JPH01132579A - Indole derivative - Google Patents
Indole derivativeInfo
- Publication number
- JPH01132579A JPH01132579A JP29227787A JP29227787A JPH01132579A JP H01132579 A JPH01132579 A JP H01132579A JP 29227787 A JP29227787 A JP 29227787A JP 29227787 A JP29227787 A JP 29227787A JP H01132579 A JPH01132579 A JP H01132579A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- indole
- solvent
- derivative
- 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 description 10
- -1 1-imidazolyl Chemical group 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims abstract 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 239000002904 solvent Substances 0.000 abstract description 10
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 206010008088 Cerebral artery embolism Diseases 0.000 abstract description 2
- 206010008132 Cerebral thrombosis Diseases 0.000 abstract description 2
- 206010011086 Coronary artery occlusion Diseases 0.000 abstract description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 abstract description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 abstract description 2
- 206010047249 Venous thrombosis Diseases 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 201000010849 intracranial embolism Diseases 0.000 abstract description 2
- 208000010125 myocardial infarction Diseases 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 abstract 2
- 208000001778 Coronary Occlusion Diseases 0.000 abstract 1
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical class C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 150000004885 piperazines Chemical class 0.000 abstract 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101001060231 Homo sapiens F-box/WD repeat-containing protein 7 Proteins 0.000 description 1
- 101000579123 Homo sapiens Phosphoglycerate kinase 1 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102100028251 Phosphoglycerate kinase 1 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は新規なインドール誘導体に関し、更に詳細には
、医薬として有用なインドール誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel indole derivatives, and more particularly to indole derivatives useful as pharmaceuticals.
従来、インドール誘導体には血小板凝集抑制作用を有す
るものがあることが知られており、この例としては１−
（５−カルボキシペンチル）−３−メチル−２−（３−
ピリゾル）インドール、１−（５−カルボキシペンチル
）−５−クロロ−３−メチル−２−（３−ピリゾル）イ
ンドール（Ｒ，Ｄ、Ｒｏｂｉｍｍｏｎ、Ｌ、Ｌｉａｕ、
Ｊ。Conventionally, it has been known that some indole derivatives have a platelet aggregation inhibitory effect, and an example of this is 1-
(5-carboxypentyl)-3-methyl-2-(3-
pyrisol)indole, 1-(5-carboxypentyl)-5-chloro-3-methyl-2-(3-pyrisol)indole (R,D,Robimmon,L,Liau,
J.
Ｔｊａｎ 、Ｙ、５ａｋａｔ＋＠ａｎｄ Ｅ、Ｋｕ ；
Ｆｅｄ、Ｐｒｏｅ、 ４３ 。Tjan, Y, 5akat+@and E, Ku;
Fed, Proe, 43.
１０３８（Ｉ９８４）’）等が挙げられる。1038 (I984)'), etc.
しかしながら、これらの化合物の血小板凝集抑制作用は
必ずしも充分ではなく、更に優れた作用を有する化合物
の提供が求められていた。However, the platelet aggregation inhibiting effect of these compounds is not necessarily sufficient, and there has been a demand for compounds with even better effects.
本発明者らは、ピペラジン環を有するインドール誘導体
を種々合成し、それらの薬理作用を検索したところ、後
述の一般式（Ｉ）で表わされる新規化合物が極めて強い
血小板凝集抑制作用を有することを見出し、本発明を完
成した。The present inventors synthesized various indole derivatives having a piperazine ring and searched for their pharmacological actions, and found that a new compound represented by the general formula (I) described below has extremely strong platelet aggregation inhibiting action. , completed the invention.
すなわち本発明は、次の一般式（Ｉ）
（式中ｂ Ｒ１は水素原子、ハロゲン原子、低級アルキ
ル基または低級アルコキシル基を示し、ｎｔ Ｆｉｚ−
イミダゾリル基または３−ビリゾル基を示し、難は１〜
５の整数を示す）
で表わされるインドール誘導体またはその酸付加塩を提
供するものである。That is, the present invention relates to the following general formula (I) (wherein b R1 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, and nt Fiz-
Indicates an imidazolyl group or a 3-bilisol group, and the difficulty is 1 to
(indicating an integer of 5) or an acid addition salt thereof.
本発明化合物（Ｉ）は、例えば次に示す方法のいずれか
によシ製造される。Compound (I) of the present invention can be produced, for example, by any of the following methods.
方法１：
次の反応式に従って、インドール−２−カルメン酸誘導
体（Ｉ）とビペラゾン誘導体（Ｉ）とを反応させて本発
明化合物（Ｉ）′ｔ−得る。Method 1: According to the following reaction formula, the indole-2-carmenic acid derivative (I) and the biperazone derivative (I) are reacted to obtain the compound (I)'t- of the present invention.
（式中ｂ”ｈＲｌ及びｎは前記と同じ意味を有する）
本反応は化合物（Ｉ）１モルに対し、化合物（Ｉ）を１
〜１１モル使用し、１〜Ｌ２モルのＮ。(In the formula, b"hRl and n have the same meanings as above.) In this reaction, 1 mole of compound (I), 1 mole of compound (I),
~11 moles used, 1-L2 moles of N.
Ｎ′−カルボニルジイミダゾール、ジシクロへキシルカ
ルメゾイミド等の縮合剤の存在下、溶媒中、室温にであ
るいは必要ならば加温して１〜２４時間反応させるとと
Ｋより実施される。溶媒としては、例えば塩化メチレン
、クロロホルム、ジエチルエーテル％ ７ ） ：ｙ
ヒドロフラン、ジオキサン等が好ましい。なお、縮合剤
としてジシクロへキシルカルメゾイミドを用いた場合、
反応を促進させる目的で４−ジメチルアミノピリジン等
の触媒を加えても良い。反応終了後、常法に従って後処
理を行ない、常法によシ再結晶、クロマトグラフィー等
の手段で精製することによシ純粋な目的物（！）を得る
ことができる。The reaction is carried out in the presence of a condensing agent such as N'-carbonyldiimidazole or dicyclohexylcarmezoimide in a solvent at room temperature or with heating if necessary for 1 to 24 hours. As a solvent, for example, methylene chloride, chloroform, diethyl ether%7):y
Hydrofuran, dioxane, etc. are preferred. In addition, when dicyclohexylcarmezoimide is used as a condensing agent,
A catalyst such as 4-dimethylaminopyridine may be added for the purpose of promoting the reaction. After completion of the reaction, a pure target product (!) can be obtained by post-treatment according to a conventional method and purification by means such as recrystallization and chromatography according to a conventional method.
方法２：
次の反応式に従って、ｌ−置換ビペラシン（ｆｆ）にイ
ミダゾール誘導体またはピリシン誘導休作）を反応させ
て本発明化合物０）を得る。Method 2: Compound 0) of the present invention is obtained by reacting l-substituted viperacin (ff) with an imidazole derivative or pyricine-induced suspension according to the following reaction formula.
（ｎ） （ｖ）
（式中、”ｈ”ｈ及びｎは前記と同じ意味を有し、Ｘは
ハロゲン原子、トシルオキシ基、メシルオキシ基等の脱
離基を示す）
本反応は化合物φ）１モルに対し、化合物（Ｖ）ｔ−１
モル使用し、塩基の存在下、溶媒中、室温ないし１２０
℃で１〜２４時間反応させることにより実施される。溶
媒としては、例えばジメチルホルムアミド、水−ゾオキ
サン（Ｉ：１）混合溶媒等が好ましい。塩基としては、
例えば炭酸カリウム、炭酸ナトリウム、ピリシン、トリ
エチルアミン等が使用できる。(n) (v) (In the formula, "h" h and n have the same meanings as above, and X represents a leaving group such as a halogen atom, tosyloxy group, mesyloxy group, etc.) This reaction is performed on the compound φ)1 Compound (V) t-1 per mole
molar, in the presence of a base, in a solvent, from room temperature to 120
It is carried out by reacting at ℃ for 1 to 24 hours. Preferred examples of the solvent include dimethylformamide, a water-zooxane (I:1) mixed solvent, and the like. As a base,
For example, potassium carbonate, sodium carbonate, pyricine, triethylamine, etc. can be used.
反応終了後溶媒を留去し、常法によシ再結晶、クロマト
グラフィー等の手段で精製することにより純粋な目的物
（Ｉ）を得ることができる。After the reaction is completed, the solvent is distilled off and purified by conventional methods such as recrystallization and chromatography to obtain pure target compound (I).
かくして得られた本発明のインドール誘導体（Ｉ）は、
更に必要に応じて、常法によシ塩酸塩、臭化水素酸塩、
硫酸塩などの無機酸塩、またはマレイン酸塩、フマール
酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩など
の有機酸塩とすることができる。The indole derivative (I) of the present invention thus obtained is:
Furthermore, if necessary, add hydrochloride, hydrobromide,
It can be an inorganic acid salt such as sulfate, or an organic acid salt such as maleate, fumarate, tartrate, citrate, methanesulfonate.
叙上の如くして得られた本発明化合物（Ｉ）について、
その血小板凝集抑制作用を試験した結果は次の通りであ
った。Regarding the compound (I) of the present invention obtained as described above,
The results of testing its platelet aggregation inhibitory effect were as follows.
雄性ウサギ（体重３ゆ）よりクエン酸加血液を採取し、
遠心分離して調製した多血小板血漿（ＰＲＰ ） ｉ用
い、以下常法に従いアラキドン酸（Ｉ００μＭ）凝集に
対する抑制作用を検討した。被検化合物は後述の実施例
で得られたものを用い、これを生理食塩水に溶解し、１
規定水酸化ナトリウム水溶液にてｐＨｔＴ付近に調整し
た後、凝集剤添加２分前にＰＲＰ中に加えた。Citrated blood was collected from a male rabbit (body weight 3 Yu),
Using platelet-rich plasma (PRP) prepared by centrifugation, the inhibitory effect on arachidonic acid (I00 μM) aggregation was examined according to a conventional method. The test compound used was the one obtained in the example below, which was dissolved in physiological saline and 1
After adjusting the pH to around pHtT with a normal aqueous sodium hydroxide solution, it was added to PRP 2 minutes before adding the flocculant.
その結果を第１表に示す。The results are shown in Table 1.
第１表
この結果から明らかな如く、本発明のインドール誘導体
（ｆ）は、強い血小板凝集抑制作用を有する。Table 1 As is clear from the results, the indole derivative (f) of the present invention has a strong platelet aggregation inhibiting effect.
本発明のインドール誘導体（Ｉ）は、上述の如く強い血
小板凝集抑制作用を有するので、血栓形成等に起因する
循環器系諸疾患、例えば静脈血栓、心筋梗塞における冠
状動脈閉鎖、肺塞栓、脳血栓、脳塞栓等の治療、予防等
に有用である。The indole derivative (I) of the present invention has a strong platelet aggregation inhibiting effect as described above, and therefore, it can be used to treat various circulatory system diseases caused by thrombus formation, such as venous thrombosis, coronary artery occlusion in myocardial infarction, pulmonary embolism, cerebral thrombosis, etc. It is useful for the treatment and prevention of cerebral embolism, etc.
〔実施例〕 。〔Example〕 .
次に実施例を挙げて更に詳細に説明するが、本発明はこ
れらに限定されるものではない。Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
実施例１
ｌ−（５−クロロ−ＩＴｉ−インドール−２−イルカル
ゴニル）−４−（３−（ＬＨ−イミダゾール−１−イル
）７０ロビル〕ピペラゾン（化合物１）の製造：
５−クロロインドール−２−カルボン酸９７８ｑを無水
テトラヒドロ７ラン２５ ｔ／ ｔｉｃ溶解し、Ｎ 、
Ｎ’−カルボニルシイミダゾール８１１Ｗｌ！を加え
て２５時間室温にて攪拌した。Example 1 Preparation of l-(5-chloro-ITi-indol-2-ylcargonyl)-4-(3-(LH-imidazol-1-yl)70rovil]piperazone (compound 1): 5-chloroindole-2 - 978 q of carboxylic acid was dissolved in 25 t/tic of anhydrous tetrahydro7 run, N,
N'-Carbonylshiimidazole 811Wl! was added and stirred at room temperature for 25 hours.
次いで１−（３−（Ｉｍ−イミダゾール−１−イル）プ
ロピル〕ビペラゾンＬＯＯｆをこれに加え、更に一夜室
温にて攪拌した。反応終了後、溶媒を減圧留去し、残査
を塩化メチレンに転溶後１規定水酸化ナトリウム水溶液
、次いで水で洗浄し、無水硫酸ナトリウムにて乾燥した
。塩化メチレンを減圧留去した後、シリカゲル７０ ’
ｔを用いてカラムクロマトグラフイーに付し、５％メタ
ノール−９５％クロロホルム溶出部より得た画分の溶媒
を減圧留去し、次いでエーテル−酢酸エチル混合溶媒に
て結晶化して化合物１の無色結晶Ｌ４２ｆ（収率７６％
）ｔ−得た。Next, 1-(3-(Im-imidazol-1-yl)propyl]biperazone LOOf was added thereto, and the mixture was further stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was converted to methylene chloride. After dissolution, it was washed with a 1N aqueous sodium hydroxide solution, then with water, and dried over anhydrous sodium sulfate.After distilling off methylene chloride under reduced pressure, silica gel 70'
The solvent of the fraction obtained from the 5% methanol-95% chloroform eluate was distilled off under reduced pressure, and then crystallized from an ether-ethyl acetate mixed solvent to obtain colorless compound 1. Crystal L42f (yield 76%
)t-obtained.
融点：１８２〜１８３℃
ＩＲ３ＩＫＢ”（ｍｌ−凰： ３２５０，１６００ｈ
Ｘ
ＮＭＲδｐｐｍ（ＣＤＣ４） ： Ｌ９１５（＋ｎ 、
２Ｈ） 、 ２４０（ｒｎ 、 ６Ｈ） 、 ａ９０
（ｍ 、６Ｈ） 、 ａ７５（ｍ 、 ＩＨ） 、ａ９
０（ｓ 、 ＬＭ） 、７０８（ｓ 、 ＬＨ） 、
？：５５（ｓ 、 ＩＨ）、 ７１５〜７７０（ｍ、３
Ｈ） 、 １１０（ｂｒ、ＩＨ）上記結晶を少量のクロ
ロホルムに溶解しエーテルを加え、水冷下攪拌しながら
エタノール塩酸を滴下して析出した無色結晶をろ取し、
化合物ｌの塩酸塩を得た。Melting point: 182-183℃ IR3IKB” (ml-凰: 3250, 1600h
X NMR δppm (CDC4): L915 (+n,
2H), 240(rn, 6H), a90
(m, 6H), a75 (m, IH), a9
0(s, LM), 708(s, LH),
? :55(s, IH), 715-770(m, 3
H), 110 (br, IH) The above crystals were dissolved in a small amount of chloroform, ether was added, and ethanol-hydrochloric acid was added dropwise while stirring under water cooling, and the precipitated colorless crystals were collected by filtration.
The hydrochloride of compound 1 was obtained.
融点：２６０〜２６５℃
実施例２
ｌ−（５−クロロ−ＩＨ−インドール−２−イルカルゼ
ニル）−４−（３−（３−ビリゾル）プロピルコピペラ
ジン（化合物２）の製造：
１−（５−クロロ−ＩＨ−インドール−２−ｌルカルボ
ニル）ピペラジン８８０１１ｇ及びｌ−クロロ−３−（
３−ｆ ＋） ツル）テロノＱン５１９１１Ｑをジメチ
ルホルムアミド１５−に溶解し、炭酸ナトリウム３５４
１１１？を加えて８０℃で８時間攪拌した。反応終了後
、溶媒を減圧留去し、残査に水を加えて塩化メチレンで
抽出し、無水硫酸ナトリウムにて乾燥した。Melting point: 260-265°C Example 2 Preparation of l-(5-chloro-IH-indol-2-ylcarzenyl)-4-(3-(3-bilisol)propylcopiperazine (compound 2): 1-(5- 88011 g of chloro-IH-indole-2-lcarbonyl)piperazine and l-chloro-3-(
3-f+)TronoQn 51911Q was dissolved in dimethylformamide 15- and sodium carbonate 354
111? was added and stirred at 80°C for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with methylene chloride, and dried over anhydrous sodium sulfate.
塩化メチレンを減圧留去後、シリカゲルカラムクロマト
グラフィーに付し、５％メタノール−９５％クロロホル
ム溶出部よシ得た画分の溶媒を減圧留去し、次いでエー
テルで結晶化して化合物２の無色結晶９５８ＩＱ（収率
７５％）を得た。After removing methylene chloride under reduced pressure, it was subjected to silica gel column chromatography, and the solvent of the obtained fraction was removed under reduced pressure from the 5% methanol-95% chloroform eluate, and then crystallized with ether to obtain colorless crystals of compound 2. 958IQ (yield 75%) was obtained.
融点：１２２〜１２３℃
ＩＲνＫ”ｃＩＬ−’ ：３２８０．１６００１ｘ
ＮＭＲδｐｐｍ（ＣＤＣｌ２ ） ： Ｌ８５（ｍ 、
２Ｈ） 、２．５０（ｍ、８Ｈ）、ａ９０（ｍ、４Ｈ
）、ａ６５（ｓ、ＬＨ）７００〜７８０（ｎ＋、５Ｈ）
、８５０（ｔｈ、２Ｈ） 。Melting point: 122-123°C IRνK"cIL-': 3280.16001x NMRδppm (CDCl2): L85 (m,
2H), 2.50 (m, 8H), a90 (m, 4H
), a65 (s, LH) 700-780 (n+, 5H)
, 850 (th, 2H).
１Ｌ３０（ｂｒ 、 ＩＨ）
実施例１と同様の方法で化合物２の塩酸塩を無色結晶と
して得た。1L30 (br, IH) Compound 2 hydrochloride was obtained as colorless crystals in the same manner as in Example 1.
融点：２４５〜２５０℃
実施例３〜８
実施例１または２と同様の方法で第２表に示す化合物３
〜８を得た。Melting point: 245-250°C Examples 3-8 Compound 3 shown in Table 2 in the same manner as in Example 1 or 2
-8 was obtained.
以下余白Margin below
Claims (1)
ル基または低級アルコキシル基を示し、Ｒ＿２は１−イ
ミダゾリル基または３−ピリジル基を示し、ｎは１〜５
の整数を示す） で表わされるインドール誘導体またはその酸付加塩。[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group, R_2 represents a 1-imidazolyl group or a 3-pyridyl group, and n is 1-5
Indole derivatives or acid addition salts thereof represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29227787A JPH01132579A (en) | 1987-11-19 | 1987-11-19 | Indole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29227787A JPH01132579A (en) | 1987-11-19 | 1987-11-19 | Indole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01132579A true JPH01132579A (en) | 1989-05-25 |
Family
ID=17779665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29227787A Pending JPH01132579A (en) | 1987-11-19 | 1987-11-19 | Indole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01132579A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5489593A (en) * | 1989-12-28 | 1996-02-06 | The Upjohn Company | Anti-aids piperazines |
| US5599930A (en) * | 1991-07-03 | 1997-02-04 | The Upjohn Company | Substituted indoles as anti-AIDS pharmaceuticals |
| EP1165084A1 (en) * | 1999-03-03 | 2002-01-02 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferases |
| WO2002072548A3 (en) * | 2001-03-09 | 2002-12-12 | Ortho Mcneil Pharm Inc | Heterocyclic compounds and their use as histamine h4 ligands. |
| EP1444204A1 (en) * | 2001-10-22 | 2004-08-11 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them |
| US7504426B2 (en) | 2002-09-06 | 2009-03-17 | Janssen Pharmaceutica N.V. | Heterocyclic compounds |
| US7772216B2 (en) | 2001-10-22 | 2010-08-10 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors and methods for designing them |
| US7838542B2 (en) | 2006-06-29 | 2010-11-23 | Kinex Pharmaceuticals, Llc | Bicyclic compositions and methods for modulating a kinase cascade |
| US7901894B2 (en) | 1999-01-13 | 2011-03-08 | The Research Foundation Of State University Of New York | Kinase inhibitors |
| EP3746430A4 (en) * | 2018-02-02 | 2021-11-03 | Padforward LLC | Inhibitors of protein arginine deiminases |
-
1987
- 1987-11-19 JP JP29227787A patent/JPH01132579A/en active Pending
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5489593A (en) * | 1989-12-28 | 1996-02-06 | The Upjohn Company | Anti-aids piperazines |
| US5563142A (en) * | 1989-12-28 | 1996-10-08 | The Upjohn Company | Diaromatic substituted compounds as anti-HIV-1 agents |
| US5599930A (en) * | 1991-07-03 | 1997-02-04 | The Upjohn Company | Substituted indoles as anti-AIDS pharmaceuticals |
| US5686610A (en) * | 1991-07-03 | 1997-11-11 | Pharmacia & Upjohn Company | Pyridyl piperazine compound |
| US7901894B2 (en) | 1999-01-13 | 2011-03-08 | The Research Foundation Of State University Of New York | Kinase inhibitors |
| EP1165084A1 (en) * | 1999-03-03 | 2002-01-02 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferases |
| EP1165084A4 (en) * | 1999-03-03 | 2002-05-15 | Merck & Co Inc | Inhibitors of prenyl-protein transferases |
| WO2002072548A3 (en) * | 2001-03-09 | 2002-12-12 | Ortho Mcneil Pharm Inc | Heterocyclic compounds and their use as histamine h4 ligands. |
| JP2004520434A (en) * | 2001-03-09 | 2004-07-08 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | Heterocyclic compounds |
| US6803362B2 (en) | 2001-03-09 | 2004-10-12 | Ortho-Mcneil Pharmaceutical Inc. | Heterocyclic compounds |
| US7129225B2 (en) | 2001-10-22 | 2006-10-31 | The Research Foundation Of State University Of New York | Protection against and treatment of hearing loss |
| US7427608B2 (en) | 2001-10-22 | 2008-09-23 | The Research Foundation Of State University Of New York | Protection against and treatment of hearing loss |
| EP1444204A4 (en) * | 2001-10-22 | 2009-11-04 | Univ New York State Res Found | Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them |
| US7772216B2 (en) | 2001-10-22 | 2010-08-10 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors and methods for designing them |
| EP1444204A1 (en) * | 2001-10-22 | 2004-08-11 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them |
| US8088768B2 (en) | 2001-10-22 | 2012-01-03 | The Research Foundation Of The State University Of New York | Protein kinase and phosphatase inhibitors |
| US7504426B2 (en) | 2002-09-06 | 2009-03-17 | Janssen Pharmaceutica N.V. | Heterocyclic compounds |
| US7838542B2 (en) | 2006-06-29 | 2010-11-23 | Kinex Pharmaceuticals, Llc | Bicyclic compositions and methods for modulating a kinase cascade |
| EP3746430A4 (en) * | 2018-02-02 | 2021-11-03 | Padforward LLC | Inhibitors of protein arginine deiminases |
| US11453676B2 (en) | 2018-02-02 | 2022-09-27 | Forward Therapeutics, Inc. | Inhibitors of protein arginine deiminases |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2000511173A (en) | Novel indolyl and benzofuranylcarboxamides as inhibitors of nitric oxide production | |
| JPS6313427B2 (en) | ||
| JPS6013788A (en) | Novel coumarin derivative | |
| JPH01132579A (en) | Indole derivative | |
| JPS62149662A (en) | N-containing heterocyclic compound | |
| US5134151A (en) | 2-picolylamine derivatives | |
| JPS6110584A (en) | Imidazoisoquinoline compound and preparation thereof | |
| US5968967A (en) | Pyrazolones derivatives | |
| US4968683A (en) | 6-oxo-pyridazine derivatives, a process for their preparation and medicaments containing these compounds | |
| US5753667A (en) | 1-oxo-2- (phenylsulphonylamino) pentylpiperidine derivatives, their preparation and their therapeutic application | |
| US5789595A (en) | Tetrahydroisoquinoline derivative and medical preparation containing the same | |
| JPS6348250A (en) | 2-acyloxypropylamine derivatives, manufacture and pharmacological composition containing them | |
| JP3077295B2 (en) | Thiazole compounds | |
| US5356922A (en) | Imidazole compounds, processes for their preparation, pharmaceuticals based on these compounds and some intermediates | |
| BE1009376A4 (en) | Carboxymethylidenecycloheptimidazole derivatives, their preparation process last and therapeutics containing compounds. | |
| JP2002520401A (en) | Piperazinone derivatives and uses thereof | |
| JPH04225955A (en) | Substituted benzhydril-2-hydroxypropylpiperazine derivatives | |
| JPH03264581A (en) | Indole derivative | |
| JP3750141B2 (en) | Thiazoline derivative | |
| JPH01131158A (en) | Substituted alkylpiperazine derivative | |
| JPS63183565A (en) | Imidazole derivative | |
| EP0101517A1 (en) | NOVEL s-TRIAZOLE(1,5-a)PYRIMIDINE DERIVATIVES | |
| JPH069575A (en) | Aminocarboxylic acid derivative, its production, and medicine containing said derivative and used for treatment of allergy, inflamation and asthama | |
| JPS6176485A (en) | Novel gamma-pyran derivative | |
| JPH07233148A (en) | Piperidine derivative and medicinal preparation containing the same |