JP2005002024A - Antipruritic agent - Google Patents
Antipruritic agent Download PDFInfo
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- JP2005002024A JP2005002024A JP2003165874A JP2003165874A JP2005002024A JP 2005002024 A JP2005002024 A JP 2005002024A JP 2003165874 A JP2003165874 A JP 2003165874A JP 2003165874 A JP2003165874 A JP 2003165874A JP 2005002024 A JP2005002024 A JP 2005002024A
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- 239000003908 antipruritic agent Substances 0.000 title abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 125000005843 halogen group Chemical group 0.000 claims abstract description 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 15
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 208000024891 symptom Diseases 0.000 claims description 10
- 230000001823 pruritic effect Effects 0.000 claims description 9
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
- 208000003251 Pruritus Diseases 0.000 abstract description 32
- -1 methylene, vinylene Chemical group 0.000 abstract description 28
- 206010003645 Atopy Diseases 0.000 abstract description 7
- 230000007803 itching Effects 0.000 abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract 2
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- 208000011580 syndromic disease Diseases 0.000 abstract 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
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- 239000003793 antidiarrheal agent Substances 0.000 description 9
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- 206010012438 Dermatitis atopic Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 125000001041 indolyl group Chemical group 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- 238000006748 scratching Methods 0.000 description 5
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
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- 208000024998 atopic conjunctivitis Diseases 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 206010063409 Acarodermatitis Diseases 0.000 description 2
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- 208000017667 Chronic Disease Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000036741 Pruritus generalised Diseases 0.000 description 2
- 241000447727 Scabies Species 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
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- 230000035807 sensation Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
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- 150000003431 steroids Chemical class 0.000 description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 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 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
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- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006622 cycloheptylmethyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 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
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000000623 heterocyclic group Chemical group 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
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、掻痒性症状の予防又は治療用薬剤（以下、止痒剤ともいう）に関し、特にアトピー症状による掻痒感の解消に効果がある止痒剤に関する。
【０００２】
【従来の技術】
近年、アトピー性皮膚炎、アトピー性結膜炎、老人性乾皮膚症などの慢性疾患患者数が急激に増加してきている。これらの疾患は原因不明の強い痒み感のために行う掻痒行動（引っ掻き行動）により発生するものと考えられている。したがって、これら慢性疾患の解消には掻痒感を解消することが非常に重要である。
【０００３】
従来、慢性皮膚炎に対しては、外用ステロイド剤、抗ヒスタミン剤、抗アレルギー剤などの薬剤が使用されている。しかし、ステロイド剤は長期連用による副作用からその使用が制限されており、抗ヒスタミン剤、抗アレルギー剤は、治療効果の点で十分満足のいくものが得られていない。
【０００４】
また、これまで止痒剤の評価は、ヒスタミン、セロトニン等の痒み惹起物質を動物の皮膚内に投与し掻痒行動を測定していたが、近年アトピー性皮膚炎による痒みの発症は、単なる肥満細胞から放出されるヒスタミン等による反応ではないと報告されている（非特許文献１）。
【０００５】
したがって、アトピー性皮膚炎の予防及び治療に対して新たな作用機序に基づく止痒剤の開発が望まれている。
【０００６】
一方、プロスタグランジン類が痒み惹起成分であるという報告はなされているが止痒剤としての使用は知られていない（非特許文献２）。
【非特許文献１】Ｊ． Ｄｅｒｍａｔｏｌｏｇｉｃａｌ Ｓｃｉｅｎｃｅ ２５， ２０−２８， ２００１
【非特許文献２】Ｊ． Ａｍ． Ａｃａｄ． Ｄｅｒｍａｔｏｌ． ４７， ２８−３２， ２００２
【０００７】
【発明が解決しようとする課題】
本発明は、新規な止痒剤、アトピー性症状の予防及び治療用薬剤を提供することを目的とする。
【０００８】
【課題を解決するための手段】
本発明者らは、上記目的を達成するべく後述の評価方法を用いて検討した結果、ある種のプロスタグランジン類がアトピー性疾患に伴う掻痒感を効果的に抑制することを見出し、さらにこの知見に基づき本発明を完成した。
【０００９】
すなわち、本発明は、式［Ｉ］
【００１０】
【化２】
［式中、Ｗ１及びＷ２は同一又は異なって水素原子、ハロゲン原子、ニトロ基又は置換若しくは無置換のＣ１−５のアルコキシ基を示し、
Ｗ３は水素原子、ハロゲン原子、水酸基、シアノ基又は置換若しくは無置換のＣ１−５のアルコキシ基を示し、
Ｗ４は水素原子又は水酸基を示し、
Ｇはハロゲン原子、置換若しくは無置換のＣ１−５のアルキル基、シアノ基、テトラゾリル基、水酸基、ＣＯ２Ｒ３（式中、Ｒ３は水素原子、置換若しくは無置換のＣ１−１０アルキル基、置換若しくは無置換のＣ３−１０のシクロアルキル基又はアリール基を示す。）又はＣＯＮＲ４Ｒ５（式中、Ｒ４及びＲ５は同一もしくは異なって水素原子、置換若しくは無置換のＣ１−１０のアルキル基、置換若しくは無置換のＣ３−１０のシクロアルキル基又はアリール基を示すか、あるいはＲ４及びＲ５が一緒になって結合する窒素原子と共に更にヘテロ原子を含有しても良い５〜６員環の複素環を形成する。）を示し、
ｐ及びｑはそれぞれ０〜３の整数を示し、
Ｘ１は酸素原子、メチレン基又はＮＨ基を示し、Ｘ２は酸素原子、硫黄原子、メチレン基、ビニレン基又はエチニレン基を示し、
Ｙはエチレン基、ビニレン基、エチニレン基、硫黄原子又は酸素原子を示し、ｔは０又は１を示し、
Ｒ１は水素原子又は置換若しくは無置換のＣ１−５のアルキル基を示し、
Ｒ２は置換若しくは無置換のＣ１−１０のアルキル基、置換若しくは無置換のＣ２−１０のアルケニル基、置換若しくは無置換のＣ２−１０のアルキニル基、置換若しくは無置換のＣ３−１０のシクロアルキル基又はアリール基を示す。］で表されるプロスタグランジンＩ誘導体、その製薬学的に許容される塩又はその水和物を有効成分とする掻痒性症状の予防又は治療用薬剤である。
【００１２】
【発明の実施の形態】
発明者らは、自然発症的にアトピー性皮膚炎様の皮膚疾患を発症するＮＣ／Ｎｇａマウスを用いて、その掻痒行動を測定することにより、自然発症的に惹起される掻痒行動に対する種々の薬剤の止痒効果について評価を行った。
【００１３】
薬剤塗布前後２４時間の各動物個体における掻痒回数について対応のある検定を行い、０．５％以下の危険率で有意差のあるものを「有効」と判定したところ、以下のプロスタグランジン類で優れた効果が確認された。
以下、本発明の止痒剤について説明する。
本発明は、式［Ｉ］で表されるプロスタグランジン誘導体を有効成分とすることを特徴とする。
本発明において、ビニレン基とは、シス又はトランスのビニレン基を意味する。
【００１４】
Ｃ１−５のアルコキシ基とは、炭素原子数１〜５の直鎖状又は分枝鎖状のアルコキシ基を示し、例えばメトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、ブトキシ基、ｔｅｒｔ−ブトキシ基、ペンチルオキシ基、ｔｅｒｔ−ペンチルオキシ基などを挙げることができる。
【００１５】
置換Ｃ１−５のアルコキシ基の例としては、アルコキシ基の水素原子をハロゲン原子、水酸基、Ｃ１−５のヒドロキシアルキル基、カルボキシル基、メルカプト基、Ｃ１−５のアルキルチオ基、グアニジル基、フェニル基、イミダゾリル基、インドリル基、アミノ基及びアミド基からなる群より選ばれる一つ以上の基で置換したアルコキシ基をあげることができる。
【００１６】
Ｃ１−５のアルキル基とは、炭素原子数１〜５の直鎖状又は分枝鎖状のアルキル基を示し、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ｔｅｒｔ−ペンチル基などを挙げることができる。
【００１７】
Ｃ１−１０のアルキル基とは、炭素原子数１〜１０の直鎖状又は分枝鎖状のアルキル基を示し、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ｔｅｒｔ−ペンチル基、ヘキシル基、イソヘキシル基、２−メチルヘキシル基、ヘプチル基、オクチル基、デシル基などを挙げることができる。
【００１８】
置換Ｃ１−１０アルキル基および置換Ｃ１−５アルキル基の置換基としては、ハロゲン原子、水酸基、Ｃ１−５のヒドロキシアルキル基、カルボキシル基、メルカプト基、Ｃ１−５のアルキルチオ基、Ｃ３−１０のシクロアルキル基、グアニジル基、アリール基、アリールオキシ基、イミダゾリル基、インドリル基、アミノ基、アミド基及びＣ１−５のアルコキシ基をあげることができる。特に水酸基、ハロゲン原子又はＣ３−１０のシクロアルキル基で置換されたＣ１−５のアルキル基である。
【００１９】
水酸基で置換されたＣ１−５のアルキル基の例としては、ヒドロキシメチル基、１−ヒドロキシエチル基、２−ヒドロキシエチル基、２−ヒドロキシプロピル基、３−ヒドロキシプロピル基、２，３−ジヒドロキシプロピル基、５−ヒドロキシペンチル基などを挙げることができる。
【００２０】
ハロゲン原子で置換されたＣ１−５のアルキル基の例としては、ジクロロメチル基、トリフルオロメチル基、ペンタフルオロエチル基、１，３−ジブロモプロピル基などを挙げることができる。
【００２１】
Ｃ３−１０のシクロアルキル基で置換されたＣ１−５のアルキル基の例としては、シクロプロピルメチル基、シクロブチルエチル基、シクロペンチルメチル基、シクロヘキシルメチル基、シクロヘプチルメチル基、シクロノニルブチル基、４−フルオロシクロヘキシルメチル基などを挙げることができる。
【００２２】
アリールオキシ基で置換されたＣ１−５のアルキル基の例としては、フェノキシメチル基、フェノキシプロピル基、クロロフェノキシエチル基、メトキシフェノキシメチル基、トリルオキシメチル基などを挙げることができる。
【００２３】
アリール基で置換されたＣ１−５のアルキル基の例としては、ベンジル基、フェネチル基、フェニルプロピル基、クロロフェネチル基、トリルメチル基、ジフェニルメチル基などを挙げることができる。
【００２４】
Ｃ２−１０のアルケニル基とは、炭素原子数２〜１０の直鎖状又は分枝鎖状のアルケニル基を示し、例えばビニル基、アリル基、プロペニル基、１−イソプロペニル基、３−ブテニル基、１，３−ブタジエニル基、２，６−ジメチル−５−ヘプテニル基、７−オクテニル基などを挙げることができる。
【００２５】
置換Ｃ２−１０のアルケニル基の例としては、アルケニル基の水素原子をハロゲン原子、水酸基、Ｃ１−５のヒドロキシアルキル基、カルボキシル基、メルカプト基、Ｃ１−５のアルキルチオ基、グアニジル基、フェニル基、イミダゾリル基、インドリル基、アミノ基、アミド基及びＣ１−５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したアルケニル基をあげることができる。
【００２６】
Ｃ２−１０のアルキニル基の例としては、エチニル基、２−プロピニル基、２−ペンチニル基、１−メチル−３−ペンチニル基、１，１−ジメチル−２−ペンチニル基、１−メチル−３−へキシニル基、４−オクチニル基などを挙げることができる。
【００２７】
置換Ｃ２−１０のアルキニル基の例としては、アルキニル基の水素原子をハロゲン原子、水酸基、Ｃ１−５のヒドロキシアルキル基、カルボキシル基、メルカプト基、Ｃ１−５のアルキルチオ基、グアニジル基、フェニル基、イミダゾリル基、インドリル基、アミノ基、アミド基及びＣ１−５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したアルキニル基をあげることができる。
【００２８】
Ｃ３−１０のシクロアルキル基の例としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロノニル基、などをあげることができる。
【００２９】
置換Ｃ３−１０のシクロアルキル基としては、シクロアルキル基の水素原子をハロゲン原子、置換もしくは無置換のＣ１−１０のアルキル基、水酸基、Ｃ１−５のヒドロキシアルキル基、カルボキシル基、メルカプト基、Ｃ１−５のアルキルチオ基、グアニジル基、フェニル基、イミダゾリル基、インドリル基、アミノ基、アミド基及びＣ１−５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したシクロアルキル基をあげることができる。
【００３０】
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子を意味する。特に、フッ素原子、塩素原子である。
【００３１】
アリール基の例としては、フェニル基、トリル基、メシチル基、クメニル基、キシリル基などを挙げることができる。
【００３２】
置換アリール基としては、アリール基の水素原子をハロゲン原子、トリフルオロメチル基、水酸基、Ｃ１−５のヒドロキシアルキル基、カルボキシル基、メルカプト基、Ｃ１−５のアルキル基、Ｃ１−５のアルコキシ基、Ｃ１−５のアルキルチオ基、グアニジル基、フェニル基、フェノキシ基、イミダゾリル基、インドリル基、シアノ基、ニトロ基、アミノ基、アミド基及びアセチルアミノ基からなる群より選ばれる一つ以上の基で置換したアリール基をあげることができる。
【００３３】
Ｒ４及びＲ５が結合している窒素原子と一緒になって更にヘテロ原子を含有しても良い５〜６員環の複素環の例としては、１−ピロリジル基、チアゾリル基、１−ピペリジル基、モルホリル基、ピペラジル基などを挙げることができる。
【００３４】
本発明の有効成分となるプロスタグランジン誘導体は以下の公報に開示された公知化合物を含む。特許第１９３３１６７号、特許第１９７４４９２号、特許第２８９３８１２号、特許第３１０２１４１号、ＷＯ００／２４７２７、特公平６−６２５９９、特開平８−２０８６３７号。
【００３５】
本発明に係る代表的な式（Ｉ）の化合物としては下記の化合物をあげることができる。
【００３６】
【表１】
【表２】
【表３】
本発明の止痒剤は、掻痒感を軽減・解消するものであれば限定はないが、特にアトピー（ＩｇＥ抗体を介した抗原特異的免疫反応によっておこる湿疹）による痒みに有効である。この点から本発明の止痒剤は、アトピー性疾患の予防又は治療用薬剤を含むものである。
【００４０】
なお、本発明において「掻痒性症状」とは、限局性ないし汎発性のかゆみ及びそれに関連する炎症を皮膚及び粘膜に有する症状をいう。例えば、疥癬、蕁麻疹、湿疹、乾皮症（老人性乾皮症、皮膚欠乏性湿疹など）、乾癬、皮膚掻痒症、痒疹があげられる。
【００４１】
なお、本発明において「アトピー症状」とは、限局性ないし汎発性のかゆみ及びそれに関連する炎症を皮膚及び粘膜に有する症状、すなわち、アトピーが原因でおこる掻痒性症状をいう。例えば、アトピー性皮膚炎およびアトピー性結膜炎があげられる。
【００４２】
本発明において「アトピー性皮膚炎」とは、増悪・寛解を繰り返す、掻痒のある湿疹を主病変とする疾患をいい、アトピー素因の個体に発生しやすい。
【００４３】
本発明の止痒剤は、経口、非経口又は局所投与のいずれかによって投与することができる。
【００４４】
本発明の止痒剤における有効成分の投与量は患者の体重、年齢、性別等により適宜増減できるが、通常１回投与あたり１ｎｇ〜１０ｍｇ、好ましくは０．１〜５００μｇであり１日に１回〜数回投与できる。
【００４５】
本発明の止痒剤は、有効成分に通常の製剤化に用いられる担体、賦形剤、その他の添加剤を用いて医薬組成物として調製することができる。
【００４６】
本発明の止痒剤は、錠剤、顆粒剤、散剤、カプセル剤、液剤、軟膏剤、クリーム剤、貼付剤、エアゾール剤などの剤形で、内服剤、注射剤、外用剤、点眼剤などの剤形で投与することができる。好ましい剤形としては、患部に直接投与できる点、投与が容易な点、全身副作用発生の可能性が低減する点などから外用剤があげられる。
【００４７】
ここで「外用剤」とは、外用液剤、エアゾール剤、外用散剤、軟膏剤、クリーム剤、ゲル剤、硬膏剤、貼付剤などがあげられる。
【００４８】
【発明の効果】
本発明により皮膚炎を惹起する掻痒行動を低減させることが可能になったので、アトピー性皮膚炎、アトピー性結膜炎、疥癬、蕁麻疹および乾皮症などの皮膚炎を予防又は改善することができる薬剤の提供が可能になった。
【００４９】
【実施例】
以下実施例および試験例により、本発明をさらに詳細に説明する。
【００５０】
なお、特に断らない限り薬剤の濃度（％）は、ｗ／ｖ％を意味する。
実施例１
下記成分を秤量し均一に混合した後、精製水とエタノールの下記容量を加え１０００ｍｌの液剤を得た。
化合物１９ ０．１ｇ
エタノール ２００ｍｌ
精製水 ８００ｍｌ
【００５１】
試験例１：ＮＣマウス自発掻痒行動に対する作用
（実験方法）
体重約３０ｇの２０週齢ＮＣ／Ｎｇａマウス（購入元ＳＬＣ）の両足に磁石を植え込み、その磁力感知により、足の動きを測定した。引っ掻き行為の内、１．５秒以上のものを掻痒行動としてその回数を継続的に測定した。掻痒行動には日内リズムがあるため、試験前日から２４時間の各動物個体の日内掻痒リズムを測定後、０．１％薬物溶液（１００％エタノールに溶解）を０．２ ｍｌ／ｍｏｕｓｅの割合で背部皮膚に塗布した。その後２４時間の掻痒行動を測定し薬物投与前後の掻痒行動数を比較した。
化合物２４の２４時間の掻痒行動数を図１に、総掻痒回数を図２に示した。化合物１９の２４時間の掻痒行動数を図３に、総掻痒回数を図４に示した。
いずれの化合物も掻痒を低減させることが確認された。
【図面の簡単な説明】
【図１】化合物２４を塗布した場合の掻痒行動数の経時変化を示す。図中、Ｃｌｏｃｋ ｈｏｕｒは測定した時刻を示し、Ｓｃｒａｔｃｈｉｎｇは掻痒行動数を示し、Ｐｒｅは化合物塗布前、Ｐｒｏは化合物塗布後を示す。
【図２】化合物２４の総掻痒回数を示す。図中、Ｓｃｒａｔｃｈｉｎｇは掻痒行動数を示し、Ｐｒｅは化合物塗布前、Ｐｒｏは化合物塗布後を示す。
【図３】化合物１９を塗布した場合の掻痒行動数の経時変化を示す。図中、Ｃｌｏｃｋ ｈｏｕｒは測定した時刻を示し、Ｓｃｒａｔｃｈｉｎｇは掻痒行動数を示し、Ｐｒｅは化合物塗布前、Ｐｒｏは化合物塗布後を示す。
【図４】化合物１９の総掻痒回数を示す。図中、Ｓｃｒａｔｃｈｉｎｇは掻痒行動数を示し、Ｐｒｅは化合物塗布前、Ｐｒｏは化合物塗布後を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a drug for the prevention or treatment of pruritic symptoms (hereinafter also referred to as an antipruritic agent), and particularly to an antipruritic agent that is effective in relieving pruritus caused by atopic symptoms.
[0002]
[Prior art]
In recent years, the number of patients with chronic diseases such as atopic dermatitis, atopic conjunctivitis, and senile dry dermatosis is increasing rapidly. These diseases are thought to be caused by pruritus behavior (scratching behavior) performed for a strong itching sensation of unknown cause. Therefore, it is very important to eliminate the itching sensation to eliminate these chronic diseases.
[0003]
Conventionally, for chronic dermatitis, drugs such as topical steroids, antihistamines and antiallergic agents have been used. However, the use of steroids is limited due to side effects due to long-term continuous use, and antihistamines and antiallergic agents have not been sufficiently satisfactory in terms of therapeutic effects.
[0004]
In the past, antipruritic drugs have been evaluated for pruritus by the administration of itchiness-inducing substances such as histamine and serotonin into the skin of animals. It has been reported that the reaction is not caused by histamine released from the blood (Non-patent Document 1).
[0005]
Therefore, it is desired to develop an antidiarrheal agent based on a new action mechanism for the prevention and treatment of atopic dermatitis.
[0006]
On the other hand, it has been reported that prostaglandins are stagnation-inducing components, but their use as antipruritic agents is not known (Non-patent Document 2).
[Non-Patent Document 1] Dermatologic Science 25, 20-28, 2001
[Non-Patent Document 2] Am. Acad. Dermatol. 47, 28-32, 2002
[0007]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel antidiarrheal agent and a drug for the prevention and treatment of atopic symptoms.
[0008]
[Means for Solving the Problems]
As a result of studies using the evaluation method described below to achieve the above object, the present inventors have found that certain prostaglandins effectively suppress the pruritus associated with atopic disease. The present invention has been completed based on the findings.
[0009]
That is, the present invention provides a compound of the formula [I]
[0010]
[Chemical 2]
[Wherein, W 1 and W 2 are the same or different and each represents a hydrogen atom, a halogen atom, a nitro group, or a substituted or unsubstituted C 1-5 alkoxy group,
W 3 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a substituted or unsubstituted C 1-5 alkoxy group,
W 4 represents a hydrogen atom or a hydroxyl group,
G is a halogen atom, substituted or unsubstituted C 1-5 alkyl group, cyano group, tetrazolyl group, hydroxyl group, CO 2 R 3 (wherein R 3 is a hydrogen atom, substituted or unsubstituted C 1-10 alkyl Represents a group, a substituted or unsubstituted C 3-10 cycloalkyl group or an aryl group.) Or CONR 4 R 5 (wherein R 4 and R 5 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C 1-10 alkyl group, substituted or unsubstituted C 3-10 cycloalkyl group or aryl group, or further containing a heteroatom together with the nitrogen atom to which R 4 and R 5 are bonded together To form a good 5- to 6-membered heterocyclic ring),
p and q each represent an integer of 0 to 3,
X 1 represents an oxygen atom, a methylene group or an NH group, X 2 represents an oxygen atom, a sulfur atom, a methylene group, a vinylene group or an ethynylene group,
Y represents an ethylene group, vinylene group, ethynylene group, sulfur atom or oxygen atom, t represents 0 or 1,
R 1 represents a hydrogen atom or a substituted or unsubstituted C 1-5 alkyl group,
R 2 represents a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 2-10 alkenyl group, a substituted or unsubstituted C 2-10 alkynyl group, a substituted or unsubstituted C 3- 10 cycloalkyl groups or aryl groups are shown. ] A prostaglandin I derivative represented by the above, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient for the prevention or treatment of pruritic symptoms.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The inventors have used various NC / Nga mice that spontaneously develop atopic dermatitis-like skin diseases, and various drugs for spontaneously induced pruritic behavior by measuring the pruritic behavior. The anti-principal effect was evaluated.
[0013]
A corresponding test was made for the number of pruritus in each animal individual 24 hours before and after drug application, and a significant difference with a risk rate of 0.5% or less was determined to be “effective”. The following prostaglandins An excellent effect was confirmed.
Hereinafter, the antidiarrheal agent of the present invention will be described.
The present invention is characterized in that a prostaglandin derivative represented by the formula [I] is used as an active ingredient.
In the present invention, the vinylene group means a cis or trans vinylene group.
[0014]
The C 1-5 alkoxy group represents a linear or branched alkoxy group having 1 to 5 carbon atoms, such as a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, a tert group. -A butoxy group, a pentyloxy group, a tert-pentyloxy group, etc. can be mentioned.
[0015]
Examples of the substituted C 1-5 alkoxy group include a hydrogen atom of an alkoxy group as a halogen atom, a hydroxyl group, a C 1-5 hydroxyalkyl group, a carboxyl group, a mercapto group, a C 1-5 alkylthio group, a guanidyl group, Examples thereof include an alkoxy group substituted with one or more groups selected from the group consisting of a phenyl group, an imidazolyl group, an indolyl group, an amino group and an amide group.
[0016]
The C 1-5 alkyl group refers to a linear or branched alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. Group, tert-butyl group, pentyl group, tert-pentyl group and the like.
[0017]
The C 1-10 alkyl group refers to a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. Group, tert-butyl group, pentyl group, tert-pentyl group, hexyl group, isohexyl group, 2-methylhexyl group, heptyl group, octyl group, decyl group and the like.
[0018]
Examples of the substituent of the substituted C 1-10 alkyl group and the substituted C 1-5 alkyl group include a halogen atom, a hydroxyl group, a C 1-5 hydroxyalkyl group, a carboxyl group, a mercapto group, a C 1-5 alkylthio group, C Examples thereof include a 3-10 cycloalkyl group, a guanidyl group, an aryl group, an aryloxy group, an imidazolyl group, an indolyl group, an amino group, an amide group, and a C 1-5 alkoxy group. In particular, it is a C 1-5 alkyl group substituted with a hydroxyl group, a halogen atom or a C 3-10 cycloalkyl group.
[0019]
Examples of the C 1-5 alkyl group substituted with a hydroxyl group include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2,3-dihydroxy. A propyl group, 5-hydroxypentyl group, etc. can be mentioned.
[0020]
Examples of the C 1-5 alkyl group substituted with a halogen atom include a dichloromethyl group, a trifluoromethyl group, a pentafluoroethyl group, a 1,3-dibromopropyl group, and the like.
[0021]
Examples of C 1-5 alkyl groups substituted with C 3-10 cycloalkyl groups include cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclononylbutyl. Group, 4-fluorocyclohexylmethyl group and the like.
[0022]
Examples of the C 1-5 alkyl group substituted with an aryloxy group include a phenoxymethyl group, a phenoxypropyl group, a chlorophenoxyethyl group, a methoxyphenoxymethyl group, and a tolyloxymethyl group.
[0023]
Examples of the C 1-5 alkyl group substituted with an aryl group include a benzyl group, a phenethyl group, a phenylpropyl group, a chlorophenethyl group, a tolylmethyl group, and a diphenylmethyl group.
[0024]
The C 2-10 alkenyl group refers to a linear or branched alkenyl group having 2 to 10 carbon atoms, such as vinyl, allyl, propenyl, 1-isopropenyl, 3-butenyl. Group, 1,3-butadienyl group, 2,6-dimethyl-5-heptenyl group, 7-octenyl group and the like.
[0025]
Examples of the substituted C 2-10 alkenyl group include a hydrogen atom of an alkenyl group as a halogen atom, a hydroxyl group, a C 1-5 hydroxyalkyl group, a carboxyl group, a mercapto group, a C 1-5 alkylthio group, a guanidyl group, Examples thereof include an alkenyl group substituted with one or more groups selected from the group consisting of a phenyl group, an imidazolyl group, an indolyl group, an amino group, an amide group, and a C 1-5 alkoxy group.
[0026]
Examples of C 2-10 alkynyl groups include ethynyl, 2-propynyl, 2-pentynyl, 1-methyl-3-pentynyl, 1,1-dimethyl-2-pentynyl, 1-methyl-3 Examples include -hexynyl group and 4-octynyl group.
[0027]
Examples of the substituted C 2-10 alkynyl group include a hydrogen atom of an alkynyl group as a halogen atom, a hydroxyl group, a C 1-5 hydroxyalkyl group, a carboxyl group, a mercapto group, a C 1-5 alkylthio group, a guanidyl group, Examples thereof include an alkynyl group substituted with one or more groups selected from the group consisting of a phenyl group, an imidazolyl group, an indolyl group, an amino group, an amide group and a C 1-5 alkoxy group.
[0028]
Examples of the C 3-10 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclononyl group, and the like.
[0029]
As the substituted C 3-10 cycloalkyl group, a hydrogen atom of the cycloalkyl group is a halogen atom, a substituted or unsubstituted C 1-10 alkyl group, a hydroxyl group, a C 1-5 hydroxyalkyl group, a carboxyl group, a mercapto A cyclo substituted with one or more groups selected from the group consisting of a group, a C 1-5 alkylthio group, a guanidyl group, a phenyl group, an imidazolyl group, an indolyl group, an amino group, an amide group, and a C 1-5 alkoxy group. An alkyl group can be mentioned.
[0030]
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. In particular, they are a fluorine atom and a chlorine atom.
[0031]
Examples of the aryl group include a phenyl group, a tolyl group, a mesityl group, a cumenyl group, and a xylyl group.
[0032]
As the substituted aryl group, a hydrogen atom of the aryl group is a halogen atom, a trifluoromethyl group, a hydroxyl group, a C 1-5 hydroxyalkyl group, a carboxyl group, a mercapto group, a C 1-5 alkyl group, or a C 1-5 alkyl group. One or more selected from the group consisting of an alkoxy group, a C 1-5 alkylthio group, a guanidyl group, a phenyl group, a phenoxy group, an imidazolyl group, an indolyl group, a cyano group, a nitro group, an amino group, an amide group, and an acetylamino group And an aryl group substituted with the above group.
[0033]
Examples of 5- to 6-membered heterocycles which may contain a heteroatom together with the nitrogen atom to which R 4 and R 5 are bonded include 1-pyrrolidyl group, thiazolyl group, 1-piperidyl group Group, morpholyl group, piperazyl group and the like.
[0034]
The prostaglandin derivative serving as the active ingredient of the present invention includes known compounds disclosed in the following publications. Japanese Patent No. 1933167, Japanese Patent No. 1974492, Japanese Patent No. 2893812, Japanese Patent No. 3102141, WO00 / 24727, Japanese Patent Publication No. 6-62599, and Japanese Patent Application Laid-Open No. 8-208637.
[0035]
As typical compounds of the formula (I) according to the present invention, the following compounds may be mentioned.
[0036]
[Table 1]
[Table 2]
[Table 3]
The antidiarrheal agent of the present invention is not limited as long as it reduces or eliminates pruritus, but is particularly effective for itching due to atopy (eczema caused by an antigen-specific immune reaction via an IgE antibody). From this point, the antidiarrheal agent of the present invention includes a preventive or therapeutic agent for atopic diseases.
[0040]
In the present invention, “pruritic symptom” refers to a symptom having localized or generalized itching and associated inflammation in the skin and mucous membranes. Examples include scabies, urticaria, eczema, psoriasis (senile psoriasis, skin deficiency eczema, etc.), psoriasis, cutaneous pruritus, and urticaria.
[0041]
In the present invention, the “atopic symptom” refers to a symptom caused by atopy, that is, a symptom having localized or generalized itching and inflammation associated therewith in the skin and mucous membranes. Examples include atopic dermatitis and atopic conjunctivitis.
[0042]
In the present invention, “atopic dermatitis” refers to a disease in which pruritus with pruritus, which repeats exacerbations and remissions, is the main lesion, and is likely to occur in individuals who are predisposed to atopy.
[0043]
The antidiarrheal agent of the present invention can be administered either by oral, parenteral or topical administration.
[0044]
The dose of the active ingredient in the antidiarrheal agent of the present invention can be appropriately increased or decreased depending on the patient's body weight, age, sex, etc., but is usually 1 ng to 10 mg, preferably 0.1 to 500 μg per dose, and once a day. Can be administered several times.
[0045]
The antidiarrheal agent of the present invention can be prepared as a pharmaceutical composition using carriers, excipients, and other additives used for normal formulation as active ingredients.
[0046]
The antidiarrheal agent of the present invention is in the form of tablets, granules, powders, capsules, liquids, ointments, creams, patches, aerosols, etc., and is used for internal use, injections, external preparations, eye drops, etc. It can be administered in a dosage form. Preferable dosage forms include external preparations because they can be administered directly to the affected area, easy to administer, and reduce the possibility of systemic side effects.
[0047]
Here, the “external preparation” includes an external solution, an aerosol, an external powder, an ointment, a cream, a gel, a plaster, a patch and the like.
[0048]
【The invention's effect】
Since it is possible to reduce pruritus causing dermatitis according to the present invention, dermatitis such as atopic dermatitis, atopic conjunctivitis, scabies, urticaria and psoriasis can be prevented or improved. The provision of drugs has become possible.
[0049]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
[0050]
Unless otherwise specified, the drug concentration (%) means w / v%.
Example 1
The following components were weighed and mixed uniformly, and then the following volumes of purified water and ethanol were added to obtain 1000 ml of liquid.
Compound 19 0.1 g
200ml ethanol
800 ml of purified water
[0051]
Test Example 1: Effects on spontaneous pruritus behavior of NC mice (experimental method)
Magnets were implanted in both feet of 20-week-old NC / Nga mice (purchased SLC) weighing about 30 g, and the movement of the feet was measured by sensing the magnetic force. The number of scratching actions was continuously measured as an itching action for 1.5 seconds or more. Since there is a circadian rhythm in pruritus behavior, after measuring the circadian rhythm of each animal for 24 hours from the day before the test, 0.1% drug solution (dissolved in 100% ethanol) was added at a rate of 0.2 ml / mouse. Applied to dorsal skin. Thereafter, the pruritic behavior for 24 hours was measured, and the number of pruritic behavior before and after drug administration was compared.
FIG. 1 shows the number of pruritic behaviors of
All of the compounds were confirmed to reduce pruritus.
[Brief description of the drawings]
FIG. 1 shows the change over time in the number of pruritus behavior when
FIG. 2 shows the total number of pruritus of
FIG. 3 shows the change over time in the number of pruritus behavior when Compound 19 is applied. In the figure, Clock hour indicates the measured time, Scratching indicates the number of pruritus actions, Pre indicates before compound application, and Pro indicates after compound application.
FIG. 4 shows the total number of pruritus of compound 19. In the figure, Scratching indicates the number of pruritus behavior, Pre indicates before compound application, and Pro indicates after compound application.
Claims (3)
Ｗ３は水素原子、ハロゲン原子、水酸基、シアノ基又は置換若しくは無置換のＣ１−５のアルコキシ基を示し、
Ｗ４は水素原子又は水酸基を示し、
Ｇはハロゲン原子、置換若しくは無置換のＣ１−５のアルキル基、シアノ基、テトラゾリル基、水酸基、ＣＯ２Ｒ３（式中、Ｒ３は水素原子、置換若しくは無置換のＣ１−１０アルキル基、置換若しくは無置換のＣ３−１０のシクロアルキル基又はアリール基を示す。）又はＣＯＮＲ４Ｒ５（式中、Ｒ４及びＲ５は同一もしくは異なって水素原子、置換若しくは無置換のＣ１−１０のアルキル基、置換若しくは無置換のＣ３−１０のシクロアルキル基又はアリール基を示すか、あるいはＲ４及びＲ５が一緒になって結合する窒素原子と共に更にヘテロ原子を含有しても良い５〜６員環の複素環を形成する。）を示し、
ｐ及びｑはそれぞれ０〜３の整数を示し、
Ｘ１は酸素原子、メチレン基又はＮＨ基を示し、Ｘ２は酸素原子、硫黄原子、メチレン基、ビニレン基又はエチニレン基を示し、
Ｙはエチレン基、ビニレン基、エチニレン基、硫黄原子又は酸素原子を示し、ｔは０又は１を示し、
Ｒ１は水素原子又は置換若しくは無置換のＣ１−５のアルキル基を示し、
Ｒ２は置換若しくは無置換のＣ１−１０のアルキル基、置換若しくは無置換のＣ２−１０のアルケニル基、置換若しくは無置換のＣ２−１０のアルキニル基、置換若しくは無置換のＣ３−１０のシクロアルキル基又はアリール基を示す。］で表されるプロスタグランジンＩ誘導体、その製薬学的に許容される塩又はその水和物を有効成分とする掻痒性症状の予防又は治療用薬剤。Formula [I]
W 3 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a substituted or unsubstituted C 1-5 alkoxy group,
W 4 represents a hydrogen atom or a hydroxyl group,
G is a halogen atom, substituted or unsubstituted C 1-5 alkyl group, cyano group, tetrazolyl group, hydroxyl group, CO 2 R 3 (wherein R 3 is a hydrogen atom, substituted or unsubstituted C 1-10 alkyl Represents a group, a substituted or unsubstituted C 3-10 cycloalkyl group or an aryl group.) Or CONR 4 R 5 (wherein R 4 and R 5 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C 1-10 alkyl group, substituted or unsubstituted C 3-10 cycloalkyl group or aryl group, or further containing a heteroatom together with the nitrogen atom to which R 4 and R 5 are bonded together To form a good 5- to 6-membered heterocyclic ring),
p and q each represent an integer of 0 to 3,
X 1 represents an oxygen atom, a methylene group or an NH group, X 2 represents an oxygen atom, a sulfur atom, a methylene group, a vinylene group or an ethynylene group,
Y represents an ethylene group, vinylene group, ethynylene group, sulfur atom or oxygen atom, t represents 0 or 1,
R 1 represents a hydrogen atom or a substituted or unsubstituted C 1-5 alkyl group,
R 2 represents a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 2-10 alkenyl group, a substituted or unsubstituted C 2-10 alkynyl group, a substituted or unsubstituted C 3- 10 cycloalkyl groups or aryl groups are shown. ] The prostaglandin I derivative represented by this, its pharmacologically acceptable salt, or its hydrate, The medicine for the prevention or treatment of the pruritic symptom.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008530137A (en) * | 2005-02-14 | 2008-08-07 | ザイモジェネティクス，インコーポレイティド | Methods for treating diseases mediated by cutaneous lymphocyte antigen positive cells |
| JP2020083892A (en) * | 2018-11-26 | 2020-06-04 | チャイロゲート インターナショナル インク．Ｃｈｉｒｏｇａｔｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃ． | BERAPROST-314d MONOHYDRATE CRYSTALS AND METHODS FOR PREPARATION THEREOF |
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| JP2893812B2 (en) * | 1989-03-14 | 1999-05-24 | 東レ株式会社 | 2,5,6,7-tetranor-4,8-inter-m-phenylene PGI (lower 2) derivative |
| WO2000024727A1 (en) * | 1998-10-23 | 2000-05-04 | Toray Industries, Inc. | 5,6,7-TRINOR-4,8-INTER-m-PHENYLENE PGI2 DERIVATIVE AND DRUGS CONTAINING THE SAME |
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| JP2004277290A (en) * | 2003-03-12 | 2004-10-07 | Taisho Pharmaceut Co Ltd | Antipruritic agent |
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| JPH0662599B1 (en) * | 1987-10-16 | 1994-08-17 | Toray Industries | |
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| JP3102141B2 (en) * | 1992-05-29 | 2000-10-23 | 東レ株式会社 | Hair restorer |
| JPH08208637A (en) * | 1995-02-03 | 1996-08-13 | Taisho Pharmaceut Co Ltd | Prostaglandin i type compound, its intermediate, their production and blood platelet agglutination suppressant |
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| JP2008530137A (en) * | 2005-02-14 | 2008-08-07 | ザイモジェネティクス，インコーポレイティド | Methods for treating diseases mediated by cutaneous lymphocyte antigen positive cells |
| JP2020083892A (en) * | 2018-11-26 | 2020-06-04 | チャイロゲート インターナショナル インク．Ｃｈｉｒｏｇａｔｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃ． | BERAPROST-314d MONOHYDRATE CRYSTALS AND METHODS FOR PREPARATION THEREOF |
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