JPH0458459B2 - - Google Patents
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- JPH0458459B2 JPH0458459B2 JP59197089A JP19708984A JPH0458459B2 JP H0458459 B2 JPH0458459 B2 JP H0458459B2 JP 59197089 A JP59197089 A JP 59197089A JP 19708984 A JP19708984 A JP 19708984A JP H0458459 B2 JPH0458459 B2 JP H0458459B2
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Description
発明の目的：
この発明は医薬として有用な新規な有機化合物
を開発し治療界に提供しようとするものである。
従来の技術：
癌治療法は外科的療法と直接或は間接に癌細胞
を死滅させる化学療法とに大別することができる
が、更に第３の方法として癌細胞の分化を促し脱
癌させる、という興味深い方法が見出されてい
る。［(a)Proc.Natl.Acad、Sci.USA 77 2936
（1980） (b)J.Med.Chem.25 1269（1982）、
Blood、62 709（1983）．(c) 細胞工学 ２ No.12
（1983）．(d)THE RECINOIDS Vol.1−２、M.
B.Sporn et al ACADEMIC PRESS 1984参照］
ビタミンＡ酸や上記参考文献(d)並びにドイツ特
許公開公報28 54 354 により式
で示される安息香酸誘導体等が薬理学的に価値有
る化合物であつて、良性又は悪性の腫瘍の局所的
又は全身的治療並びに上記疾患の予防に使用でき
ることが報告せられている。それら化合物は、ま
た、にきび、かいせん、その他の肥厚するか又は
病理的に変化した角化を伴う皮膚病やアレルギー
や炎症性疾患の全身的又は局所的治療に適してい
る。
発明の構成：
本発明は、一般式（）
（式中R1，R2，R3，R4及びR5のうち隣接するこ
とのない２つの基が独立に低中級アルキル基を示
し、他は水素原子を示す。また、R6は水酸基、
低級アルコキシ基、−NR7R6基（式中R7とR8は独
立に水素原子又は低級アルキル基を示す）を意味
し、Ｘは
OBJECT OF THE INVENTION: The purpose of this invention is to develop novel organic compounds useful as medicines and provide them to the therapeutic community. Conventional technology: Cancer treatment methods can be roughly divided into surgical therapy and chemotherapy that directly or indirectly kills cancer cells, but a third method is to promote differentiation of cancer cells to eliminate cancer. An interesting method has been discovered. [(a)Proc.Natl.Acad, Sci.USA 77 2936
(1980) (b) J.Med.Chem. 25 1269 (1982),
Blood, 62 709 (1983). (c) Cell Engineering 2 No.12
(1983). (d)THE RECINOIDS Vol.1-2, M.
B.Sporn et al ACADEMIC PRESS 1984] According to vitamin A acid and the above reference (d) as well as German Patent Publication No. 28 54 354, the formula It has been reported that benzoic acid derivatives shown in the following are pharmacologically valuable compounds and can be used for local or systemic treatment of benign or malignant tumors and prevention of the above-mentioned diseases. The compounds are also suitable for the systemic or local treatment of acne, acne, other skin diseases involving thickened or pathologically altered keratosis, as well as allergic and inflammatory diseases. Structure of the invention: The present invention is based on the general formula () (In the formula, two groups that are not adjacent among R 1 , R 2 , R 3 , R 4 and R 5 independently represent a lower intermediate alkyl group, and the others represent a hydrogen atom. Also, R 6 is a hydroxyl group. ,
Lower alkoxy group, -NR 7 R 6 group (in the formula, R 7 and R 8 independently represent a hydrogen atom or a lower alkyl group), and X is
【式】−Ｎ＝Ｎ−
を意味する）で示される安息香酸誘導体が癌細胞
殊に白血病細胞の分化を形態的及び機能的に促進
させる化合物であつて、上記の第３の方法による
癌治療に使用出来ることがわかつた。
即ち、本発明の化合物について、ヒト急性前骨
髄性白血病HL60細胞を用いて夥粒球への分化を
核の形態及びニトロブルーテトラゾリウム
（NBT）の還元能によつて判定する癌細胞の分化
誘導試験を行つたが、その方法は以下のとおりで
ある。HL−60細胞を５％牛胎児血清を含む
RPMI 1640倍地にて継代培養し、対数増殖期の
細胞が細胞数３×104／mlとなるように同培上地
で希釈調製し、次いで所定の濃度の被験薬物を加
え、５日間培養後に細胞を固定し、Wright−
Giemsa染色を行い、核の形態を判定する。
また、同様の処理によつて得た細胞を遠心分離
し一定細胞数になるように５％血清を含むRPMI
培地で希釈し、200ngのTPAを加え、0.1％の
NBTの存在下に20分37℃で培養する。次いで黒
く着色した細胞を検鏡計数し、NBT還元能のあ
る細胞の割合を算出する。
本発明の化合物はＸ基により、安息香酸とアル
キール置換フエニール基とが結合されていること
を特徴としている。その際Ｘ基がA benzoic acid derivative represented by the formula -N=N- is a compound that morphologically and functionally promotes the differentiation of cancer cells, particularly leukemia cells, and the cancer treatment according to the third method described above I found out that it can be used for. That is, the cancer cell differentiation induction test for the compound of the present invention uses human acute promyelocytic leukemia HL60 cells and determines differentiation into granulocytes based on nuclear morphology and nitroblue tetrazolium (NBT) reducing ability. The method is as follows. HL-60 cells containing 5% fetal bovine serum
Subculture in RPMI 1640 medium, dilute cells in the same medium so that the number of cells in the logarithmic growth phase is 3 x 10 4 /ml, then add the test drug at a predetermined concentration, and incubate for 5 days. After culturing, cells were fixed and Wright−
Perform Giemsa staining to determine nuclear morphology. In addition, cells obtained by the same treatment were centrifuged and mixed with RPMI containing 5% serum to maintain a constant cell number.
Dilute in medium and add 200ng TPA, 0.1%
Incubate at 37 °C for 20 min in the presence of NBT. Next, the cells colored black are counted using a microscope, and the percentage of cells capable of reducing NBT is calculated. The compound of the present invention is characterized in that benzoic acid and an alkyl-substituted phenyl group are bonded via an X group. At that time, the X group
【式】−Ｎ＝Ｎ−
であつて、R1、R2、R3、R4及びR5としては特に
中程度の大きさを有するものが有利で、殊にイソ
プロピル基、ブチル基、シクロペンチル基である
ものが良い。
R7及びR8としては水素原子、メチル基が特に
有効である。そうして、R6は水素基及びメトキ
シ基がよい。
本発明の一般式（）で示される化合物は
(a) 一般式（）の基Ｘが−CO−CH＝CH−基
を示す化合物を対応するアセトフエノン誘導体
とテレフタアルデヒド酸エステル又はその誘導
体とを塩基の存在下縮合させることにより、
(b) Ｘが−Ｎ＝Ｎ−基である化合物は対応するア
ニリンの誘導体を酸接触の存在又は非存在下で
パラニトロソ安息香酸と縮合することにより
(c) Ｘが−NH−CO−基である化合物は対応す
るアニリン誘導体をテレフタール酸の反応性誘
導体（酸ハロゲニド又はエステル等）でアシル
化することにより製造し、その様にして得られ
た化合物を所望により加水分解することにより
製造することができる。
本発明の化合物（表１）につき前述のような方
法により分化誘導試験を試みたところ、それら化
合物の活性の発現は何れも10-6モル以下の濃度で
ある。
参考例 １
176mg（１ｍmol）のｐ−tert.−ブチルアセト
フエノンと164mg（１ｍmol）のテレフタルアル
デヒド酸メチルエステルとを８mlのエタノールに
溶かし、1N苛性ソーダ10mlを加えて一晩室温で
撹拌する。反応終了後、反応液を稀塩酸で酸性に
し、酢酸エチルで抽出する。抽出液をPHが７にな
るまで水で洗い、無水硫酸ナトリウムで脱水、溶
媒を留去して（）式（R3＝ｔ−ブチル；Ｘ＝
COCH＝CH−；R6＝OHなる目的化合物を得る。
融点245〜246℃
（収率75.2％）
分析結果
C20H20O3
計算値（％） Ｃ；77.90、Ｈ；6.54
実験値（％） Ｃ；77.62、Ｈ；6.43
上記の様にして得られたカルボン酸にメタノー
ル中でジアゾメタンのエーテル溶液を加えること
により、メチルエステルが定量的に得られた。
融点 119〜120.5℃
参考例 ２
100mg（0.287ｍmol）のｐ−［(E)−２−（５，
６，７，８−テトラヒドロ−５，５，８，８−テ
トラメチル−２−ナフチル）エテニル］安息香酸
メチルエステルを５mlのクロロホルムに溶かし、
50mg（0.289ｍmol）のｍ−クロル過安息香酸を
クロロホルムに溶かした溶液に加えて２時間還流
する。原料消失後、反応液を冷却して不溶物を濾
去し、1N炭酸ソーダ水溶液、1N重炭酸ソーダ水
溶液及び飽和食塩水で順次洗つた後、無水硫酸ソ
ーダで脱水し溶媒を留去すれば、エポキシ体
（）式（R3とR4は−Ｃ（CH3）2CH2CH2C
（CH3）2−でＸは−CH−CH−基、R6＝OCH3）
が得られる。融点163〜166℃
（収率92.0％）
このエポキシ体（エステル）をエタノール中
1N苛性ソーダで加水分解し塩酸で中和した後、
酢酸エチルで抽出し、溶媒を留去し酢酸エチルか
ら再結することにより対応するカルボン酸を得
た。
融点 215〜216℃
元素分析値
C23H26O3として
計算値（％） Ｃ；78.32、Ｈ；7.48
実験値（％） Ｃ；79.03、Ｈ；7.74
参考例 ３
５，５，８，８−テトラメチル−５，６，７，
８−テトラヒドロナフタリン（1.2ｇ）を、硫酸
中で硝酸−硫酸によりニトロ化することにより、
２−ニトロ誘導体を得た。mp.71〜72℃（0.9ｇ、
メタノールから再結晶）。このニトロ体をアルコ
ール中Pd−Ｃを触媒として接触還元し、２−ア
ミノ−５，５，８，８−テトラメチル−５，６，
７，８−テトラヒドロナフタリンを得た。mp.72
〜73℃（ヘキサンから再結晶）。
このアミノ体（0.2ｇ）を酢酸（10ml）に溶か
し、トリクロル酢酸（0.1ｇ）を加え、小過剰の
４−ニトロソ安息香酸メチルエステルを混合し、
室温下２時間放置する。メタノールを留去し、メ
タノールから再結晶することにより、融点
118.5〜119.5℃のアゾ化合物（R3、R4＝−Ｃ
（CH3）2CH2CH2C（CH3）2−、R6＝OCH3、Ｘ＝
−Ｎ＝Ｎ−）0.32ｇを得る。
元素分析
C22H26N2O2
計算値 Ｃ；75.40、Ｈ；7.48、Ｎ；7.99
実験値 Ｃ；75.28、Ｈ；7.29、Ｎ；7.81
上記のアゾ化合物をメタノール中、1Nの苛性
ソーダで加水分解し、例２と同様に、あと処理す
ることにより対応するカルボン酸を得ることが出
来た。融点287〜288℃
参考例 ４
参考例３で得られたニトロ体（100mg）を、含
水テトラヒドロフラン（30ml）に溶かし、アルミ
ニウムアマルガム（アルミホイル300ｇとHgCl25
％水溶液30mlから作る）により還元し、対応する
ヒドロキシルアミン誘導体を得る。これを精製す
ることなしに、少過剰のｐ−ニトロソ安息香酸エ
チルエステルと反応させて、アゾキシ誘導体
（R3，R4＝−Ｃ（CH3）2CH2CH2C（CH3）2−、R6
＝OCH3、Ｘ＝−Ｎ＝Ｎ（Ｏ）−）を得る。mp.114
〜115℃（ヘキサンから再結晶）。MASS：
M+366
参考例 ５
参考例３によりえられた２−アミノ−５，５，
８，８−テトラメチル−５，６，７，８−テトラ
ヒドロフタリン（１ｍmol）を、テレフタル酸ク
ロリドモノメチルエステル（1.1ｍmol）とをピ
リジン中常温で反応させる、定量的収率で、一般
式（）（R3，R4＝−Ｃ（CH3）2CH2CH2C
（CH3）2−、Ｘ＝NH−CO−、R6＝OCH3）で示
される化合物が得られた。
融点211〜212℃（メチレンクロリドヘキサンから
再結晶）。
このものをメタノールに溶かし、1N苛性ソー
ダにより室温で２時間反応させ、稀塩酸で中和
し、酢酸エチルで抽出し、溶媒を留去して得られ
る結晶を酢酸エチル−ヘキサンから再結し、
mp.205.5〜206.5℃の（）式中（R3，R4＝−Ｃ
（CH3）2CH2CH2C（CH3）2−、Ｘ＝−NH−CO−、
R6＝OH）で示されるテレフタル酸アミド誘導体
を得た。
参考例 ６
３，４−ジエチル安息香酸クロリド（1.1ｍ
mol）を４−アミノ安息香酸メチルエステル（１
ｍmol）と無水ピリジン10ml中、室温で５時間反
応させる。水を加えてクロロホルムで抽出し、稀
塩酸、ついで水で洗いクロロホルムを留去する。
生成物をメタノールから再結晶し、（）式
（R3，R4＝Et、Ｘ＝−CO−NH−、R6＝OCH3）
mp.162〜165℃を得る。収率定量的。
参考例の方法に準じて本発明の化合物を製造し
た（表１参照）。表中合成法の欄の(a)−(g)の記号
はそれぞれ特許請求の範囲１中に記載の合成方法
(a)−(g)がそれら化合物の合成に使用されたことを
示すものである。[Formula] -N=N-, and R 1 , R 2 , R 3 , R 4 and R 5 are preferably of medium size, especially isopropyl, butyl, cyclopentyl The one that is the basis is good. Hydrogen atoms and methyl groups are particularly effective as R 7 and R 8 . Thus, R 6 is preferably a hydrogen group or a methoxy group. The compound represented by the general formula () of the present invention includes (a) a compound in which the group X in the general formula () represents a -CO-CH=CH- group, a corresponding acetophenone derivative and a terephthaldehydic acid ester or a derivative thereof; (b) Compounds in which X is -N=N- can be prepared by condensing the corresponding derivative of aniline with paranitrosobenzoic acid in the presence or absence of acid contact (c) Compounds in which X is an -NH-CO- group are prepared by acylating the corresponding aniline derivative with a reactive derivative of terephthalic acid (such as an acid halide or ester), and the compound thus obtained is optionally It can be produced by hydrolysis. When a differentiation induction test was attempted using the compounds of the present invention (Table 1) using the method described above, all of these compounds exhibited activity at concentrations of 10 -6 mol or less. Reference Example 1 176 mg (1 mmol) of p-tert.-butylacetophenone and 164 mg (1 mmol) of terephthalaldehyde acid methyl ester are dissolved in 8 ml of ethanol, 10 ml of 1N caustic soda is added, and the mixture is stirred overnight at room temperature. After the reaction is completed, the reaction solution is made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water until the pH reached 7, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off to obtain the formula (R 3 = t-butyl;
The target compound COCH=CH-; R 6 =OH is obtained.
Melting point 245-246℃ (yield 75.2%) Analysis result C 20 H 20 O 3 Calculated value (%) C; 77.90, H; 6.54 Experimental value (%) C; 77.62, H; 6.43 Obtained as above The methyl ester was quantitatively obtained by adding an ethereal solution of diazomethane in methanol to the prepared carboxylic acid. Melting point 119-120.5℃ Reference example 2 100 mg (0.287 mmol) of p-[(E)-2-(5,
Dissolve 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid methyl ester in 5 ml of chloroform,
A solution of 50 mg (0.289 mmol) of m-chloroperbenzoic acid in chloroform is added and refluxed for 2 hours. After the raw materials have disappeared, the reaction solution is cooled and insoluble materials are removed by filtration, washed sequentially with a 1N aqueous sodium carbonate solution, a 1N aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the epoxy compound. () Formula (R 3 and R 4 are -C(CH 3 ) 2 CH 2 CH 2 C
( CH3 ) 2- , X is -CH-CH- group, R6 = OCH3 )
is obtained. Melting point 163-166℃ (yield 92.0%) This epoxy body (ester) was dissolved in ethanol.
After hydrolysis with 1N caustic soda and neutralization with hydrochloric acid,
The corresponding carboxylic acid was obtained by extraction with ethyl acetate, evaporation of the solvent, and recrystallization from ethyl acetate. Melting point 215-216℃ Elemental analysis value C 23 H 26 O 3 Calculated value (%) C; 78.32, H; 7.48 Experimental value (%) C; 79.03, H; 7.74 Reference example 3 5, 5, 8, 8- Tetramethyl-5,6,7,
By nitrating 8-tetrahydronaphthalene (1.2 g) with nitric acid-sulfuric acid in sulfuric acid,
A 2-nitro derivative was obtained. mp.71-72℃ (0.9g,
recrystallized from methanol). This nitro compound was catalytically reduced in alcohol using Pd-C as a catalyst, and 2-amino-5,5,8,8-tetramethyl-5,6,
7,8-tetrahydronaphthalene was obtained. mp.72
~73°C (recrystallized from hexane). This amino compound (0.2 g) was dissolved in acetic acid (10 ml), trichloroacetic acid (0.1 g) was added, and a small excess of 4-nitrosobenzoic acid methyl ester was mixed.
Leave at room temperature for 2 hours. By distilling off methanol and recrystallizing from methanol, the melting point
Azo compound (R 3 , R 4 = -C
( CH3 ) 2CH2CH2C ( CH3 ) 2- , R6 = OCH3 , X =
-N=N-) 0.32 g is obtained. Elemental analysis C 22 H 26 N 2 O 2 Calculated value C; 75.40, H; 7.48, N; 7.99 Experimental value C; 75.28, H; 7.29, N; 7.81 Hydrolysis of the above azo compound with 1N caustic soda in methanol However, in the same manner as in Example 2, the corresponding carboxylic acid could be obtained by post-treatment. Melting point: 287-288°C Reference Example 4 The nitro compound (100 mg) obtained in Reference Example 3 was dissolved in hydrous tetrahydrofuran (30 ml), and aluminum amalgam (300 g of aluminum foil and HgCl 2 5
% aqueous solution) to give the corresponding hydroxylamine derivative. Without purification, this was reacted with a slight excess of p-nitrosobenzoic acid ethyl ester to form an azoxy derivative (R 3 , R 4 = -C(CH 3 ) 2 CH 2 CH 2 C(CH 3 ) 2 - , R6
= OCH 3 , X=-N=N(O)-) is obtained. mp.114
~115°C (recrystallized from hexane). MASS:
M + 366 Reference Example 5 2-Amino-5,5, obtained by Reference Example 3
The general formula ( )(R 3 , R 4 =-C(CH 3 ) 2 CH 2 CH 2 C
( CH3 ) 2- , X=NH-CO-, R6 = OCH3 ) was obtained. Melting point 211-212°C (recrystallized from methylene chloride hexane). This product was dissolved in methanol, reacted with 1N caustic soda at room temperature for 2 hours, neutralized with dilute hydrochloric acid, extracted with ethyl acetate, the solvent was distilled off, and the resulting crystals were re-crystallized from ethyl acetate-hexane.
mp.205.5~206.5℃ () In the formula (R 3 , R 4 = -C
( CH3 ) 2CH2CH2C ( CH3 ) 2- , X =-NH-CO-,
A terephthalic acid amide derivative represented by R 6 =OH) was obtained. Reference example 6 3,4-diethylbenzoic acid chloride (1.1m
mol) to 4-aminobenzoic acid methyl ester (1
mmol) in 10 ml of anhydrous pyridine at room temperature for 5 hours. Add water, extract with chloroform, wash with dilute hydrochloric acid and then water, and distill off the chloroform.
The product was recrystallized from methanol and given the formula (R 3 , R 4 = Et, X = -CO-NH-, R 6 = OCH 3 )
Obtain mp.162-165℃. Yield quantitative. The compound of the present invention was produced according to the method of Reference Example (see Table 1). The symbols (a) to (g) in the synthesis method column in the table are the synthesis methods described in claim 1, respectively.
This shows that (a)-(g) were used in the synthesis of these compounds.
【表】【table】
【表】【table】
Claims (1)
ことのない２つの基が独立に低中級アルキル基を
示し、他は水素原子を示す。また、R6は水酸基、
低級アルコキシ基、−NR7R8基（式中R7とR8は独
立に水素原子又は低級アルキル基を示す）を意味
し、Ｘは 【式】【式】−Ｎ＝Ｎ− を意味する）で示される安息香酸誘導体。[Claims] 1 General formula () (In the formula, two groups that are not adjacent among R 1 , R 2 , R 3 , R 4 and R 5 independently represent a lower intermediate alkyl group, and the others represent a hydrogen atom. hydroxyl group,
Lower alkoxy group, -NR 7 R 8 group (in the formula, R 7 and R 8 independently represent a hydrogen atom or a lower alkyl group), X means [Formula] [Formula] -N=N- ) Benzoic acid derivatives.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19708984A JPS6176440A (en) | 1984-09-19 | 1984-09-19 | Benzoic acid derivative |
| EP85108383A EP0170105B1 (en) | 1984-07-07 | 1985-07-05 | Benzoic acid derivatives |
| DE8585108383T DE3580134D1 (en) | 1984-07-07 | 1985-07-05 | BENZOESAEUR DERIVATIVES. |
| AT85108383T ATE57522T1 (en) | 1984-07-07 | 1985-07-05 | BENZOIC DERIVATIVES. |
| US06/753,036 US4703110A (en) | 1984-07-07 | 1985-07-08 | Benzoic acid derivatives having a para substituent which is a substituted phenyl group connected by a linking radical; useful in neoplastic cell differentiation and diagnosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19708984A JPS6176440A (en) | 1984-09-19 | 1984-09-19 | Benzoic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6176440A JPS6176440A (en) | 1986-04-18 |
| JPH0458459B2 true JPH0458459B2 (en) | 1992-09-17 |
Family
ID=16368539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19708984A Granted JPS6176440A (en) | 1984-07-07 | 1984-09-19 | Benzoic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6176440A (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4939156A (en) * | 1987-07-11 | 1990-07-03 | Meiji Seika Kaisha, Ltd. | New tetramethyl-cis-diaza-bicyclo{4.2.0}octane-3,5-dione derivatives having differentiation-inducing activity and antiviral activity |
| KR960014911B1 (en) * | 1990-03-20 | 1996-10-21 | 시오노기세이야꾸 가부시끼가이샤 | New preparation method of benzoic acid derivative |
| ATE365158T1 (en) | 1999-04-28 | 2007-07-15 | Inst Med Molecular Design Inc | PYRIMIDINE CARBOXYLIC ACID DERIVATIVES |
| ES2349461T3 (en) | 2000-09-01 | 2011-01-03 | Toko Pharmaceutical Ind. Co. Ltd | CRYSTAL PRODUCTION PROCEDURE OF A BENZOIC ACID DERIVATIVE. |
| CA2432409A1 (en) | 2000-12-26 | 2002-07-11 | Research Foundation Itsuu Laboratory | Tropolone derivative |
| WO2002064601A1 (en) | 2001-02-09 | 2002-08-22 | Hiroyuki Kagechika | Dicarba-closo-dodecarborane derivatives |
| US20050202055A1 (en) * | 2004-03-11 | 2005-09-15 | Koichi Shudo, Tokyo, Japan | Anti-wrinkle agent |
| WO2007029760A1 (en) | 2005-09-09 | 2007-03-15 | R & R Inc. | Pharmaceutical for use in prevention and/or treatment of bowel disease |
| JP2008179570A (en) * | 2007-01-25 | 2008-08-07 | R&R Inc | Medicine for preventing and/or treating internal organ adhesion |
| US7902260B2 (en) | 2007-02-28 | 2011-03-08 | Kemphys Ltd. | Medicament for preventive and/or therapeutic treatment of lower urinary tract symptom |
| EP2143428B1 (en) | 2007-03-30 | 2015-11-04 | TMRC Co., Ltd. | Tamibarotene capsule preparation |
| CN101821229B (en) | 2007-08-15 | 2013-06-05 | 财团法人乙卯研究所 | Tricyclic amine compound |
| EP2189443B1 (en) | 2007-08-15 | 2013-10-23 | Research Foundation Itsuu Laboratory | Tricyclic amide compound |
| EA201070272A1 (en) | 2007-08-15 | 2010-10-29 | Рисерч Фаундейшн Ицуу Лэборетери | 5-MEMBER HETEROCYCLIC COMPOUND |
| CN101888991A (en) | 2007-10-31 | 2010-11-17 | 财团法人乙卯研究所 | Retinoid Prodrug Compounds |
| WO2013005753A1 (en) | 2011-07-05 | 2013-01-10 | 公益財団法人乙卯研究所 | Deuterated phenylpropionic acid derivative |
| WO2025018279A1 (en) | 2023-07-14 | 2025-01-23 | 国立大学法人 岡山大学 | Therapeutic agent for human graft versus host disease and combination thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5528911A (en) * | 1978-08-21 | 1980-02-29 | Nippon Chemiphar Co Ltd | New penicillin and cephalosporin derivative and their preparation |
| DE3202065A1 (en) * | 1982-01-23 | 1983-08-04 | Basf Ag, 6700 Ludwigshafen | Substituted N-(5-tetrazolyl)benzamides, the preparation thereof and pharmaceutical compositions containing these |
| JPS58164603A (en) * | 1982-03-24 | 1983-09-29 | Tatatomi Nishikubo | Production of self-sensitizing photopolymer |
| JPS6122047A (en) * | 1984-07-07 | 1986-01-30 | Koichi Shiyudo | Benzoic acid derivative |
-
1984
- 1984-09-19 JP JP19708984A patent/JPS6176440A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6176440A (en) | 1986-04-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |