JPH0458458B2 - - Google Patents
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- Publication number
- JPH0458458B2 JPH0458458B2 JP59141194A JP14119484A JPH0458458B2 JP H0458458 B2 JPH0458458 B2 JP H0458458B2 JP 59141194 A JP59141194 A JP 59141194A JP 14119484 A JP14119484 A JP 14119484A JP H0458458 B2 JPH0458458 B2 JP H0458458B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- acid
- compound
- 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.)
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- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- -1 terephthalaldehyde acid ester Chemical class 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CYTWMXYLKADNKE-UHFFFAOYSA-N 4-nitrosobenzoic acid Chemical compound OC(=O)C1=CC=C(N=O)C=C1 CYTWMXYLKADNKE-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- SNBCETWLOKEFMT-UHFFFAOYSA-N 3,4-diethylbenzoyl chloride Chemical compound CCC1=CC=C(C(Cl)=O)C=C1CC SNBCETWLOKEFMT-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- JMHSCWJIDIKGNZ-UHFFFAOYSA-N 4-carbamoylbenzoic acid Chemical class NC(=O)C1=CC=C(C(O)=O)C=C1 JMHSCWJIDIKGNZ-UHFFFAOYSA-N 0.000 description 1
- AMDKYPNODLTUMY-UHFFFAOYSA-N 5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-amine Chemical compound NC1=CC=C2C(C)(C)CCC(C)(C)C2=C1 AMDKYPNODLTUMY-UHFFFAOYSA-N 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 238000002738 Giemsa staining Methods 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- OORGGNYDIUQRDG-UHFFFAOYSA-N [3-[4-[(5-methyl-4-oxothieno[2,3-d][1,3]oxazin-2-yl)methyl]benzoyl]phenyl]-[3-[4-[(5-methyl-4-oxothieno[2,3-d][1,3]oxazin-2-yl)methyl]benzoyl]phenyl]imino-oxidoazanium Chemical compound O1C(=O)C=2C(C)=CSC=2N=C1CC(C=C1)=CC=C1C(=O)C(C=1)=CC=CC=1N=[N+]([O-])C(C=1)=CC=CC=1C(=O)C(C=C1)=CC=C1CC(OC1=O)=NC2=C1C(C)=CS2 OORGGNYDIUQRDG-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- QKVJSTCHTZXKHI-UHFFFAOYSA-N ethyl 4-nitrosobenzoate Chemical compound CCOC(=O)C1=CC=C(N=O)C=C1 QKVJSTCHTZXKHI-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
- CAFWWZWJFFJXTF-UHFFFAOYSA-N methyl 4-nitrosobenzoate Chemical compound COC(=O)C1=CC=C(N=O)C=C1 CAFWWZWJFFJXTF-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- ZODDGFAZWTZOSI-UHFFFAOYSA-N nitric acid;sulfuric acid Chemical compound O[N+]([O-])=O.OS(O)(=O)=O ZODDGFAZWTZOSI-UHFFFAOYSA-N 0.000 description 1
- NLRKCXQQSUWLCH-IDEBNGHGSA-N nitrosobenzene Chemical class O=N[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 NLRKCXQQSUWLCH-IDEBNGHGSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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、さらに第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。［Proc.Natl.Acad.USA772936（1980）、J.
Med.Chem.251269（1982）、Blood、62709（1983）．
細胞工学２No.12（1983）．］
ドイツ特許公開公報28 54 354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及びR2は独立に低中級アルキルを示し、
また両者が一緒になつて低級アルキル基を有する
こともある５〜６員環のシクロアルキル基を形成
することができ、R3は水酸基、低級アルコキシ
基、−NR4R5基（式中、R4とR5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 broadly 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. [Proc.Natl.Acad.USA 77 2936 (1980), J.
Med.Chem. 25 1269 (1982), Blood, 62 709 (1983).
Cell Engineering 2 No. 12 (1983). ] General formula according to German Patent Publication No. 28 54 354 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, R 1 and R 2 independently represent lower intermediate alkyl,
In addition, both can be combined to form a 5- to 6-membered cycloalkyl group that may have a lower alkyl group, and R 3 is a hydroxyl group, a lower alkoxy group, -NR 4 R 5 group (in the formula, R 4 and R 5 independently represent a hydrogen atom or a lower alkyl group), and X is
【式】−Ｎ ＝Ｎ−[Formula]-N =N-
【式】【formula】
【式】
（式中、R6とR7は独立に水素原子または低級ア
ルキル基を示す）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判つ
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−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、その方法は以下の通りであ
る。HL−60細胞を５％牛胎児血清を含む
RPMI1640培地にて継代培養し、対数増殖期の細
胞が細胞数３×104／mlとなるように同上培地で
希釈調制し、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[Formula] (wherein R 6 and R 7 independently represent a hydrogen atom or a lower alkyl group) The benzoic acid derivative represented by It has been found that these compounds can be used in the treatment of cancer according to the third method described above. That is, the cancer cell differentiation induction test for the compound of the present invention uses human acute promyelocytic leukemia HL60 cells to determine differentiation into granulocytes based on nuclear morphology and nitroblue-tetrazolium (NBT) reducing ability. The method was as follows. HL-60 cells containing 5% fetal bovine serum
Subculture in RPMI1640 medium, adjust the dilution with 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 culture the cells for 5 days. Fixed, 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−[Formula]-N =N-
【式】【formula】
【式】
であつて、R1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が一緒になつて、５又は５員環状アルキル基
であるものが良い。これに反してR1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。
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。
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−Ｃ（R6）＝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によ
り、
(b) Ｘが[Formula] In which R 1 and R 2 are preferably of medium size, in particular isopropyl groups,
Butyl group, cyclopentyl group and R 1 and
It is preferable that R 2 together represent a 5 or 5-membered cyclic alkyl group. On the other hand, almost no effect is observed when both R 1 and R 2 are hydrogen atoms. Hydrogen atoms and methyl groups are particularly effective as R 6 and R 7 . Thus, R 3 is preferably a hydroxyl group or a methoxy group. The compound represented by the general formula () of the present invention is characterized in that (a) the group X in the general formula () is -CO-C(R 6 )=CH
(b) By condensing a compound showing a group with a corresponding acetophenone derivative and a terephthalaldehyde acid ester or a derivative thereof in the presence of a base, (b)
【式】基
を示す化合物を対応するＸ基が
−Ｃ（R6）＝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
パラニトロソ安息香酸と縮合することにより
(d) Ｘが−Ｎ（Ｏ）＝Ｎ−基である化合物は
対応するフエニルヒドロキ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（Ｏ）＝Ｎ−基または−Ｎ（Ｏ）＝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（R6）−Ｃ（Ｏ）−基である化合物は
対応するアニリン誘導体をテルフタール酸の反
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（R6）−である化合物はパ
ラアミノ安息酸又はその誘導体、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。
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R1，R2が
エチル基、ｔ−ブチル基、又は両者が一緒になつ
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10-8ないし10-10モルでも
活性を示している。
参考例
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
攪拌する。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（R1＝ｔ−ブチル；R2＝
Ｈ、Ｘ＝COCH＝CH−；R3＝OH）なる目的化
合物を得る。融点245〜246℃（収率75.2％）
分析結果
C20H20H3
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℃
実施例 １
同様にして、式（）中R1とR2とが−Ｃ
（CH3）2CH2CH2C（CH3）2−で示され、Ｘは＝
CO・CH＝CH−基で、R3がOH及びOCH3であ
る化合物を得ることができた。
実施例 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
クロロホロ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（R1とR2は−Ｃ（CH3）2CH2CH2C
（CH3）2−でＸは[Formula] By oxidizing a compound in which the corresponding X group is -C(R 6 )=C(R 7 )- group using an epoxidizing agent, (c) X is -N=N - group by condensing the corresponding derivative of aniline with p-nitrosobenzoic acid in the presence or absence of an acid catalyst (d) Compounds where X is -N(O)=N- (e) By condensing enylhydroxyamine and p-nitrosobenzoic acid or its derivative in the same manner as in section (c),
(f) X is a -N(R 6 )-C(O)- group by condensing the compound with the corresponding nitrosobenzene derivative and parahydroxyaminobenzoic acid or a derivative thereof in the same manner as in section (c). (g) Compounds where Manufactured by acylation with benzoic acid or a derivative thereof, or a corresponding reactive derivative of benzoic acid (acid halogen or ester, etc.) using a conventional method, and optionally hydrolyzing the compound thus obtained. can do. 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. Among them, particularly strong compounds, such as compounds in which R 1 and R 2 are ethyl group, t-butyl group, or both together form a 6-membered cyclic alkyl group, are 10 - It shows activity even at 8 to 10 -10 mol. Reference example 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 1 = t-butyl; R 2 =
The desired compound (H, X=COCH=CH-; R 3 =OH) is obtained. Melting point 245-246℃ (yield 75.2%) Analysis result C 20 H 20 H 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°C Example 1 Similarly, in formula (), R 1 and R 2 are -C
(CH 3 ) 2 CH 2 CH 2 C (CH 3 ) 2 −, and X is =
It was possible to obtain a compound in which R 3 is OH and OCH 3 with a CO·CH=CH− group. 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,
Add 50 mg (0.289 mmol) of m-chloroperbenzoic acid in chloroform and reflux 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 1 and R 2 are -C(CH 3 ) 2 CH 2 CH 2 C
(CH 3 ) 2 − and X is
【式】基、R3＝
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
C23H26O3として
計算値（％） Ｃ；78.82、Ｈ；7.48
実験値（％） Ｃ；79.03、Ｈ；7.74
実施例 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−ニトロソ安息香酸エ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（R1、R2＝−Ｃ
（CH3）2CH2CH2C（CH3）2−、R3＝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℃
実施例 ４
実施例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
ニウムアマルガル（アルミホイル300mgとHgCl25
％水溶液30mlから作る）により還元し、対応する
ヒドロキシアミン誘導体を得る。これを精製する
ことなしに、小過剰のｐ−ニトロソ安息香酸メチ
ルエステルと反応させて、アゾキシ誘導体（R1、
R2＝−Ｃ（CH3）2CH2CH2C（CH3）2−、R3＝
OCH3、Ｘ＝−Ｎ＝Ｎ（Ｏ）−）を得る。mp.114〜
115℃（ヘキサンから再結晶）
ΓMASS：M+＝366
実施例 ５
実施例３により得られた２−アミノ−５，５，
８，８−テトラメチル−５，６，７，８−テトラ
ヒドロナフタリン（１ｍmol）とテレフタル酸ク
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（）（R1、R2＝−Ｃ（CH3）2CH2CH2C
（CH3）2−、Ｘ＝NH−CO−、Ｒ＝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（R1、R2＝−Ｃ
（CH3）2CH2CH2C（CH3）2−、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。
実施例 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、ついで水を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
（R1，R2＝Et、Ｘ＝−CO−NH−、R3＝OCH3）
mp.162〜165℃を得る。収率定量的。
同様にして次表の化合物が合成された。表中合
成法の欄(a)−(f)の記号はそれぞれ明細書中に記載
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。[Formula] group, R 3 = OCH 3 ) 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 As C 23 H 26 O 3 Calculated value (%) C; 78.82, H; 7.48 Experimental value (%) C; 79.03, H; 7.74 Example 3 5,5,8,8-tetra Methyl-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 ethyl ester was mixed.
Leave at room temperature for 2 hours. By distilling off methanol and recrystallizing from methanol, the melting point is 118.5.
~119.5°C azo compound (R 1 , R 2 = -C
( CH3 ) 2CH2CH2C ( CH3 ) 2- , R3 = 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 Example 4 The nitro compound (100 mg) obtained in Example 3 was dissolved in hydrous tetrahydrofuran (30 ml), and aluminum amargal (300 mg of aluminum foil and HgCl 2 5
% aqueous solution) to give the corresponding hydroxyamine derivative. Without purification, this was reacted with a small excess of p-nitrosobenzoic acid methyl ester to form the azoxy derivative (R 1 ,
R 2 = -C (CH 3 ) 2 CH 2 CH 2 C (CH 3 ) 2 -, R 3 =
OCH 3 , X=-N=N(O)-) is obtained. mp.114〜
115°C (recrystallized from hexane) ΓMASS: M + =366 Example 5 2-Amino-5,5, obtained in Example 3
8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalene (1 mmol) and terephthalic acid chloride monomethyl ester (1.1 mmol) are reacted in pyridine at room temperature, with quantitative yield, the general formula () ( R 1 , R 2 =-C(CH 3 ) 2 CH 2 CH 2 C
A compound represented by ( CH3 ) 2- , X=NH-CO-, R= 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 1 , R 2 = -C
( CH3 ) 2CH2CH2C ( CH3 ) 2- , X =-NH-CO-,
A terephthalic acid amide derivative represented by R 3 =OH) was obtained. Example 6 3,4-diethylbenzoic acid chloride (1.1 m
mol) to 4-aminobenzoic acid methyl ester (1
mmol) in 10 ml of anhydrous pyridine at room temperature for 5 hours. Add water and 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 1 , R 2 = Et, X = -CO-NH-, R 3 = OCH 3 )
Obtain mp.162-165℃. Yield quantitative. The compounds shown in the following table were synthesized in the same manner. The symbols in the synthesis method columns (a) to (f) in the table indicate that the synthesis methods (a) to (f) described in the specification were used for the synthesis, respectively.
【表】【table】
【表】
｜
CH３ O
[Table] ｜
CH3O
Claims (1)
また両者が一緒になつて低級アルキル基を有する
こともある５〜６員環のシクロアルキル基を形成
することができ、R3は水酸基、低級アルコキシ
基、−NR4R5基（式中、R4とR5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− 【式】【式】 【式】 （式中、R6とR7は独立に水素原子または低級ア
ルキル基を示す）を意味する）で示される安息香
酸誘導体。[Claims] 1 General formula (): (In the formula, R 1 and R 2 independently represent lower intermediate alkyl,
In addition, both can be combined to form a 5- to 6-membered cycloalkyl group that may have a lower alkyl group, and R 3 is a hydroxyl group, a lower alkoxy group, -NR 4 R 5 group (in the formula, R 4 and R 5 independently represent a hydrogen atom or a lower alkyl group), and X is [Formula] [Formula] -N = N- [Formula] [Formula] [Formula ] A benzoic acid derivative represented by R 7 independently represents a hydrogen atom or a lower alkyl group.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14119484A JPS6122047A (en) | 1984-07-07 | 1984-07-07 | Benzoic acid derivative |
| DE8585108383T DE3580134D1 (en) | 1984-07-07 | 1985-07-05 | BENZOESAEUR DERIVATIVES. |
| EP85108383A EP0170105B1 (en) | 1984-07-07 | 1985-07-05 | Benzoic acid 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 |
|---|---|---|---|
| JP14119484A JPS6122047A (en) | 1984-07-07 | 1984-07-07 | Benzoic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6122047A JPS6122047A (en) | 1986-01-30 |
| JPH0458458B2 true 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) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6176440A (en) * | 1984-09-19 | 1986-04-18 | Koichi Shiyudo | Benzoic acid derivative |
| ATE365158T1 (en) | 1999-04-28 | 2007-07-15 | Inst Med Molecular Design Inc | PYRIMIDINE CARBOXYLIC ACID DERIVATIVES |
| CA2420962C (en) | 2000-09-01 | 2009-11-24 | Toko Pharmaceutical Ind. Co., Ltd. | Method for preparing crystal of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid |
| KR20030077558A (en) | 2000-12-26 | 2003-10-01 | 재단법인 이쯔우 연구소 | Tropolone derivative |
| CA2433417C (en) * | 2001-01-18 | 2010-10-19 | Welichem Biotech Inc. | Novel 1,2-diphenylethene derivatives for treatment of immune diseases |
| US20050202055A1 (en) | 2004-03-11 | 2005-09-15 | Koichi Shudo, Tokyo, Japan | Anti-wrinkle agent |
| JP5042839B2 (en) | 2005-09-09 | 2012-10-03 | 有限会社ケムフィズ | Medicament for 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 |
| TW200922553A (en) | 2007-08-15 | 2009-06-01 | Res Found Itsuu Lab | Five-membered heterocyclic compound |
| AU2008287819A1 (en) | 2007-08-15 | 2009-02-19 | Research Foundation Itsuu Laboratory | Tricyclic amine compound |
| TW200920351A (en) | 2007-08-15 | 2009-05-16 | Res Found Itsuu Lab | Tricyclic amide compound |
| EP2216322A4 (en) | 2007-10-31 | 2011-09-21 | Res Found Itsuu Lab | 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 |
Citations (3)
| 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 |
-
1984
- 1984-07-07 JP JP14119484A patent/JPS6122047A/en active Granted
Patent Citations (3)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6122047A (en) | 1986-01-30 |
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