JPH0114915B2 - - Google Patents
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- Publication number
- JPH0114915B2 JPH0114915B2 JP7387181A JP7387181A JPH0114915B2 JP H0114915 B2 JPH0114915 B2 JP H0114915B2 JP 7387181 A JP7387181 A JP 7387181A JP 7387181 A JP7387181 A JP 7387181A JP H0114915 B2 JPH0114915 B2 JP H0114915B2
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- JP
- Japan
- Prior art keywords
- group
- compound
- acid
- ring
- general formula
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 21
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 18
- -1 methylenedioxy group Chemical group 0.000 claims description 13
- HYMJHROUVPWYNQ-UHFFFAOYSA-N 2-amino-1,3-thiazol-4-one Chemical class NC1=NC(=O)CS1 HYMJHROUVPWYNQ-UHFFFAOYSA-N 0.000 claims description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 102000016912 Aldehyde Reductase Human genes 0.000 description 3
- 108010053754 Aldehyde reductase Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- NOLHRFLIXVQPSZ-UHFFFAOYSA-N 1,3-thiazolidin-4-one Chemical class O=C1CSCN1 NOLHRFLIXVQPSZ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 150000001473 2,4-thiazolidinediones Chemical class 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- CHASIMSFVOHAOU-UHFFFAOYSA-N ethyl 2-(3,4-diethoxyphenyl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=CC=C(OCC)C(OCC)=C1 CHASIMSFVOHAOU-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000002826 placenta Anatomy 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007749 Cataract diabetic Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229950005228 bromoform Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000007025 diabetic cataract Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- CRPGRUONUFDYBG-UHFFFAOYSA-N risarestat Chemical compound C1=C(OCC)C(OCCCCC)=CC=C1C1C(=O)NC(=O)S1 CRPGRUONUFDYBG-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
本発明は医薬などの合成中間体として有用な新
規2−イミノチアゾリジン−4−オン誘導体およ
びその合成法に関する。
さらに詳しくは、本発明は、
1 一般式
(式中Rは環上にアルコキシ基および水酸基か
らなる群から選ばれた置換基を2個有するかま
たは環上の隣接する位置にメチレンジオキシ基
を有するフエニル基を示す)で表わされる2−
イミノチアゾリジン−4−オン誘導体
2 酸性条件下、一般式
(式中、Rは前記と同意義であり、R1は水素
または低級アルキル基を示す。)で表わされる
化合物をチオ尿素と反応させることを特徴とす
る一般式()で表わされる2−イミノチアゾ
リジン−4−オン誘導体の製造法、
に関する。
前記一般式()および()中、Rの置換基
としてあげられるアルコキシ基としては、たとえ
ばメトキシ、エトキシ、n−プロポキシ、i−プ
ロポキシ、n−ブトキシ、i−ブトキシ、n−ペ
ンチルオキシ、i−ペンチルオキシ、ネオペンチ
ルオキシ、n−ヘキシルオキシ、i−ヘキシルオ
キシなど炭素数1〜7のものがあげられる。これ
らRの置換基はベンゼン環の任意の位置に置換し
うる。R1で示される低級アルキル基としてはメ
チル、エチル、n−プロピル、i−プロピル、n
−ブチル、i−ブチル、t−ブチルなど炭素数1
〜4のものがあげられる。
一般式()で表わされる2−イミノチアゾリ
ジン−4−オン誘導体は、たとえば一般式()
で表わされる化合物とチオ尿素とを酸性条件下に
反応させることによつて得ることができる。この
反応は通常溶媒中で行なわれ、該溶媒としては、
たとえばアルコール類(例、メタノール、エタノ
ール、プロパノール、ブタノール、エチレングリ
コールモノメチルエーテル)、エーテル類(例、
テトラヒドロフラン、ジオキサン)、ジメチルス
ルホキシド、スルホラン、ジメチルホルムアミド
などがあげられる。酸性条件は酸を存在させるこ
とによつてつくることができる。上記酸として
は、たとえば酢酸、塩酸、リン酸、硫酸などがあ
げられる。これらの酸は通常化合物()に対し
て0.5〜5当量用いられる。化合物()とチオ
尿素の接触割合は特に限定されないが通常はチオ
尿素を少し過剰(モル比)に用い、好ましくはチ
オ尿素を1〜2倍モル用いるのがよい。反応温
度、反応時間などの反応条件は原料化合物の種
類、溶媒の種類、酸の種類および量などによつて
異なるが通常70〜100℃で20分間以上、好ましく
は30分間〜十数時間である。このようにして一般
式()で表わされる化合物が得られる。化合物
()には下記式で示されるように、互変異性体
が考えられるが、便宜上これらを単に化合物
()として表わす。
本発明の目的化合物()は常法によりたとえ
ば塩酸、硫酸、酢酸、シユウ酸など種々の酸との
塩を形成させることができる。
本発明の方法によれば従来公知の2−イミノチ
アゾリジン−4−オン誘導体の製造法に比べ工程
数が短く、かつ目的物の収率もよい。
このようにして得られる2−イミノ−チアゾリ
ジン−4−オン誘導体()は公知の分離精製手
段たとえば濃縮、減圧濃縮、溶媒抽出、晶出、再
結晶、転溶、クロマトグラフイーなどにより単離
精製することができる。
本発明の目的化合物である2−イミノチアゾリ
ジン−4−オン誘導体()は、ラツト・レンズ
または人の胎盤から単離されたアルドース還元酵
素の酵素活性を阻害する能力およびラツト水晶体
培養法による水分流入抑制能力を有し、人または
哺乳動物の糖尿病性白内障、神経疾患および網膜
症等に有用であることが期待されているチアゾリ
ジン−2,4−ジオン誘導体()
(式中Rは前記と同意義である)に導くことがで
きる。
化合物()から化合物()へ導びくには化
合物()をたとえば酸加水分解すればよい。こ
の酸加水分解反応は適当な溶媒中(たとえばエタ
ノールなど)水および鉱酸の存在下加熱すること
により行なわれる。酸の添加量は通常化合物
()1モルに対し0.1〜10モル、好ましくは0.2
〜3モル、水の添加量は化合物()1モルに対
し通常大過剰量である。加熱時間は通常数時間〜
十数時間である。
また原料化合物()は、たとえば、下記の反
応によつて得ることができる。
(式中のRは前記と同意義である)
上記(1)の反応は、よく知られているフリーデル
クラフト(Friedel Crafts)反応によるアシル化
につづく還元反応であり、(2)の反応は文献記載
(J.Org.Chew、33巻、2565頁、1963年)の反応で
ある。
以下に実施例、参考例および実験例を記載して
本発明をより具体的に説明する。
参考例 1
(a) 粉末塩化アルミニウム8.53gをジクロルメタ
ン100mlに懸濁し、氷冷下エチル塩化オキザリ
ル8.8gついでオルトジエトキシベンゼン10.9
gのジクロルメタン20ml溶液を滴加し、室温で
1時間かきまぜる。氷−水に注ぎ有機層を分取
後、水洗、乾燥(MgSO4)する。溶媒を留去
すると、3,4−ジエトキシフエニルグリオキ
シル酸エチルエステルの結晶10.7g(62.9%)
が得られる。ヘキサンから再結晶する。無色針
状晶。m.p40−41゜。
(b) 3,4−ジエトキシフエニルグリオキシル酸
エチルエステル6.0gをエタノール70mlにとか
し、水素化ホウ素ナトリウム0.67gを加え5℃
で30分かきまぜる。酢酸4mlを加えた後、炭酸
水素ナトリウム飽和水溶液300mlに注ぎエーテ
ルで抽出する。水洗、乾燥(MgSO4)後エー
テルを留去すると、2−(3,4−ジエトキシ
フエニル)−2−ヒドロキシ酢酸エチルの油状
物6.2g(100%)が得られる。
IR νNeat naxcm-1:3480、1735
NMR δppm CDCl3中:1.18(3H、t、J=
7)、1.40(6H、t、J=7)、3.73(1H、d、
J=6)、4.04(4H、q、J=7)、4.15(2H、
q、J=7)、5.0(1H、d、J=6)、6.7〜
7.3(3H、m)
参考例 2
参考例1と同様にして、2−(2,4−ジエト
キシフエニル)−2−ヒドロキシ酢酸エチルの油
状物を合成した。
IR νNeat naxcm-1:3480、1730
NMR δppm CDCl3中:1.17(3H、t、J=
7)、1.36(6H、t、J=7)、3.61(1H、d、
J=6)、3.95(4H、q、J=7)、4.13(2H、
q、J=7)、5.12(1H、d、J=6)、6.2〜
6.5(2H、m)、7.05(1H、d、J=9)
参考例 3
水酸化カリウム21.5g、塩化リチウム8.14gを
水80mlにとかし、氷冷下ブロモホルム24.3g、3
−エトキシ−4−n−ペンチルオキシベンズアル
デヒド22.7gのジオキサン80ml溶液を順次加え
る。5℃で24時間、次いで35℃で24時間かきまぜ
た後、水300mlに注ぎ、エーテルで抽出する。水
層を6N−HClで酸性化後、エーテルで抽出し、
このエーテル層を水洗後乾燥(MgSO4)する。
エーテルを留去すると2−(3−エトキシ−4−
n−ベンチルオキシフエニル)−2−ヒドロキシ
酢酸の結晶18.5g(68.3%)が得られる。酢酸エ
チル・ヘキサンから再結晶する。無色針状晶。
m.p90−91℃。
参考例 4
参考例2と同様にして表1に示す化合物を合成
した。
The present invention relates to novel 2-iminothiazolidin-4-one derivatives useful as synthetic intermediates for pharmaceuticals and the like, and a method for synthesizing the same. More specifically, the present invention comprises 1 general formula (wherein R represents a phenyl group having two substituents selected from the group consisting of an alkoxy group and a hydroxyl group on the ring, or a methylenedioxy group at an adjacent position on the ring)
Iminothiazolidin-4-one derivative 2 Under acidic conditions, general formula (wherein, R has the same meaning as above, and R 1 represents hydrogen or a lower alkyl group) is reacted with thiourea. A method for producing a thiazolidin-4-one derivative. In the above general formulas () and (), examples of the alkoxy group as a substituent for R include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, n-pentyloxy, i- Examples include those having 1 to 7 carbon atoms, such as pentyloxy, neopentyloxy, n-hexyloxy, and i-hexyloxy. These substituents for R can be substituted at any position on the benzene ring. The lower alkyl group represented by R 1 is methyl, ethyl, n-propyl, i-propyl, n
-Butyl, i-butyl, t-butyl, etc. with 1 carbon number
~4 things can be mentioned. The 2-iminothiazolidin-4-one derivative represented by the general formula () is, for example, a derivative represented by the general formula ()
It can be obtained by reacting the compound represented by and thiourea under acidic conditions. This reaction is usually carried out in a solvent, and the solvent is
For example, alcohols (e.g. methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether), ethers (e.g.
(tetrahydrofuran, dioxane), dimethyl sulfoxide, sulfolane, dimethylformamide, etc. Acidic conditions can be created by the presence of an acid. Examples of the above acids include acetic acid, hydrochloric acid, phosphoric acid, and sulfuric acid. These acids are usually used in an amount of 0.5 to 5 equivalents based on the compound (). The contact ratio between the compound () and thiourea is not particularly limited, but it is usually preferable to use thiourea in a slight excess (molar ratio), preferably 1 to 2 times the mole of thiourea. Reaction conditions such as reaction temperature and reaction time vary depending on the type of raw material compound, type of solvent, type and amount of acid, etc., but are usually 70 to 100°C for 20 minutes or more, preferably 30 minutes to more than 10 hours. . In this way, a compound represented by the general formula () is obtained. Compound () may have tautomers as shown in the following formula, but for convenience, these are simply expressed as compound (). The object compound () of the present invention can be formed into a salt with various acids such as hydrochloric acid, sulfuric acid, acetic acid, and oxalic acid by conventional methods. According to the method of the present invention, the number of steps is shorter than the conventional method for producing 2-iminothiazolidin-4-one derivatives, and the yield of the target product is also good. The 2-imino-thiazolidin-4-one derivative () obtained in this manner is isolated and purified by known separation and purification means such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution, chromatography, etc. can do. The object compound of the present invention, a 2-iminothiazolidin-4-one derivative (2-iminothiazolidin-4-one derivative), has the ability to inhibit the enzymatic activity of aldose reductase isolated from rat lenses or human placenta, and has the ability to inhibit water influx by the rat lens culture method. Thiazolidine-2,4-dione derivatives () that have suppressive ability and are expected to be useful for diabetic cataracts, neurological diseases, retinopathy, etc. in humans and mammals. (wherein R has the same meaning as above). In order to derive compound () from compound (), compound () may be subjected to acid hydrolysis, for example. This acid hydrolysis reaction is carried out by heating in a suitable solvent (such as ethanol) in the presence of water and a mineral acid. The amount of acid added is usually 0.1 to 10 mol, preferably 0.2 mol, per 1 mol of compound ().
~3 mol, and the amount of water added is usually in large excess per 1 mol of compound (). Heating time is usually several hours.
It's more than ten hours. Further, the raw material compound () can be obtained, for example, by the following reaction. (R in the formula has the same meaning as above) The reaction (1) above is a reduction reaction following acylation by the well-known Friedel Crafts reaction, and the reaction (2) is a reduction reaction following acylation by the well-known Friedel Crafts reaction. This is the reaction described in the literature (J.Org.Chew, vol. 33, p. 2565, 1963). The present invention will be explained in more detail by describing Examples, Reference Examples, and Experimental Examples below. Reference Example 1 (a) 8.53 g of powdered aluminum chloride was suspended in 100 ml of dichloromethane, 8.8 g of ethyl oxalyl chloride was added under ice cooling, and then 10.9 g of orthodiethoxybenzene was added.
20 ml of dichloromethane solution was added dropwise and stirred at room temperature for 1 hour. After pouring into ice-water and separating the organic layer, it is washed with water and dried (MgSO 4 ). When the solvent was distilled off, 10.7 g (62.9%) of crystals of 3,4-diethoxyphenylglyoxylic acid ethyl ester were obtained.
is obtained. Recrystallize from hexane. Colorless needle crystals. m.p40−41°. (b) Dissolve 6.0 g of 3,4-diethoxyphenylglyoxylic acid ethyl ester in 70 ml of ethanol, add 0.67 g of sodium borohydride, and heat at 5°C.
Stir for 30 minutes. After adding 4 ml of acetic acid, the mixture was poured into 300 ml of saturated aqueous sodium bicarbonate solution and extracted with ether. After washing with water and drying (MgSO 4 ), the ether is distilled off to obtain 6.2 g (100%) of an oily product of 2-(3,4-diethoxyphenyl)-2-hydroxyethyl acetate. IR ν Neat nax cm -1 : 3480, 1735 NMR δppm CDCl 3 medium: 1.18 (3H, t, J=
7), 1.40 (6H, t, J=7), 3.73 (1H, d,
J=6), 4.04 (4H, q, J=7), 4.15 (2H,
q, J=7), 5.0 (1H, d, J=6), 6.7~
7.3 (3H, m) Reference Example 2 In the same manner as in Reference Example 1, an oily product of 2-(2,4-diethoxyphenyl)-2-hydroxyethyl acetate was synthesized. IR ν Neat nax cm -1 : 3480, 1730 NMR δppm CDCl 3 medium: 1.17 (3H, t, J=
7), 1.36 (6H, t, J=7), 3.61 (1H, d,
J=6), 3.95 (4H, q, J=7), 4.13 (2H,
q, J=7), 5.12 (1H, d, J=6), 6.2~
6.5 (2H, m), 7.05 (1H, d, J = 9) Reference example 3 Dissolve 21.5 g of potassium hydroxide and 8.14 g of lithium chloride in 80 ml of water, and add 24.3 g of bromoform under ice cooling.
A solution of 22.7 g of -ethoxy-4-n-pentyloxybenzaldehyde in 80 ml of dioxane is successively added. After stirring at 5°C for 24 hours and then at 35°C for 24 hours, it is poured into 300 ml of water and extracted with ether. The aqueous layer was acidified with 6N-HCl and extracted with ether.
This ether layer is washed with water and then dried (MgSO 4 ).
When the ether is distilled off, 2-(3-ethoxy-4-
18.5 g (68.3%) of crystals of n-bentyloxyphenyl)-2-hydroxyacetic acid are obtained. Recrystallize from ethyl acetate/hexane. Colorless needle crystals.
m.p90−91℃. Reference Example 4 The compounds shown in Table 1 were synthesized in the same manner as in Reference Example 2.
【表】
実施例 1
2−(3,4−ジエトキシフエニル)−2−ヒド
ロキシ酢酸エチル2.68gをエチレングリコールモ
ノメチルエーテル30mlにとかし、濃塩酸3.3ml、
チオ尿素1.52gを加え、80℃で2時間かきまぜ
る。冷却後、炭酸水素ナトリウム飽和水溶液200
mlに注ぎ析出する結晶を取する。エタノールか
ら再結晶すると5−(3,4−ジエトキシフエニ
ル)−2−イミノ−チアゾリジン−4−オンの無
色板状晶1.55g(55.4%)が得られる。m.p.222−
223℃。
実施例 2
2−(3−エトキシ−4−n−ペンチルオキシ
フエニル)−2−ヒドロキシ酢酸2.8gをエチレン
グリコールモノメチルエーテル30mlに溶かし、濃
塩酸3.3ml、チオ尿素1.52gを加え90℃で4時間
かきまぜる。冷却後、炭酸水素ナトリウム飽和水
溶液200mlに注ぎ析出する結晶を取する。エタ
ノールから再結晶すると5−(3−エトキシ−4
−n−ペンチルオキシフエニル)−2−イミノ−
チアゾリジン−4−オンの無色針状晶1.85g
(57.5%)が得られる。m.p.220−222℃(分解)。
実施例 3
前記実施例1および2と同様にして化合物No.1
〜6を合成した。[Table] Example 1 2.68 g of 2-(3,4-diethoxyphenyl)-2-hydroxyethyl acetate was dissolved in 30 ml of ethylene glycol monomethyl ether, 3.3 ml of concentrated hydrochloric acid,
Add 1.52g of thiourea and stir at 80℃ for 2 hours. After cooling, add 200 ml of saturated aqueous sodium bicarbonate solution.
ml and collect the crystals that precipitate. Recrystallization from ethanol gives 1.55 g (55.4%) of colorless platelets of 5-(3,4-diethoxyphenyl)-2-imino-thiazolidin-4-one. mp222−
223℃. Example 2 2.8 g of 2-(3-ethoxy-4-n-pentyloxyphenyl)-2-hydroxyacetic acid was dissolved in 30 ml of ethylene glycol monomethyl ether, 3.3 ml of concentrated hydrochloric acid and 1.52 g of thiourea were added, and the mixture was heated at 90°C. Stir the time. After cooling, pour into 200 ml of a saturated aqueous solution of sodium hydrogen carbonate to remove the precipitated crystals. Recrystallization from ethanol yields 5-(3-ethoxy-4
-n-pentyloxyphenyl)-2-imino-
1.85 g of colorless needles of thiazolidin-4-one
(57.5%) is obtained. mp220−222℃ (decomposition). Example 3 Compound No. 1 was prepared in the same manner as in Examples 1 and 2 above.
~6 was synthesized.
【表】
参考例 5
5−(3−エトキシ−4−n−ペンチルオキシ
フエニル)−2−イミノ−チアゾリジン−4−オ
ン3.2gをエタノール30ml−2N・HCl30mlに溶か
し、還流下に12時間加熱する。冷却後、水100ml
を加え析出する結晶を取する。80%エタノール
から再結晶すると、5−(3−エトキシ−4−n
−ペンチルオキシフエニル)−チアゾリジン−2,
4−ジオンの無色板状晶2.8g(86.7%)が得ら
れる。m.p.104−105℃。
参考例 6
2−(3−エトキシ−4−n−ペンチルオキシ
フエニル)−2−ヒドロキシ酢酸2.82gをエチレ
ングリコールモノメチルエーテル30mlにとかし、
濃塩酸3.3ml、チオ尿素1.52gを加え90℃で4時
間かきまぜる。ついで2規定塩酸15mlを加え、8
時間還流下に加熱する。冷却後水に注ぎ析出する
結晶を取し、80%エタノールから再結晶する
と、5−(3−エトキシ−4−n−ペンチルオキ
シフエニル)チアゾリジン−2,4−ジオンの無
色板状晶2.55g(78.9%)が得られる。m.p.104−
105℃。
参考例 7
参考例5と同様にして表3の化合物を合成し
た。[Table] Reference Example 5 3.2 g of 5-(3-ethoxy-4-n-pentyloxyphenyl)-2-imino-thiazolidin-4-one was dissolved in 30 ml of ethanol and 30 ml of 2N HCl and heated under reflux for 12 hours. do. After cooling, 100ml of water
Add and collect the crystals that precipitate. Recrystallization from 80% ethanol yields 5-(3-ethoxy-4-n
-pentyloxyphenyl)-thiazolidine-2,
2.8 g (86.7%) of colorless platelet crystals of 4-dione are obtained. mp104−105℃. Reference Example 6 2.82g of 2-(3-ethoxy-4-n-pentyloxyphenyl)-2-hydroxyacetic acid was dissolved in 30ml of ethylene glycol monomethyl ether,
Add 3.3 ml of concentrated hydrochloric acid and 1.52 g of thiourea and stir at 90°C for 4 hours. Then add 15ml of 2N hydrochloric acid and
Heat under reflux for an hour. After cooling, pour into water to collect the precipitated crystals, and recrystallize from 80% ethanol to obtain 2.55 g of colorless plate crystals of 5-(3-ethoxy-4-n-pentyloxyphenyl)thiazolidine-2,4-dione. (78.9%) is obtained. mp104−
105℃. Reference Example 7 The compounds shown in Table 3 were synthesized in the same manner as in Reference Example 5.
【表】
実験例 1
チアゾリジン−2,4−ジオン誘導体()の
アルドース還元酵素活性の阻害作用をS.Haymen
et al.、Journal of Biological Chemistry、
Vol.240、877(1965)およびJin H.Kinoshita et
al.、Metabolism、Vol.28、Nr.4、Suppl 1、
462(1979)等に記載された方法に準じて試験し
た。試験に使用した酵素は人胎盤からとつた部分
的に精製されたアルドース還元酵素である。各化
合物について得られた結果は10-6モルの濃度にお
ける酵素活性を阻害%として表4に示してある。[Table] Experimental Example 1 The inhibitory effect of thiazolidine-2,4-dione derivative () on aldose reductase activity was evaluated by S. Haymen.
et al., Journal of Biological Chemistry,
Vol.240, 877 (1965) and Jin H. Kinoshita et al.
al., Metabolism, Vol.28, Nr.4, Suppl 1,
462 (1979) and others. The enzyme used in the test was partially purified aldose reductase from human placenta. The results obtained for each compound are shown in Table 4 as % inhibition of enzyme activity at a concentration of 10 -6 molar.
【表】
実験例 2
各化合物のラツト水晶体培養法による水分流入
抑制効果をH.Obazawa et al.Invest.
Ophthalmol Vol13、Nr.3、204(1974)に記載さ
れた方法によつて試験した。
各化合物について得られた結果は10-6モルの濃
度におけるレンズへの水分流入抑制率(%)とし
て表5に示してある。[Table] Experimental Example 2 H. Obazawa et al. Invest. H. Obazawa et al. Invest.
Tested according to the method described in Ophthalmol Vol 13, Nr. 3, 204 (1974). The results obtained for each compound are shown in Table 5 as the inhibition rate (%) of water inflow into the lens at a concentration of 10 -6 molar.
Claims (1)
なる群から選ばれた置換基を2個有するかまたは
環上の隣接する位置にメチレンジオキシ基を有す
るフエニル基を示す)で表わされる2−イミノチ
アゾリジン−4−オン誘導体。 2 酸性条件下、一般式 (式中、Rは環上にアルコキシ基および水酸基か
らなる群から選ばれた置換基を2個有するかまた
は環上の隣接する位置にメチレンジオキシ基を有
するフエニル基を、R1は水素または低級アルキ
ル基を示す)で表わされる化合物をチオ尿素と反
応させることを特徴とする一般式 (式中、Rは前記と同意義)で表わされる2−イ
ミノチアゾリジン−4−オン誘導体の製造法。[Claims] 1. General formula (wherein R represents a phenyl group having two substituents selected from the group consisting of an alkoxy group and a hydroxyl group on the ring, or a methylenedioxy group at an adjacent position on the ring) Iminothiazolidin-4-one derivatives. 2 Under acidic conditions, general formula (In the formula, R is a phenyl group having two substituents selected from the group consisting of an alkoxy group and a hydroxyl group on the ring or a methylenedioxy group at an adjacent position on the ring, and R 1 is hydrogen or General formula characterized by reacting a compound represented by (representing a lower alkyl group) with thiourea A method for producing a 2-iminothiazolidin-4-one derivative represented by the formula (wherein R has the same meaning as above).
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7387181A JPS57188579A (en) | 1981-05-15 | 1981-05-15 | 2-iminothiazolidin-4-one derivative and its preparation |
DK215082A DK215082A (en) | 1981-05-15 | 1982-05-13 | PROCEDURE FOR PREPARING 2-IMINOTIAZOLIDE INGREDIATES |
ES512185A ES8303374A1 (en) | 1981-05-15 | 1982-05-14 | 2-iminothiazolidin-4-one derivative and its preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7387181A JPS57188579A (en) | 1981-05-15 | 1981-05-15 | 2-iminothiazolidin-4-one derivative and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57188579A JPS57188579A (en) | 1982-11-19 |
JPH0114915B2 true JPH0114915B2 (en) | 1989-03-14 |
Family
ID=13530681
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7387181A Granted JPS57188579A (en) | 1981-05-15 | 1981-05-15 | 2-iminothiazolidin-4-one derivative and its preparation |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPS57188579A (en) |
DK (1) | DK215082A (en) |
ES (1) | ES8303374A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2152396T3 (en) * | 1994-04-06 | 2001-02-01 | Shionogi & Co | DERIVED FROM PHENYLACETIC ACID WITH REPLACEMENT IN GAMMA, ITS PROCEDURE FOR OBTAINING AND AGRICULTURAL BACTERICIDE CONTAINING IT. |
AU2868601A (en) * | 2000-01-27 | 2001-08-07 | Ribotargets Ltd | Biaryl compounds, their preparation and their use in therapy |
-
1981
- 1981-05-15 JP JP7387181A patent/JPS57188579A/en active Granted
-
1982
- 1982-05-13 DK DK215082A patent/DK215082A/en not_active Application Discontinuation
- 1982-05-14 ES ES512185A patent/ES8303374A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
DK215082A (en) | 1982-11-16 |
ES512185A0 (en) | 1983-02-01 |
JPS57188579A (en) | 1982-11-19 |
ES8303374A1 (en) | 1983-02-01 |
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