JPH01156965A - Thiohydantoin compound - Google Patents
Thiohydantoin compoundInfo
- Publication number
- JPH01156965A JPH01156965A JP63187252A JP18725288A JPH01156965A JP H01156965 A JPH01156965 A JP H01156965A JP 63187252 A JP63187252 A JP 63187252A JP 18725288 A JP18725288 A JP 18725288A JP H01156965 A JPH01156965 A JP H01156965A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- thiohydantoin
- lower alkyl
- compound
- 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.)
- Pending
Links
- -1 Thiohydantoin compound Chemical class 0.000 title claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 125000005504 styryl group Chemical group 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000000062 cyclohexylmethoxy group Chemical group [H]C([H])(O*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 10
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical class O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 abstract description 7
- 238000006482 condensation reaction Methods 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 208000002177 Cataract Diseases 0.000 abstract description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 3
- 239000001632 sodium acetate Substances 0.000 abstract description 3
- 235000017281 sodium acetate Nutrition 0.000 abstract description 3
- 239000012046 mixed solvent Substances 0.000 abstract description 2
- 238000010992 reflux Methods 0.000 abstract description 2
- 229960000583 acetic acid Drugs 0.000 abstract 2
- 150000001323 aldoses Chemical class 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 230000000055 hyoplipidemic effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 description 7
- 102000016912 Aldehyde Reductase Human genes 0.000 description 4
- 108010053754 Aldehyde reductase Proteins 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- ZGORSQKUJLUPJU-UHFFFAOYSA-N 2-(4-oxo-2-sulfanylideneimidazolidin-1-yl)acetic acid Chemical compound OC(=O)CN1CC(=O)NC1=S ZGORSQKUJLUPJU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JZCCPNPPRGRWHS-UHFFFAOYSA-N 5-propyl-1,2-oxazole-3-carbaldehyde Chemical compound CCCC1=CC(C=O)=NO1 JZCCPNPPRGRWHS-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical class NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Chemical class 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- 244000309464 bull Species 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
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000006286 dichlorobenzyl group Chemical group 0.000 description 1
- 125000004188 dichlorophenyl group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004175 fluorobenzyl group Chemical group 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 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
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、新規なチオヒダントイン化合物に関するもの
である。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel thiohydantoin compounds.
本発明化合物は、血糖低下作用、脂質低下作用及びアル
ドース・リダクターゼ阻害作用等を有し、糖尿病用剤及
び白内障用剤等の医薬として有用である。The compound of the present invention has a hypoglycemic effect, a lipid-lowering effect, an aldose reductase inhibitory effect, and the like, and is useful as a medicine such as a diabetic agent and a cataract agent.
従来の技術及びその問題点
Ｃｈｅｍ、Ｐｈａｒｍ、 Ｂｕｌｌ、、 ３０． ３２
４４（１９８２）には、本発明化合物に類似したチオヒ
ダントイン誘導体が記載されており、該化合物がアルド
ース・リダクターゼ阻害作用を有することが示されてい
る。しかしながら、その作用効果は十分でなく、更に優
れたアルドース・リダクターゼ阻害作用を有し、また血
糖低下作用、脂質低下作用をも併せ持つ化合物の開発が
要望されている。Conventional techniques and their problems Chem, Pharm, Bull, 30. 32
44 (1982) describes a thiohydantoin derivative similar to the compound of the present invention, and it has been shown that this compound has an aldose reductase inhibitory effect. However, its effects are not sufficient, and there is a need for the development of a compound that has even better aldose reductase inhibitory action and also has blood sugar lowering action and lipid lowering action.
問題点を解決するための手段
本発明者は、上記従来技術の問題点に鑑みて鋭意研究を
重ねた結果、下記一般式（Ｉ）で表わされる新規なチオ
ヒダントイン化合物が優れた血糖低下作用、脂質低下作
用及びアルドース・リダクターゼ阻害作用を有し、糖尿
病用剤及び白内障用剤等の医薬として極めて有用である
ことを見出し、本発明を完成した。Means for Solving the Problems As a result of extensive research in view of the problems of the prior art described above, the present inventors have discovered that a novel thiohydantoin compound represented by the following general formula (I) has an excellent hypoglycemic effect, The present invention was completed based on the discovery that it has a lipid-lowering effect and an aldose reductase inhibitory effect, and is extremely useful as a drug for diabetes and cataract.
即ち本発明は、下記一般式（Ｉ）で表わされる新規なチ
オヒダントイン化合物に係る。That is, the present invention relates to a novel thiohydantoin compound represented by the following general formula (I).
〔式中、Ｒ４はベンゾイソキサゾリル基、テトラ基、ト
リフルオロメチル基、メトキシ基、フェネチル基、ベン
ジロキシ基、エトキシカルボニル基、シクロプロピル基
、イソブチルシクロヘキシル基、シクロへキシルメトキ
シ基、フェニル基、ハロゲノフェニル基、メトキシフェ
ニル基、テトラハイドロピラニル基、チエニル基又はピ
リジニル基を示す。Ｒ３、Ｒ，は同−又は相異なって水
素原子、低級アルキル基、カルボキシメチル基、又はハ
ロゲノベンジル基を示す。〕
上記一般式（Ｉ）においてＲ２で定義されるハロゲン原
子としては、フッ素、塩素、臭素、沃素を、又ハロゲノ
フェニル基としてはフルオロフェニル、クロロフェニル
、ブロモフェニル、ジクロロフェニル、ブロモフルオロ
フェニル基等を例示することができる。Ｒ２、Ｒ３、Ｒ
４で定義される低級アルキル基としては炭素数１〜６の
アルキル基、例えばメチル、エチル、プロピル、１ＳＯ
−プロピル、ブチル、１ｓｏ−ブチル、ｔｅｒｔ−ブチ
ル、ペンチル、ヘキシル基等を例示することができる。[In the formula, R4 is a benzisoxazolyl group, a tetra group, a trifluoromethyl group, a methoxy group, a phenethyl group, a benzyloxy group, an ethoxycarbonyl group, a cyclopropyl group, an isobutylcyclohexyl group, a cyclohexylmethoxy group, a phenyl group , halogenophenyl group, methoxyphenyl group, tetrahydropyranyl group, thienyl group or pyridinyl group. R3, R, are the same or different and represent a hydrogen atom, a lower alkyl group, a carboxymethyl group, or a halogenobenzyl group. ] Examples of the halogen atom defined by R2 in the above general formula (I) include fluorine, chlorine, bromine, and iodine, and examples of the halogenophenyl group include fluorophenyl, chlorophenyl, bromophenyl, dichlorophenyl, and bromofluorophenyl groups. can do. R2, R3, R
The lower alkyl group defined in 4 is an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1SO
Examples include -propyl, butyl, 1so-butyl, tert-butyl, pentyl, and hexyl groups.
またＲ３、Ｒ４で定義されるノ１０ゲノベンジル基とし
ては、フルオロベンジル、クロロベンジル、ブロモベン
ジル、ジクロロベンジル、ブロモフルオロベンジル基等
を例示することができる。Examples of the 10genobenzyl group defined by R3 and R4 include fluorobenzyl, chlorobenzyl, bromobenzyl, dichlorobenzyl, and bromofluorobenzyl groups.
本発明に係る前記一般式（Ｉ）で表わされるチオヒダン
トイン化合物は、例えば下記反応工程式に示すように、
一般式（ＩＩ）で表わされるアルデヒド誘導体と一般式
（ｍ）で表わされるチオヒダントイン誘導体との縮合反
応により製造することができる。The thiohydantoin compound represented by the general formula (I) according to the present invention is, for example, as shown in the following reaction scheme:
It can be produced by a condensation reaction between an aldehyde derivative represented by general formula (II) and a thiohydantoin derivative represented by general formula (m).
〔式中、Ｒ１、Ｒ２、Ｒ３は前記に同じ。〕上上記縮合
窓は、公知のアルドール縮合、クネベナゲル縮合反応等
と同様の条件下に行うことができ、触媒の存在下適当な
溶媒中にて行なわれる。[In the formula, R1, R2, and R3 are the same as above. ] The above-mentioned condensation window can be carried out under the same conditions as the known aldol condensation reaction, Knevenagel condensation reaction, etc., and is carried out in a suitable solvent in the presence of a catalyst.
本縮合反応に使用される触媒としては、水酸化カリウム
、水酸化ナトリウム、水酸化カルシウム、炭酸ナトリウ
ム、炭酸水素ナトリウム、ナトリウムメトキサイド、ナ
トリウムエトキサイド、酢酸ナトリウム等のアルカリ金
属もしくはアルカリ土類金属の水酸化物、炭酸塩、アル
コキサイド、その有機酸塩またはメチルアミン、エチル
アミン、ジエヂルアミン、トリエチルアミン、アニリン
、ニコチン、ピリジン、ピペリジン、アンモニア等のア
ミン類及び無水酢酸、無水プロピオン酸等の有機酸無水
化物が用いられる。触媒の使用割合は、適宜選択できる
が、通常アルデヒド誘導体（ＩＩ）に対し０．１〜３．
０倍モル程度使用するのが好ましい。アルデヒド誘導体
（ｎ）とチオヒダントイン誘導体（ＩＩＩ）の使用割合
は、適宜選択できるが、通常アルデヒド誘導体（ＩＩ）
に対しチオヒダントイン誘導体（ＩＩＩ）を１．０〜２
．０倍モル程度使用するのが好ましい。反応は、通常加
熱下で行なわれ、一般には溶媒の還流温度において有利
に進行する。溶媒としては、例えばメタノール、エタノ
ール等のアルコール類、テトラヒドロフラン、ジオキサ
ン等のエーテル類及び酢酸等の有機酸が用いられる。上
記反応により生成した本発明の新規チオヒダントイン化
合物は、通常の分離手段、例えば再結晶、カラムクロマ
トグラフィー等により容易に単離可能である。Catalysts used in this condensation reaction include alkali metals or alkaline earth metals such as potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, and sodium acetate. Hydroxides, carbonates, alkoxides, their organic acid salts, amines such as methylamine, ethylamine, diethylamine, triethylamine, aniline, nicotine, pyridine, piperidine, ammonia, and organic acid anhydrides such as acetic anhydride and propionic anhydride. used. The ratio of the catalyst to be used can be selected as appropriate, but is usually 0.1 to 3.
It is preferable to use about 0 times the mole amount. The ratio of aldehyde derivative (n) and thiohydantoin derivative (III) to be used can be selected as appropriate, but usually aldehyde derivative (II)
and thiohydantoin derivative (III) from 1.0 to 2
．． It is preferable to use about 0 times the mole amount. The reaction is usually carried out under heating, and generally proceeds advantageously at the reflux temperature of the solvent. As the solvent, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and organic acids such as acetic acid are used. The novel thiohydantoin compound of the present invention produced by the above reaction can be easily isolated by conventional separation means such as recrystallization, column chromatography, etc.
本発明は、一般式（Ｉ）で表わされるチオヒダントイン
化合物のいずれの幾何異性体をも包含する。また、一般
式（Ｉ）で表わされるチオヒダントイン化合物のアルカ
リ金属塩、アルカリ土類金属塩、塩基性アミノ酸との塩
、有機塩基との塩、水和物等も包含する。アルカリ金属
塩としては例えばナトリウム、カリウム等の塩を、アル
カリ土類金属塩としては例えばカルシウム、マグネシウ
ム等の塩を夫々挙げることができる。塩基性アミノ酸の
塩としては例えばアルギニン、リジン等の塩を、有機塩
基との塩としてはトリス（ヒドロキシメチル）アミノメ
タン、シイツブ。ヒルアミ。The present invention includes any geometric isomers of the thiohydantoin compound represented by general formula (I). It also includes alkali metal salts, alkaline earth metal salts, salts with basic amino acids, salts with organic bases, hydrates, etc. of the thiohydantoin compound represented by general formula (I). Examples of the alkali metal salts include sodium and potassium salts, and examples of the alkaline earth metal salts include calcium and magnesium salts. Examples of salts of basic amino acids include salts of arginine and lysine, and examples of salts with organic bases include tris(hydroxymethyl)aminomethane and salts. Hiruami.
等の塩を例示することができる。For example, salts such as
上記縮合反応において出発原料となる一般式（ＩＩ）の
アルデヒド誘導体は、通常公知の化合物であるかまたは
公知の方法によって容易に製造される〔ガッチェンタ
キミ力 イタリアーナ（Ｇａｚｚ、Ｃｈｉｍ、 Ｉ ｔ
ａｌ、）、７３．９９ （１９４３）、テトラヘドロン
（Ｔｅｔｒａｈｅｄｒｏｎ） 、 ２３゜４６９７
（１９６７））。The aldehyde derivative of general formula (II), which serves as a starting material in the above condensation reaction, is a commonly known compound or can be easily produced by a known method [Gatchenta
Kimiriki Italiana (Gazz, Chim, It
al,), 73.99 (1943), Tetrahedron, 23°4697
(1967)).
また一般式（ＩＩ［）で表わされるチオヒダントイン誘
導体も、通常公知の化合物であるかまたは公知の方法に
よって容易に製造される。例えば、ジャーナル オブ
アメリカン ケミカル ソサイエティ−（Ｊ、Ａｍ、Ｃ
ｈｅｍ、Ｓｏｃ、）、４ヱ、２４０（１９２５）等に記
載の方法に準じて容易に製造できる。The thiohydantoin derivative represented by the general formula (II[) is also a commonly known compound or can be easily produced by a known method. For example, Journal of
American Chemical Society (J, Am, C
It can be easily produced according to the method described in, eg, Hem, Soc.
実施例 次に実施例を挙げて本発明を更に具体的に説明する。Example Next, the present invention will be explained in more detail with reference to Examples.
実施例１
４−（５−プロピル−３−イソキサゾリルメチレン）−
２−チオヒダントイン−１−酢酸（化合物ｌ−１）の製
造
５−プロピルイソキサゾール−３−アルデヒド２．０ｇ
、２−チオヒダントイン−１−酢酸２．８ｇ、酢酸ナト
リウム３．９ｇを無水酢酸１．６−と酢酸４０−の混液
に加え、３時間還流した。放冷後、反応液に水を加え析
出する結晶を炉底し、枦取した結晶を酢酸−水（３：
１）の混合溶媒より再結晶して、４− （５−プロピル
−３−イソキサゾリルメチレン）−２−チオヒダントイ
ン−１−酢酸（化合物ニー１）を２．５ｇＣ収率５９％
）得た。Example 1 4-(5-propyl-3-isoxazolylmethylene)-
Production of 2-thiohydantoin-1-acetic acid (compound l-1) 2.0 g of 5-propylisoxazole-3-aldehyde
, 2.8 g of 2-thiohydantoin-1-acetic acid, and 3.9 g of sodium acetate were added to a mixture of 1.6- and 40-acetic anhydride, and the mixture was refluxed for 3 hours. After cooling, water was added to the reaction solution to remove precipitated crystals from the bottom of the furnace, and the collected crystals were mixed with acetic acid-water (3:
Recrystallization from the mixed solvent of 1) yielded 2.5 g of 4-(5-propyl-3-isoxazolylmethylene)-2-thiohydantoin-1-acetic acid (compound 1) in a yield of 59%.
)Obtained.
ｍｐ、 ２０７〜２０９℃
元素分析（Ｃ１２Ｈｔ３Ｎ３ｏ４ｓとして）ＣＨＮ
計算値（％） ４８，８１ ４．４４ １４．２
３実測値（％） ４９．０１ ４．４１ １４．
１３実施例２
実施例１と同様な方法により第１表に示す化合物Ｉ−２
〜ｌ−３７を合成した。mp, 207-209℃ Elemental analysis (as C12Ht3N3o4s) CHN Calculated value (%) 48,81 4.44 14.2
3 Actual measurement value (%) 49.01 4.41 14.
13 Example 2 Compound I-2 shown in Table 1 was prepared in the same manner as in Example 1.
~l-37 was synthesized.
Claims (1)
ドロベンゾイソキサゾリル基、スチリル基、α−メチル
スチリル基又は基▲数式、化学式、表等があります▼ を示す。ここで、Ｒ＿２はハロゲン原子、低級アルキル
基、トリフルオロメチル基、メトキシ基、フェネチル基
、ベンジルロキシ基、エトキシカルボニル基、シクロプ
ロピル基、イソブチルシクロヘキシル基、シクロヘキシ
ルメトキシ基、フェニル基、ハロゲノフェニル基、メト
キシフェニル基、テトラハイドロピラニル基、チエニル
基又はピリジニル基を示す。Ｒ＿３、Ｒ＿４は同一又は
相異なって水素原子、低級アルキル基、カルボキシメチ
ル基、又はハロゲノベンジル基を示す。〕で表わされる
チオヒダントイン化合物。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is benzisoxazolyl group, tetrahydrobenzisoxazolyl group, styryl group, α-methylstyryl group or group ▲ Numerical formula, There are chemical formulas, tables, etc. ▼ Shows. Here, R_2 is a halogen atom, a lower alkyl group, a trifluoromethyl group, a methoxy group, a phenethyl group, a benzyloxy group, an ethoxycarbonyl group, a cyclopropyl group, an isobutylcyclohexyl group, a cyclohexylmethoxy group, a phenyl group, a halogenophenyl group, It represents a methoxyphenyl group, a tetrahydropyranyl group, a thienyl group, or a pyridinyl group. R_3 and R_4 are the same or different and represent a hydrogen atom, a lower alkyl group, a carboxymethyl group, or a halogenobenzyl group. ] A thiohydantoin compound represented by
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63187252A JPH01156965A (en) | 1987-09-29 | 1988-07-26 | Thiohydantoin compound |
| AU24842/88A AU2484288A (en) | 1987-09-29 | 1988-09-27 | Thiohydantoin compounds |
| PCT/JP1988/000979 WO1989002890A1 (en) | 1987-09-29 | 1988-09-27 | Thiohydantoin compounds |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24559187 | 1987-09-29 | ||
| JP62-245591 | 1987-09-29 | ||
| JP63187252A JPH01156965A (en) | 1987-09-29 | 1988-07-26 | Thiohydantoin compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01156965A true JPH01156965A (en) | 1989-06-20 |
Family
ID=26504234
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63187252A Pending JPH01156965A (en) | 1987-09-29 | 1988-07-26 | Thiohydantoin compound |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH01156965A (en) |
| WO (1) | WO1989002890A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05953A (en) * | 1990-11-27 | 1993-01-08 | Otsuka Pharmaceut Factory Inc | Agent for prevention and treatment of cataract |
| JPH05170653A (en) * | 1991-12-25 | 1993-07-09 | Otsuka Pharmaceut Factory Inc | Treating agent for diabetes mellitus |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5912261A (en) * | 1994-12-20 | 1999-06-15 | Nippon Zoki Pharmaceutical Co., Ltd. | Carboxyalkyl heterocyclic derivatives |
| US5681843A (en) * | 1994-12-20 | 1997-10-28 | Nippon Zoki Pharmaceutical Co., Ltd. | Parabanic acid derivatives |
| US6197806B1 (en) | 1995-12-20 | 2001-03-06 | Nippon Zoki Pharmaceutical Co., Ltd. | Eliminating agent for activated oxygen and free radicals |
| JPH10182460A (en) * | 1996-12-27 | 1998-07-07 | Nippon Zoki Pharmaceut Co Ltd | 3-deoxyglucosone generation inhibitor |
| AU754989B2 (en) | 1998-11-16 | 2002-11-28 | Nippon Zoki Pharmaceutical Co., Ltd. | A therapeutic agent for intractable vasculitis |
| JP4711523B2 (en) | 2001-02-13 | 2011-06-29 | 日本臓器製薬株式会社 | Hypoalbuminemia improving agent |
| WO2011075784A1 (en) * | 2009-12-23 | 2011-06-30 | Peter Maccallum Cancer Institute | Compounds, preparations and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR79384B (en) * | 1982-08-20 | 1984-10-22 | Hoechst Uk Ltd |
-
1988
- 1988-07-26 JP JP63187252A patent/JPH01156965A/en active Pending
- 1988-09-27 WO PCT/JP1988/000979 patent/WO1989002890A1/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05953A (en) * | 1990-11-27 | 1993-01-08 | Otsuka Pharmaceut Factory Inc | Agent for prevention and treatment of cataract |
| JPH05170653A (en) * | 1991-12-25 | 1993-07-09 | Otsuka Pharmaceut Factory Inc | Treating agent for diabetes mellitus |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1989002890A1 (en) | 1989-04-06 |
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