JPS6122047A - Benzoic acid derivative - Google Patents

Benzoic acid derivative

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Publication number
JPS6122047A
JPS6122047A JP14119484A JP14119484A JPS6122047A JP S6122047 A JPS6122047 A JP S6122047A JP 14119484 A JP14119484 A JP 14119484A JP 14119484 A JP14119484 A JP 14119484A JP S6122047 A JPS6122047 A JP S6122047A
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Japan
Prior art keywords
group
derivative
formula
acid
tables
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.)
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JP14119484A
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Japanese (ja)
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JPH0458458B2 (en
Inventor
Koichi Shiyudo
紘一 首藤
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Individual
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Individual
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Priority to JP14119484A priority Critical patent/JPS6122047A/en
Priority to EP85108383A priority patent/EP0170105B1/en
Priority to AT85108383T priority patent/ATE57522T1/en
Priority to DE8585108383T priority patent/DE3580134D1/en
Priority to US06/753,036 priority patent/US4703110A/en
Publication of JPS6122047A publication Critical patent/JPS6122047A/en
Publication of JPH0458458B2 publication Critical patent/JPH0458458B2/ja
Granted legal-status Critical Current

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  • Epoxy Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

NEW MATERIAL:The benzoic acid derivative of formula I (R1 and R2 are H, lower or medium alkyl or together form a 5-6-membered cycloalkyl, at least one of R1 and R2 is not H; R3 is OH, lower alkoxy or -NR4R5; R4 and R5 are H or lower alyl; X is group of formula II, formula III, -N=N-, etc.; R6 and R7 are H or lower alkyl). USE:It has the activity to morphologically and functionally promote the differentiation of cancer cell, especially leukemia cell, and is useful as a drug. PREPARATION:The objective compound of formula I can be prepared by condensing the compound of formula I wherein X is -CO-C(R6)=CH- with corresponding acetophenone derivative and a terephthalaldehydic acid ester or its derivative in the presence of a base. As an alternative method, the objective compound wherein the group X is formula III is produced by oxidizing a compound wherein the corresponding group X is C(R6)=C(R7) with an epoxidizing agent.

Description

【発明の詳細な説明】 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。DETAILED DESCRIPTION OF THE INVENTION Object of the Invention: The present invention seeks to develop and provide to the therapeutic community novel organic compounds useful as pharmaceuticals.

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、さらに第３
の方法として癌細胞の分化を促し脱硼さぜるという興味
深い方法が見出されている。Conventional technology: Cancer treatment methods can be broadly divided into surgical therapy and chemotherapy that directly or indirectly kills cancer cells.
As a method for this, an interesting method has been discovered that promotes the differentiation of cancer cells and removes their ossification.

［Ｐｒｏｃ、Ｎａｔｌ、Ａｃａｄ、Ｓｃ１．ＵＳＡ　７
７２９３Ｂ　（１９８０）、Ｊ、Ｍｅｄ、Ｃｈｅｍ、’
−２５１２６９（１９８２）、Ｂｌｏｏｄ、８２７０９
（＋９８３）、細胞工学　Ｌ　　Ｎｏ、１２　（１９８
３）、］ドイツ特許公開公報２８５４３５４　　により
一般式で示される安息香酸誘導体等が薬理学的に価値有
る化合物であって、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ｈている。それら化合物は、また、にきび、か′い
ぜん、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。[Proc, Natl, Acad, Sc1. USA 7
7293B (1980), J.Med.Chem.'
-251269 (1982), Blood, 82709
(+983), Cell Engineering L No. 12 (198
3),] Benzoic acid derivatives represented by the general formula according to German Patent Publication No. 2854354 are pharmacologically valuable compounds and are used for the local or systemic treatment of benign or malignant tumors and the prevention of the above-mentioned diseases. We are reporting what we can do. The compounds are also suitable for the systemic or local treatment of acne, acne, other skin diseases involving thickened or pathologically altered keratosis, allergies and inflammatory diseases.

発明の構成： いま、一般式（Ｉ） 式中Ｒ工及び、Ｒ２は水素原子、低中級アルキールを示
し、両者が一緒になってシクロアルキール基を形成する
ことができるが、双方が共に水素原子であってはならず
、Ｒ３は水酸基、低級アルコキシ基、−ＮＲ６Ｒ７基（
式中Ｒ６とＲ７とは水素原子又は低級アルキール基を示
す）をそしてＸは〇− を意味する、て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
であって、上記の第３の方法による癌治療に使用出来る
ことが判った。Structure of the invention: Now, general formula (I) In the formula, R and R2 represent a hydrogen atom or a lower intermediate alkyl, and both can form a cycloalkyl group together, but when both are hydrogen It must not be an atom, and R3 is a hydroxyl group, lower alkoxy group, -NR6R7 group (
In the formula, R6 and R7 represent a hydrogen atom or a lower alkyl group), and X represents 〇-. The benzoic acid derivative shown in the formula promotes the differentiation of cancer cells, especially leukemia cells, both morphologically and functionally. It has been found that the compound can be used for cancer treatment according to the third method described above.

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細胞を用いて移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）の還元能によっ
て判定する癌細胞の分化誘導試験を行ったが、その方法
は以下の通りである。Specifically, the compound of the present invention was subjected to a cancer cell differentiation induction test using human acute promyelocytic leukemia HL60 cells, in which differentiation into granulocytes was determined by nuclear morphology and nitroblue tetrazolium (NBT) reducing ability. However, the method is as follows.

ＨＬ−６０細胞を５％牛脂児血清を含むＲＰＭｌ　１８
４０培地にて継代培養し、対数増殖期の細胞が細胞数３
Ｘ１０　　／鵬ｌとなるように同上培地で希釈調製し、
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、ｆｒｉｇｈｔ−Ｇｌｅｍｓａ染色を行い、
核の形態を判定する。HL-60 cells in RPM1 containing 5% tallow serum 18
40 medium, and the number of cells in logarithmic growth phase is 3.
Dilute with the same medium to give a ratio of X10/Peng,
Next, a predetermined concentration of the test drug was added, and after culturing for 5 days, the cells were fixed and subjected to flight-Glemsa staining.
Determine nuclear morphology.

また、同様の処理によっ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ＲＰＮ　Ｉ培地で希釈
し、２００ｎｇのＴＰＡを加え、０．１％のＮＢＴの存
在下に２０分３７″Ｃ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。In addition, cells obtained by the same treatment were centrifuged, diluted with RPN I medium containing 5% serum to a constant cell number, added with 200 ng of TPA, and incubated in the presence of 0.1% NBT for 20 minutes. Culture at 37''C. Next, black colored cells are counted using a microscope, and the percentage of cells capable of reducing NBT is calculated.

本発明の化合物はＸ基により、安息香酸とアルキール置
換フェ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 てあって、Ｒ□及びＲ２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、
シクロペンチル基のもの及びＲ１及びＲ２が一緒になっ
て、５又は６員環状アルキル基であるものが良い。これ
に反してＲ□及びＲ２が共に、水素原子のものには殆ど
効果が認められない。The compound of the present invention is characterized in that benzoic acid and an alkyl-substituted phenyl group are bonded through an X group. In this case, it is advantageous to have an X group and R□ and R2 of medium size, in particular isopropyl, butyl,
Those with a cyclopentyl group and those where R1 and R2 together are a 5- or 6-membered cyclic alkyl group are preferred. On the other hand, almost no effect is observed when both R□ and R2 are hydrogen atoms.

Ｒ６及びＲ７としては水素原子、メチル基が特に有効で
ある。そうして、Ｒ３は水酸基及びメトキシ基がよい。Hydrogen atoms and methyl groups are particularly effective as R6 and R7. Thus, R3 is preferably a hydroxyl group or a methoxy group.

本発明の一般式（Ｉ）で示される化合物は（ａ、）一般
式（Ｉ）の基Ｘが−Ｃｏ−Ｃ（Ｒ６）＝ＣＨ−基を示す
化合物を対応するアセトフェノン誘導体とテレフタルア
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、 を示す化合物を対応するＸ基が −Ｃ（Ｒ）＝Ｃ，（Ｒ７）−基 を示す化合物をエポキシ化剤を用いて酸化することによ
り （ｃ）Ｘが−Ｎ＝Ｎ−基である化合物は対応するアニリ
ンの誘導体を酸触媒の存在又は非存在下でバラニトロソ
安息香酸と縮合することにより（ｄ）Ｘが−Ｎ（０）＝
Ｎ−基または−Ｎ＝Ｎ（０）−基である化合物は 対応するフェニルヒドロキシアミンとパラニトロソ安息
香酸又はその誘導体とを（Ｃ）項におけると同様に縮合
させることにより （ｅ）Ｘが−Ｎ＝Ｎ（０）−基または−Ｎ（０）＝Ｎ−
基である化合物は対応するニトロソベンゼン誘導体とバ
ラヒドロキシアミノ安息香酸又はその誘導体と（Ｃ５項
におけると同様に縮合させことにより （ｆ）Ｘが−Ｎ　（Ｒ６）−Ｃ（０）−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 （ｇ）Ｘが一〇（０）−Ｎ（Ｒ６）−である化合物はパ
ラアミノ安息香酸又はその誘導体を、対応する安息香酸
の反応性誘導体（酸ハロゲン又はエステル等）で常法に
より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。The compound represented by the general formula (I) of the present invention includes (a) a compound in which the group X of the general formula (I) represents a -Co-C(R6)=CH- group, a corresponding acetophenone derivative and a terephthalaldehyde acid ester; or a derivative thereof in the presence of a base, and by oxidizing a compound in which the corresponding X group represents a -C(R)=C, (R7)- group using an epoxidizing agent. (c) Compounds in which X is -N=N- can be prepared by condensing the corresponding aniline derivative with varanitrosobenzoic acid in the presence or absence of an acid catalyst (d) in which X is -N(0)=
Compounds in which the N- group or -N=N(0)- group can be prepared by condensing the corresponding phenylhydroxyamine and para-nitrosobenzoic acid or its derivatives in the same manner as in section (C). =N(0)- group or -N(0)=N-
The compound which is a group is condensed with the corresponding nitrosobenzene derivative and parahydroxyaminobenzoic acid or a derivative thereof (as in Section C5), whereby (f) X is -N (R6)-C(0)- group. Compounds can be prepared by acylating the corresponding aniline derivative with a reactive derivative of terephthalic acid (such as an acid halide or ester). Produce the derivative by acylating it with the corresponding reactive derivative of benzoic acid (acid halogen or ester, etc.) in a conventional manner, and optionally hydrolyze the compound thus obtained. I can do it.

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。その中、
特に強力なもの例えばＲ□、Ｒ２がエチル基、ｔ−ブチ
ル基、又は両者が一緒になって６員環状アルキル基を形
成している化合物は表２から明らかなように１０　ない
し１ｏ−１０モルでも活性を示している。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 a concentration of 10-6 mol or less. Among them,
Particularly strong compounds, such as compounds in which R□ and R2 are ethyl groups, t-butyl groups, or both together form a 6-membered cyclic alkyl group, have a concentration of 10 to 10-10 moles, as shown in Table 2. However, it is showing activity.

爽五桝−１ １７８ｍｇ　（１ｍ１ｏｌ）のｐ　−ｔｅｒｔ、−ブチ
ルアセトフェノンと１６４ｍｇ（１腸１ｄｏｌ）のテレ
フタルアルデヒド 溶かし、ＩＮ苛性ソーダＩＯｍ＋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（Ｉ）
式（Ｒ□＝ｔ−ブチル；Ｒ２＝Ｈ１Ｘ＝ＣＯＣＨ＝ＣＨ
−；Ｒ３＝ＯＨ）なる目的化合物を得る。融点２４５〜
２４６°Ｃ（収率７５．２％） 分析結果　（、ＨＯ 計算値（％）　　Ｃ；７７．９０　、Ｈ；６．５４実験
値（％）　　Ｃ；７７．８２　、Ｈ；ｌｉ、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。Sōgomasu-1 178 mg (1 ml) of p-tert,-butylacetophenone and 164 mg (1 dol per infusion) of terephthalaldehyde were dissolved, IN caustic soda IOm+ was added, and the mixture was 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 (I)
Formula (R□=t-butyl; R2=H1X=COCH=CH
-; R3=OH) is obtained. Melting point 245~
246°C (yield 75.2%) Analysis result (, HO Calculated value (%) C; 77.90, H; 6.54 Experimental value (%) C; 77.82, H; li, 43 above The methyl ester was quantitatively obtained by adding an ethereal solution of diazomethane in methanol to the carboxylic acid obtained in the same manner.

融点　１１９〜１２０．５’　Ｃ 同様にして、式（Ｉ）中Ｒ□とＲ２とが−Ｃ（ＣＨ３）
２ＣＨ２ＣＨ２Ｃ（ＣＨ３）２−で示され、Ｘは＝ＣＨ
・ＣＨ＝ＣＨ−基で、ＲがＯＨ及びＯＣＨ３である化合
物を得ることができた。Melting point 119-120.5'C Similarly, in formula (I), R□ and R2 are -C(CH3)
2CH2CH2C(CH3)2-, X is =CH
- It was possible to obtain compounds in which the group CH=CH- and R is OH and OCH3.

１００　ｍｇ　（０，２８７ｍｍｏｌ）の１）−［（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）エテニルコ安息香
酸メチルエステル ｍｇ　（０．２８９　ｍｍｏｌ）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。100 mg (0,287 mmol) of 1)-[(E
)-2-(5,6゜7.8-tetrahydro-5,5,8
, 8-tetramethyl-2-naphthyl) ethenylcobenzoic acid methyl ester (mg (0.289 mmol)) was added to a solution of m-chloroperbenzoic acid dissolved in chloroform and refluxed for 2 hours.

原料消失後、反．応液を冷却して不溶物を濾去し、ＩＮ
炭酸ソーダ水溶液、ＩＮ重炭酸ソーダ水溶液及び飽和食
塩水で順次洗った後、無水硫酸ソーダで脱水し溶媒を留
去すれば、エポキシ体（Ｉ）式％式％） このエポキシ体（エステル）をエタノール中ＩＮ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。After the raw materials disappeared, the The reaction solution was cooled, insoluble matters were removed by filtration, and IN
After sequentially washing with an aqueous solution of sodium carbonate, an aqueous IN sodium bicarbonate solution, and saturated saline, dehydration is performed over anhydrous sodium sulfate and the solvent is distilled off. After hydrolysis with caustic soda and neutralization with hydrochloric acid, extraction was performed with ethyl acetate, the solvent was distilled off, and the corresponding carboxylic acid was obtained by recrystallization from ethyl acetate.

融点　２１５〜２１Ｂ”Ｃ 元素分析　Ｃ２３Ｈ２６０３として 計算値（％）　　Ｃ　；７Ｂ．８２　、Ｈ　；７．４Ｂ
実験値（％）　　Ｃ　；７９．０３　、Ｈ　；７．７４
実１１殉−」Ｌ ５、５，８．８−テトラメチル−５．８．７．８−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。ｒｒｌ．７１〜７２’Ｃ（０．９　ｇ，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−５．８，７．８−テトラヒドロナフ
タリンを得た。ｍｐ．７２〜７３°Ｃ（ヘキサンから再
結晶このアミノ体（０．２　ｇ）を酢酸（１０＋ｌ）に
溶カし、トリクロル酢酸（０．１　ｇ）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”Ｃのアゾ化合物（Ｒ，Ｒ＝−：ｑ（ＣＨ３■Ｈ２Ｃ
ＩＩ２Ｃ（ＣＨ３）２−、Ｒ３＝ＯＣＨ３、Ｘ＝−Ｎ＝
Ｎ−）０．３２ｇを得る。Melting point 215-21B"C Elemental analysis Calculated value as C23H2603 (%) C; 7B.82, H; 7.4B
Experimental value (%) C: 79.03, H: 7.74
5,5,8.8-tetramethyl-5.8.7.8-tetrahydronaphthalene (1.2 g) was dissolved in sulfuric acid with nitric acid.
A 2-nitro derivative was obtained by nitration with sulfuric acid. rrl. 71-72'C (0.9 g, recrystallized from methanol). This nitro body was converted into Pd-
Catalytic reduction using C as a catalyst, 2-amino-5.5.8.
8-tetramethyl-5.8,7.8-tetrahydronaphthalene was obtained. mp. 72-73°C (recrystallized from hexane) Dissolve this amino compound (0.2 g) in acetic acid (10+l), add trichloroacetic acid (0.1 g), and add a small excess of 4-nitrosobenzoic acid methyl ester. were mixed and allowed to stand at room temperature for 2 hours. Methanol was distilled off and recrystallized from methanol, resulting in a solution with a melting point of 118, 5 to 119.
5”C azo compound (R, R=-:q(CH3■H2C
II2C(CH3)2-, R3=OCH3, X=-N=
Obtain 0.32 g of N-).

元素分析　　Ｃ２２Ｈ２６Ｎ２０２ 計算値　　　Ｃ　；　７５．４０　、Ｈ　；　７．４８
，　Ｎ　；　７．９９実験値　　　Ｃ　；　７５．２１
１　、Ｈ　；　７．２９、Ｎ　；　７．８１上記のアゾ
化合物をメタノール中、ＩＮ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’　
Ｃ 実［ 実施例３で得られたニトロ体（１００■ｇ）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３００ｍｇと■ｇｃ１２５％
水溶液３０１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−ニトロン安息香酸メチルエステルと反応
させて、アゾキシ誘導体（Ｒ□ｌ　Ｒ２＝−　Ｃ　（Ｃ
１１３）２ＣＨ２Ｃ１１２Ｃ（ＣＩ（３）２．−、Ｒ３
＝ＯＣＨ３、Ｘ＝−Ｎ＝Ｎ　（０）−）を得る。Elemental analysis C22H26N202 Calculated value C; 75.40, H; 7.48
, N; 7.99 Experimental value C; 75.21
1, H; 7.29, N; 7.81 The above azo compound was hydrolyzed with IN caustic soda in methanol, and the corresponding carboxylic acid could be obtained by post-treatment in the same manner as in Example 2. . Melting point 287-288'
C Fruit [The nitro compound (100 g) obtained in Example 3 was dissolved in water-containing tetrahydrofuran (30 ml), and aluminum amalgam (300 mg of aluminum foil and gc 125%
(prepared from aqueous solution 301) to obtain the corresponding hydroxylamine derivative. Without purification, this was reacted with a slight excess of p-nitrone benzoic acid methyl ester to form an azoxy derivative (R□l R2=-C (C
113) 2CH2C112C (CI(3)2.-, R3
=OCH3, X=-N=N (0)-) is obtained.

ｍｐ．　　１　１　４　〜１　１　５°Ｃ（ヘキサンか
ら再結晶）。ＭＡＳＳ　：Ｍ”　＝３８８ 実［ 実施例３により得られた２−アミノ−５，５。mp. 114-115°C (recrystallized from hexane). MASS: M'' = 388 Real 2-amino-5,5 obtained according to Example 3.

８、８−テトラメチル−５．８，７．８−テトラヒドロ
ナフタリン（１鵬鳳Ｏｌ）とテレフタル酸クロリドモノ
メチルエステル ン中常温で反応させる、定量的収率で、一般式（％式％
） される化合物が得られた。8,8-Tetramethyl-5.8,7.8-tetrahydronaphthalene (1Pengfeng Ol) is reacted with terephthalic acid chloride monomethyl esterne at room temperature, with quantitative yield, general formula (% formula %
) A compound was obtained.

融点２１１〜２１２°Ｃ（メチレンクロリドヘキサンか
ら再結晶）。Melting point 211-212°C (recrystallized from methylene chloride hexane).

このものをメタノールに溶かし、ＩＮ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Ｘ　ｍｐ。This material was dissolved in methanol, reacted with IN caustic soda at room temperature for 2 hours, neutralized with dilute hydrochloric acid, extracted with ethyl acetate, the solvent was distilled off, and the obtained crystals were re-consolidated from ethyl acetate-hexane. .

２０５、５〜２０８．５’Ｃの（Ｉ）式中（Ｒ□ｌ　Ｒ
２　＝−Ｃ（ＣＨ３）２ＣＨ２ＣＭ２Ｃ（Ｃ［１３）２
７、ｘ＝−ＮＨ−ＣＯ−、Ｒ３＝ＯＨ）で示される、テ
レフタル酸アミド誘導体を得た。205,5-208.5'C in formula (I) (R□l R
2 =-C(CH3)2CH2CM2C(C[13)2
7, x=-NH-CO-, R3=OH), a terephthalic acid amide derivative was obtained.

実［ ３、４−ジエチル安息香酸クロリド（１．１ｍ腸ｏ１）
を４−アミ７安息香酸メチルエステル（１ｍｍｏｌ）と
無水ピリジン１０１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、（Ｉ）式（Ｒ．Ｒ＝Ｅｔ，Ｘ＝−ＣＯ−ＮＨ−、
Ｒ＝ＯＣＨ３）ｍｐ．１８２〜１６５°Ｃを得る。収率
定量的。Fruit [3,4-diethylbenzoic acid chloride (1.1 m intestine o1)
is reacted with 4-ami7benzoic acid methyl ester (1 mmol) in anhydrous pyridine 101 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 is recrystallized from methanol and has the formula (I) (R.R=Et, X=-CO-NH-,
R=OCH3)mp. Obtain 182-165°C. Yield quantitative.

同様にして次表の化合物が合成された。表中合成法の欄
のａ）−ｆ）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）−ｆ）がその合成に使用されたことを
示している。The compounds shown in the following table were synthesized in the same manner. The symbols a) to f) in the synthesis method column in the table indicate that the synthesis methods a) to f) described in claim 1 were used for the synthesis, respectively.

〕喀１０　　　　００　　　＋　　　油　魅゛僧　−　
−　油　　　　国　ρ　　　ρ　　　−　油℃７ 手続補正書（自発） 昭和５９年９月１９日 昭和５９年特許願第１４１１８４号 ３、補正をする者 事件との関係：特許出願人 住所　東京都目黒区東山２−２５　三宿住宅８−１０２
氏名　首藤　紘− ４、代理人 住所　東京都渋谷区神宮前２−２−３９−４１７あるを
「（Ｒ１，Ｒ２・・・」と訂正し、同８行目に「Ｒ＝Ｏ
ＣＨ３）」とあるを「Ｒ３＝ＯＣＨ３）」と訂正する。] 10 00 + oil charmer -
- Oil country ρ ρ - Oil ℃7 Procedural amendment (voluntary) September 19, 1980 Patent application No. 141184 of 1981 3, Person making the amendment Relationship to the case: Patent applicant address Higashiyama, Meguro-ku, Tokyo 2-25 Mishuku Jutaku 8-102
Name: Hiro Shuto-4, Agent Address: 2-2-39-417 Jingumae, Shibuya-ku, Tokyo Aru was corrected to “(R1, R2...”), and “R=O” was added to the 8th line of the same line.
CH3)” should be corrected to read “R3=OCH3).”

（３）同第５頁５行のｒ−ＮＲ６Ｒ７基（式中Ｒ６とＲ
とは」をｒ＝、ＮＲＲ基（式中ＲとＲとは」と訂正し、
同頁８行及び同第１頁下より４行目に続けて、それぞれ
行を改めて、「（式中Ｒ６とＲとは水素または低級アル
キル基を示す）」を挿入する。(3) r-NR6R7 group on page 5, line 5 (in the formula, R6 and R
"What is " is corrected to r=, NRR group (in the formula, R and R are"),
Continuing from line 8 of the same page and line 4 from the bottom of the first page of the same page, insert "(in the formula, R6 and R represent hydrogen or a lower alkyl group)" in each new line.

（４）萌細書の末頁の表２にｒ−Ｃｏ−ＣＨ＝ＣＨ−Ｊ
とあるを、ｒ−ｃｏ−ｃＨ＝ｃＨ−」と訂正する。(4) In Table 2 on the last page of Moesaisho, r-Co-CH=CH-J
Correct the statement to read "r-co-cH=cH-".

手続補正書（方式） １．事件の表示 安息香酸誘導体 ３、補正をする者 事件との関係：特許出願人 ４、代理人 住所　東京都渋谷区神宮前２−２−３９−４１７住所　
東京都渋谷区神宮前２−２−３９−４１７昭和５９年１
０月９日（発送日：昭和５９年１０月３０日）師塾・−
１九今りProcedural amendment (formality) 1. Case description Benzoic acid derivative 3, person making the amendment Relationship to the case: Patent applicant 4, agent address: 2-2-39-417 Jingumae, Shibuya-ku, Tokyo
1981 2-2-39-417 Jingumae, Shibuya-ku, Tokyo
October 9th (Shipping date: October 30th, 1981) Shijuku -
19th anniversary

Claims (3)

【特許請求の範囲】[Claims] （１）一般式（ I ） 式中Ｒ＿１及びＲ＿２は水素原子、低中級アルキールを
示し、また両者が一緒になって５〜６員環のシクロアル
キール基を形成することができるが、双方が共に水素原
子であってはならず、Ｒ＿３は水酸基、低級アルコキシ
基、−ＮＲ＿４Ｒ＿５基（式中Ｒ＿４とＲ＿５は水素原
子又は低級アルキール基を示す）を意味し、Ｘは ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼
、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、▲数式、化学式、表等があります▼
、 ▲数式、化学式、表等があります▼ を意味するで示される安息香酸誘導体(1) General formula (I) In the formula, R_1 and R_2 represent a hydrogen atom or a lower intermediate alkyl, and both can be combined to form a 5- to 6-membered cycloalkyl group, but both Both cannot be hydrogen atoms, R_3 means a hydroxyl group, lower alkoxy group, -NR_4R_5 group (in the formula, R_4 and R_5 represent a hydrogen atom or a lower alkyl group), and X is a ▲ mathematical formula, chemical formula, table, etc. There are ▼, ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Benzoic acid derivatives denoted by （２）（ａ）一般式（ I ）の基Ｘが−ＣＯ−Ｃ（Ｒ＿
６）＝ＣＨ−基を示す化合物を対応するアセトフェノン
誘導体とテレフタル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▲数式、化学式、表等があります▼基 を示す化合物を対応するＸ基が ▲数式、化学式、表等があります▼基 を示す化合物をエポキシ化剤を用いて酸化することによ
り （ｃ）Ｘが−Ｎ＝Ｎ−基である化合物は対応するアニリ
ンの誘導体を酸触媒の存在又は非存在下でパラニトロソ
安息香酸エステルと縮合することにより （ｄ）Ｘが−Ｎ（Ｏ）＝Ｎ−基または−Ｎ＝Ｎ（Ｏ）−
基である化合物は対応するフェニルヒドロキシアミンと
パラニトロソ安息香酸又はその誘導体とを（ｃ）項にお
けると同様に縮合させることにより （ｅ）Ｘが−Ｎ＝Ｎ（Ｏ）−基または−Ｎ（Ｏ）＝Ｎ−
基である化合物を対応するニトロソベンゼン誘導体とパ
ラヒドロキシアミノ安息香酸又はその誘導体と（ｃ）項
におけると同様に縮合させことにより （ｆ）Ｘが−Ｎ（Ｒ＿６）−Ｃ（Ｏ）−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 （ｇ）Ｘが−Ｃ（Ｏ）−Ｎ（Ｒ＿６）−である化合物は
パラアミノ安息香酸又はその誘導体を、対応する安息香
酸の反応性誘導体（酸ハロゲニド又はエステル等）で常
法により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
ことを特徴とする一般式（ I ） ▲数式、化学式、表等があります▼（ I ） （式中Ｒ＿１、Ｒ＿２、Ｒ＿３、Ｒ＿４、Ｒ＿５、Ｒ＿
６及びＲ＿７は上記の意味を有する）で示される安息香
酸誘導体の製造方法(2) (a) Group X in general formula (I) is -CO-C(R_
6) By condensing a compound showing a =CH- group with a corresponding acetophenone derivative and a terephthalaldehyde acid ester or its derivative in the presence of a base, (b) By oxidizing the compound showing the group using an epoxidizing agent, the corresponding X group is ▲ There are mathematical formulas, chemical formulas, tables, etc. By condensing a derivative of aniline with paranitrosobenzoic acid ester in the presence or absence of an acid catalyst, (d) X is an -N(O)=N- group or -N=N(O)-
(e) X is -N=N(O)- group or -N(O )=N-
(f) X is a -N(R_6)-C(O)- group by condensing the compound with the corresponding nitrosobenzene derivative and parahydroxyaminobenzoic acid or its derivative in the same manner as in section (c). (g) Compounds where X is -C(O)-N(R_6)- can be prepared by acylating the corresponding aniline derivative with a reactive derivative of terephthalic acid (such as an acid halide or ester). or a derivative thereof, with a corresponding reactive derivative of benzoic acid (acid halide or ester, etc.) by a conventional method, and the compound thus obtained is hydrolyzed as desired. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1, R_2, R_3, R_4, R_5, R_
6 and R_7 have the above meanings) （３）一般式（ I ）で示される安息香酸誘導体を含有
することを特徴とする癌細胞殊に白血病細胞の分化誘導
剤(3) An agent for inducing differentiation of cancer cells, particularly leukemia cells, characterized by containing a benzoic acid derivative represented by general formula (I)
JP14119484A 1984-07-07 1984-07-07 Benzoic acid derivative Granted JPS6122047A (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP14119484A JPS6122047A (en) 1984-07-07 1984-07-07 Benzoic acid derivative
EP85108383A EP0170105B1 (en) 1984-07-07 1985-07-05 Benzoic acid derivatives
AT85108383T ATE57522T1 (en) 1984-07-07 1985-07-05 BENZOIC DERIVATIVES.
DE8585108383T DE3580134D1 (en) 1984-07-07 1985-07-05 BENZOESAEUR 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
JP14119484A JPS6122047A (en) 1984-07-07 1984-07-07 Benzoic acid derivative

Publications (2)

Publication Number Publication Date
JPS6122047A true JPS6122047A (en) 1986-01-30
JPH0458458B2 JPH0458458B2 (en) 1992-09-17

Family

ID=15286342

Family Applications (1)

Application Number Title Priority Date Filing Date
JP14119484A Granted JPS6122047A (en) 1984-07-07 1984-07-07 Benzoic acid derivative

Country Status (1)

Country Link
JP (1) JPS6122047A (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6176440A (en) * 1984-09-19 1986-04-18 Koichi Shiyudo Benzoic acid derivative
JP2004529085A (en) * 2001-01-18 2004-09-24 ウェリケム バイオテック インコーポレーテッド Novel 1,2-diphenylethene derivatives for treating immune diseases
US6869959B1 (en) 1999-04-28 2005-03-22 Institute Of Medicinal Molecular Design Inc. Heterocyclic carboxylic acid derivatives
WO2005087220A1 (en) * 2004-03-11 2005-09-22 R & R Inc. Antiwrinkling preparation
US7259187B2 (en) 2000-12-26 2007-08-21 Research Foundation Itsuu Laboratory Tropolone derivatives
US7314639B2 (en) 2000-09-01 2008-01-01 Toko Pharmaceutical Ind. Co., Ltd. Process for the production of crystals of a benzoic acid derivative
JP2008179570A (en) * 2007-01-25 2008-08-07 R&R Inc Medicine for preventing and/or treating internal organ adhesion
WO2009022720A1 (en) 2007-08-15 2009-02-19 Research Foundation Itsuu Laboratory Five-membered heterocyclic compound
WO2009022722A1 (en) 2007-08-15 2009-02-19 Research Foundation Itsuu Laboratory Tricyclic amine compound
US7902260B2 (en) 2007-02-28 2011-03-08 Kemphys Ltd. Medicament for preventive and/or therapeutic treatment of lower urinary tract symptom
US8071647B2 (en) 2005-09-09 2011-12-06 Kemphys Ltd. Method for treatment of adhesion of the intestines
US8232300B2 (en) 2007-08-15 2012-07-31 Research Foundation Itsuu Laboratory Tricyclic amide compound
WO2013005753A1 (en) 2011-07-05 2013-01-10 公益財団法人乙卯研究所 Deuterated phenylpropionic acid derivative
US8633335B2 (en) 2007-10-31 2014-01-21 Research Founation Itsuu Laboratory Retinoid prodrug compound
JP2017160261A (en) * 2017-06-12 2017-09-14 チョンシー ユー Positively charged water-soluble prodrugs of retinoids and retinoid-like compounds with very high skin penetration rates

Citations (3)

* Cited by examiner, † Cited by third party
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
JPS58128340A (en) * 1982-01-23 1983-07-30 バスフ　アクチエンゲゼルシヤフト Phenylethylene derivative, manufacture and medicine
JPS58164603A (en) * 1982-03-24 1983-09-29 Tatatomi Nishikubo Production of self-sensitizing photopolymer

Patent Citations (3)

* Cited by examiner, † Cited by third party
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
JPS58128340A (en) * 1982-01-23 1983-07-30 バスフ　アクチエンゲゼルシヤフト Phenylethylene derivative, manufacture and medicine
JPS58164603A (en) * 1982-03-24 1983-09-29 Tatatomi Nishikubo Production of self-sensitizing photopolymer

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0458459B2 (en) * 1984-09-19 1992-09-17 Koichi Shudo
JPS6176440A (en) * 1984-09-19 1986-04-18 Koichi Shiyudo Benzoic acid derivative
US6869959B1 (en) 1999-04-28 2005-03-22 Institute Of Medicinal Molecular Design Inc. Heterocyclic carboxylic acid derivatives
US7314639B2 (en) 2000-09-01 2008-01-01 Toko Pharmaceutical Ind. Co., Ltd. Process for the production of crystals of a benzoic acid derivative
US7259187B2 (en) 2000-12-26 2007-08-21 Research Foundation Itsuu Laboratory Tropolone derivatives
JP2004529085A (en) * 2001-01-18 2004-09-24 ウェリケム バイオテック インコーポレーテッド Novel 1,2-diphenylethene derivatives for treating immune diseases
US8030360B2 (en) 2004-03-11 2011-10-04 Kemphys Ltd. Anti-wrinkle agent
WO2005087220A1 (en) * 2004-03-11 2005-09-22 R & R Inc. Antiwrinkling preparation
US8168677B2 (en) 2005-09-09 2012-05-01 Kemphys Ltd. Method for treatment of inflammatory bowel disease
US8071647B2 (en) 2005-09-09 2011-12-06 Kemphys Ltd. Method for treatment of adhesion of the intestines
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
WO2009022722A1 (en) 2007-08-15 2009-02-19 Research Foundation Itsuu Laboratory Tricyclic amine compound
US8143260B2 (en) 2007-08-15 2012-03-27 Research Foundation Itsuu Laboratory Tricyclic amine compound
WO2009022720A1 (en) 2007-08-15 2009-02-19 Research Foundation Itsuu Laboratory Five-membered heterocyclic compound
US8232300B2 (en) 2007-08-15 2012-07-31 Research Foundation Itsuu Laboratory Tricyclic amide compound
US8722730B2 (en) 2007-08-15 2014-05-13 Research Foundation Itsuu Laboratory 5-membered heterocyclic compound
US8633335B2 (en) 2007-10-31 2014-01-21 Research Founation Itsuu Laboratory Retinoid prodrug compound
WO2013005753A1 (en) 2011-07-05 2013-01-10 公益財団法人乙卯研究所 Deuterated phenylpropionic acid derivative
JP2017160261A (en) * 2017-06-12 2017-09-14 チョンシー ユー Positively charged water-soluble prodrugs of retinoids and retinoid-like compounds with very high skin penetration rates

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