JPS6237623B2 - - Google Patents
Info
- Publication number
- JPS6237623B2 JPS6237623B2 JP57015099A JP1509982A JPS6237623B2 JP S6237623 B2 JPS6237623 B2 JP S6237623B2 JP 57015099 A JP57015099 A JP 57015099A JP 1509982 A JP1509982 A JP 1509982A JP S6237623 B2 JPS6237623 B2 JP S6237623B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- general formula
- formula
- represented
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- BOIZHGCLUSQNLD-UHFFFAOYSA-N acetic acid;1h-indole Chemical class CC(O)=O.C1=CC=C2NC=CC2=C1 BOIZHGCLUSQNLD-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 229960000905 indomethacin Drugs 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 231100000397 ulcer Toxicity 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 208000007107 Stomach Ulcer Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 201000005917 gastric ulcer Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- -1 butanediol compound Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- UCVODTZQZHMTPN-UHFFFAOYSA-N heptanoyl chloride Chemical compound CCCCCCC(Cl)=O UCVODTZQZHMTPN-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 208000013465 muscle pain Diseases 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
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
Description
本発明は新規なインドール酢酸エステル誘導
体、更に詳細には、次の一般式（）
〔式中、Ｒは水素原子、基−COR1（ここでR1
はアルキル基、アルケニル基を示す）又は基
The present invention provides novel indole acetate derivatives, more specifically, the following general formula () [In the formula, R is a hydrogen atom, a group -COR 1 (here R 1
represents an alkyl group, an alkenyl group) or a group
【式】（ここでR2は水素原子、ハロ
ゲン原子、シアノ基、低級アルキル基、フエニル
基を、R3は水素原子、低級アルキル基、フエニ
ル基を、R4は低級アルキル基、低級アルキルオ
キシ基、アシルオキシ基又はハロゲン原子で置換
されていても良いフエニル基を示す）を示す〕で
表わされるインドール酢酸エステル誘導体並びに
その製造法に関する。
現在、インドメタシンは非ステロイド性消炎鎮
痛剤として頭痛、歯痛、腰痛、筋肉痛及びリウマ
チ性疾患等の治療に繁用されている医薬である。
しかしながら、インドメタシンを経口投与した
場合、潰瘍発生を伴なう胃腸障害等の副作用の発
生が知られていた。すなわち、リウマチ性疾患の
治療の如く長期間投与が必要な場合のみならず短
期間投与の場合でさえ胃の充血、出血等の好まし
くない症状を惹き起すことも少なくなく、その投
与方法、投与量が制限されているのが現状であつ
た。
そこで、本発明者らはインドメタシンの上記副
作用を軽減すべく鋭意研究をおこなつた結果、イ
ンドメタシンにブタンジオール化合物を反応させ
て得られた前記式（）で表わされるインドール
酢酸エステル誘導体はインドメタシンと同等の消
炎鎮痛作用を有しながらその副作用はインドメタ
シンと比べ非常に軽微であることを見出し本発明
を完成した。
すなわち、本発明の目的は、非ステロイド性消
炎鎮痛剤として有用な新規なインドール酢酸エス
テル誘導体（）を提供せんとするにある。
また、本発明の他の目的は、新規なインドール
酢酸エステル誘導体（）を製造する方法を提供
せんとするにある。
本発明の化合物（）は、例えば次のいずれか
の方法により公知のエステル化反応を利用して製
造することができる。
インドメタシン（）又はその反応性誘導体
に２，３−ブタンジオール（）を反応させて
インドール酢酸エステル（ａ）を製造する。
で得られたインドール酢酸エステル（
ａ）に、カルボン酸（）又はその反応性誘導
体を反応させてインドール酢酸エステル誘導体
（ｂ）を製造する。
（式中R5は前記したR1及び[Formula] (where R 2 is a hydrogen atom, halogen atom, cyano group, lower alkyl group, phenyl group, R 3 is a hydrogen atom, lower alkyl group, phenyl group, R 4 is a lower alkyl group, lower alkyloxy The present invention relates to an indole acetate derivative represented by the following formula, and a method for producing the same. Currently, indomethacin is a nonsteroidal anti-inflammatory analgesic drug that is frequently used to treat headaches, toothaches, lower back pains, muscle pains, rheumatic diseases, and the like. However, when indomethacin is orally administered, it has been known that side effects such as gastrointestinal disorders accompanied by ulcer formation occur. In other words, not only when long-term administration is required, such as in the treatment of rheumatic diseases, but even when administered for a short period of time, undesirable symptoms such as gastric congestion and bleeding are often caused, and the method and dosage of administration are important. Currently, there are restrictions on Therefore, the present inventors conducted intensive research to reduce the above-mentioned side effects of indomethacin, and as a result, an indole acetate derivative represented by the above formula () obtained by reacting indomethacin with a butanediol compound was found to be equivalent to indomethacin. The present invention was completed based on the discovery that while it has an anti-inflammatory and analgesic effect, its side effects are much smaller than that of indomethacin. That is, an object of the present invention is to provide a novel indole acetate derivative () useful as a nonsteroidal anti-inflammatory analgesic. Another object of the present invention is to provide a method for producing a novel indole acetate derivative (). The compound () of the present invention can be produced using a known esterification reaction, for example, by any of the following methods. Indole acetate (a) is produced by reacting indomethacin () or its reactive derivative with 2,3-butanediol (). Indole acetate (
Indole acetate derivative (b) is produced by reacting a) with carboxylic acid () or a reactive derivative thereof. (In the formula, R 5 is the above-mentioned R 1 and
【式】を
意味する）
２，３−ブタンジオールモノエステル誘導体
（）にインドメタシン（）又はその反応性
誘導体を反応させて、インドール酢酸エステル
誘導体（ｂ）を製造する。
（式中R5は前記と同じ）
本方法において、インドメタシン（）及びカ
ルボン酸（）の反応性誘導体としては、酸ハロ
ゲニド、酸無水物、混合酸無水物等が挙げられ、
この場合、反応はピリジン、トリメチルアミン、
トリエチルアミン等の第三級アミン；炭酸アルカ
リ、水酸化アルカリ、水素化アルカリ等の脱酸剤
の存在下行うのが好ましい。
また上記反応は適当な反応溶媒中でおこなうこ
とが好ましく、反応溶媒としてはエーテル、テト
ラヒドロフラン、ベンゼン、トルエン、クロロホ
ルム、ジクロメタン等の反応に関与しない溶媒が
好ましい。
斯くの如く得られる本発明化合物（）の消炎
効果及び潰瘍形成抑制効果について試験した結果
並びにインドメタシン及び公知のインドール酢酸
エステル誘導体と胃潰瘍形成作用を比較した結果
を示す。
(1) 消炎効果及び潰瘍形成制効果
体重200ｇ前後の雄性ドンリユウ系ラツトを
一群７匹とし48時間絶食した後、被検化合物を
１％カルボキシメチルセルロースナトリウム水
溶液に懸濁して経口投与した。被検化合物投与
60分後ラツトの足蹠容積を容積測定器を用いて
測定し、次いで１％カラゲニン生理食塩水溶液
の0.1mlを右後肢足蹠皮下に注入し、３時間後
における浮腫強度を１％カルボキシメチルセル
ロースナトリウム水溶液を投与した対照群と比
較して浮腫抑制率を求めた。
更に４時間後にラツトを屠殺して、全胃を摘
出し、胃損傷抑制効果を潰瘍係数で示した。こ
の結果を第１表に示す。The indole acetate derivative (b) is produced by reacting the 2,3-butanediol monoester derivative (2) with indomethacin (2) or a reactive derivative thereof. (In the formula, R 5 is the same as above) In this method, the reactive derivatives of indomethacin () and carboxylic acid () include acid halogenides, acid anhydrides, mixed acid anhydrides, etc.
In this case, the reaction involves pyridine, trimethylamine,
It is preferable to carry out the reaction in the presence of a tertiary amine such as triethylamine; a deoxidizing agent such as an alkali carbonate, an alkali hydroxide, or an alkali hydride. Further, the above reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent is preferably a solvent that does not participate in the reaction, such as ether, tetrahydrofuran, benzene, toluene, chloroform, or dichloromethane. The results of testing the anti-inflammatory effect and anti-ulceration effect of the compound () of the present invention thus obtained, and the results of comparing the gastric ulcer-forming effect with indomethacin and known indole acetate derivatives are shown. (1) Anti-inflammatory effect and anti-ulcer effect A group of seven male rats weighing around 200 g were fasted for 48 hours, and then the test compound was suspended in a 1% sodium carboxymethyl cellulose aqueous solution and orally administered. Test compound administration
After 60 minutes, the rat's footpad volume was measured using a volumetric device, and then 0.1ml of 1% carrageenan saline solution was subcutaneously injected into the right hind footpad, and the edema intensity was measured after 3 hours with 1% carboxymethylcellulose sodium. The edema suppression rate was determined in comparison with a control group administered with an aqueous solution. After a further 4 hours, the rats were sacrificed, the whole stomach was removed, and the effect of suppressing gastric damage was expressed by the ulcer index. The results are shown in Table 1.
【表】
(2) 胃潰瘍形成作用
本発明化合物及び公知のインドール酢酸エス
テル誘導体について、それらのUD50値を求
め、これを対照であるインドメタシンのUD50
値と比較することにより胃潰瘍形成作用の低下
を調べた。この結果を第２表に示す。
（実験方法）
体重170〜200ｇのウイスター系雄性ラツトを24
時間絶食させた後、0.5％カルボキシメチルセル
ロースナトリウム水溶液に懸濁させた被検化合物
を0.3〜0.6ml／100ｇとなる様に経口投与した。
被検化合物投与５時間後にラツトを撲殺してその
全胃を摘出し、５％ホルマリン溶液を注入して胃
壁を固定した。この胃を切開し、胃の粘膜障害を
肉眼的に観察し、オール−オア−ノン（all−or
−none）の判定をおこない、リツチフイールド
−ウイルコクソン法により、50％潰瘍誘発量
（UD50値）を算出した。
（結果）[Table] (2) Gastric ulcer-forming effect The UD 50 values of the compounds of the present invention and known indole acetate derivatives were determined, and this was compared to the UD 50 of indomethacin as a control.
The reduction in gastric ulcer-forming effect was investigated by comparing the values. The results are shown in Table 2. (Experimental method) 24 male Wistar rats weighing 170 to 200 g
After fasting for an hour, a test compound suspended in a 0.5% sodium carboxymethyl cellulose aqueous solution was orally administered at a dose of 0.3 to 0.6 ml/100 g.
Five hours after administration of the test compound, the rats were bludgeoned to death, their entire stomachs were removed, and a 5% formalin solution was injected to fix the stomach wall. The stomach was incised and gastric mucosal damage was visually observed.
-none), and the 50% ulcer-inducing dose (UD 50 value) was calculated by the Richfield-Wilcoxon method. (result)
【表】
示の化合物。
注4：USP.3468907に開示の化合物。
第１表及び第２表から明らかな如く、本発明化
合物は、カラゲニン浮腫に対し高い抑制率を示す
とともに、非ステロイド性消炎鎮痛物質の副作用
である潰瘍発生が非常に軽微であることが明らか
に認められる。
次に本発明の実施例を挙げて説明する。
実施例１ （化合物１の合成）
インドメタシン17.9ｇをベンゼン200mlに懸濁
し、これに塩化チオニル20mlを加え60〜70℃で５
時間撹拌した。反応後、過剰の塩化チオニル及び
ベンゼンを減圧留去して炎黄色結晶のインドメタ
シンの酸クロリドを得た。
この酸クロリドをテトラヒドロフラン80mlに溶
解し、２，３−ブタンジオール4.5ｇ、ピリジン
10ml及びテトラハイドロフラン150mlの混液中に
少しずつ滴下した。滴下後室温にて４時間撹拌
し、溶媒を減圧留去した。残渣をクロロホルムに
転溶し、水、10％塩酸、水の順に洗い無水硫酸マ
グネシウムにて乾燥した。クロロホルムを留去し
残渣をカラムクロマトグラフイー（シリカゲル）
にて精製し、淡黄色結晶の第３表記載の化合物
1.15.5ｇ（収率72.1％）を得た。
融点106〜108℃
実施例２ （化合物３の合成）
2.15ｇの化合物1.をテトラヒドロフラン15mlに
溶解し、ピリジン１mlを加え、氷冷撹拌しながら
エナント酸クロリド0.78ｇのエーテル溶液10mlを
滴下した。同温度で30分、更に室温に戻して４時
間撹拌後、溶媒を減圧下留去し、残渣をクロロホ
ルムに転容して、水、10％塩酸、水、飽和炭酸水
素ナトリウム溶液、水の順に洗い無水硫酸マグネ
シウムで乾燥した。クロロホルムを減圧下留去し
残渣をカラムクロマトグラフイー（シリカゲル）
にて精製し黄色液体の第３表記載の化合物3.2.25
ｇ（収率83％）を得た。
実施例３ （化合物20の合成）
２，３−ブタンジオール4.5ｇをテトラヒドロ
フラン60mlに溶解しピリジン５mlを加え、氷冷撹
拌下、α−シアノケイヒ酸クロリド9.5ｇのテト
ラヒドロフラン溶液30mlを滴下した。同温度で30
分、室温に戻して４時間撹拌後、溶媒を減圧下留
去し、残渣をクロロホルムに転溶した。クロロホ
ルム層を水、10％塩酸、水、飽和炭酸水素ナトリ
ウム溶液、水の順に洗い無水硫酸マグネシウムで
乾燥した。クロロホルムを減圧下留去し、残渣を
カラムクロマトグラフイー（シリカゲル）にて精
製し淡黄色液体のモノエステル体5.86ｇ（収率48
％）を得た。
このモノエステル体2.45ｇをテトラヒドロフラ
ン30mlに溶解し、ピリジン２mlを加え、氷冷下撹
拌しながら、インドメタシンの酸クロリド3.76ｇ
のテトラヒドロフラン溶液20mlを滴下した。同温
度で30分、更に室温に戻して４時間撹拌後、溶媒
を減圧下留去し、残渣をクロロホルムに転溶し
て、水、10％塩酸、水、飽和炭酸水素ナトリウム
溶液、水の順に洗い無水硫酸マグネシウムで乾燥
した。クロロホルムを減圧下留去し残渣をカラム
クロマトグラフイー（シリカゲル）にて精製し黄
色液体の第３表記載の化合物20.4.15ｇ（収率71
％）を得た。
実施例 ４
実施例１，２又は３と同様にして第３表の化合
物を得た。尚表中には実施例１〜３で得た化合物
もあわせて記載した。[Table] Compounds shown.
Note 4: Compound disclosed in USP.3468907.
As is clear from Tables 1 and 2, the compound of the present invention shows a high inhibition rate against carrageenan edema, and it is clear that the occurrence of ulcers, which is a side effect of non-steroidal anti-inflammatory analgesic substances, is very slight. Is recognized. Next, examples of the present invention will be described. Example 1 (Synthesis of Compound 1) 17.9 g of indomethacin was suspended in 200 ml of benzene, 20 ml of thionyl chloride was added thereto, and the mixture was heated at 60 to 70°C for 50 minutes.
Stir for hours. After the reaction, excess thionyl chloride and benzene were distilled off under reduced pressure to obtain indomethacin acid chloride as flame-yellow crystals. Dissolve this acid chloride in 80 ml of tetrahydrofuran, add 4.5 g of 2,3-butanediol and pyridine.
It was dropped little by little into a mixed solution of 10 ml and 150 ml of tetrahydrofuran. After the addition, the mixture was stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed successively with water, 10% hydrochloric acid, and water, and dried over anhydrous magnesium sulfate. Distill the chloroform and subject the residue to column chromatography (silica gel)
The compound listed in Table 3 was purified as pale yellow crystals.
1.15.5g (yield 72.1%) was obtained. Melting point: 106-108°C Example 2 (Synthesis of Compound 3) 2.15 g of Compound 1. was dissolved in 15 ml of tetrahydrofuran, 1 ml of pyridine was added, and 10 ml of an ether solution containing 0.78 g of enanthyl chloride was added dropwise while stirring under ice cooling. After stirring at the same temperature for 30 minutes, returning to room temperature and stirring for 4 hours, the solvent was distilled off under reduced pressure, the residue was transferred to chloroform, and water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution, and water were added in the following order: Washed and dried over anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure and the residue was subjected to column chromatography (silica gel).
Compound 3.2.25 of Table 3 as a yellow liquid purified by
g (yield 83%) was obtained. Example 3 (Synthesis of Compound 20) 4.5 g of 2,3-butanediol was dissolved in 60 ml of tetrahydrofuran, 5 ml of pyridine was added thereto, and 30 ml of a solution of 9.5 g of α-cyanocinnamyl chloride in tetrahydrofuran was added dropwise while stirring under ice cooling. 30 at the same temperature
After returning to room temperature and stirring for 4 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution, and water in this order, and dried over anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain 5.86 g of monoester as a pale yellow liquid (yield: 48
%) was obtained. Dissolve 2.45 g of this monoester in 30 ml of tetrahydrofuran, add 2 ml of pyridine, and add 3.76 g of indomethacin acid chloride while stirring under ice cooling.
20 ml of a tetrahydrofuran solution was added dropwise. After stirring at the same temperature for 30 minutes, returning to room temperature and stirring for 4 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, followed by water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution, and water. Washed and dried over anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain 20.4.15 g of the compound listed in Table 3 as a yellow liquid (yield: 71
%) was obtained. Example 4 The compounds shown in Table 3 were obtained in the same manner as in Example 1, 2 or 3. In addition, the compounds obtained in Examples 1 to 3 are also listed in the table.
【表】【table】
【表】【table】
【表】【table】
Claims (1)
はアルキル基、アルケニル基を示す）又は基
【式】（ここでR2は水素原子、ハロゲ ン原子、シアノ基、低級アルキル基、フエニル基
を、R3は水素原子、低級アルキル基、フエニル
基を、R4は低級アルキル基、低級アルキルオキ
シ基、アシルオキシ基又はハロゲン原子で置換さ
れていても良いフエニル基を示す）を示す〕で表
わされるインドール酢酸エステル誘導体。 ２ 一般式（） で表わされる化合物又はその反応性誘導体に一般
式（） で表わされる２，３−ブタンジオールを反応させ
ることを特徴とする一般式（ａ） で表わされるインドール酢酸エステルの製造法。 ３ 一般式（ａ） で表わされるインドール酢酸エステルに一般式
（） R5COOH （） 〔式中、R5はアルキル基、アルケニル基、基
【式】（ここでR2は水素原子、ハロゲン 原子、シアノ基、低級アルキル基、フエニル基
を、R3は水素原子、低級アルキル基、フエニル
基を、R4は低級アルキル基、低級アルキルオキ
シ基、アシルオキシ基又はハロゲン原子で置換さ
れていても良いフエニル基を示す）を示す〕で表
わされるカルボン酸又はその反応性誘導体を反応
させることを特徴とする一般式（ｂ） （式中R5は前記と同じ） で表わされるインドール酢酸エステル誘導体の製
造法。 ４ 一般式（） （式中R5は前記と同じ） で表わされる２，３−ブタンジオールモノエステ
ル誘導体に一般式（） で表わされる化合物又はその反応性誘導体を反応
させることを特徴とする一般式（ｂ） （式中R5は前記と同じ） で表わされるインドール酢酸エステル誘導体の製
造法。[Claims] First-order general formula () [In the formula, R is a hydrogen atom, a group -COR 1 (here R 1
represents an alkyl group, an alkenyl group) or a group [Formula] (where R 2 is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, or a phenyl group, and R 3 is a hydrogen atom, a lower alkyl group, or a phenyl group) , R 4 represents a lower alkyl group, a lower alkyloxy group, an acyloxy group, or a phenyl group optionally substituted with a halogen atom]. 2 General formula () The compound represented by or its reactive derivative has the general formula () General formula (a) characterized by reacting 2,3-butanediol represented by A method for producing indole acetate represented by 3 General formula (a) Indole acetate represented by the general formula () R 5 COOH () [where R 5 is an alkyl group, an alkenyl group, a group [formula] (where R 2 is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl R3 represents a hydrogen atom, a lower alkyl group, a phenyl group, R4 represents a lower alkyl group, a lower alkyloxy group, an acyloxy group, or a phenyl group optionally substituted with a halogen atom) General formula (b) characterized by reacting a carboxylic acid represented by ] or a reactive derivative thereof (In the formula, R 5 is the same as above.) A method for producing an indole acetate derivative represented by: 4 General formula () (In the formula, R 5 is the same as above.) A 2,3-butanediol monoester derivative represented by the general formula () General formula (b) characterized by reacting a compound represented by or a reactive derivative thereof (In the formula, R 5 is the same as above.) A method for producing an indole acetate derivative represented by:
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1509982A JPS58134077A (en) | 1982-02-02 | 1982-02-02 | Novel indoleacetic ester derivative and preparation thereof |
| CA000411293A CA1187488A (en) | 1982-02-02 | 1982-09-13 | Indoleacetic ester derivatives and process for preparing same |
| GB08226787A GB2125786B (en) | 1982-02-02 | 1982-09-20 | Esters of indomethacin |
| DE19823235850 DE3235850A1 (en) | 1982-02-02 | 1982-09-28 | NEW INDOLESSIC ACID ESTER DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| IT49205/82A IT1149095B (en) | 1982-02-02 | 1982-10-05 | DOLACETIC ESTER DERIVATIVES AND PROCESS FOR PREPARING THEM |
| CH6750/82A CH649532A5 (en) | 1982-02-02 | 1982-11-19 | INDOLESSIC ACID ESTER DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. |
| FR8220317A FR2520739B1 (en) | 1982-02-02 | 1982-12-03 | NEW INDOLEACETIC ESTER DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1509982A JPS58134077A (en) | 1982-02-02 | 1982-02-02 | Novel indoleacetic ester derivative and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58134077A JPS58134077A (en) | 1983-08-10 |
| JPS6237623B2 true JPS6237623B2 (en) | 1987-08-13 |
Family
ID=11879389
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1509982A Granted JPS58134077A (en) | 1982-02-02 | 1982-02-02 | Novel indoleacetic ester derivative and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58134077A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0711322U (en) * | 1993-07-29 | 1995-02-21 | 住友重機械プラスチックマシナリー株式会社 | Injection molding machine |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR940007001A (en) * | 1992-09-16 | 1994-04-26 | 최승주 | New N-cinnaylyl-2-methyl-5-methoxy-3-indole acetic acid ester, preparation method thereof and pharmaceutical preparation containing same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52156862A (en) * | 1976-06-22 | 1977-12-27 | Hisamitsu Pharmaceut Co Inc | Novel indoleacetic acid ester derivatives |
| JPS5476578A (en) * | 1977-11-28 | 1979-06-19 | Sumitomo Chem Co Ltd | Novel indomethacin glyceride derivative |
| JPS5490174A (en) * | 1977-12-27 | 1979-07-17 | Kanebo Ltd | Novel indomethacin derivatives and their preparation |
-
1982
- 1982-02-02 JP JP1509982A patent/JPS58134077A/en active Granted
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52156862A (en) * | 1976-06-22 | 1977-12-27 | Hisamitsu Pharmaceut Co Inc | Novel indoleacetic acid ester derivatives |
| JPS5476578A (en) * | 1977-11-28 | 1979-06-19 | Sumitomo Chem Co Ltd | Novel indomethacin glyceride derivative |
| JPS5490174A (en) * | 1977-12-27 | 1979-07-17 | Kanebo Ltd | Novel indomethacin derivatives and their preparation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0711322U (en) * | 1993-07-29 | 1995-02-21 | 住友重機械プラスチックマシナリー株式会社 | Injection molding machine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58134077A (en) | 1983-08-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0223537B2 (en) | ||
| JPH059424B2 (en) | ||
| CH623037A5 (en) | ||
| CA1187488A (en) | Indoleacetic ester derivatives and process for preparing same | |
| JPS6237623B2 (en) | ||
| JPH0234951B2 (en) | ||
| JPH0118899B2 (en) | ||
| JPS6234034B2 (en) | ||
| EP3022177B1 (en) | Indole-3-carbinol derivatives | |
| JPH0244284B2 (en) | ||
| JPS604809B2 (en) | Novel 2-(m-benzoyl)phenylpropionate derivative | |
| JPS6313985B2 (en) | ||
| JPH0326180B2 (en) | ||
| JPS59161358A (en) | Novel indoleacetic acid ester derivative and its preparation | |
| JPH0219815B2 (en) | ||
| US4112114A (en) | Esters of 2-substituted-5-oxo-5H-dibenzo[a,d]cycloheptenes having pharmaceutical activity, and methods and compositions for the use thereof | |
| JPS62207236A (en) | Phenoxyalkanoic acid derivative | |
| JPS6127977A (en) | 4,5-dihydro-3,3-diphenyl-4-hydrocarbyl aminomethylfuran-2(3h)-one | |
| JPS62149672A (en) | 4h-benzo(4, 5) cyclohepta (1, 2-b) thiophene derivative | |
| JPS6130669B2 (en) | ||
| JPH02193965A (en) | Novel 2-halogenated n-indolylethyl-sulfonamide, preparation thereof,and use thereof in drug | |
| JPS6136817B2 (en) | ||
| JPH02138168A (en) | Sulfonanilide derivative | |
| KR800001215B1 (en) | Process for indole acetic ester | |
| KR800001216B1 (en) | Process for indole acetic ester |