JPH0670040B2 - 4H-quinolidin-4-one derivative - Google Patents
4H-quinolidin-4-one derivativeInfo
- Publication number
- JPH0670040B2 JPH0670040B2 JP3060387A JP3060387A JPH0670040B2 JP H0670040 B2 JPH0670040 B2 JP H0670040B2 JP 3060387 A JP3060387 A JP 3060387A JP 3060387 A JP3060387 A JP 3060387A JP H0670040 B2 JPH0670040 B2 JP H0670040B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- nmr
- cdcl
- formula
- cyano
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- ZUVKZCTUVRLOAQ-UHFFFAOYSA-N quinolizin-4-one Chemical class C1=CC=CN2C(=O)C=CC=C21 ZUVKZCTUVRLOAQ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002723 alicyclic group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 description 25
- 229910052739 hydrogen Inorganic materials 0.000 description 21
- 230000016784 immunoglobulin production Effects 0.000 description 20
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- 238000000921 elemental analysis Methods 0.000 description 18
- -1 thiocarbamoyl group Chemical group 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 11
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 108060003951 Immunoglobulin Proteins 0.000 description 5
- 102000018358 immunoglobulin Human genes 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000026935 allergic disease Diseases 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
- 230000000694 effects Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000009610 hypersensitivity Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- UHBMFGPURFTEIV-UHFFFAOYSA-N o-methyl 2-cyano-3-methylbut-2-enethioate Chemical compound COC(=S)C(C#N)=C(C)C UHBMFGPURFTEIV-UHFFFAOYSA-N 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- 206010039083 rhinitis Diseases 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 210000004988 splenocyte Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- CYPIVWYFSMLNCW-UHFFFAOYSA-N 2-pyridin-2-yl-n-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide Chemical compound C1CC2=CC=CC=C2CC1NC(=O)CC1=CC=CC=N1 CYPIVWYFSMLNCW-UHFFFAOYSA-N 0.000 description 1
- UXVCEKRAZBZVSL-UHFFFAOYSA-N 2-pyridin-2-ylacetamide Chemical class NC(=O)CC1=CC=CC=N1 UXVCEKRAZBZVSL-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000244186 Ascaris Species 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- YQYOIBXOGOGXFI-UHFFFAOYSA-N dichloromethane;ethoxyethane;methanol Chemical compound OC.ClCCl.CCOCC YQYOIBXOGOGXFI-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- KHXAESYTNKTPIB-UHFFFAOYSA-N methyl 4-[[(2-pyridin-2-ylacetyl)amino]methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CNC(=O)CC1=CC=CC=N1 KHXAESYTNKTPIB-UHFFFAOYSA-N 0.000 description 1
- GHYSBYXCHNQSRT-UHFFFAOYSA-N methyl 4-[[(3-cyano-2-methylsulfanyl-4-oxoquinolizine-1-carbonyl)amino]methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CNC(=O)C1=C2C=CC=CN2C(=O)C(C#N)=C1SC GHYSBYXCHNQSRT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- MDYAZAKBWUFCMC-UHFFFAOYSA-N n,n-di(propan-2-yl)-2-pyridin-2-ylacetamide Chemical compound CC(C)N(C(C)C)C(=O)CC1=CC=CC=N1 MDYAZAKBWUFCMC-UHFFFAOYSA-N 0.000 description 1
- FHNWTENEPDBMHC-UHFFFAOYSA-N n,n-dibenzyl-2-pyridin-2-ylacetamide Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)C(=O)CC1=CC=CC=N1 FHNWTENEPDBMHC-UHFFFAOYSA-N 0.000 description 1
- DWNBPTFCJWHEND-UHFFFAOYSA-N n,n-dicyclohexyl-2-pyridin-2-ylacetamide Chemical compound C1CCCCC1N(C1CCCCC1)C(=O)CC1=CC=CC=N1 DWNBPTFCJWHEND-UHFFFAOYSA-N 0.000 description 1
- PJFKHEQNLJRZFG-UHFFFAOYSA-N n,n-diethyl-2-pyridin-2-ylacetamide Chemical compound CCN(CC)C(=O)CC1=CC=CC=N1 PJFKHEQNLJRZFG-UHFFFAOYSA-N 0.000 description 1
- QLHDWUTYJOTHBM-UHFFFAOYSA-N n-(3-phenylpropyl)-2-pyridin-2-ylacetamide Chemical compound C=1C=CC=CC=1CCCNC(=O)CC1=CC=CC=N1 QLHDWUTYJOTHBM-UHFFFAOYSA-N 0.000 description 1
- LJCGSUZHOMCPIF-UHFFFAOYSA-N n-(4-anilinophenyl)-2-pyridin-2-ylacetamide Chemical compound C=1C=C(NC=2C=CC=CC=2)C=CC=1NC(=O)CC1=CC=CC=N1 LJCGSUZHOMCPIF-UHFFFAOYSA-N 0.000 description 1
- PELWENYNXIJWRI-UHFFFAOYSA-N n-benzyl-2-pyridin-2-ylacetamide Chemical compound C=1C=CC=CC=1CNC(=O)CC1=CC=CC=N1 PELWENYNXIJWRI-UHFFFAOYSA-N 0.000 description 1
- ZDUPIONFTNTRBO-UHFFFAOYSA-N n-benzyl-n-methyl-2-pyridin-2-ylacetamide Chemical compound C=1C=CC=NC=1CC(=O)N(C)CC1=CC=CC=C1 ZDUPIONFTNTRBO-UHFFFAOYSA-N 0.000 description 1
- YJVNZSYFVCBGJL-UHFFFAOYSA-N n-benzyl-n-propan-2-yl-2-pyridin-2-ylacetamide Chemical compound C=1C=CC=NC=1CC(=O)N(C(C)C)CC1=CC=CC=C1 YJVNZSYFVCBGJL-UHFFFAOYSA-N 0.000 description 1
- RKFDTWKFUFYNQE-UHFFFAOYSA-N n-cyclohexyl-2-pyridin-2-ylacetamide Chemical compound C1CCCCC1NC(=O)CC1=CC=CC=N1 RKFDTWKFUFYNQE-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940043515 other immunoglobulins in atc Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は免疫グロブリンＥ（以下IgEという）抗体産生
抑制作用を有し、IgEに起因する疾患、例えばある種の
気管支喘息、鼻炎、皮膚炎、過敏症等の治療剤として有
用な新規な4H−キノリジン−４−オン誘導体に関するも
のである。TECHNICAL FIELD OF THE INVENTION The present invention has an inhibitory action on immunoglobulin E (hereinafter referred to as IgE) antibody production, and diseases caused by IgE, such as certain bronchial asthma, rhinitis, dermatitis, and hypersensitivity. The present invention relates to a novel 4H-quinolizin-4-one derivative useful as a therapeutic agent for diseases and the like.
従来の技術 免疫グロブリン（以下Igという）は生体の免疫反応を司
るたん白としてよく知られている。近年、この免疫グロ
ブリンクラスの１つであるIgEが種々の疾患、例えばあ
る種の気管支喘息、鼻炎、皮膚炎、過敏症等の原因物質
であることが明らかになって以来、IgE抗体産生を抑制
する化合物は、それらの疾患の原因療法的な治療剤とし
て有用であるとしてその出現が嘱望されている。2. Description of the Related Art Immunoglobulin (hereinafter referred to as Ig) is well known as a protein that controls the immune response of the living body. In recent years, since it has been revealed that IgE, which is one of the immunoglobulin classes, is the causative agent of various diseases such as bronchial asthma, rhinitis, dermatitis, and hypersensitivity, it suppresses IgE antibody production. Compounds are expected to be useful as therapeutic agents for causative therapy of these diseases.
これまで、IgE抗体産生を抑制する化合物としていくつ
かの化合物が見出され、報告されている。しかしなが
ら、いずれも免疫前、免疫時あるいは免疫直後に投与し
て、免疫応答誘導期でのIgE抗体産生に対する抑制効果
が認められているのみで、その後の長期にわたる持続的
なIgE抗体産生に対する作用については確認されていな
い〔日本特許公開公報昭54-130516号、同昭62-76号
等〕。So far, several compounds have been found and reported as compounds that suppress IgE antibody production. However, all of them were administered before or during immunization or immediately after immunization, and only an inhibitory effect on IgE antibody production during the immune response induction period was observed. Has not been confirmed [Japanese Patent Publication No. 54-130516, No. 62-76, etc.].
本発明のような4H−キノリジン−４−オン誘導体とし
て、一般式 （式中のＲはメチル基またはエチル基である）で表され
る化合物が既に知られている（薬学雑誌、89巻、２号、
203〜208ページ、1969年）。しかしながら、これらの化
合物は単に合成上の興味から合成されたもので、その薬
理作用については全く開示されていない。The 4H-quinolizin-4-one derivative of the present invention has the general formula A compound represented by the formula (R in the formula is a methyl group or an ethyl group) is already known (Pharmaceutical Journal, Vol. 89, No. 2,
203-208, 1969). However, these compounds are merely synthesized from synthetic interests, and their pharmacological actions are not disclosed at all.
また、式 で表される化合物が抗腫瘍活性を示すことが報告されて
いるが、他の作用、特にIgE抗体産生抑制作用について
は全く開示されていない（薬学雑誌97巻、９号、1039〜
1045ページ、1977年）。Also, the formula It has been reported that the compound represented by the formula (1) shows antitumor activity, but no other action, particularly the action of suppressing IgE antibody production is disclosed (Pharmaceutical Journal, Vol. 97, No. 9, 1039-).
1045, 1977).
さらに、一般式 （式中のR11はカルボキシ基、アミド化されたカルボキ
シ基、シアノ基、チオカルバモイル基またはテトラゾリ
ル基、R17は水素またはアリール基、R12は水素、ヒドロ
キシ基、低級アルキル基または低級アルコキシ基、R13
は水素、ヒドロキシ基、低級アルキル基、低級アルコキ
シ基、低級アルケニルオキシ基、適当な置換基を有して
いてもよいアリール基、アリールチオ基、アロイル基、
アル（低級）アルキル基、アレーンスルホニル基、適当
な置換基を有していてもよいアリールアミノ基またはア
リールオキシ基をそれぞれ意味し、R12およびR13はキノ
リジノン環のいかなる位置にも位置することができ、か
つ互いに結合して、-CH2CH2CH2-、-CH=CH-または-CH=CH
-CH=CH-を形成することができる）で表される化合物
が、ラットを用いた水浸拘束ストレス潰瘍実験および受
身皮膚アナフィラキシ−反応に対してそれぞれ抑制作用
を有することが報告されているが、IgE抗体産生に対す
る作用については全く開示されていない（日本特許公開
公報昭60-222482号）。Furthermore, the general formula (In the formula, R 11 is a carboxy group, amidated carboxy group, cyano group, thiocarbamoyl group or tetrazolyl group, R 17 is hydrogen or an aryl group, R 12 is hydrogen, a hydroxy group, a lower alkyl group or a lower alkoxy group. , R 13
Is hydrogen, hydroxy group, lower alkyl group, lower alkoxy group, lower alkenyloxy group, optionally substituted aryl group, arylthio group, aroyl group,
Ar (lower) alkyl group, arenesulfonyl group, arylamino group which may have an appropriate substituent or aryloxy group, respectively, and R 12 and R 13 may be located at any position of the quinolidinone ring. And bonded to each other, -CH 2 CH 2 CH 2- , -CH = CH- or -CH = CH
It is reported that the compound represented by -CH = CH-) has an inhibitory effect on the water immersion restraint stress ulcer experiment using rats and the passive skin anaphylactic reaction, respectively. , No effect on IgE antibody production was disclosed (Japanese Patent Publication No. Sho 60-222482).
発明が解決しようとする問題点 IgEはある種の条件下で抗原感作によりその産生が誘導
され、その産生はその後長期にわたり持続することが動
物実験で確認されている〔イムノロジー（Immunolog
y）、21巻、11〜15ページ、1971年〕。Problems to be Solved by the Invention It has been confirmed in animal experiments that IgE induces its production by antigen sensitization under certain conditions, and that its production continues for a long period of time thereafter [immunology (Immunolog
y), vol. 21, pp. 11-15, 1971].
臨床上でも、気管支喘息などの疾患患者においては、特
異抗原に対するIgE抗体の持続的産生が認められる例が
多いことが報告されている。It has been reported clinically that in patients with diseases such as bronchial asthma, continuous production of IgE antibody against a specific antigen is observed in many cases.
従って、IgEに起因する疾患の治療に用いるIgE抗体産生
抑制剤は免疫応答誘導期でのIgE抗体産生のみならず、
その後の持続的なIgE抗体産生を抑制するものでなけれ
ばならない。Therefore, the IgE antibody production inhibitor used for the treatment of diseases caused by IgE is not limited to IgE antibody production in the immune response induction period,
It should suppress the subsequent persistent IgE antibody production.
また、免疫グロブリンクラスの中にはIgEのほかに各種
のグロブリンがあり、これらは生体防禦において重要な
働きをするものがほとんどである。例えば、免疫グロブ
リンの中では最も大量に産生される免疫グロブリンＧ
（IgG）などが感染防禦において重要な働きをすること
はよく知られている。In addition, there are various globulins in addition to IgE in the immunoglobulin class, and most of these play an important role in biological protection. For example, immunoglobulin G, which is the most abundant immunoglobulin produced,
It is well known that (IgG) plays an important role in infection control.
IgE抗体産生を抑制する場合、このような他の免疫グロ
ブリンの抗体産生に対しては影響を与えないこともまた
必要である。When suppressing IgE antibody production, it is also necessary not to affect the antibody production of such other immunoglobulins.
IgE抗体がある種の気管支喘息、鼻炎、皮膚炎、過敏症
などの惹起抗体であることが明らかにされて以来、IgE
抗体産生抑制剤に関する研究が多く行われているが、こ
れまでIgE抗体産生を抑制すると報告されている化合物
はすべて、免疫前、免疫時あるいは免疫直後に投与さ
れ、免疫応答誘導期でのIgE抗体産生を抑制することが
確認されているのみで、持続性のIgE抗体産生に対する
作用は確認されていない。また、IgE抗体産生に対する
作用と他のIg抗体産生に対する作用との選択性も低いも
のがほとんどである。Since the IgE antibody was revealed to be an antibody that induces certain types of bronchial asthma, rhinitis, dermatitis, hypersensitivity, etc.
Although many studies have been conducted on antibody production inhibitors, all compounds that have been reported to suppress IgE antibody production until now are administered before, during or immediately after immunization, and the IgE antibody in the immune response induction period is used. It has only been confirmed that production is suppressed, but no effect on persistent IgE antibody production has been confirmed. In addition, most of them have low selectivity between the action on IgE antibody production and the action on other Ig antibody production.
本発明の目的は、従来のIgE抗体産生抑制剤とは異な
り、感染防禦等に重要なIgE抗体等の産生にはあまり影
響を与えず、しかも持続性のIgE抗体産生に対して作用
する選択的なIgE抗体産生抑制作用を有し、IgEに起因す
る種々の疾患治療剤として有用な新規な4H−キノリジン
−４−オン誘導体を提供することである。The purpose of the present invention is, unlike conventional IgE antibody production inhibitors, does not significantly affect the production of IgE antibodies and the like which are important for protection against infection, etc., and is selective for acting on persistent IgE antibody production. Another object of the present invention is to provide a novel 4H-quinolizin-4-one derivative having a strong IgE antibody production inhibitory action and useful as a therapeutic agent for various diseases caused by IgE.
問題点を解決するための手段 本発明者らは選択的IgE抵抗産生抑制作用を有し、IgEに
起因する疾患治療剤として有用な化合物を見出すべく鋭
意研究を重ねた結果、ある種の4H−キノリジン−４−オ
ン誘導体において良好な結果が得られ、その目的を達成
できることを見出し、本発明を成すに至った。Means for solving the problem The present inventors have a selective IgE resistance production inhibitory action, as a result of repeated studies to find a compound useful as a therapeutic agent for diseases caused by IgE, as a result, a certain 4H- The inventors have found that good results were obtained with the quinolidin-4-one derivative, and that the object could be achieved, and completed the present invention.
すなわち、本発明は一般式 （式中のR1およびR2は同じでも異なっていてもよく、そ
れぞれ水素原子、置換基を有することもある低級アルキ
ル基または低級アルケニル基、置換基を有することもあ
る脂環状基、アリール基または異項環基、ただし、R1と
R2が共に水素原子である化合物を除くものであり、R3は
低級アルキル基である）で表される4H−キノリジン−４
−オン誘導体を提供するものである。That is, the present invention has the general formula (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom, a lower alkyl group or a lower alkenyl group which may have a substituent, an alicyclic group which may have a substituent, an aryl group. Or a heterocyclic group, provided that R 1 and
R 2 is in which together except a compound having a hydrogen atom, represented by R 3 is a lower alkyl group) 4H-quinolizine -4
-On derivatives are provided.
本発明において低級アルキル基とは炭素１〜６の直鎖状
または枝分かれ状のアルキル基を、低級アルケニル基と
は炭素数３〜６の直鎖状または枝分かれ状のアルケニル
基をそれぞれ意味する。In the present invention, the lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and the lower alkenyl group means a straight-chain or branched alkenyl group having 3 to 6 carbon atoms.
また、脂環状基とは、炭素数３〜10の単環または多環式
の脂環状炭化水素基、例えばシクロヘキシル基、1,2,3,
4−テトラヒドロナフチル基などを、アリール基とはフ
ェニル基、ナフチル基などのような芳香族炭化水素基
を、異項環基とは少なくとも１個の異種原子を含む５〜
７員環の飽和、不飽和環状基をそれぞれ意味する。The alicyclic group is a monocyclic or polycyclic alicyclic hydrocarbon group having 3 to 10 carbon atoms, such as cyclohexyl group, 1,2,3,
4-tetrahydronaphthyl group, etc., an aryl group is an aromatic hydrocarbon group such as a phenyl group, a naphthyl group, etc., and a heterocyclic group is at least one hetero atom.
It means a 7-membered saturated or unsaturated cyclic group, respectively.
本発明の一般式（Ｉ）で表される化合物は新規化合物で
あり、以下のような方法により製造することができる。
すなわち、一般式 （式中のR1およびR2は前記と同じ意味をもつ）で表され
る２−ピリジルアセトアミド誘導体と、一般式 （式中のR3は前記と同じ意味をもつ）で表される化合物
とを反応させることにより製造することができる。The compound represented by formula (I) of the present invention is a novel compound and can be produced by the following method.
That is, the general formula (Wherein R 1 and R 2 have the same meanings as described above), and a 2-pyridylacetamide derivative represented by the general formula It can be produced by reacting with a compound represented by the formula (R 3 in the formula has the same meaning as described above).
本発明の製造方法で出発原料として用いられる一般式
（II）の化合物は一部新規化合物が含まれるが、２−ピ
リジル酢酸と、一般式 （式中のR1およびR2は前記と同じ意味をもつ）で表され
るアミン誘導体とを用い、常法に従い反応することによ
って製造することができるペプタイド（Peptides;Ed.by
E.Scoffone,North-Holland Phb.Co.,Amsterdam）、17
ページ、1969年〕。The compound of the general formula (II) used as a starting material in the production method of the present invention includes a part of a novel compound. (R 1 and R 2 in the formula have the same meanings as described above), and can be produced by reacting in accordance with a conventional method (Peptides; Ed.
E.Scoffone, North-Holland Phb.Co., Amsterdam), 17
Page, 1969].
また、もう一方の出発原料として用いられる一般式（II
I）の化合物はシアノ酢酸メチル、二硫化炭素および一
般式 R3−Ｘ （Ｖ） （式中のR3は前記と同じ意味をもち、Ｘは酸残基であ
る）で表される化合物を用い、文献記載の方法あるいは
その類似方法に従って製造することができる〔ヘミッシ
ュ ベリヒテ（Chem.Ber.）95巻、2861〜2870ページ、1
962年〕。In addition, the general formula (II
The compound of I) is methyl cyanoacetate, carbon disulfide and a compound represented by the general formula R 3 —X (V) (wherein R 3 has the same meaning as described above and X is an acid residue). It can be used according to the method described in the literature or a method similar thereto [Hemisch Berichte (Chem. Ber.) 95, 2861 to 2870, 1
962].
本発明の製造方法は既に知られた方法であり、文献記載
の方法に従い容易に行うことができる（薬学雑誌、89
巻、２号、203〜208ページ、1969年）。The production method of the present invention is a known method, and can be easily performed according to the method described in the literature (Pharmaceutical Journal, 89
Vol. 2, No. 203-208, 1969).
本発明の製造方法を好適に実施するには、一般式（II）
の化合物とこれと等モルの一般式（III）の化合物を不
活性有機溶媒中あるいは無溶媒で、100〜120℃で２〜10
時間加熱し、常法に従い処理、精製して目的物を得る。In order to preferably carry out the production method of the present invention, the compound represented by the general formula (II)
And a compound of general formula (III) in equimolar amounts thereto in an inert organic solvent or without solvent at 100 to 120 ° C for 2 to 10
The product is heated for a period of time, treated and purified according to a conventional method to obtain the desired product.
本発明の一般式（Ｉ）の化合物はジニトロフェニル化し
たアスカリスたん白（DNP-As）に対してアドプティブ
セカンダリー レスポンス（adoptive secondary respo
nse）を示しているBALB/c系マウスの脾細胞を用いた、
試験管内（in vitro）でのIg産生量測定試験〔セルラー
イムノロジー（Cellular Immunology）、58巻、188〜
201ページ、1981年〕において顕著なIgE抵抗産生抑制作
用を示す。The compounds of general formula (I) of the present invention are adaptive to dinitrophenylated Ascaris protein (DNP-As).
Secondary response (adoptive secondary respo
nse) showing BALB / c mouse splenocytes,
In vitro Ig production measurement test [Cellular Immunology, Volume 58, 188-
201, 1981] shows a remarkable inhibitory effect on IgE resistance production.
本発明の一般式（Ｉ）の化合物を実際の治療に用いる場
合、適当な医薬品添加剤、例えば、賦形剤、結合剤、滑
沢剤、崩壊剤、溶解補助剤、安定化剤等を加えて常法に
従い種々の剤型、例えば散剤、錠剤、カプセル用、シロ
ップ剤、注射剤などを調製し、経口的あるいは非経口的
に投与する。When the compound of the general formula (I) of the present invention is used for the actual treatment, suitable pharmaceutical additives such as excipients, binders, lubricants, disintegrants, solubilizers, stabilizers, etc. are added. Various dosage forms such as powders, tablets, capsules, syrups, and injections are prepared according to a conventional method and administered orally or parenterally.
本発明の一般式（Ｉ）の化合物の投与量または治療有効
量は対象となる患者の年令、性別、疾患の度合および治
療条件などによって変化するが、人または動物の治療に
用いる場合の１日投与量は、経口投与の場合、概ね0.1
〜10mg/kg、非経口投与の場合、概ね0.02〜5mg/kgであ
る。The dose or therapeutically effective amount of the compound of the general formula (I) of the present invention varies depending on the age, sex, degree of disease and treatment condition of the target patient, but when used for treatment of humans or animals, The daily dose is approximately 0.1 for oral administration.
-10 mg / kg, and for parenteral administration, it is generally 0.02-5 mg / kg.
発明の効果 本発明の一般式（Ｉ）で表される4H−キノリジン−４−
オン誘導体はDNP-Asに対してadoptive secondary respo
nseを示しているBALB/c系マウスの脾細胞を用いたIg産
生量測定試験で、10-8〜10-5g/mlの濃度で約40〜80％程
度のIgE抗体産生抑制作用を示す。EFFECT OF THE INVENTION 4H-quinolizine-4-represented by the general formula (I) of the present invention
On-derivative is an adaptive secondary respo for DNP-As
In the Ig production measurement test using splenocytes of BALB / c mouse showing nse, it shows about 40 to 80% suppression of IgE antibody production at a concentration of 10 -8 to 10 -5 g / ml. .
実施例 本発明の内容を以下の参考例および実施例を用いてさら
に詳細に説明する。なお、各参考例および実施例中の化
合物の融点はすべて未補正である。EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.
参考例１ N,N−ジベンジル−２−ピリジルアセトアミド ２−ピリジル酢酸塩酸塩（413mg）、ジベンジルアミン
（470mg）、１−ヒドロキシベンゾトリアゾール（321m
g）の乾燥ピリジン（5ml）溶液に1,3−ジシクロヘキシ
ルカルボジイミド（637mg）を加え、室温で15時間攪拌
する。析出結晶をろ去後、減圧下に溶媒を留去し、残渣
を１規定塩酸に溶解する。この塩酸溶液をジエチルエー
テル（25ml）で２回洗浄した後、２規定カセイソーダー
水溶液を加えてpH11とする。析出した油状物を塩化メチ
レン（50ml）で抽出し、無水硫酸ナトリウムで乾燥後、
減圧下に溶媒を留去し、N,N−ジベンジル−２−ピリジ
ルアセトアミド（486mg）を得る。Reference Example 1 N, N-dibenzyl-2-pyridylacetamide 2-pyridylacetic acid hydrochloride (413 mg), dibenzylamine (470 mg), 1-hydroxybenzotriazole (321 m
1,3-Dicyclohexylcarbodiimide (637 mg) was added to a solution of g) in dry pyridine (5 ml), and the mixture was stirred at room temperature for 15 hours. The precipitated crystals are filtered off, the solvent is distilled off under reduced pressure, and the residue is dissolved in 1N hydrochloric acid. The hydrochloric acid solution is washed twice with diethyl ether (25 ml), and 2N caustic soda aqueous solution is added to adjust the pH to 11. The precipitated oily matter was extracted with methylene chloride (50 ml) and dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain N, N-dibenzyl-2-pyridylacetamide (486 mg).
NMR（CDCl3） δ:4.02（s,2H）,4.61（d,4H）,7.10〜7.41（m,12H）,
7.65（dt,1H）,8.51（d,1H） 参考例２ 参考例１と同様にして下記化合物を得る。NMR (CDCl 3 ) δ: 4.02 (s, 2H), 4.61 (d, 4H), 7.10 to 7.41 (m, 12H),
7.65 (dt, 1H), 8.51 (d, 1H) Reference Example 2 In the same manner as in Reference Example 1, the following compound is obtained.
（１）N,N−ジシクロヘキシル−２−ピリジルアセトア
ミド NMR（CDCl3） δ:1.00〜1.80（m,18H）,2.48（m,2H）,2.87（m,11H）,
3.70（m,1H）,3.90（s,2H）,7.14（dd,1H）,7.34（d.1
H）,7.62（dt,1H）,8.52（d,1H） （２）N,N−ジエチル−２−ピリジルアセトアミド NMR（CDCl3） δ:1.12（m,6H）,3.40（m,4H）,3.90（s,2H）,7.16（d
d,1H）,7.38（d.1H）,7.64（dt,1H）,8.52（d,1H） （３）N,N−ジイソプロピル−２−ピリジルアセトアミ
ド NMR（CDCl3） δ:1.04（d,6H）,1.40（d,6H）,3.90（s,2H）,7.15（d
d,1H）,7.36（d.1H）,7.64（dt,1H）,8.52（d,1H） （４）N,N−イソブチル−２−ピリジルアセトアミド NMR（CDCl3） δ:0.83（d,6H）,0.91（d,6H）,1.99（m,2H）,3.21（d,
4H）,3.93（s,2H）,7.14（dd,1H）,7.37（d.1H）,7.62
（dt,1H）,8.51（d,1H） （５）N,N−ジヘキシル−２−ピリジルアセトアミド NMR（CDCl3） δ:0.88（m,6H）,1.27（br,12H）,1.49（m,4H）,3.31
（m,4H）,3.89（s,2H）,7.16（dd,1H）,7.37（d.1H）,
7.63（dt,1H）,8.52（d,1H） （６）Ｎ−ベンジル−Ｎ−メチル−２−ピリジルアセト
アミド NMR（CDCl3） δ:2.95and3.00（s,3H）,3.97and4.00（S,2H）,4.62and
4.69（s,2H）,7.08〜7.41（m,7H）,7.64（m.1H）,8.49a
nd8.54（d,1H） （７）Ｎ−フェニル−Ｎ−（２−フェニルアミノエチ
ル）−２−ピリジルアセトアミド NMR（CDCl3） δ:3.29（t,2H）,3.66（s,2H）,4.04（t,2H）,6.57（d,
2H）,6.68（t,1H）,7.10〜7.40（m,9H）,7.57（dt,1
H）,8.49（d,1H） （８）Ｎ−ベンジル−Ｎ−イソプロピル−２−ピリジル
アセトアミド NMR（CDCl3） δ:1.04and1.11（d,6H）,3.79and4.06（s,2H）,4.54and
（s,2H）,4.44and4.84（m,1H）,7.10〜7.70（m,8H）,8.
49and8.55（d,1H） （９）Ｎ−シクロヘキシル−Ｎ−イソプロプル−２−ピ
リジルアセトアミド NMR（CDCl3） δ:1.05and1.38（d,6H）,0.90〜1.82（m,9H）,2.47（b
r,1H）,2.91and3.37（br,1H）,3.69and4.18（m,1H）,7.
15（dd,1H）,7.35（d,1H）,7.63（dt,1H）,8.52（d,1
H） （10）Ｎ−アリル−Ｎ−シクロヘキシル−２−ピリジル
アセトアミド NMR（CDCl3） δ:0.95〜1.85（m,10H）,3.85（s,2H）,3.88and4.42
（m,1H）,3.97（s,2H）,5.00〜5.30（m,2H）,5.82（m,1
H）,7.15（m,1H）,7.35（t,1H）,7.63（m,1H）,8.52
（m,1H） （11）Ｎ−（３−フェニルプロピル）−２−ピリジルア
セトアミド NMR（CDCl3） δ:1.82（m,2H）,2.59（t,2H）,3.28（q,2H）,7.10〜7.
40（m,8H）,7.66（dt,1H）,8.56（d,1H） （12）Ｎ−シクロヘキシル−２−ピリジルアセトアミド NMR（CDCl3） δ:1.10〜1.90（m,10H）,3.71（s,2H）,3.75（m,1H）,
7.15（br,1H）,7.23（dd,1H）,7.32（d,1H）,7.69（dt,
1H）,8.55（d,1H） （13）Ｎ−ベンジル−２−ピリジルアセトアミド NMR（CDCl3） δ:3.79（s,2H）,4.47（s,2H）,7.17〜7.37（m,8H）,7.
67（dt,1H）,8.51（d,1H） （14）Ｎ−（４−アニリノフェニル）−２−ピリジルア
セトアミド NMR（CDCl3） δ:3.86（s,2H）,5.66（br,1H）,6.87（t,1H）,6.97〜
7.06（m,4H）,7.20〜7.26（m,3H）,7.31（d,1H）,7.44
（d,2H）,7.70（bt,1H）,8.01（br,1H）,8.61（d,1H） （15）Ｎ−（４−フェニル−２−チアゾリル）−２−ピ
リジルアセトアミド NMR（CDCl3） δ:3.99（s,2H）,7.12（s,1H）,7.27〜7.43（m,5H）,7.
72（dt,1H）,7.86（d,2H）,8.72（dd,1H） （16）Ｎ−（1,2,3,4−テトラヒドロ−２−ナフチル）
２−ピリジルアセトアミド NMR（CDCl3） δ:1.67〜2.10（m,4H）,2.77（m,2H）,3.78（s,2H）,5.
17（m,1H）,7.15〜7.33（m,6H）,7.43（br,1H）,7.67
（dt,1H）,8.46（d,1H） （17）Ｎ−（４−メトキシカルボニルベンジル）−２−
ピリジルアセトアミド NMR（CDCl3） δ:3.83（s,2H）,3.90（s,3H）,4.52（d,2H）,7.20〜7.
47（m,5H）,7.71（m,1H）,7.82〜8.00（m,2H）,8.51and
8.60（d,1H） 参考例３ メチル ２−シアノ−3,3−ジメチルチオアクリラート シアノ酢酸メチル9.0mlにナトリウムメトキシド（Na4.2
0gと53mlの無水メタノールより合成）と二硫化炭素（5.
3ml）を温度を18℃以下に保ちながら徐々に滴下する。
滴下終了後、氷冷下30分攪拌し、さらにジメチル硫酸
（16.5ml）を30分間かけて加え、室温で１時間攪拌す
る。反応液に水125mlを加え析出した結晶をろ取、メタ
ノールから再結晶することによりメチル ２−シアノ−
3,3−ジメチルチオアクリラート（13.0g）を得る。(1) N, N-dicyclohexyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 1.00 to 1.80 (m, 18H), 2.48 (m, 2H), 2.87 (m, 11H),
3.70 (m, 1H), 3.90 (s, 2H), 7.14 (dd, 1H), 7.34 (d.1
H), 7.62 (dt, 1H), 8.52 (d, 1H) (2) N, N-diethyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 1.12 (m, 6H), 3.40 (m, 4H), 3.90 (s, 2H), 7.16 (d
d, 1H), 7.38 (d.1H), 7.64 (dt, 1H), 8.52 (d, 1H) (3) N, N-diisopropyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 1.04 (d, 6H ), 1.40 (d, 6H), 3.90 (s, 2H), 7.15 (d
d, 1H), 7.36 (d.1H), 7.64 (dt, 1H), 8.52 (d, 1H) (4) N, N-isobutyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 0.83 (d, 6H ), 0.91 (d, 6H), 1.99 (m, 2H), 3.21 (d,
4H), 3.93 (s, 2H), 7.14 (dd, 1H), 7.37 (d.1H), 7.62
(Dt, 1H), 8.51 ( d, 1H) (5) N, N- dihexyl-2-pyridyl acetamide NMR (CDCl 3) δ: 0.88 (m, 6H), 1.27 (br, 12H), 1.49 (m, 4H), 3.31
(M, 4H), 3.89 (s, 2H), 7.16 (dd, 1H), 7.37 (d.1H),
7.63 (dt, 1H), 8.52 (d, 1H) (6) N-benzyl-N-methyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 2.95and3.00 (s, 3H), 3.97and4.00 ( S, 2H), 4.62and
4.69 (s, 2H), 7.08 to 7.41 (m, 7H), 7.64 (m.1H), 8.49a
nd8.54 (d, 1H) (7 ) N- phenyl-N-(2-phenylamino-ethyl) -2-pyridyl acetamide NMR (CDCl 3) δ: 3.29 (t, 2H), 3.66 (s, 2H), 4.04 (t, 2H), 6.57 (d,
2H), 6.68 (t, 1H), 7.10 to 7.40 (m, 9H), 7.57 (dt, 1
H), 8.49 (d, 1H) (8) N-benzyl-N-isopropyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 1.04and1.11 (d, 6H), 3.79and4.06 (s, 2H) , 4.54and
(S, 2H), 4.44and4.84 (m, 1H), 7.10 ~ 7.70 (m, 8H), 8.
49and8.55 (d, 1H) (9) N-cyclohexyl-N-isoprop-2-pyridylacetamide NMR (CDCl 3 ) δ: 1.05and1.38 (d, 6H), 0.90 to 1.82 (m, 9H), 2.47 (B
r, 1H), 2.91and3.37 (br, 1H), 3.69and4.18 (m, 1H), 7.
15 (dd, 1H), 7.35 (d, 1H), 7.63 (dt, 1H), 8.52 (d, 1
H) (10) N-allyl-N-cyclohexyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 0.95 to 1.85 (m, 10H), 3.85 (s, 2H), 3.88and4.42
(M, 1H), 3.97 (s, 2H), 5.00 to 5.30 (m, 2H), 5.82 (m, 1
H), 7.15 (m, 1H), 7.35 (t, 1H), 7.63 (m, 1H), 8.52
(M, 1H) (11) N- (3-phenylpropyl) -2-pyridylacetamide NMR (CDCl 3 ) δ: 1.82 (m, 2H), 2.59 (t, 2H), 3.28 (q, 2H), 7.10 ~ 7.
40 (m, 8H), 7.66 (dt, 1H), 8.56 (d, 1H) (12) N-cyclohexyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 1.10 to 1.90 (m, 10H), 3.71 (s) , 2H), 3.75 (m, 1H),
7.15 (br, 1H), 7.23 (dd, 1H), 7.32 (d, 1H), 7.69 (dt,
1H), 8.55 (d, 1H) (13) N-benzyl-2-pyridylacetamide NMR (CDCl 3 ) δ: 3.79 (s, 2H), 4.47 (s, 2H), 7.17 to 7.37 (m, 8H), 7.
67 (dt, 1H), 8.51 (d, 1H) (14) N- (4-anilinophenyl) -2-pyridylacetamide NMR (CDCl 3 ) δ: 3.86 (s, 2H), 5.66 (br, 1H) , 6.87 (t, 1H), 6.97〜
7.06 (m, 4H), 7.20 ~ 7.26 (m, 3H), 7.31 (d, 1H), 7.44
(D, 2H), 7.70 ( bt, 1H), 8.01 (br, 1H), 8.61 (d, 1H) (15) N- (4- phenyl-2-thiazolyl) -2-pyridyl acetamide NMR (CDCl 3) δ: 3.99 (s, 2H), 7.12 (s, 1H), 7.27 ~ 7.43 (m, 5H), 7.
72 (dt, 1H), 7.86 (d, 2H), 8.72 (dd, 1H) (16) N- (1,2,3,4-tetrahydro-2-naphthyl)
2-Pyridylacetamide NMR (CDCl 3 ) δ: 1.67 to 2.10 (m, 4H), 2.77 (m, 2H), 3.78 (s, 2H), 5.
17 (m, 1H), 7.15 to 7.33 (m, 6H), 7.43 (br, 1H), 7.67
(Dt, 1H), 8.46 (d, 1H) (17) N- (4-methoxycarbonylbenzyl) -2-
Pyridylacetamide NMR (CDCl 3 ) δ: 3.83 (s, 2H), 3.90 (s, 3H), 4.52 (d, 2H), 7.20 to 7.
47 (m, 5H), 7.71 (m, 1H), 7.82 ~ 8.00 (m, 2H), 8.51and
8.60 (d, 1H) Reference Example 3 Methyl 2-cyano-3,3-dimethylthioacrylate 9.0 ml of methyl cyanoacetate was added with sodium methoxide (Na4.20).
Synthesized from 0 g and 53 ml of anhydrous methanol) and carbon disulfide (5.
3 ml) is gradually added dropwise while keeping the temperature below 18 ° C.
After completion of dropping, the mixture is stirred under ice cooling for 30 minutes, dimethylsulfate (16.5 ml) is added over 30 minutes, and the mixture is stirred at room temperature for 1 hour. 125 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from methanol to give methyl 2-cyano-
3,3-Dimethylthioacrylate (13.0 g) is obtained.
融点:85〜86℃ NMR（CDCl3） δ:2.61（s,3H）,2.78（s,3H）,3.84（s,3H） 実施例１ ３−シアノ−N,N−ベンジル−２−メチルチオ−4H−キ
ノリジン−４−オン−１−カルボキサミド N,N−ジベンジル−２−ピリジルアセトアミド（486mg）
とメチル ２−シアノ−3,3−ジメチルチオアクリラー
ト（312mg）の混合物を120℃で10時間加熱後、反応液を
シリカゲルカラムクロマトグラフィーに付し、塩化メチ
レン−ジエチルエーテル−メタノール（1:1:0.2）の混
合溶媒で溶出することにより、３−シアノ−N,N−ジベ
ンジル−２−メチルチオ−4H−キノリジン−４−オン−
１−カルボキサミド（260mg）を淡黄色結晶として得
る。Melting point: 85-86 ° C NMR (CDCl 3 ) δ: 2.61 (s, 3H), 2.78 (s, 3H), 3.84 (s, 3H) Example 1 3-Cyano-N, N-benzyl-2-methylthio- 4H-quinolizin-4-one-1-carboxamide N, N-dibenzyl-2-pyridylacetamide (486 mg)
After heating a mixture of methyl 2-cyano-3,3-dimethylthioacrylate (312 mg) at 120 ° C for 10 hours, the reaction mixture was subjected to silica gel column chromatography, and methylene chloride-diethyl ether-methanol (1: 1). : 0.2) in a mixed solvent of 3-cyano-N, N-dibenzyl-2-methylthio-4H-quinolidin-4-one-
1-carboxamide (260 mg) is obtained as pale yellow crystals.
融点:85〜87℃ IR（KBr）:2210,1660,1620cm-1 NMR（CDCl3） δ:2.74（s,3H）,4.29（s,2H）,4.65（d,1H）,5.09（d,
1H）,6.88（m,2H）,7.12〜7.23（m,4H）,7.36〜7.50
（m,6H）,7.57（dt,1H）,9.15（d,1H） 元素分析値：（C26H21N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 71.05 4.82 9.56 実測値 70.66 4.73 9.46 実施例２ 実施例１と同様にして下記化合物を得る。Melting point: 85-87 ° C IR (KBr): 2210, 1660, 1620 cm -1 NMR (CDCl 3 ) δ: 2.74 (s, 3H), 4.29 (s, 2H), 4.65 (d, 1H), 5.09 (d,
1H), 6.88 (m, 2H), 7.12 ~ 7.23 (m, 4H), 7.36 ~ 7.50
(M, 6H), 7.57 ( dt, 1H), 9.15 (d, 1H) Elemental analysis: (C 26 H 21 N 3 O as 2 S) C% H% N % Calculated 71.05 4.82 9.56 Found 70.66 4.73 9.46 Example 2 In the same manner as in Example 1, the following compound is obtained.
（１）３−シアノ−N,N−ジシクロヘキシル−２−メチ
ルチオ−4H−キノリジン−４−オン−１−カルボキサミ
ド 融点:268〜271℃ IR（KBr）:2210,1660,1620cm-1 NMR（CDCl3） δ:0.83〜2.07（m,18H）,2.60〜2.88（m,2H）,2.77（s,
3H）,3.16（m,2H）,7.24（dd,1H）,7.54（d,1H）,7.68
（dt,1H）,9.23（d,1H） 元素分析値：（C24H29N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 68.05 6.90 9.92 実測値 68.36 6.96 9.84 （２）３−シアノ−N,N−ジエルチ−２−メチルチオ−4
H−キノリジン−４−オン−１−カルボキサミド 融点:170.5〜171.5℃ IR（KBr）:2210,1660,1620cm-1 NMR（DMSO-d6） δ:1.07（t,3H）,1.36（t,3H）,2.78（s,3H）,3.30（q,
2H）,3.68（m,2H）,7.60〜7.71（m,2H）,8.16（dt,1
H）,9.28（d,1H） 元素分析値：（C16H17N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 60.93 5.43 13.32 実測値 60.85 5.49 13.00 （３）３−シアノ−N,N−ジイソプロピル−２−メチル
チオ−4H−キノリジン−４−オン−１−カルボキサミド 融点:241〜242.5℃ IR（KBr）:2210,1660,1620cm-1 NMR（CDCl3） δ:1.03（d,3H）,1.28（d,3H）,1.63（d,3H）,1.66（d,
3H）,2.79（s,3H）,3.55〜3.71（m,2H）,7.25（dt,1
H）,7.53（d,1H）,7.70（dt,1H）,9.23（d,1H） 元素分析値：（C18H21N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 62.95 6.16 12.23 実測値 62.77 6.16 11.96 （４）３−シアノ−N,N−ジイソブチル−２−メチルチ
オ−4H−キノリジン−４−オン−１−カルボキシサミド 融点:167℃ IR（KBr）:2200,1660,1610cm-1 NMR（CDCl3） δ:0.61（d,3H）,0.80（d,3H）,1.06（d,3H）,1.07（d,
3H）,1.75（s,1H）,2.22（m,1H）,2.91（dd,1H）,2.76
（m,3H）,3.00〜3.13（m,2H）,3.87（dd,1H）,7.28（d
d,1H）,7.59（d,1H）,7.71（dt,1H）,9.25（d,1H） 元素分析値：（C20H25N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 64.66 6.78 11.31 実測値 64.54 6.80 11.28 （５）３−シアノ−N,N−ジヘキシル−２−メチルチオ
−4H−キノリジン−４−オン−１−カルボキサミド 融点:94〜95℃ IR（KBr）:2210,1665,1625cm-1 NMR（CDCl3） δ:0.73（t,3H）,0.93（t,3H）,1.00〜1.83（m,16H）,
2.77（s,3H）,3.10（t,2H）,3.43（m,1H）,3.74（m,1
H）,7.29（dd,1H）,7.52（d,1H）,7.70（dt,1H）,9.24
（d,1H） 元素分析値：（C24H33N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 67.41 7.78 9.83 実測値 66.85 8.00 9.71 （６）Ｎ−ベンジル−３−シアノ−Ｎ−メチル−２−メ
チルチオ−4H−キノリジン−４−オン−１−カルボキサ
ミド 融点:191〜193℃ IR（KBr）:2210,1680,1625cm-1 NMR（CDCl3） δ:2.77（t,3H）,2.80（s,3H）,4.82（d,1H）,4.88（d,
1H）,7.20〜7,53（m,7H）,7.69（dt,1H）,9.24（d,1H） 元素分析値：（C20H17N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 66.10 4.71 11.56 実測値 65.83 4.59 11.10 （７）３−シアノ−２−メチルチオ−Ｎ−フェニル−Ｎ
−（２−フェニルアミノエチル）−4H−キノリジン−４
−オン−１−カルボキサミド 融点:65〜75℃ IR（KBr）:2200,1660,1620cm-1 NMR（CDCl3） δ:2.69（s,3H）,3.45（m,2H）,3.93（dt,1H）,4.62
（m,1H）,6.66（d,2H）,6.78（t,1H）,7.04〜7.25（m,9
H）,7.57（dt,1H）,7.82（d,1H）,9.07（d,1H） 元素分析値：（C26H22N4O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 68.70 4.88 12.33 実測値 68.50 4.77 12.11 （８）Ｎ−ベンジル−３−シアノ−Ｎ−イソプロピル−
２−メチルチオ−4H−キノリジン−４−オン−１−カル
ボキサミド 融点:220〜223℃ IR（KBr）:2210,1675,1620cm-1 NMR（CDCl3） δ:1.01（d,3H）,1.22（d,3H）,2.78（s,3H）,3.86（m,
1H）,4.72（d,1H）,4.87（d,1H）,7.24〜7.60（m,7H）,
7.68（dt,1H）,9.25（d,1H） 元素分析値：（C22H21N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 67.50 5.41 10.73 実測値 67.17 5.29 10.55 （９）３−シアノ−Ｎ−シクロヘキシル−Ｎ−イソプロ
ピル−２−メイルチオ−4H−キノリジン−４−オン−１
−カルボキサミド 融点:204〜206℃ IR（KBr）:2210,1665,1625cm-1 NMR（CDCl3） δ:0.85〜2.10（m,16H）,2.78（s,3H）,3.11（m,1H）,
3.67（m,1H）,7.25（m,1H）,7.53（d,1H）,7.69（m,1
H）,9.23（dd,1H） 元素分析値：（C21H25N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 65.77 6.57 10.96 実測値 65.40 6.43 10.75 （10）Ｎ−アリル−３−シアノ−Ｎ−シクロヘキシル−
２−メチルチオ−4H−キノリジン−４−オン−１−カル
ボキサミド 融点:189〜191℃ IR（KBr）:2200,1670,1620cm-1 NMR（CDCl3） δ:0.85〜2.06（m,10H）,2.77（s,3H）,3.25and3.73
（m,1H）,4.17and4.55（m,2H）,4.67and5.40（d,1H）,
4.77and5.25（d,1H）,5.50and6.07（m,1H）,7.25（m,1
H）,7.50（m,1H）,7.70（m,1H）,9.23（t,1H） 元素分析値：（C21H23N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 66.12 6.08 11.01 実測値 65.81 6.08 10.80 （11）３−シアノ−２−メチルチオ−Ｎ−（３−フェニ
ルプロピル）−4H−キノリジン−４−オン−１−カルボ
キサミド 融点:169.5〜171℃ IR（KBr）:3280,2210,1660,1640,1625cm-1 NMR（CDCl3） δ:2.06（m,2H）,2.66（s,3H）,2.83（t,2H）,3.59（q,
2H）,6.77（br,1H）,7.17〜7.36（m,6H）,7.72〜7.87
（m,2H）,9.21（d,1H） 元素分析値：（C21H19N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 66.51 4.99 11.13 実測値 66.82 5.07 11.13 （12）３−シアノ−Ｎ−シクロヘキシル−２−メチルチ
オ−4H−キノリジン−４−オン−１−カルボキサミド 融点:245〜248℃ IR（KBr）:3280,2210,1650,1620cm-1 NMR（DMSO-d6） δ:1.20〜2.10（m,10H）,2.77（s,3H）,3.93（m,1H）,
7.67（dt,1H）,7.81（d,1H）,8.16（dt,1H）,8.62（d,1
H）,9.28（d,1H） 元素分析値：（C18H19N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 63.32 5.61 12.31 実測値 63.40 5.58 12.16 （13）Ｎ−ベンジル−３−シアノ−２−メチルチオ−4H
−キノリジン−４−オン−１−カルボキサミド 融点:219〜221℃ IR（KBr）:3325,2210,1660,1640,1620cm-1 NMR（CDCl3） δ:2.59（s,3H）,4.74（d,2H）,7.16〜7.51（m,7H）,7.
72〜7.86（m,2H）,9.12（d,1H） 元素分析値：（C19H15N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 65.31 4.33 12.03 実測値 65.25 4.17 11.49 （14）Ｎ−（４−アニリノフェニル）−３−シアノ−２
−メチルチオ−4H−キノリジン−オン−１−カルボキサ
ミド 融点:300℃以上 IR（KBr）:3350,3250,2210,1660,1645,1625cm-1 NMR（DMSO-d6） δ:2.68（s,3H）,6.79（t,1H）,7.02〜7.27（m,6H）,7.
55〜7.64（m,3H）,7.81（d,1H）,8.06（dt,1H）,8.13
（brs,1H）,9.21（d,1H）,10.05（brs,1H） 元素分析値：（C24H18N4O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 67.59 4.25 13.14 実測値 67.58 4.11 12.97 （15）３−シアノ−２−メチルチオ−Ｎ−（４−フェニ
ル−２−チアゾリル）4H−キノリジン−４−オン−１−
カルボキサミド 融点:183〜185℃ IR（KBr）:3420,2210,1660,1625cm-1 NMR（CDCl3） δ:2.50（s,3H）,6.79〜7.70（m,9H）,8.92（d,1H）,1
3.16（br,1H） 元素分析値：（C21H14N4O2S2として） Ｃ％ Ｈ％ Ｎ％ 計算値 60.27 3.37 13.39 実測値 59.50 3.12 12.96 （16）３−シアノ−２−メチルチオ−Ｎ−（1,2,3,4−
テトラヒドロ−２−ナフチル）−4H−キノリジン−４−
オン−１−カルボキサミド 融点:248〜250℃ IR（KBr）:2210,1665,1625cm-1 NMR（DMSO-d6） δ:1.72〜2.14（m,4H）,2.67（s,3H）,2.75（m,2H）,5.
23（q,1H）,7.07〜7.24（m,3H）,7.48（d,1H）,7.57
（t,1H）,7.81（d,1H）,8.09（dt,1H）,8.95（d,1H）,
9.28（d,1H） 元素分析値：（C22H19N3O2Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 67.85 4.92 10.79 実測値 67.96 4.91 10.65 （17）３−シアノ−Ｎ−（４−メトキシカルボニルベン
ジル）−２−メチルチオ−4H−キノリジン−４−オン−
１−カルボキサミド 融点:206℃ IR（KBr）:3250,2200,1715,1650,1620cm-1 NMR（CDCl3） δ:2.58（s,3H）,3.93（s,3H）,4.80（d,2H）,7.33（m,
1H）,7.45（br,1H）,7.58（d,2H）,7.71（m,2H）,8.08
（d,2H）,9.14（d,1H） 元素分析値：（C21H17N3O4Sとして） Ｃ％ Ｈ％ Ｎ％ 計算値 61.90 4.21 10.31 実測値 61.44 4.09 10.25(1) 3-Cyano-N, N-dicyclohexyl-2-methylthio-4H-quinolidin-4-one-1-carboxamide Melting point: 268 to 271 ° C IR (KBr): 2210,1660,1620cm -1 NMR (CDCl 3 ) Δ: 0.83 to 2.07 (m, 18H), 2.60 to 2.88 (m, 2H), 2.77 (s,
3H), 3.16 (m, 2H), 7.24 (dd, 1H), 7.54 (d, 1H), 7.68
(Dt, 1H), 9.23 (d, 1H) Elemental analysis value: (as C 24 H 29 N 3 O 2 S) C% H% N% Calculated value 68.05 6.90 9.92 Measured value 68.36 6.96 9.84 (2) 3-cyano -N, N-Dierti-2-methylthio-4
H-quinolidin-4-one-1-carboxamide Melting point: 170.5 to 171.5 ° C IR (KBr): 2210, 1660, 1620 cm -1 NMR (DMSO-d 6 ) δ: 1.07 (t, 3H), 1.36 (t, 3H ), 2.78 (s, 3H), 3.30 (q,
2H), 3.68 (m, 2H), 7.60 to 7.71 (m, 2H), 8.16 (dt, 1
H), 9.28 (d, 1H) Elemental analysis value: (as C 16 H 17 N 3 O 2 S) C% H% N% Calculated value 60.93 5.43 13.32 Measured value 60.85 5.49 13.00 (3) 3-Cyano-N, N-diisopropyl-2-methylthio-4H-quinolidin-4-one-1-carboxamide Melting point: 241 to 242.5 ° C IR (KBr): 2210, 1660, 1620 cm -1 NMR (CDCl 3 ) δ: 1.03 (d, 3H) , 1.28 (d, 3H), 1.63 (d, 3H), 1.66 (d,
3H), 2.79 (s, 3H), 3.55 to 3.71 (m, 2H), 7.25 (dt, 1
H), 7.53 (d, 1H), 7.70 (dt, 1H), 9.23 (d, 1H) Elemental analysis value: (as C 18 H 21 N 3 O 2 S) C% H% N% Calculated value 62.95 6.16 12.23 Found 62.77 6.16 11.96 (4) 3-cyano -N, N-diisobutyl-2-methylthio -4H- quinolizin-4-one-1-Karubokishisamido mp: 167 ℃ IR (KBr): 2200,1660,1610cm - 1 NMR (CDCl 3 ) δ: 0.61 (d, 3H), 0.80 (d, 3H), 1.06 (d, 3H), 1.07 (d,
3H), 1.75 (s, 1H), 2.22 (m, 1H), 2.91 (dd, 1H), 2.76
(M, 3H), 3.00 to 3.13 (m, 2H), 3.87 (dd, 1H), 7.28 (d
d, 1H), 7.59 (d , 1H), 7.71 (dt, 1H), 9.25 (d, 1H) Elemental analysis: (as C 20 H 25 N 3 O 2 S) C% H% N% Calculated 64.66 6.78 11.31 Found 64.54 6.80 11.28 (5) 3-Cyano-N, N-dihexyl-2-methylthio-4H-quinolidin-4-one-1-carboxamide Melting point: 94-95 ° C IR (KBr): 2210,1665, 1625 cm -1 NMR (CDCl 3 ) δ: 0.73 (t, 3H), 0.93 (t, 3H), 1.00 to 1.83 (m, 16H),
2.77 (s, 3H), 3.10 (t, 2H), 3.43 (m, 1H), 3.74 (m, 1
H), 7.29 (dd, 1H), 7.52 (d, 1H), 7.70 (dt, 1H), 9.24
(D, 1H) Elemental analysis value: (as C 24 H 33 N 3 O 2 S) C% H% N% Calculated value 67.41 7.78 9.83 Measured value 66.85 8.00 9.71 (6) N-benzyl-3-cyano-N- Methyl-2-methylthio-4H-quinolidin-4-one-1-carboxamide Melting point: 191-193 ° C IR (KBr): 2210, 1680, 1625 cm -1 NMR (CDCl 3 ) δ: 2.77 (t, 3H), 2.80 (S, 3H), 4.82 (d, 1H), 4.88 (d,
1H), 7.20~7,53 (m, 7H ), 7.69 (dt, 1H), 9.24 (d, 1H) Elemental analysis: (as C 20 H 17 N 3 O 2 S) C% H% N% calculated Value 66.10 4.71 11.56 Found 65.83 4.59 11.10 (7) 3-Cyano-2-methylthio-N-phenyl-N
-(2-Phenylaminoethyl) -4H-quinolidine-4
-On-1-carboxamide Melting point: 65 to 75 ° C IR (KBr): 2200, 1660, 1620 cm -1 NMR (CDCl 3 ) δ: 2.69 (s, 3H), 3.45 (m, 2H), 3.93 (dt, 1H ), 4.62
(M, 1H), 6.66 (d, 2H), 6.78 (t, 1H), 7.04 to 7.25 (m, 9
H), 7.57 (dt, 1H), 7.82 (d, 1H), 9.07 (d, 1H) Elemental analysis value: (as C 26 H 22 N 4 O 2 S) C% H% N% Calculated value 68.70 4.88 12.33 Found 68.50 4.77 12.11 (8) N-benzyl-3-cyano-N-isopropyl-
2-Methylthio-4H-quinolidin-4-one-1-carboxamide Melting point: 220-223 ° C IR (KBr): 2210, 1675, 1620 cm -1 NMR (CDCl 3 ) δ: 1.01 (d, 3H), 1.22 (d , 3H), 2.78 (s, 3H), 3.86 (m,
1H), 4.72 (d, 1H), 4.87 (d, 1H), 7.24 ~ 7.60 (m, 7H),
7.68 (dt, 1H), 9.25 (d, 1H) Elemental analysis: (C 22 H 21 N 3 O as 2 S) C% H% N % Calculated 67.50 5.41 10.73 Found 67.17 5.29 10.55 (9) 3- Cyano-N-cyclohexyl-N-isopropyl-2-mailthio-4H-quinolizin-4-one-1
-Carboxamide Melting point: 204 to 206 ° C IR (KBr): 2210, 1665, 1625 cm -1 NMR (CDCl 3 ) δ: 0.85 to 2.10 (m, 16H), 2.78 (s, 3H), 3.11 (m, 1H),
3.67 (m, 1H), 7.25 (m, 1H), 7.53 (d, 1H), 7.69 (m, 1
H), 9.23 (dd, 1H) Elemental analysis value: (as C 21 H 25 N 3 O 2 S) C% H% N% Calculated value 65.77 6.57 10.96 Measured value 65.40 6.43 10.75 (10) N-allyl-3- Cyano-N-cyclohexyl-
2-Methylthio-4H-quinolidin-4-one-1-carboxamide Melting point: 189 to 191 ° C IR (KBr): 2200, 1670, 1620 cm -1 NMR (CDCl 3 ) δ: 0.85 to 2.06 (m, 10H), 2.77 (S, 3H), 3.25and3.73
(M, 1H), 4.17and4.55 (m, 2H), 4.67and5.40 (d, 1H),
4.77and5.25 (d, 1H), 5.50and6.07 (m, 1H), 7.25 (m, 1
H), 7.50 (m, 1H), 7.70 (m, 1H), 9.23 (t, 1H) Elemental analysis value: (as C 21 H 23 N 3 O 2 S) C% H% N% Calculated value 66.12 6.08 11.01 Found 65.81 6.08 10.80 (11) 3-Cyano-2-methylthio-N- (3-phenylpropyl) -4H-quinolidin-4-one-1-carboxamide Melting point: 169.5-171 ° C IR (KBr): 3280,2210 , 1660,1640,1625cm -1 NMR (CDCl 3 ) δ: 2.06 (m, 2H), 2.66 (s, 3H), 2.83 (t, 2H), 3.59 (q,
2H), 6.77 (br, 1H), 7.17 ~ 7.36 (m, 6H), 7.72 ~ 7.87
(M, 2H), 9.21 (d, 1H) Elemental analysis value: (as C 21 H 19 N 3 O 2 S) C% H% N% Calculated value 66.51 4.99 11.13 Measured value 66.82 5.07 11.13 (12) 3-cyano -N-cyclohexyl-2-methylthio-4H-quinolidin-4-one-1-carboxamide Melting point: 245 to 248 ° C IR (KBr): 3280, 2210, 1650, 1620 cm -1 NMR (DMSO-d 6 ) δ: 1.20 ~ 2.10 (m, 10H), 2.77 (s, 3H), 3.93 (m, 1H),
7.67 (dt, 1H), 7.81 (d, 1H), 8.16 (dt, 1H), 8.62 (d, 1
H), 9.28 (d, 1H) Elemental analysis value: (as C 18 H 19 N 3 O 2 S) C% H% N% Calculated value 63.32 5.61 12.31 Actual value 63.40 5.58 12.16 (13) N-benzyl-3- Cyano-2-methylthio-4H
-Quinolidin-4-one-1-carboxamide Melting point: 219 to 221 ° C IR (KBr): 3325,2210,1660,1640,1620cm -1 NMR (CDCl 3 ) δ: 2.59 (s, 3H), 4.74 (d, 2H), 7.16 to 7.51 (m, 7H), 7.
72〜7.86 (m, 2H), 9.12 (d, 1H) Elemental analysis value: (as C 19 H 15 N 3 O 2 S) C% H% N% Calculated value 65.31 4.33 12.03 Measured value 65.25 4.17 11.49 (14) N- (4-anilinophenyl) -3-cyano-2
-Methylthio-4H-quinolidin-one-1-carboxamide Melting point: 300 ° C or higher IR (KBr): 3350, 3250, 2210, 1660, 1645, 1625 cm -1 NMR (DMSO-d 6 ) δ: 2.68 (s, 3H) , 6.79 (t, 1H), 7.02 to 7.27 (m, 6H), 7.
55 ~ 7.64 (m, 3H), 7.81 (d, 1H), 8.06 (dt, 1H), 8.13
(Brs, 1H), 9.21 (d, 1H), 10.05 (brs, 1H) Elemental analysis value: (as C 24 H 18 N 4 O 2 S) C% H% N% Calculated value 67.59 4.25 13.14 Measured value 67.58 4.11 12.97 (15) 3-Cyano-2-methylthio-N- (4-phenyl-2-thiazolyl) 4H-quinolizin-4-one-1-
Carboxamide Melting point: 183-185 ° C IR (KBr): 3420, 2210, 1660, 1625cm -1 NMR (CDCl 3 ) δ: 2.50 (s, 3H), 6.79 to 7.70 (m, 9H), 8.92 (d, 1H) , 1
3.16 (br, 1H) Elemental analysis value: (as C 21 H 14 N 4 O 2 S 2 ) C% H% N% Calculated value 60.27 3.37 13.39 Measured value 59.50 3.12 12.96 (16) 3-Cyano-2-methylthio- N- (1,2,3,4-
Tetrahydro-2-naphthyl) -4H-quinolizine-4-
On-1-carboxamide Melting point: 248 to 250 ° C. IR (KBr): 2210, 1665, 1625 cm −1 NMR (DMSO-d 6 ) δ: 1.72 to 2.14 (m, 4H), 2.67 (s, 3H), 2.75 ( m, 2H), 5.
23 (q, 1H), 7.07 to 7.24 (m, 3H), 7.48 (d, 1H), 7.57
(T, 1H), 7.81 (d, 1H), 8.09 (dt, 1H), 8.95 (d, 1H),
9.28 (d, 1H) Elemental analysis value: (as C 22 H 19 N 3 O 2 S) C% H% N% Calculated value 67.85 4.92 10.79 Measured value 67.96 4.91 10.65 (17) 3-Cyano-N- (4- Methoxycarbonylbenzyl) -2-methylthio-4H-quinolizin-4-one-
1-carboxamide Melting point: 206 ° C IR (KBr): 3250, 2200, 1715, 1650, 1620cm -1 NMR (CDCl 3 ) δ: 2.58 (s, 3H), 3.93 (s, 3H), 4.80 (d, 2H) , 7.33 (m,
1H), 7.45 (br, 1H), 7.58 (d, 2H), 7.71 (m, 2H), 8.08
(D, 2H), 9.14 (d, 1H) Elemental analysis value: (as C 21 H 17 N 3 O 4 S) C% H% N% Calculated value 61.90 4.21 10.31 Measured value 61.44 4.09 10.25
Claims (7)
れぞれ水素原子、置換基を有することもある低級アルキ
ル基または低級アルケニル基、置換基を有することもあ
る脂環状基、アリール基または異項環基であり、R3は低
級アルキル基である）で表される4H−キノリジン−４−
オン誘導体。1. A general formula (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom, a lower alkyl group or a lower alkenyl group which may have a substituent, an alicyclic group which may have a substituent, an aryl group. Or a heterocyclic group and R 3 is a lower alkyl group) 4H-quinolizin-4-
On derivative.
れぞれ水素原子、置換基を有することもある低級アルキ
ル基または低級アルケニル基、置換基を有することもあ
る脂環状基、アリール基または異項環基である）で表さ
れる特許請求の範囲第１項記載の4H−キノリジン−４−
オン誘導体。2. General formula (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom, a lower alkyl group or a lower alkenyl group which may have a substituent, an alicyclic group which may have a substituent, an aryl group. Or a heterocyclic group), 4H-quinolidine-4-, according to claim 1.
On derivative.
−４−オン誘導体。3. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by
−４−オン誘導体。4. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by
−４−オン誘導体。5. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by
−４−オン誘導体。6. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by
−４−オン誘導体。7. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3060387A JPH0670040B2 (en) | 1987-02-12 | 1987-02-12 | 4H-quinolidin-4-one derivative |
| US07/147,549 US4877795A (en) | 1987-01-30 | 1988-01-25 | 4H-quinolizin-4-one compounds useful for the treatment of allergic bronchial asthma, allergic rhinitis atropic dermatitis and the like |
| EP88300660A EP0277755A1 (en) | 1987-01-30 | 1988-01-27 | 4H-quinolizin-4-one compounds exhibiting therapeutic activities |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3060387A JPH0670040B2 (en) | 1987-02-12 | 1987-02-12 | 4H-quinolidin-4-one derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63198680A JPS63198680A (en) | 1988-08-17 |
| JPH0670040B2 true JPH0670040B2 (en) | 1994-09-07 |
Family
ID=12308444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3060387A Expired - Lifetime JPH0670040B2 (en) | 1987-01-30 | 1987-02-12 | 4H-quinolidin-4-one derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0670040B2 (en) |
-
1987
- 1987-02-12 JP JP3060387A patent/JPH0670040B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63198680A (en) | 1988-08-17 |
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