JP2014523886A - 置換シンナムアミド誘導体、その製造方法及び使用 - Google Patents
置換シンナムアミド誘導体、その製造方法及び使用 Download PDFInfo
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- JP2014523886A JP2014523886A JP2014517419A JP2014517419A JP2014523886A JP 2014523886 A JP2014523886 A JP 2014523886A JP 2014517419 A JP2014517419 A JP 2014517419A JP 2014517419 A JP2014517419 A JP 2014517419A JP 2014523886 A JP2014523886 A JP 2014523886A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- isobutyl
- trifluoromethyl
- methylenedioxycinnamamide
- hydrocarbyl
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical class NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 7
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical class O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
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- 239000003814 drug Substances 0.000 claims description 24
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
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- FCTUWJWLIKLVOX-UHFFFAOYSA-N piperidin-1-yl-[7-(trifluoromethyl)-1,3-benzodioxol-5-yl]methanone Chemical compound C=1C=2OCOC=2C(C(F)(F)F)=CC=1C(=O)N1CCCCC1 FCTUWJWLIKLVOX-UHFFFAOYSA-N 0.000 claims description 7
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- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
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- 239000001530 fumaric acid Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
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- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 2
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- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 238000010531 catalytic reduction reaction Methods 0.000 claims 1
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 1
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- 238000006482 condensation reaction Methods 0.000 abstract 1
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- 229940100688 oral solution Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940053544 other antidepressants in atc Drugs 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 229960003770 reboxetine Drugs 0.000 description 1
- CBQGYUDMJHNJBX-RTBURBONSA-N reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 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
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CEIJFEGBUDEYSX-FZDBZEDMSA-N tandospirone Chemical compound O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 CEIJFEGBUDEYSX-FZDBZEDMSA-N 0.000 description 1
- 229950000505 tandospirone Drugs 0.000 description 1
- ZAVXXBAIPSQJGS-UHFFFAOYSA-B tetracalcium;tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ZAVXXBAIPSQJGS-UHFFFAOYSA-B 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/52—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
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Abstract
【化1】
Description
R1はH、OH、F、Cl、Br、I、OCH3、OCF3、OCHF2、OCH2F、CF3、CHF2、CH2F、CH3、CH3CH2、CF3CH2、CN、NO2、NH2又はCOOR3であり、ここで該R3はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル又はC6〜C10芳香族ヒドロカルビルであり、
nは0、1、2又は3を表し、
Xは=O、=S、H、SH又はSR3であり、
YはN若しくはNR3、O又はSであり、ここで、該R3はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル又はC6〜C10芳香族ヒドロカルビルであり、
R2はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル、C6〜C10芳香族ヒドロカルビル、C1〜C10ヒドロキシアルキル若しくはN−置換ピペラジン誘導体基であるか、又はR2は隣接するYとテトラヒドロピロリル基、ピペリジル基若しくはヘキサメチレンイミノ基を形成する基である)
の化合物及びその薬学的に許容可能な酸付加塩を提供することである。
nが0、1、2又は3を表し、
Xが=Oであり、
YがN又はNHであり、
R2がH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル、C6〜C10芳香族ヒドロカルビル、C1〜C10ヒドロキシアルキル若しくはN−置換ピペラジン誘導体基であるか、又はR2が隣接するYとテトラヒドロピロリル基、ピペリジル基若しくはヘキサメチレンイミノ基を形成する基である。
R1はH、OH、F、Cl、Br、I、OCH3、OCF3、OCHF2、OCH2F、CF3、CHF2、CH2F、CH3、CH3CH2、CF3CH2、CN、NO2、NH2又はCOOR3であり、ここで、該R3はC1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル又はC6〜C10芳香族ヒドロカルビルであり、
R2はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル、C6〜C10芳香族ヒドロカルビル、C1〜C10ヒドロキシアルキル又はN−置換ピペラジン誘導体基である)
の構造で与えられる。
N−イソブチル−5’−メトキシ−3’,4’−メチレンジオキシシンナムアミド(I−1)
1 材料
1.1 試薬
本発明の方法に照らして、化合物I−1、I−2、I−3、I−4、I−5、I−6、I−7、I−8、I−9、I−10、I−11、I−12及びI−13を合成した(純度95%超)。それらの化合物を使用前に2% Tween−80水溶液に加えて1mg/mlの薬物化合物を含有する溶液を得た。
C57BL/6マウスはBeijing Vital River Experimental Animal Co. Ltd.から購入した。動物認証番号はSCXK(Beijing)2006−0009であった。
YLS−1A多機能マウス自律神経活動記録器はShandong Institute of Medical Instrumentsにより提供された。
体重18g〜22g、6週齢〜8週齢の雄性C57BL/6マウス240匹を2日〜3日間飼育して順応させた。
マウス110匹をランダムに選択してそれらの自律神経活動の回数を観察した。マウスをYLS−1A多機能マウス自律神経活動記録器に入れ、1分間順応させた後、1分目の終わりから4分目までの期間、マウスの活動を計測した。自律神経活動の回数が70〜140の間のマウス96匹を選別し、ランダムに8群に分け、薬物化合物を表1に列記した用量で1日1回7日間連続して胃内投与した。溶媒対照群には同体積の2% Tween−80水溶液を投与した。6日目の投与30分後に全てのマウスを自律神経活動記録器に入れた。1分間順応させた後、1分目の終わりから4分目までの期間、マウスの活動を計測した。
マウス130匹をランダムに選択してその自律神経活動の回数を観察した。方法は実験1と同一であった。自律神経活動の回数が70〜140の間のマウス108匹を選別し、ランダムに9群に分け、薬物化合物を表2に列記した用量で1日1回7日間連続して胃内投与した。溶媒対照群には同体積の2% Tween−80水溶液を投与した。6日目の投与30分後、各マウスの自律神経活動の回数を観察した。7日目の投与30分後、尾懸垂試験における無動時間を観察した。方法は実験1と同一であった。
SPSS10.0解析ソフトウェアを用い、一元配置分散分析法で結果を解析して群間の有意性を比較した。
実験1を用いて自律神経活動の回数及び尾懸垂試験におけるマウスの無動時間に対する化合物I−1、I−2、I−3、I−4、I−5、I−6の効果を評価した。表1に示すように、溶媒対照群と比較して、塩酸フルオキセチンを10mg/kgの用量で1週間胃内投与すると、マウスの自律神経活動に対する効果はなく、尾懸垂試験における無動時間を有意に低減させることができた(p<0.01)。化合物I−4又はI−5を10mg/kgの用量で胃内投与しても、尾懸垂試験におけるマウスの無動時間を有意に低減させることができた(p<0.05、p<0.01)が、マウスの自律神経活動に対する影響はなかった。他の投与群に関しては、尾懸垂試験におけるマウスの無動時間が様々な程度で低減したが、統計学的な差はなかった。I−1と比較して、I−4又はI−5は尾懸垂試験におけるマウスの無動に拮抗する効果がより良好であった(p<0.05)。
1 材料
1.1 試薬
本発明の方法に照らして、化合物I−1、I−2、I−3、I−4、I−5、I−6、I−7、I−8、I−9、I−10、I−11、I−12及びI−13を合成した(純度95%超)。2% Tween−80水溶液を加えて1mg/mlの薬物化合物を含有する溶液を調製した。
C57BL/6マウスはBeijing Vital River Experimental Animal Co. Ltd.から購入した。動物認証番号はSCXK(Beijing)2006−0009であった。
YLS−1A多機能マウス自律神経活動記録器はShandong Institute of Medical Instrumentsにより提供された。
体重18g〜22g、6週齢〜8週齢の雄性C57BL/6マウス240匹を2日〜3日間飼育して順応させた。
雄C57BL/6マウス120匹をランダムに選択してそれらの自律神経活動の回数を観察した。マウスをYLS−1A多機能マウス自律神経活動記録器に入れ、1分間順応させた後、1分目の終わりから4分目までの期間、マウスの活動を計測した。自律神経活動の回数が70〜140の間のマウス96匹を選別し、ランダムに8群に分け、薬物化合物を表3に列記した用量で1日1回7日間連続して胃内投与した。溶媒対照群には同体積の2% Tween−80水溶液を投与した。正常対照群を除いて、最後の投与から30分後、各群にレセルピンを4mg/kgの用量で腹腔内注射した。次に、運動不能、眼瞼下垂及び体表温度を観察した。
C57BL/6マウス120匹をランダムに選択してその自律神経活動の回数を観察した。方法は実験1と同一であった。自律神経活動の回数が70〜140の間のマウス100匹を選別し、ランダムに10群に分け、薬物化合物を表4に列記した用量で1日1回7日間連続して胃内投与した。正常群及び溶媒対照群のマウスに同体積の2% Tween−80水溶液を投与した。正常対照群を除いて、最後の投与から30分後、各群にレセルピンを4mg/kgの用量で腹腔内注射した。次に、運動不能、眼瞼下垂及び体表温度を観察した。観察方法は実験1と同一であった。
SPSS10.0解析ソフトウェアを用い、一元配置分散分析法で結果を解析して群間の有意性を比較した。
レセルピン拮抗薬(Reserpine reversal)は小胞再取り込み阻害薬であると考えられており、これが伝達物質を小胞から外に出し、更にモノアミンオキシダーゼによる伝達物質の分解を容易にする。したがって、NE、E、DA及び5−HT等が枯渇し、これが生理学的又は行動学的な変化を生じ、結果的にうつ症状が観察される。
1 材料
1.1 試薬
化合物I−5、I−10、I−13は本発明の方法に従って合成した(純度95%超)。2% Tween−80水溶液を加えて1mg/mlの薬物化合物を含有する溶液を調製した。
C57BL/6マウスはBeijing Vital River Experimental Animal Co. Ltd.から購入した。動物認証番号はSCXK(Beijing)2006−0009であった。
YLS−1A多機能マウス自律神経活動記録器はShandong Institute of Medical Instrumentsにより提供された。
1日〜2日間飼育して順応させた後、体重18g〜22g、6週齢〜8週齢の雄性C57BL/6マウス80匹をYLS−1A多機能マウス自律神経活動記録器に入れた。1分目の終わりから4分目までの期間、マウスの活動を計測した。自律神経活動の回数が70〜140の間のマウス60匹を選別し、ランダムに6群に分け、薬物化合物を表5に列記した用量で1日1回7日間連続して胃内投与した。溶媒対照群には同体積の2% Tween−80水溶液を投与した。6日目の投与後、マウスを水深10cm及び25℃の筒型水槽に入れてマウスを強制水泳させた。15分後、マウスを取り出し、乾燥し及びケージに戻した。24時間後、最後の胃内投与から30分後、マウスを直径10cm、高さ30cm及び水深10cmのガラス瓶に入れ、瓶内の水の温度を25℃にした。マウスは互いに影響を及ぼさないように不透明なパーティションで隔離した。2分間順応させた後、2分目の終わりから6分目までの累計の無動時間を記録した。上記無動状態はマウスがもがくことを止めるか又は水面に浮き、四肢を少し動かすだけで全身が僅かに丸くなって、その鼻孔を空気に曝しながらその頭を水上に浮かせたままになることを指す。
SPSS10.0解析ソフトウェアを用い、一元配置分散分析法で結果を解析して群間の有意性を比較した。
結果に示すように、溶媒対照群と比較して、化合物I−5、I−10、I−13はマウスでの強制水泳試験において用量範囲内で無動時間を短縮する効果を有した。それは統計学的に有意であった(p<0.05、p<0.01)。I−5はマウスでの強制水泳試験における無動時間に対して用量依存的な効果を示した。
13C NMR(CDCl3,100MHz)δ166.19、149.49、143.85、140.90、136.93、129.97、119.64、109.18、102.05、101.04、56.83、47.33、28.87、20.38;
ESIMS: 278.1[M+H]+
13C NMR(CDCl3,100MHz):δ165.32、151.37、144.62、138.53、132.27、129.83、122.31、117.12、111.64、104.20、47.42、28.23、20.36;
ESIMS: 293.1[M+H]+
13C NMR(CDCl3,100MHz):δ165.93、150.75、147.20、139.35、131.53、131.49、120.47、106.46、106.85、101.29、70.86、47.35、28.86、20.39;
ESI−MS:374.0[M+H]+
13C NMR(CDCl3,100MHz):δ165.87、149.23、145.59、139.62、130.52、123.68、120.60、114.43、105.57、102.41、47.34、28.85、20.37;
ESI−MS:282.1[M+H]+
13C NMR(CDCl3,100MHz):δ165.97、149.60、146.31、139.08、129.81、123.80、121.63、121.29、119.36、109.49、103.09、47.42、28.84、20.35;
ESI−MS:316.1[M+H]+
13C NMR(CDCl3,100MHz):δ166.45、149.46、143.82、140.94、138.97、136.15、131.52、125.42、123.83、108.08、101.94、100.28、56.78、47.26、28.87、20.40;
ESI−MS:304.2[M+H]+
13C NMR(CDCl3,100MHz):δ166.53、149.10、148.36、140.58、129.57、123.92、119.36、108.65、106.54、101.59、47.35、28.87、20.35;
ESI−MS:248.1[M+H]+
13C NMR(CDCl3,100MHz):δ166.24、149.44、146.15、140.62、130.01、123.89、121.19、119.26、117.28、109.40、102.91、37.43、35.98;
19F NMR(CDCl3,400MHz):δ−61.48
ESI−MS:310.1[M+Na]+
13C NMR(CDCl3,100MHz):δ165.23、149.42、146.08、140.59、130.16、123.91、121.20、119.22、117.66、109.36、102.89、42.30、41.13、15.13、13.19;
19F NMR(CDCl3,400MHz):δ−61.48
ESI−MS:338.1[M+Na]+
13C NMR(CDCl3,100MHz):δ164.86、149.43、146.06、140.47、130.19、123.93、121.23、119.06、117.64、109.43、102.89、47.07、43.44、26.77、25.68、24.64;
19F NMR(CDCl3,400MHz):δ−61.46
ESI−MS:350.1[M+Na]+
13C NMR(CDCl3,100MHz):δ171.44、148.91、143.54、135.21、124.21、121.51、117.42、112.01、102.29、46.89、38.39、31.27、28.44、19.98;
19F NMR(CDCl3,400MHz):δ−119.72;
ESI−MS:340.1[M+Na]+
13C NMR(CDCl3,100MHz):δ165.73、149.27、147.56、129.47、123.79、121.08、117.73、110.40、103.19、47.57、28.59、20.16;
19F NMR(CDCl3,400MHz):δ−61.45;
ESI−MS:312.1[M+Na]+
13C NMR(CDCl3,100MHz):δ168.37、148.91、146.11、130.45、123.82、121.12、117.72、110.69、102.91、102.91、29.73、24.53;
19F NMR(CDCl3,400MHz):δ−61.48;
ESI−MS:324.1[M+Na]+
N−イソブチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド(I−5)を取り、常法に従ってデンプン、デキストリン、微結晶セルロース及びステアリン酸マグネシウムと混合して湿式顆粒を製造した。錠剤は機械打抜きにより製造し、コーティング工程を実施してコーティング錠を得た。各錠剤はN−イソブチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド20mgを含有した。用法:1日2回及び1回1錠〜2錠。
60メッシュ篩を用いて篩い分けしたN−イソブチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド(I−5)、ラクトース及びヒドロキシプロピルセルロース(HPC)を十分に混合し、適量のTween−80を加えた後、3%ヒドロキシプロピルメチルセルロース(HMPC)水溶液を加え、20メッシュ篩を通過させた。得られた顆粒を焼成オーブン内で空気乾燥した。乾燥した材料にタルク粉末を加え、十分に混合し、カプセル殻に充填した。各カプセルはN−イソブチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド20mgを含有した。用法:1日2回及び1回1カプセル〜2カプセル。
Claims (10)
- 一般式(I)
R1はH、OH、F、Cl、Br、I、OCH3、OCF3、OCHF2、OCH2F、CF3、CHF2、CH2F、CH3、CH3CH2、CF3CH2、CN、NO2、NH2又はCOOR3であり、ここで該R3はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル又はC6〜C10芳香族ヒドロカルビルであり、
nは0、1、2又は3を表し、
Xは=O、=S、H、SH又はSR3であり、
YはN若しくはNR3、O又はSであり、ここで、該R3はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル又はC6〜C10芳香族ヒドロカルビルであり、
R2はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル、C6〜C10芳香族ヒドロカルビル、C1〜C10ヒドロキシアルキル若しくはN−置換ピペラジン誘導体基であるか、又はR2は隣接するYとテトラヒドロピロリル基、ピペリジル基若しくはヘキサメチレンイミノ基を形成する基である)
の化合物又はその薬学的に許容可能な酸付加塩。 - 一般式(II):
R1はH、OH、F、Cl、Br、I、OCH3、OCF3、OCHF2、OCH2F、CF3、CHF2、CH2F、CH3、CH3CH2、CF3CH2、CN、NO2、NH2又はCOOR3であり、ここで、該R3はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル又はC6〜C10芳香族ヒドロカルビルであり、
R2はH、C1〜C10直鎖ヒドロカルビル、C3〜C10分枝鎖ヒドロカルビル、C3〜C10環状ヒドロカルビル、C6〜C10芳香族ヒドロカルビル、C1〜C10ヒドロキシアルキル又はN−置換ピペラジン誘導体基である)
の置換シンナムアミド誘導体である、請求項1に記載の化合物又はその薬学的に許容可能な酸付加塩。 - 前記化合物が、
N−イソブチル−5’−メトキシ−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−ニトロ−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−ヨード−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−クロロ−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5−(5’−メトキシ−3’,4’−メチレンジオキシフェニル)ペンタジエンアミド、
N−イソブチル−3’,4’−メチレンジオキシシンナムアミド、
N,N−ジメチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド、
N,N−ジエチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド、
1−(5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナミル)−ピペリジン、
N−イソブチル−3−(5’−トリフルオロメチル−3’,4’−メチレンジオキシフェニル)−プロピオンアミド、
N−イソブチル−5−トリフルオロメチル−3,4−メチレンジオキシベンズアミド及び
1−(5−トリフルオロメチル−3,4−メチレンジオキシベンゾイル)−ピペリジンからなる群より選択される、請求項1に記載の化合物又はその薬学的に許容可能な酸付加塩。 - 前記薬学的に許容可能な酸付加塩が、前記一般式(I)の化合物に以下の酸:硫酸、塩酸、臭化水素酸、リン酸、酒石酸、フマル酸、マレイン酸、クエン酸、酢酸、ギ酸、メタンスルホン酸、p−トルエンスルホン酸、シュウ酸又はコハク酸を反応させることにより製造される、請求項1〜4のいずれか一項に記載の化合物又はその薬学的に許容可能な酸付加塩。
- 請求項1〜5のいずれか一項に記載の化合物又はその薬学的に許容可能な酸付加塩を含有する医薬組成物。
- 更に薬学的に許容可能な担体(複数の場合もあり)を含有する、請求項6に記載の医薬組成物。
- 請求項1〜5のいずれか一項に記載の化合物又はその薬学的に許容可能な酸付加塩の製造方法であって、
a.ウィッティヒ反応又はウィッティヒ−ホーナー反応により置換ピペロナール誘導体にエトキシホルミルメチレントリフェニルホスフィン又はホスホノ酢酸トリエチルを反応させて置換ケイ皮酸誘導体を得る工程と、
b.前記置換ケイ皮酸誘導体から該置換ケイ皮酸誘導体のアシル化誘導体(ハロゲン化アシル、アジド、無水物、活性エステルを含む)を得て、該アシル化誘導体に有機アミンを反応させてアミド誘導体を得る工程、代替的には、前記置換ケイ皮酸誘導体に有機アミン及び縮合剤(HATU、HBTU、EDCI、DCC等)を反応させてアミド誘導体を得る工程、又は、
5’−トリフルオロメチル−3’,4’−メチレンジオキシケイ皮酸を出発原料として用いてそのアシル化誘導体(ハロゲン化アシル、アジド、無水物、活性エステルを含む)を得て、該アシル化誘導体に有機アミンを反応させてアミド誘導体を得る工程、若しくは5’−トリフルオロメチル−3’,4’−メチレンジオキシケイ皮酸に有機アミン及び縮合剤(HATU、HBTU、EDCI、DCC等)を反応させてアミド誘導体を得る工程と、
側鎖に炭素−炭素二重結合を含有する誘導体を接触水素化又は水素化ホウ素ナトリウムで還元することにより側鎖に炭素−炭素単結合を含有する誘導体を製造する工程と、
を含む、製造方法。 - うつ型精神疾患を予防及び治療する薬物の製造における、請求項1〜3のいずれか一項に記載の化合物又はその薬学的に許容可能な酸付加塩の使用。
- 前記化合物が、
N−イソブチル−5’−メトキシ−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−ニトロ−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−ヨード−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−クロロ−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド、
N−イソブチル−5−(5’−メトキシ−3’,4’−メチレンジオキシフェニル)ペンタジエンアミド、
N−イソブチル−3’,4’−メチレンジオキシシンナムアミド、
N,N−ジメチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド、
N,N−ジエチル−5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナムアミド、
1−(5’−トリフルオロメチル−3’,4’−メチレンジオキシシンナミル)−ピペリジン、
N−イソブチル−3−(5’−トリフルオロメチル−3’,4’−メチレンジオキシフェニル)−プロピオンアミド、
N−イソブチル−5−トリフルオロメチル−3,4−メチレンジオキシベンズアミド及び
1−(5−トリフルオロメチル−3,4−メチレンジオキシベンゾイル)−ピペリジンからなる群より選択される、請求項9に記載の使用。
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JP2019503368A (ja) * | 2016-01-27 | 2019-02-07 | タスリー・ファーマシューティカル・グループ・カンパニー・リミテッドTasly Pharmaceutical Group Co., Ltd. | 抗不安薬の製造における置換シンナムアミド誘導体の使用 |
US10874636B2 (en) | 2016-01-27 | 2020-12-29 | Tasly Pharmaceutical Group Co., Ltd. | Application of substituted cinnamamide derivatives in preparation of anti-anxiety medication |
JP2021501211A (ja) * | 2017-11-01 | 2021-01-14 | スーゾー イーファー バイオメディカルテクノロジー コーポレーション | 大葉蒟抽出物、及びその調製方法と応用 |
JP7212051B2 (ja) | 2017-11-01 | 2023-01-24 | スーゾー イーファー バイオメディカルテクノロジー コーポレーション | 大葉蒟抽出物、及びその調製方法と応用 |
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KR101861656B1 (ko) | 2018-05-28 |
TW201309666A (zh) | 2013-03-01 |
US20140121242A1 (en) | 2014-05-01 |
CN102850317B (zh) | 2017-02-08 |
EP2725018B1 (en) | 2017-04-19 |
KR20140036294A (ko) | 2014-03-25 |
ZA201400188B (en) | 2017-08-30 |
AU2012276114B2 (en) | 2016-08-04 |
NZ618801A (en) | 2015-12-24 |
KR20170082641A (ko) | 2017-07-14 |
AU2012276114A1 (en) | 2014-01-09 |
CN102850317A (zh) | 2013-01-02 |
CA2838495C (en) | 2018-06-05 |
WO2013000399A1 (zh) | 2013-01-03 |
EP2725018A4 (en) | 2015-05-20 |
TWI579277B (zh) | 2017-04-21 |
EP2725018A1 (en) | 2014-04-30 |
CN103687850A (zh) | 2014-03-26 |
CA2838495A1 (en) | 2013-01-03 |
AR086773A1 (es) | 2014-01-22 |
CN103687850B (zh) | 2016-03-09 |
JP6078059B2 (ja) | 2017-02-08 |
RU2587668C2 (ru) | 2016-06-20 |
US10071989B2 (en) | 2018-09-11 |
RU2014102302A (ru) | 2015-08-10 |
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