JPH06298732A - Indole derivative - Google Patents
Indole derivativeInfo
- Publication number
- JPH06298732A JPH06298732A JP6017950A JP1795094A JPH06298732A JP H06298732 A JPH06298732 A JP H06298732A JP 6017950 A JP6017950 A JP 6017950A JP 1795094 A JP1795094 A JP 1795094A JP H06298732 A JPH06298732 A JP H06298732A
- Authority
- JP
- Japan
- Prior art keywords
- group
- indole
- dementia
- formula
- carboxanilide
- 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
- 150000002475 indoles Chemical class 0.000 title claims abstract 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000001713 cholinergic effect Effects 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 7
- 239000012442 inert solvent Substances 0.000 abstract description 7
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 abstract description 6
- 206010012289 Dementia Diseases 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 206010008118 cerebral infarction Diseases 0.000 abstract description 4
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 3
- 239000012320 chlorinating reagent Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- ULIIRFTUEBBSPU-UHFFFAOYSA-N n-(2-chlorophenyl)-n-methyl-1h-indole-2-carboxamide Chemical compound C=1C2=CC=CC=C2NC=1C(=O)N(C)C1=CC=CC=C1Cl ULIIRFTUEBBSPU-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- GUMVEYKDOAQLGN-UHFFFAOYSA-N 1h-indole-2-carbonyl chloride Chemical compound C1=CC=C2NC(C(=O)Cl)=CC2=C1 GUMVEYKDOAQLGN-UHFFFAOYSA-N 0.000 abstract description 2
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 abstract description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 2
- 208000023105 Huntington disease Diseases 0.000 abstract description 2
- 206010026749 Mania Diseases 0.000 abstract description 2
- 238000009835 boiling Methods 0.000 abstract description 2
- 208000013677 cerebrovascular dementia Diseases 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 206010043118 Tardive Dyskinesia Diseases 0.000 abstract 1
- 230000032683 aging Effects 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- -1 t-butoxy group Chemical group 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 210000005036 nerve Anatomy 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 3
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 210000000653 nervous system Anatomy 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 description 2
- WGNNILPYHCKCFF-UHFFFAOYSA-N 2-chloro-n-methylaniline Chemical compound CNC1=CC=CC=C1Cl WGNNILPYHCKCFF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- PWBZRPGDHRHWLR-UHFFFAOYSA-N n-(3-chlorophenyl)-n-methyl-1h-indole-2-carboxamide Chemical compound C=1C2=CC=CC=C2NC=1C(=O)N(C)C1=CC=CC(Cl)=C1 PWBZRPGDHRHWLR-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- ZCEKHRLLGYTRRN-UHFFFAOYSA-N n-(4-methylphenyl)-1h-indole-2-carboxamide Chemical compound C1=CC(C)=CC=C1NC(=O)C1=CC2=CC=CC=C2N1 ZCEKHRLLGYTRRN-UHFFFAOYSA-N 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 108010056851 pirenzepine receptor Proteins 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 108091006084 receptor activators Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、コリン作動性神経不全
の改善作用を有するインドール−２−カルボキサミド誘
導体に関する。TECHNICAL FIELD The present invention relates to an indole-2-carboxamide derivative having an action of improving cholinergic nerve failure.
【０００２】[0002]
【従来の技術】近年、アルツハイマー病やアルツハイマ
ー型老年痴呆が大きな問題となっているが、これらの疾
患はコリン作動性神経の変性、脱落と深く関わりあって
いることが知られている［ホワイトハウス，Ｐ．Ｊ．
ら，サイエンス，第２１５巻，第１２３７ページ（１９
８２年）など］。2. Description of the Related Art Recently, Alzheimer's disease and senile dementia of the Alzheimer's type have become major problems. It is known that these diseases are deeply associated with degeneration and loss of cholinergic nerves [White House , P .; J.
Et al., Science, Volume 215, Page 1237 (19
1982) etc.].
【０００３】コリン作動性神経の記憶への関与は、アセ
チルコリン系拮抗剤をヒトに投与すると、記憶障害が惹
起されることからも示される。従って、コリン作動性神
経系の賦活薬が、アルツハイマー病をはじめとする種々
の痴呆症の治療薬となり得る。コリン作動性神経系の賦
活薬としては、アセチルコリンエステラーゼ阻害剤の
他、ムスカリン性アセチルコリンレセプターを直接刺激
するムスカリン性アゴニストなどがある。ムスカリン性
アセチルコリンレセプターは、Ｍ１型、Ｍ２型の２つの
サブタイプからなり、Ｍ１型は主に中枢神経系に、Ｍ２
型は主に末梢組織に分布している。Ｍ２型レセプター賦
活薬では副作用につながる可能性が大きいため、Ｍ１型
選択性の高い化合物が有用なコリン作動性神経系の賦活
薬となり得る。The involvement of cholinergic nerves in memory is also shown by the fact that administration of acetylcholine antagonists to humans causes memory impairment. Therefore, a cholinergic nervous system activator can be a therapeutic agent for various dementia including Alzheimer's disease. Examples of the cholinergic nervous system activator include an acetylcholinesterase inhibitor and a muscarinic agonist that directly stimulates a muscarinic acetylcholine receptor. The muscarinic acetylcholine receptor is composed of two subtypes, M1 type and M2 type, and the M1 type is mainly in the central nervous system and M2.
The type is mainly distributed in peripheral tissues. Since M2 type receptor activators are highly likely to cause side effects, compounds having high M1 type selectivity can be useful cholinergic nervous system activators.
【０００４】[0004]
【発明が解決しようとする課題】本発明の目的は、コリ
ン作動性神経不全に対して優れた効果を有し、かつ安全
性の高い新しい化合物を提供することにある。An object of the present invention is to provide a novel compound having an excellent effect on cholinergic neuropathy and having high safety.
【０００５】[0005]
【課題を解決するための手段】本発明者らは、前記課題
を解決すべく、鋭意研究を進めた結果、ある種のインド
ール−２−カルボキサミド誘導体がＭ１型レセプターに
対し、強い親和性と良好な選択性を示すことを見いだ
し、本発明を完成した。Means for Solving the Problems As a result of intensive research aimed at solving the above problems, the present inventors have found that certain indole-2-carboxamide derivatives have a strong affinity and a good affinity for M1 type receptors. The present invention has been completed by discovering that it exhibits high selectivity.
【０００６】本発明は、式The present invention has the formula
【０００７】 [0007]
【０００８】（式中、Ｒ1はアルキル基を示し、Ｒ2は
「低級アルキル基、低級アルコキシ基、低級アルカノイ
ル基、ハロゲン原子またはニトロ基」から選ばれる基の
１〜３個で置換されたフェニル基を示す。）で表される
インドール誘導体である。(In the formula, R 1 represents an alkyl group, and R 2 is substituted with 1 to 3 groups selected from "lower alkyl group, lower alkoxy group, lower alkanoyl group, halogen atom or nitro group". A phenyl group is shown).
【０００９】本発明において、アルキル基とは炭素原子
数１〜１０、好ましくは炭素原子数１〜５の直鎖または
分枝鎖状のアルキル基であり、たとえばメチル基、エチ
ル基、プロピル基、イソプロピル基、ブチル基、イソブ
チル基、ｔ−ブチル基、オクチル基、デシル基などであ
る。低級アルキル基とは炭素原子数１〜４の直鎖または
分枝鎖状のアルキル基であり、たとえばメチル基、エチ
ル基、プロピル基、イソプロピル基、ブチル基、イソブ
チル基、ｔ−ブチル基などである。低級アルコキシ基と
は炭素原子数１〜４の直鎖または分枝状のアルコキシ基
であり、たとえばメトキシ基、エトキシ基、プロポキシ
基、イソプロポキシ基、ブトキシ基、ｔ−ブトキシ基で
ある。低級アルカノイル基とは炭素原子数２〜５の直鎖
または分枝鎖状のアルカノイル基であり、たとえばアセ
チル基、プロピオニル基、ブチリル基などである。In the present invention, the alkyl group is a linear or branched alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, such as methyl group, ethyl group, propyl group, Examples thereof include isopropyl group, butyl group, isobutyl group, t-butyl group, octyl group and decyl group. The lower alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a t-butyl group. is there. The lower alkoxy group is a linear or branched alkoxy group having 1 to 4 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group and a t-butoxy group. The lower alkanoyl group is a linear or branched alkanoyl group having 2 to 5 carbon atoms, and examples thereof include an acetyl group, a propionyl group and a butyryl group.
【００１０】本発明の化合物は、たとえば下記に示す方
法に従って製造することができる。すなわち、まず、イ
ンドール−２−カルボン酸をクロル化剤と不活性溶媒
中、溶媒の沸点で反応させることによりインドール−２
−カルボン酸クロリドとする。ここで、クロル化剤と
は、塩化チオニル、オキシ塩化リン、五塩化リンなどで
ある。また、不活性溶媒とは、ジクロロエタン、クロロ
ホルム、四塩化炭素、ベンゼン、トルエン、キシレン、
Ｎ，Ｎ−ジメチルホルムアミドなどであり、これらを単
独でまたは混合しても用いることができる。The compound of the present invention can be produced, for example, according to the method shown below. That is, first, indole-2-carboxylic acid is reacted with a chlorinating agent in an inert solvent at the boiling point of the solvent to give indole-2.
-As carboxylic acid chloride. Here, the chlorinating agent is thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like. Further, the inert solvent, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene,
N, N-dimethylformamide and the like, which can be used alone or in combination.
【００１１】次に、インドール−２−カルボン酸クロリ
ドと、式Next, the indole-2-carboxylic acid chloride and the formula
【００１２】 [0012]
【００１３】（式中、Ｒ1およびＲ2は前記と同意義であ
る。）で表される化合物を不活性溶媒中、反応させるこ
とにより、本発明の化合物を製造することができる。不
活性溶媒には、前記クロル化の反応における不活性溶媒
の例示と同じものを用いることができる。The compound of the present invention can be produced by reacting the compound represented by the formula (wherein R 1 and R 2 are as defined above) in an inert solvent. As the inert solvent, the same ones as the examples of the inert solvent in the chlorination reaction can be used.
【００１４】[0014]
【発明の効果】本発明により、コリン作動性神経の不全
に伴う疾患、たとえば、アルツハイマー病、アルツハイ
マー型老年痴呆、ハンチントン舞踏病、晩発性運動障
害、躁病などの改善・治療に優れた薬剤を提供すること
が可能となった。また、脳虚血、脳硬塞、脳出血などの
脳血管障害に起因した痴呆（脳血管性痴呆）、精神障
害、加齢に伴う記憶障害、パーキンソン病に伴う痴呆症
などにもコリン作動性神経の不全が起こっている場合が
多いので、これらの疾患の改善・治療も期待できる。INDUSTRIAL APPLICABILITY According to the present invention, a drug excellent in the improvement and treatment of diseases associated with cholinergic nerve deficiency, such as Alzheimer's disease, Alzheimer's dementia of the elderly, Huntington's chorea, late movement disorder, and mania. It is now possible to provide. Also, dementia due to cerebrovascular disorders such as cerebral ischemia, cerebral infarction, and cerebral hemorrhage (cerebrovascular dementia), mental disorders, memory disorders with age, dementia with Parkinson's disease, etc. Since there are many cases where symptoms occur, improvement / treatment of these diseases can be expected.
【００１５】[0015]
【実施例】以下、実施例および試験例を挙げて本発明を
更に詳細に説明する。 実施例 ２’−クロル−Ｎ−メチルインドール−２−カルボキサ
ニリドの製造 インドール−２−カルボン酸０．５ｇ、塩化チオニル
０．６８ｍｌおよびベンゼン１０ｍｌ、さらにＮ，Ｎ−
ジメチルホルムアミド（ＤＭＦ）を触媒量加え、２０分
加熱還流した。この反応液を減圧下濃縮し、残渣をＤＭ
Ｆ２０ｍｌに溶解した。この中に、２−クロル−Ｎ−メ
チルアニリンを加え、室温にて２時間攪拌た。反応液を
水に注ぎ、析出した結晶を濾取し、残渣をエタノールよ
り再結晶して無色プリズム晶０．４３ｇを得た。 ｍ．ｐ．２１１〜２１２℃EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples. Example 2 Production of 2'-chloro-N-methylindole-2-carboxanilide 0.5 g of indole-2-carboxylic acid, 0.68 ml of thionyl chloride and 10 ml of benzene, and further N, N-.
Dimethylformamide (DMF) was added in a catalytic amount, and the mixture was heated under reflux for 20 minutes. This reaction solution was concentrated under reduced pressure, and the residue was DM
It was dissolved in 20 ml of F. 2-Chloro-N-methylaniline was added thereto and stirred at room temperature for 2 hours. The reaction solution was poured into water, the precipitated crystals were collected by filtration, and the residue was recrystallized from ethanol to obtain 0.43 g of colorless prism crystals. m. p. 211-212 ° C
【００１６】２−クロル−Ｎ−メチルアニリンの代わり
に対応するアミン類を用い、同様な方法により以下の化
合物を製造した。ただし、かっこ内は再結晶溶媒を示
す。 ３’−クロル−Ｎ−メチルインドール−２−カルボキサ
ニリド ｍ．ｐ．１９５〜１９８℃（エタノール） ４’−クロル−Ｎ−メチルインドール−２−カルボキサ
ニリド ｍ．ｐ．２１９〜２２２℃（エタノール） Ｎ−メチル−４’−ニトロインドール−２−カルボキサ
ニリド ｍ．ｐ．２２４〜２２７℃（エタノール） ３’−アセチル−Ｎ−メチルインドール−２−カルボキ
サニリド ｍ．ｐ．１７３〜１７５℃（エタノール） Ｎ−ｎ−プロピルインドール−２−カルボキサニリド ｍ．ｐ．１８１〜１８３℃（エタノール） ３’−フルオロ−Ｎ−メチルインドール−２−カルボキ
サニリド ｍ．ｐ．２０７〜２０８℃（エタノール） ３’−メトキシ−Ｎ−メチルインドール−２−カルボキ
サニリド ｍ．ｐ．２００〜２０２℃（エタノール） ３’−メチル−Ｎ−メチルインドール−２−カルボキサ
ニリド ｍ．ｐ．２１０〜２１２℃（エタノール） ２’−フルオロ−Ｎ−メチルインドール−２−カルボキ
サニリド ｍ．ｐ．２０５〜２０６℃（エタノール） ４’−フルオロ−Ｎ−メチルインドール−２−カルボキ
サニリド ｍ．ｐ．２２０〜２２１℃（エタノール） ２’，３’−ジフルオロ−Ｎ−メチルインドール−２−
カルボキサニリド ｍ．ｐ．２０２〜２０３℃（エタノール） ２’，４’−ジフルオロ−Ｎ−メチルインドール−２−
カルボキサニリド ｍ．ｐ．２１１〜２１２℃（エタノール） ２’，５’−ジフルオロ−Ｎ−メチルインドール−２−
カルボキサニリド ｍ．ｐ．１９９〜２００℃（エタノール） ３’，４’−ジフルオロ−Ｎ−メチルインドール−２−
カルボキサニリド ｍ．ｐ．２２１〜２２２℃（エタノール） ２’，３’，４’−トリフルオロ−Ｎ−メチルインドー
ル−２−カルボキサニリド ｍ．ｐ．２１０〜２１１℃（エタノール） ３’−フルオロ−Ｎ，４’−メチルインドール−２−カ
ルボキサニリド ｍ．ｐ．２１０〜２１１℃（エタノール） ３’−フルオロ−２’−メトキシ−Ｎ−メチルインドー
ル−２−カルボキサニリド ｍ．ｐ．１９９〜２００℃（エタノール） ３’−フルオロ−４’−メトキシ−Ｎ−メチルインドー
ル−２−カルボキサニリド ｍ．ｐ．２２２〜２２４℃（エタノール） Ｎ−エチル−３’−フルオロインドール−２−カルボキ
サニリド ｍ．ｐ．１６６〜１６７℃（エタノール） 試験例 ムスカリン性アセチルコリンレセプターへの結合性は、
フリードマン（Ｆｒｅｅｄｍａｎ）らの方法［Ｅｕｒ．
Ｊ．Ｐｈａｒｍａｃｏｌ．，第１５６巻，第１３３ペー
ジ（１９８８年）］を一部改変して測定した。The following compounds were prepared in a similar manner using the corresponding amines instead of 2-chloro-N-methylaniline. However, the recrystallization solvent is shown in the parentheses. 3'-chloro-N-methylindole-2-carboxanilide m. p. 195-198 ° C (ethanol) 4'-chloro-N-methylindole-2-carboxanilide m.p. p. 219-222 ° C (ethanol) N-methyl-4'-nitroindole-2-carboxanilide m.p. p. 224-227 ° C. (ethanol) 3′-acetyl-N-methylindole-2-carboxanilide m.p. p. 173-175 ° C (ethanol) N-n-propylindole-2-carboxanilide m.p. p. 181-183 [deg.] C. (ethanol) 3'-fluoro-N-methylindole-2-carboxanilide m.p. p. 207-208 ° C (ethanol) 3'-methoxy-N-methylindole-2-carboxanilide m.p. p. 200-202 ° C (ethanol) 3'-methyl-N-methylindole-2-carboxanilide m. p. 210-212 ° C. (ethanol) 2′-fluoro-N-methylindole-2-carboxanilide m.p. p. 205-206 ° C (ethanol) 4'-fluoro-N-methylindole-2-carboxanilide m.p. p. 220-221 ° C. (ethanol) 2 ′, 3′-difluoro-N-methylindole-2-
Carboxanilide m. p. 202-203 ° C (ethanol) 2 ', 4'-difluoro-N-methylindole-2-
Carboxanilide m. p. 211-212 ° C (ethanol) 2 ', 5'-difluoro-N-methylindole-2-
Carboxanilide m. p. 199-200 ° C (ethanol) 3 ', 4'-difluoro-N-methylindole-2-
Carboxanilide m. p. 221 to 222 ° C. (ethanol) 2 ′, 3 ′, 4′-trifluoro-N-methylindole-2-carboxanilide m.p. p. 210 to 211 ° C. (ethanol) 3′-fluoro-N, 4′-methylindole-2-carboxanilide m.p. p. 210-211 ° C (ethanol) 3'-fluoro-2'-methoxy-N-methylindole-2-carboxanilide m.p. p. 199-200 ° C. (ethanol) 3′-fluoro-4′-methoxy-N-methylindole-2-carboxanilide m.p. p. 222-224 ° C (ethanol) N-ethyl-3'-fluoroindole-2-carboxanilide m.p. p. 166-167 ° C (Ethanol) Test Example Binding to muscarinic acetylcholine receptor is
The method of Freedman et al. [Eur.
J. Pharmacol. , 156, 133 (1988)] with some modifications.
【００１７】すなわち、ラット大脳皮質シナプトソーム
膜画分（Ｍ１型レセプターに富む）を用いた［3Ｈ］−
ピレンゼピン−レセプター結合実験系にて、サンプルの
結合阻害率を測定し、Ｍ１結合性を求めた。That is, [ 3 H] -using rat cerebral cortex synaptosome membrane fraction (rich in M1 type receptor)
The pirenzepine-receptor binding experiment system was used to measure the binding inhibition rate of the sample to determine the M1 binding property.
【００１８】さらに、ラット心臓膜画分（Ｍ２型レセプ
ターに富む）を用いた［3Ｈ］−Ｎ−メチルスコポラミ
ン−レセプター結合実験系での結合阻害率からＭ２結合
性を求め、Ｍ２／Ｍ１結合性比を計算することにより、
Ｍ１選択性を評価した。Further, the M2 binding property was determined from the binding inhibition rate in a [ 3 H] -N-methylscopolamine-receptor binding experimental system using rat heart membrane fraction (rich in M2 type receptor), and M2 / M1 binding was determined. By calculating the sex ratio,
The M1 selectivity was evaluated.
【００１９】その結果を表１に示した。The results are shown in Table 1.
【００２０】[0020]
【表１】 [Table 1]
【００２１】（注） ａ；２’−クロル−Ｎ−メチルインドール−２−カルボ
キサニリド ｂ；３’−クロル−Ｎ−メチルインドール−２−カルボ
キサニリド(Note) a; 2'-chloro-N-methylindole-2-carboxanilide b; 3'-chloro-N-methylindole-2-carboxanilide
───────────────────────────────────────────────────── フロントページの続き (72)発明者 丸橋 正史 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 溝部 文夫 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 花田 和紀 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masafumi Maruhashi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Fumio Mizobe 3-24-1, Takada, Toshima-ku, Tokyo Taisho (72) Inventor Kazuki Hanada 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.
Claims (1)
基、低級アルコキシ基、低級アルカノイル基、ハロゲン
原子またはニトロ基」から選ばれる基の１〜３個で置換
されたフェニル基を示す。）で表されるインドール誘導
体。1. A formula (In the formula, R 1 represents an alkyl group, and R 2 represents a phenyl group substituted with 1 to 3 groups selected from “lower alkyl group, lower alkoxy group, lower alkanoyl group, halogen atom or nitro group”. Indole derivative represented by.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6017950A JPH06298732A (en) | 1993-02-16 | 1994-02-15 | Indole derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2659393 | 1993-02-16 | ||
| JP5-26593 | 1993-02-16 | ||
| JP6017950A JPH06298732A (en) | 1993-02-16 | 1994-02-15 | Indole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06298732A true JPH06298732A (en) | 1994-10-25 |
Family
ID=26354552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6017950A Pending JPH06298732A (en) | 1993-02-16 | 1994-02-15 | Indole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06298732A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996003377A1 (en) * | 1994-07-27 | 1996-02-08 | Sankyo Company, Limited | Heterocyclic compounds, useful as allosteric effectors at muscarinic receptors |
| WO2000051970A1 (en) * | 1999-02-26 | 2000-09-08 | Fujisawa Pharmaceutical Co., Ltd. | Amide compounds for the potentiation of cholinergic activity |
| WO2002012189A1 (en) * | 2000-08-09 | 2002-02-14 | Mitsubishi Pharma Corporation | Fused bicyclic amide compounds and medicinal use thereof |
| US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
| US7678363B2 (en) | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| EP2258357A2 (en) | 2005-08-26 | 2010-12-08 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
-
1994
- 1994-02-15 JP JP6017950A patent/JPH06298732A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996003377A1 (en) * | 1994-07-27 | 1996-02-08 | Sankyo Company, Limited | Heterocyclic compounds, useful as allosteric effectors at muscarinic receptors |
| US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
| US7485651B2 (en) | 1998-03-31 | 2009-02-03 | Acadia Pharmaceuticals, Inc. | Compounds with activity on muscarinic receptors |
| WO2000051970A1 (en) * | 1999-02-26 | 2000-09-08 | Fujisawa Pharmaceutical Co., Ltd. | Amide compounds for the potentiation of cholinergic activity |
| WO2002012189A1 (en) * | 2000-08-09 | 2002-02-14 | Mitsubishi Pharma Corporation | Fused bicyclic amide compounds and medicinal use thereof |
| US7112594B2 (en) | 2000-08-09 | 2006-09-26 | Mitsubishi Pharma Corporation | Fused bicyclic amide compounds and medicinal use thereof |
| US7678363B2 (en) | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| EP2258357A2 (en) | 2005-08-26 | 2010-12-08 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| EP2258358A2 (en) | 2005-08-26 | 2010-12-08 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| EP2275096A2 (en) | 2005-08-26 | 2011-01-19 | Braincells, Inc. | Neurogenesis via modulation of the muscarinic receptors |
| EP2275095A2 (en) | 2005-08-26 | 2011-01-19 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
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