酸剤として過剰の上記化合物(■)、ト
リエチルアミン、ピリジン、ジアザビシクロウンデセン
等の有機塩基、または水酸化ナトリウム、水酸化カリウ
ム、炭酸カリウム等の無機塩基を存在させることは反応
を円滑に進める上で好ましい。During the reaction, the presence of an excess of the above compound (■) as a deoxidizing agent, an organic base such as triethylamine, pyridine, or diazabicycloundecene, or an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. may inhibit the reaction. It is preferable to proceed smoothly.
〈合成経路C〉
(ただし式中、X、Y、Z、R’、R2,R’、a 、
b 及びmは既に定義したとおりである。)
本経路は置換ケイ皮酸アミド誘導体(IV)とフェニル
アルキルアミン誘導体(IX)との反応により化合物(
I)を得る製造法である。化合物(IX)は化合物(I
V)のO,S〜5当量用いる。反応溶媒、反応時間、反
応温度、脱酸剤等の条件は合成経路Bと同様である。<Synthesis route C> (However, in the formula, X, Y, Z, R', R2, R', a,
b and m are as defined above. ) This route produces the compound (
This is a production method for obtaining I). Compound (IX) is compound (I
5 equivalents of O, S of V) are used. Conditions such as reaction solvent, reaction time, reaction temperature, deoxidizing agent, etc. are the same as in synthetic route B.
く合成経路D〉
(ただし式中、X、Y、Z、R’、R”、R’、a、b
及びmは既に定義したとおりである。)
本経路は置換ケイ皮酸アミド誘導体(V)とノ・ロゲン
化アルキル又はアルキルスルホネート(X)との反応に
より化合物(1)を得る製造法である。Synthetic route D> (wherein, X, Y, Z, R', R'', R', a, b
and m are as defined above. ) This route is a production method in which compound (1) is obtained by reacting a substituted cinnamic acid amide derivative (V) with a non-rogenated alkyl or alkyl sulfonate (X).
化合物(X)は化合物(V)に対してO,S −S当量
用いる。反応溶媒、反応温度、反応時間、脱酸剤につい
ては合成経路Bと同様である。Compound (X) is used in an O, S -S equivalent amount relative to compound (V). The reaction solvent, reaction temperature, reaction time, and deoxidizing agent are the same as in synthetic route B.
〈合成経路E〉
(Vl)
(ただし式中、X、Y、Z、RF、R’、a 、b及び
mは既に定義したとおりであり、R1は前述した定義ラ
イドまだはアルキルスルホネート(xl)との反応によ
る化合物(I)の製造法である。アルキルハライド(ま
たはアルキルスルホネート) (XI)は化合物(’l
i’l)に対し、0.2〜5当量用いる。反応溶媒は反
応に関与しなければ特に限定されないが、例えばベンゼ
ン、トルエン、キシレン等の芳香族炭化水素;テトラヒ
ドロフラン、ジオキサン、エチレングリコールジエチル
エーテル等のエーテル類:アセトン、メチルエチルケト
ン等のケトン類;酢酸エチル、ジメチルホルムアミド、
ジメチルアセトアミド、ジメチルスルホキシド等が挙げ
られる。反応温度はo−ao。<Synthetic route E> (Vl) (wherein, This is a method for producing compound (I) by reaction with alkyl halide (or alkyl sulfonate) (XI).
i'l), 0.2 to 5 equivalents are used. The reaction solvent is not particularly limited as long as it does not participate in the reaction, but includes, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and ethylene glycol diethyl ether; ketones such as acetone and methyl ethyl ketone; and ethyl acetate. , dimethylformamide,
Examples include dimethylacetamide, dimethylsulfoxide, and the like. The reaction temperature was o-ao.
℃、好ましくは30〜750℃で、反応時間はo、s
−u g時間、好ましくは7〜29時間である。反応に
際し、金属ナトリウム、水素化ナトリウム、ナトリウム
アミド、カリウムt−ブトキシド等の塩基を存在させる
と反応が円滑に進行する。℃, preferably 30-750℃, reaction time o, s
-ug hours, preferably 7 to 29 hours. During the reaction, the reaction proceeds smoothly if a base such as sodium metal, sodium hydride, sodium amide, potassium t-butoxide, etc. is present.
次に、本発明を実施例により、さらに具体的に説明する
が、これら実施例により、本発明は何ら制限を受けるも
のではない。Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited in any way by these Examples.
実施例/ (化合物嶌/)
N−シンナモイル−N′−シクロプロピルメチル−N’
−(3,11−ジメトキシフェネチル)プロピレンーハ
3−ジアミンの合成
ケイ皮酸2 、y g vq (/、b /mmol)
及びトリエチルアミン/ A 、? my (7,4/
mmol)を塩化メチレンg−に溶解し、得られた溶液
にクロロ炭酸エチル/ ? p ray (/、b /
mmol )を氷冷下した後室温でへS時間攪拌した
。この溶液にN−シクロプロピルメチル−N−(3,I
f−ジメトキシフェネチル)プロピレン−/、3−ジア
ミン’+<7/rn9(ハ乙/mmol)の塩化メチレ
ン溶液q、gmtを氷冷下部下した。室温でさらにS時
間攪拌した後、反応溶液を水洗し、硫酸マグネシウムで
乾燥後、溶媒を減圧下留去した。残渣をシリカゲルカラ
ムクロマトグラフィー(展開溶媒;塩化メチレン−メタ
ノール;ro/l)により精製して下記物性の上記目的
物を得た。Example/ (Compound/) N-cinnamoyl-N'-cyclopropylmethyl-N'
Synthesis of -(3,11-dimethoxyphenethyl)propylene-3-diamine cinnamic acid 2,y g vq (/, b/mmol)
and triethylamine/A,? my (7,4/
mmol) in methylene chloride, and to the resulting solution was added ethyl chlorocarbonate/? p ray (/,b/
mmol) was cooled with ice, and then stirred at room temperature for several hours. Add this solution to N-cyclopropylmethyl-N-(3,I
A methylene chloride solution of q, gmt of f-dimethoxyphenethyl)propylene-/,3-diamine'+<7/rn9 (ha/mmol) was poured under ice-cooling. After further stirring at room temperature for S hours, the reaction solution was washed with water, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride-methanol; ro/l) to obtain the above-mentioned target product having the following physical properties.
収 量 ; 、34g■ (収率5q%)融 点
;油状物質
赤外吸収スペクトル(純粋+ Cn1−’ ) :32
gθ、/A!;!;、/A/3./!;/θ、/θ3θ
質量スペクトル(m/z);
弘22.λり/ (基準ピーク)
実施例2 (化合物A2)
N −(u、5−ジメトキシフェネチル)−N−メチル
−N’−(3−メチルシンナモイル)プロピレン−/、
J−シアミンノ合成
下記物性の上記目的物を得だ。Yield: 34g (yield: 5q%) Melting point: Oily substance infrared absorption spectrum (pure + Cn1-'): 32
gθ, /A! ;! ;, /A/3. /! ; /θ, /θ3θ
Mass spectrum (m/z); Hiroshi 22. λ/ (Reference peak) Example 2 (Compound A2) N-(u,5-dimethoxyphenethyl)-N-methyl-N'-(3-methylcinnamoyl)propylene-/,
J-cyamino synthesis The above-mentioned target product with the following physical properties was obtained.
融 点 ;油状物質
赤外吸収スペクトル(純粋+ Crn−’ ) ;32
70、//、!0./1.20,1500質量スペクト
ル(m/z);
、797. sg (基準ピーク)実施例3 (化
合物4.7)
/ −(3,ta−ジメトキシシンナモイル)−り−(
#−(、?、Q−ジメトキシフェネチル)メチルアミノ
)ピペリジンの合成
実施例/と同様の方法により、3−メチルケイ皮酸とN
−(2,!;−ジメトキシフェネチル)−N−メチルグ
ロビレンーハ3−ジアミンカラCH。Melting point; Oily substance infrared absorption spectrum (pure + Crn-'); 32
70, //,! 0. /1.20,1500 mass spectrum (m/z); , 797. sg (Reference peak) Example 3 (Compound 4.7) / -(3,ta-dimethoxycinnamoyl)-ri-(
Synthesis Example of #-(,?,Q-dimethoxyphenethyl)methylamino)piperidine/3-methylcinnamic acid and N
-(2,!;-dimethoxyphenethyl)-N-methylglobylene-3-diaminecara CH.
β−(3,弘−ジメトキシフェネチル)メチルアミン/
Ag■(0,g Ammol )及びトリエチルアミン
/ 901rli (0,7&mmol )をトルエン
2−に溶解し、この溶液に3.タージメトキシシンナモ
イル−タートシルオキシピペラジンJ4’6■(0,7
ffmmol )のトルエン溶液2−を加え10時間、
還流下攪拌した。室温まで冷却した後、水で洗浄し硫酸
ナトリウムで乾燥後、減圧下溶媒を留去した。得られた
粗生成物をシリカゲルカラムクロマトグラフィー(展開
溶媒;塩化メチレン/メタノール=20/1)により精
製し、下記物性の上記目的物を得た。β-(3,Hiro-dimethoxyphenethyl)methylamine/
Ag (0, g Ammol) and triethylamine/901rli (0,7 mmol) were dissolved in toluene, and 3. Tadimethoxycinnamoyl-tartosyloxypiperazine J4'6■ (0,7
Add a toluene solution 2- of ffmmol) for 10 hours.
The mixture was stirred under reflux. After cooling to room temperature, the mixture was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (developing solvent: methylene chloride/methanol = 20/1) to obtain the above-mentioned target product having the following physical properties.
収 量 ;20θ■(収率タダ%)
融 点 ;油状物質
赤外吸収スペクトル(純粋+l1M?!−’) ;/
63!; 、/390 、/!;0! 、102θ質量
スペクトル(m/z):
’II、9,377、/9/、gダ(基準ピーク)実施
例1I(化合物ムダ)
N−(3,y−ジメトキシフェネチル)−Nメチル−N
’−<3−トリフルオロメチルシンナモイル)プロピレ
ンーハ3−ジアミンの合成
N−(34−ジメトキシフェネチル)−N−メチルプロ
ピレン−/、3−ジアミン337■(7,3/mmol
)を2〜!のジオキサンに溶解した。Yield: 20θ■ (yield free%) Melting point: Infrared absorption spectrum of oily substance (pure+l1M?!-');/
63! ; , /390, /! ;0! , 102θ mass spectrum (m/z): 'II, 9,377, /9/, gda (reference peak) Example 1I (compound waste) N-(3,y-dimethoxyphenethyl)-Nmethyl-N
Synthesis of N-(34-dimethoxyphenethyl)-N-methylpropylene-/,3-diamine 337■ (7,3/mmol
) 2~! of dioxane.
この溶液に炭酸カリウム/ Ogmf<0.79mmo
l)の水溶液コーを加え、水冷下、攪拌しなから3トリ
フルオロメチルシンナモイルクロリド335m1(ハ’
I 3 mmol )のジオキサン溶液コーを滴下した
。室温でS時間攪拌した後、水を加え塩化メチレンで抽
出した。有機層を硫酸ナトリウムで乾燥後、減圧下で溶
媒を留去し粗生成物を得た。これをシリカゲルカラムク
ロマトグラフィー(展開液;塩化メチレン/メタノール
:to/1)で精製し、下記物性の上記目的物を得た。Add potassium carbonate/Ogmf<0.79mmo to this solution.
Add 335 ml of 3-trifluoromethylcinnamoyl chloride (H'
A solution of I 3 mmol) in dioxane was added dropwise. After stirring at room temperature for S hours, water was added and extracted with methylene chloride. After drying the organic layer over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (developing solution: methylene chloride/methanol: to/1) to obtain the above-mentioned target product having the following physical properties.
収 量 ;376■(収率6ダ%)
融 点 ;油状物質
赤外吸収スペクトル(純粋+ (:tn−’ ) ;
32KO,/44θ、/6コo、1sio、io3゜質
量スペクトル(m / z″に
グj/、j−ざ (基準ピーク)
実施例S (化合物As)
N−(3,11−ジメトキシシンナモイル)−N’−(
3,グージメトキシ7エネチル) −N、N’−ジメチ
ルプロピレン−/、3−ジアミンの合成e 30181
(/、9 mmol )を出発物質として、下記物性
の上記目的物を得た。Yield: 376■ (yield: 6%) Melting point: Infrared absorption spectrum of oily substance (pure + (:tn-');
32KO, /44θ, /6koo, 1sio, io3° mass spectrum (m/z″) )-N'-(
Synthesis of 3,Gudimethoxy7enethyl) -N,N'-dimethylpropylene-/,3-diamine e 30181
(/, 9 mmol) as a starting material, the above-mentioned target product having the following physical properties was obtained.
収 量 ; λ g 6■(収率q 0% )融
点 ;油状物質
赤外吸収スペクトル(純粋、 crn−’); /A’
IO、/!;9!;質量スペクトル(M”/Z);
ゲタb、30!;、242./9/
(基準イオンピーク)
実施例6〜+x(表7〜8中の化合物−,6〜!り実施
例ダと同様にして、対応する置換ケイ皮酸クロリド及び
アミン類を出発物質として各種の置換ケイ皮酸アミド誘
導体を合成した。←→→峰iミi−; 各化合物と、そ
の融点、赤外吸収スペクトル及び質量スペクトルの測定
結果を表/1表コ及び表3に示す。Yield: λ g 6 (yield q 0%)
Point; Oily substance infrared absorption spectrum (pure, crn-');/A'
IO, /! ;9! ;Mass spectrum (M"/Z); Geta b, 30!;, 242./9/ (Reference ion peak) Examples 6~+x (Compounds -, 6~! in Tables 7 and 8) In the same manner, various substituted cinnamic acid amide derivatives were synthesized using the corresponding substituted cinnamic acid chlorides and amines as starting materials. and mass spectrum measurement results are shown in Tables 1 and 3.
実施例亭と同様の方法により、N−(3,9ジメトキシ
フエネチル) −N、N’−ジメチルグロピレンーハ3
−ジアミン亭03■(i、6mmol )と3.タージ
メトキシシンナモイルクロリドこれより、本発明の化合
物の医薬としての特徴である抗頻脈作用と血管拡張作用
における薬理試験について述べる。By the same method as in Example Tei, N-(3,9dimethoxyphenethyl)-N,N'-dimethylgropylene-ha 3
-Diaminetei 03■ (i, 6 mmol) and 3. Tadimethoxycinnamoyl chloride Hereinafter, pharmacological tests on the antitachycardia effect and vasodilator effect, which are the characteristics of the compound of the present invention as a pharmaceutical, will be described.
実施例4t7
本発明の化合物の抗頻脈作用について、モルモットを使
用して薬理試験を行った。その方法と結果を以下に示す
。Example 4t7 A pharmacological test was conducted on the antitachycardia effect of the compound of the present invention using guinea pigs. The method and results are shown below.
体重約SθopのHartlay系雄性モルモットを使
用した。後頭部を殴打し頚部を脱臼させた後、心臓を分
離摘出した。クレプス−ヘンスライド液(KH液)中で
?j%02−j%CO□ガス通気下、心室筋、血管およ
び周囲の結合組織を剥離し、左右の心房を切り離した。Hartlay male guinea pigs weighing approximately Sθop were used. After hitting him in the back of the head and dislocating his neck, his heart was separated and removed. In Krebs-Henslide solution (KH solution)? Under j%02-j%CO□ gas ventilation, ventricular muscle, blood vessels, and surrounding connective tissue were peeled off, and the left and right atria were separated.
右心耳にセルフインをかけ、反対側を結紮し、糸をビッ
クアンプにかけて、q!;%0□−5%CO2ガス通気
下、37℃でKHH2O2を満たした栄養槽内に約0.
.111の張力をかけて固定した。インキュベーション
開始から30分後にKH液を交換しさらに30分間放置
し、心房の動きが安定になってからイングロテレノール
/θ−8Mを加えた。Apply a self-in to the right atrial appendage, ligate the other side, apply the thread to the big amplifier, and q! ;%0□-5% In a nutrient tank filled with KHH2O2 at 37°C under CO2 gas aeration, approximately 0.0% was placed.
.. It was fixed with a tension of 111. Thirty minutes after the start of incubation, the KH solution was replaced, and the mixture was left to stand for an additional 30 minutes. After the movement of the atrium became stable, ingroterenol/θ-8M was added.
約7S分後、心拍数が安定してから本発明の化合物を累
積的に加えていき、該化合物添加前の心拍数を30%低
下させる薬物濃度(EC3o)を求めた。その結果を下
記表ダに示す。After about 7 S minutes, after the heart rate stabilized, the compound of the present invention was added cumulatively, and the drug concentration (EC3o) that reduced the heart rate by 30% before addition of the compound was determined. The results are shown in the table below.
表 q
※ 比較のため、ニー(N−メチル−N(3,クージメ
トキシフェネチル)アミノプロピルl −s、6−シメ
トキシフタリミジンーl−オフ(AQA−J?)(特開
昭!;l−//3gl、l、号公報参照。〕についても
同様の試験を行った。Table q * For comparison, nee (N-methyl-N(3, cudimethoxyphenethyl) aminopropyl l -s, 6-cymethoxyphthalimidine-l-off (AQA-J?) (JP-A-Sho!; l -//3gl, l, see publication.] was also subjected to a similar test.
実施例グg
本発明の化合物のラット摘出血管におけるノルエピネフ
ィリン(NE)による収縮に対する弛緩作用について、
薬理試験を行った。その方法と結果を以下に示す、
ウィスター系雄性ラットを使用した。後頭部を殴打し、
放血させた後、胸部大動脈を摘出した。クレプス−ヘン
スライド液(KH液)中で脂肪組織を除去し、幅約3p
mに切断して輪状片を作製し、さらに長袖方向に切開し
た切片なqs%0□−5%CO2通気下、37℃でKH
H2O2を満たした栄養槽内に輪層筋の走行に沿って懸
垂固定し、30分毎にKH液を交換しながらインキーベ
ーションした。(張力o、sg)約/時間抜ノルエピネ
フリン(NE)#7−7Mを加え収縮させた後KH液で
洗浄し、これを1時間おきに繰り返し、3度目の収縮を
させた標本に本発明の化合物を加えた。−0分間弛緩さ
せた後、塩酸バパペリン3×10−5Mを加え、約20
分間最大弛緩となるまで収縮力を測定した。Example g Regarding the relaxing effect of the compound of the present invention on the contraction induced by norepinephrine (NE) in isolated rat blood vessels,
Pharmacological tests were conducted. The method and results are shown below. Male Wistar rats were used. Hit the back of the head,
After exsanguination, the thoracic aorta was removed. Adipose tissue was removed in Krebs-Henslid solution (KH solution), and the width was approximately 3p.
A ring-shaped piece was prepared by cutting into m, and the section was further incised in the long sleeve direction.
The animal was suspended and fixed in a nutrient tank filled with H2O2 along the course of the orbicularis muscle, and incubation was performed while replacing the KH solution every 30 minutes. (Tension o, sg) approx./hour Norepinephrine (NE) #7-7M was added and contracted, then washed with KH solution. This was repeated every hour, and after the third contraction, the present invention was applied to the specimen. compound was added. After relaxing for -0 minutes, add 3 x 10-5 M of bapaperine hydrochloride and
Contractile force was measured until maximum relaxation was reached in minutes.
該化合物の弛緩率は、バパベリンによる最大弛緩に対す
る百分率で表した。その結果を下記表5に示す。The relaxation rate of the compound was expressed as a percentage of the maximum relaxation by bapaverine. The results are shown in Table 5 below.
表 S に示した。Table S It was shown to.
表 6 ※ 比較データとして同様の試験を行った。Table 6 *A similar test was conducted as comparative data.
実施例ダテ 急性毒性試験
本発明の化合物の急性毒性試験をマウスを用いて行った
のでその方法と結果を以下に示した。Examples Acute toxicity test Acute toxicity tests of the compounds of the present invention were conducted using mice, and the methods and results are shown below.
〈方 法〉
JCI:ICRマウス(SPF)の雄(6局舎)に対し
、7%トラガント水溶液に懸濁した本発明の化合物をマ
ウス用金属製胃ゾンデによる強制投与で経口投与し、7
日間の観察期間を経た後、Litchfield−Wi
lcoxon法により、急性毒性値(LD5o)を算出
した。その結果を下記表6〔発明の効果〕
本発明の化合物は抗頻脈作用、血管拡張作用などの薬理
作用を有し、坑不整脈薬、坑狭心症薬、坑高血圧薬など
の循環系の医薬として有用である。<Method> The compound of the present invention suspended in a 7% aqueous tragacanth solution was orally administered to male JCI:ICR mice (SPF) (6 stations) by forced administration using a metal stomach tube for mice.
After a two-day observation period, Litchfield-Wi
Acute toxicity value (LD5o) was calculated by lcoxon method. The results are shown in Table 6 below. [Effects of the Invention] The compounds of the present invention have pharmacological effects such as antitachycardia and vasodilatory effects, and are effective against circulatory system effects such as antiarrhythmic drugs, antianginal drugs, and antihypertensive drugs. It is useful as a medicine.
出 願 人applicant
Claims (1)
ン原子、トリフルオロメチル基、炭素数1〜5のアルキ
ル基、または炭素数1〜5のアルコキシ基を表わし、a
、b及びmはそれぞれ独立して1〜3の整数を表わし、
Zは炭素数2〜4の置換されていてもよいアルキレン基
を表わし、R^1は水素原子、炭素数1〜8のアルキル
基またはベンジル基を表わし、R^2は炭素数1〜8の
アルキル基またはベンジル基を表わす。またR^1とZ
は互いに連結して次式▲数式、化学式、表等があります
▼または次式 ▲数式、化学式、表等があります▼(式中、R^2は前
記と同意義)で示される環状ジアミノ基を表わしてもよ
くR^2とZは互いに連結して次式▲数式、化学式、表
等があります▼または 次式▲数式、化学式、表等があります▼(式中、R^1
は前記と同意義)で示される環状ジアミノ基を表わして
もよい。〕で示される置換ケイ皮酸アミド誘導体または
それらの薬学的に許容される酸付加塩。(1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X and Y are each independently a hydrogen atom, a halogen atom, a trifluoromethyl group, or a carbon number of 1 to 5 represents an alkyl group or an alkoxy group having 1 to 5 carbon atoms, and a
, b and m each independently represent an integer of 1 to 3,
Z represents an optionally substituted alkylene group having 2 to 4 carbon atoms, R^1 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or a benzyl group, and R^2 represents an optionally substituted alkylene group having 1 to 8 carbon atoms; Represents an alkyl group or a benzyl group. Also R^1 and Z
are connected to each other to form a cyclic diamino group represented by the following formula ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or the following formula ▲ There is a mathematical formula, chemical formula, table, etc. ▼ (wherein R^2 has the same meaning as above) R^2 and Z may be connected to each other to form the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1
may represent a cyclic diamino group represented by (same meaning as above). ] Substituted cinnamic acid amide derivatives or pharmaceutically acceptable acid addition salts thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29311288A JPH02138161A (en) | 1988-11-19 | 1988-11-19 | Substituted cinnamamide derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29311288A JPH02138161A (en) | 1988-11-19 | 1988-11-19 | Substituted cinnamamide derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH02138161A true JPH02138161A (en) | 1990-05-28 |
Family
ID=17790582
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP29311288A Pending JPH02138161A (en) | 1988-11-19 | 1988-11-19 | Substituted cinnamamide derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH02138161A (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02306951A (en) * | 1989-05-19 | 1990-12-20 | Eisai Co Ltd | Butenoic acid or propenoic acid derivative |
WO1994022826A1 (en) * | 1993-04-07 | 1994-10-13 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients |
US8445516B2 (en) | 2004-01-29 | 2013-05-21 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutical composition for promoting angiogenesis |
CN105646289A (en) * | 2016-04-01 | 2016-06-08 | 南阳师范学院 | 4-Carbamate-3-methoxy cinnamate aminoalkyl amide compound and preparation method and application thereof |
EP4219445A1 (en) * | 2019-03-07 | 2023-08-02 | Arbormentis LLC | Compositions and methods of use comprising substances with neural plasticity actions administered at non-psychedelic / psychotomimetic dosages and formulations |
-
1988
- 1988-11-19 JP JP29311288A patent/JPH02138161A/en active Pending
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02306951A (en) * | 1989-05-19 | 1990-12-20 | Eisai Co Ltd | Butenoic acid or propenoic acid derivative |
WO1994022826A1 (en) * | 1993-04-07 | 1994-10-13 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients |
US5656642A (en) * | 1993-04-07 | 1997-08-12 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing piperidine derivative as active ingredient |
US5760058A (en) * | 1993-04-07 | 1998-06-02 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing piperidine derivative as active ingredient |
US8445516B2 (en) | 2004-01-29 | 2013-05-21 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutical composition for promoting angiogenesis |
CN105646289A (en) * | 2016-04-01 | 2016-06-08 | 南阳师范学院 | 4-Carbamate-3-methoxy cinnamate aminoalkyl amide compound and preparation method and application thereof |
EP4219445A1 (en) * | 2019-03-07 | 2023-08-02 | Arbormentis LLC | Compositions and methods of use comprising substances with neural plasticity actions administered at non-psychedelic / psychotomimetic dosages and formulations |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU607935B2 (en) | Benzo-fused cycloalkane and oxa- and thia- cycloalkane trans-1,2-diamine derivatives | |
PT94026A (en) | PROCESS FOR THE PREPARATION OF A DERIVATIVE OF OXADIAZOLE AND ITS SALTS, USEFUL FOR THE TREATMENT OF DEMENTIA | |
JPS61233654A (en) | N-(2-amino alicyclic)-arylacylamide and manufacture | |
GB2145416A (en) | Benzoic acid derivatives | |
NZ194614A (en) | 4-(3-substitutedamino-2-hydroxypropoxy)indoles | |
EP0147475B1 (en) | Aminocyclohexanol derivatives having an expectorant activity, process for their preparation and pharmaceutical compositions containing them | |
KR20050085697A (en) | N-(indolethyl-)cycloamine compounds | |
EP0018076A1 (en) | 9-Aminoalkylfluorenes, process therefor and antiarrhythmic formulations thereof | |
US20030114442A1 (en) | Substituted piperazine derivatives as mtp inhibitors | |
JPH02138161A (en) | Substituted cinnamamide derivative | |
GB2142021A (en) | 1 4-dihydropyridine derivatives their preparation and pharmaceutical compositions containing them | |
US3562276A (en) | Diarylcyclopropane piperazides possessing enhanced antihistaminic,antiserotoninic and antiexudative activity | |
NZ318434A (en) | Naphthamide derivatives of 3 beta-amino azabicyclo octane or nonane as neuroleptic or antipsychotic agents | |
HUT70557A (en) | N,n'-disubstituted amine derivative, pharmaceutical compositions containing them and process for producing the compounds and the compositions | |
AU637938B2 (en) | Phenoxyacetic acid compounds, method for production thereof, and pharmaceutical preparations containing same | |
HU176675B (en) | Process for preparing substituted sulphoximides and pharmaceutical nreparations containing such active material | |
JPH02138162A (en) | N-phenylalkyl substituted-beta-amino acid amide derivative | |
US3644356A (en) | Adamantanopyrimidine compounds and intermediates therefor | |
IE58577B1 (en) | Novel benzamides and their preparation and therapeutic application | |
JPH02138170A (en) | Cyclic amine-3-carboxylic acid amide derivative | |
KR800000537B1 (en) | Process for the preparation of amin-pheny-etahnolamines | |
JPH03184963A (en) | Dibenzoxazepine derivative | |
CA1302405C (en) | Ergoline derivatives | |
JPH02138172A (en) | Beta-amino acid amide derivative | |
US2674615A (en) | 1-arylcycloalkane 1-thiocar-boxylates |