JP4525964B2 - Pulmonary hypertension preventive and therapeutic agent - Google Patents
Pulmonary hypertension preventive and therapeutic agent Download PDFInfo
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- JP4525964B2 JP4525964B2 JP2003548846A JP2003548846A JP4525964B2 JP 4525964 B2 JP4525964 B2 JP 4525964B2 JP 2003548846 A JP2003548846 A JP 2003548846A JP 2003548846 A JP2003548846 A JP 2003548846A JP 4525964 B2 JP4525964 B2 JP 4525964B2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Description
［技術分野］
本発明は、肺高血圧症予防治療剤に関する。
［従来の技術］
肺高血圧症とは、種々の心肺疾患に続発し、肺静脈圧が異常に上昇する重篤な疾患である。その中で、臨床的に原因を確定することの出来ない肺高血圧症は、原発性肺高血圧症と呼ばれ、３０歳を中心とした若年女性に好発し、生命予後が５年以内といわれ、生命を脅かす疾患である。肺高血圧症、特に原発性肺高血圧症の予防および治療剤としては、プロスタサイクリン誘導体があるが、重症例には使えないことがある、長期の投与が必要である、減量するとリバウンドを起こし急死する危険性もある、といった問題があり、満足な結果は得られていない。 一方、一般式（Ｉ）で示される化合物は、Ｒｈｏキナーゼ、ミオシン軽鎖リン酸化酵素、プロテインキナーゼＣといったキナーゼ阻害活性を有し、血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用等を示し、血管拡張剤（特に、狭心症治療剤）、高血圧治療剤、脳、心臓保護剤、動脈硬化症治療剤等において有効な物質であることは、既に公知である（例えば特許文献１〜９、および非特許文献１〜４参照）。
しかし、高血圧症と肺高血圧症とは、発生機序も異なり、高血圧症に適用できる薬物が、同様に肺高血圧症にも有用であるとはいえない。また、動脈硬化症に適応できる薬物が、同様に肺高血圧症にも有用であるとはいえない。一般式（Ｉ）で示される化合物が、肺高血圧症の予防、治療に有用であること、および一般式（Ｉ）で示される化合物と、プロスタサイクリン誘導体およびエンドセリン拮抗剤から選ばれる１つ以上の治療薬を併用した肺高血圧予防治療剤が、肺高血圧症に有用である旨や、それを示唆する記載はいずれにも見出せない。
また、非特許文献５には、低酸素状態によって誘導される肺高血圧症があること、低酸素状態は一酸化窒素シンターゼ（ｅｃＮＯＳ）を抑制し血管収縮を引き起こすことが記載され、一般式（Ｉ）で示される化合物が、ｅｃＮＯＳ抑制と関連すること、よって、低酸素状態により誘導される肺高血圧症に有効であるかもしれないことが記載されている。しかしながら、非特許文献５では、低酸素状態によって誘導される肺高血圧症に対する一般式（Ｉ）の化合物の有効性を推定しているに過ぎず、実際に有効性が確認されているわけではない。また、低酸素による肺高血圧モデルにおいては有効である薬でも、それ以外の、例えば、肺血管に病変があるような肺高血圧モデルには有効でないこともあり（非特許文献６参照）、非特許文献５は、一般式（Ｉ）の化合物が、肺高血圧症、特に原発性肺高血圧症に有用であることを示唆するものではない。
＜文献名＞
特許文献１：特開昭６１−１５２６５８号公報
特許文献２：特開昭６１−２２７５８１号公報
特許文献３：特開平２−２５６６１７号公報
特許文献４：特開平４−２６４０３０号公報
特許文献５：特開平６−０５６６６８号公報
特許文献６：特開平６−０８０５６９号公報
特許文献７：特開平７−８０８５４号公報
特許文献８：国際公開９８／０６４３３号パンフレット
特許文献９：国際公開００／０３７４６号パンフレット
非特許文献１：Ｂｒ．Ｊ．Ｐｈａｒｍａｃｏｌ．，９８，ｐ１０９１（１９８９），
非特許文献２：Ｊ．Ｐｈａｒｍａｃｏｌ．Ｅｘｐ．Ｔｈｅｒ．，２５９，ｐ７３８（１９９１）
非特許文献３：Ｃｉｒｃｕｌａｔｉｏｎ，９６，ｐ４３５７（１９９７）
非特許文献４：Ｃａｒｄｉｏｖａｓｃ．Ｒｅｓ．，４３，ｐ１０２９（１９９９）
非特許文献５：Ｓｕｐｐｌｅ．Ｃｉｒｃ．１０４，Ｎｏ１７，１００１（２００１．１０．２３）
非特許文献６：日本臨床５９，Ｎｏ６，ｐ１０７６−１０８０、（２００１）
非特許文献７：Ｃｈｅｍ．Ｐｈａｒａｍ．Ｂｕｌｌ．，４０，（３）ｐ７７０−７７３（１９９２）
［発明の開示］
以上のような状況の中で、従来より、肺高血圧症、とりわけ原発性肺高血圧症を予防もしくは治療するための有用で副作用のない医薬の提供が望まれていた。
本発明者らは、一般式（Ｉ）で示される化合物、または、その酸付加塩もしくは水和物について、鋭意研究を重ねた結果、該化合物が上記血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用など、従来知られている作用からは全く予期できない肺高血圧症の予防、治療効果を見出した。さらに一般式（Ｉ）で示される化合物と、プロスタサイクリン誘導体およびエンドセリン拮抗剤から各々薬剤として許容できる少なくとも１つ以上の治療薬を併用することで、驚くべきことに、それぞれ単独での使用に比して、肺高血圧症の予防、治療効果が飛躍的に上昇することを見出し、本発明を完成した。
すなわち、本発明は、下記一般式（Ｉ）
本発明の一般式（Ｉ）で示される化合物は、公知の方法、例えば、非特許文献７、特許文献１等に記載されている方法に従って合成することができる。また、その酸付加塩は、薬学上許容される非毒性の塩が好ましく、例えば塩酸、臭化水素酸、リン酸、硫酸等の無機酸、および酢酸、クエン酸、酒石酸、乳酸、コハク酸、フマル酸、マレイン酸、メタンスルホン酸等の有機酸の塩を挙げることができる。また、水和物としては、例えば１／２水和物、１水和物、３水和物を挙げることができる。
薬剤として許容できる本発明の前記（ａ）で表される化合物と併用されるプロスタサイクリン誘導体としては、ベラプロストナトリウム、エポプロステノールナトリウムなどが、エンドセリン拮抗剤としてはボセンタンなどが挙げられる。
本発明の、肺高血圧症予防治療剤を、投与に適した形の製剤として調整するのに際しては、上述の一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物を、公知の医薬上許容される担体と混合することが例としてあげられる。この担体としては、例えば、ゼラチン；乳糖、グルコース等の糖類；小麦、米、とうもろこし澱粉等の澱粉類；ステアリン酸等の脂肪酸；ステアリン酸カルシウム、ステアリン酸マグネシウム等の脂肪酸塩；タルク；植物油；ステアリンアルコール、ベンジルアルコール等のアルコール；ガム；ポリアルキレングリコール等が挙げられる。
また、液状担体としては、一般に水、生理食塩液、デキストロースまたは類似の糖溶液、エチレングリコール、プロピレングリコール、ポリエチレングリコール、ポリプロピレングリコール等のグルコール類が挙げられる。カプセル剤となす場合には、ゼラチンを用いてカプセルを調整することが好ましい。
以上のような担体と一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物よりなる本発明の肺高血圧症予防治療剤中に含まれる有効成分の下限は、０．０１重量％以上が好ましく、上限は８０重量％以下、さらに好ましくは６０重量％以下の有効成分を含む例が挙げられる。
投与方法は、経口投与や非経口投与が挙げられる。経口投与に適した剤形としては、例えば錠剤、カプセル剤、粉剤、顆粒剤、液剤、エリキシル剤等が挙げられ、非経口投与に適した剤形としては、液剤が挙げられる。非経口的に例えば筋肉内注射、静脈内注射、皮下注射で投与する場合、一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物を等張にするために、食塩または、グルコース等の他の溶質を添加した無菌溶液として投与される。
注射により投与する場合の溶解液としては、例えば、滅菌水、塩酸リドカイン溶液（筋肉内注射用）、生理食塩液、ブドウ糖、静脈内注射用溶液、電解質溶液（静脈内注射用）等が例示される。このようにして溶解した場合の有効成分の下限は、好ましくは０．０１重量％以上、さらに好ましくは０．１重量％以上、また上限は好ましくは２０重量％以下、さらに好ましくは１０重量％以下の有効成分を含むように調整する。経口投与の液剤の場合、０．０１−２０重量％の有効成分を含む懸濁液またはシロップが好ましい例として挙げられる。この場合における担体としては、香料、シロップ、製剤的ミセル体等の水様賦形剤が挙げられる。
本発明の肺高血圧症予防治療剤の一般式（Ｉ）で示される化合物投与量は、被投与者の年齢、健康状態、体重、症状の程度、同時処置があるならばその種類、処置頻度、所望の効果の性質、あるいは投与経路や投与計画などによって異なるが、非経口投与で０．０１−２０ｍｇ／ｋｇ・日、好ましくは０．０５−１０ｍｇ／ｋｇ・日、より好ましくは０．１−１０ｍｇ／ｋｇ・日が例として挙げられる。経口投与で０．０２−１００ｍｇ／ｋｇ・日、好ましくは０．０５−２０ｍｇ／ｋｇ・日、より好ましくは０．１−１０ｍｇ／ｋｇ・日が例として挙げられる。
併用投与する場合には、１日用量として、一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物とプロスタサイクリン誘導体の用量比が１：１から１００００００：１、一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物とエンドセリン拮抗剤の用量比が１０００：１から１：５０００となるよう投与しうる。一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物とプロスタサイクリン誘導体およびエンドセリン拮抗剤とは、ひとつの混合物としてもよいが、混合せず、同時投与もしくは逐次投与により、併用してもよい。そして、このように混合せず併用する場合も本発明における肺高血圧症治療予防剤剤の概念として含む。
同時もしくは逐次投与する場合、同一の投与経路でもよいし、一方は経口、他方は非経口というように異なる投与経路でもよい。プロスタサイクリン誘導体およびエンドセリン拮抗剤の投与方法としては非経口投与、および経口投与が挙げられる。
［発明を実施するための最良の形態］
以下に実施例を挙げ、この発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。
＜実施例１＞
モノクロタリン誘発ラット原発性肺高血圧モデルを用いて、一般式（Ｉ）（式中Ｒ１は水素原子）の効果を検討した。モノクロタリン誘発ラット肺高血圧モデルは、病理学的にはモノクロタリン投与早期に、肺動脈内皮細胞の傷害と、血管周囲を中心とした炎症細胞の浸潤が見られ、その後中膜の肥厚を生じ、その病態が原発性肺高血圧症に類似していると考えられている。なお、アンギオテンシンコンバーティングエンザイム阻害剤のように、低酸素による肺高血圧モデルにおいては有効である薬でも、本モノクロタリン誘発ラット肺高血圧モデルでは効果が認められないといったことがあり（非特許文献６の「モノクロタリン（ｍｏｎｏｃｒｏｔａｌｉｎｅ）誘発肺高血圧動物モデル」参照）、本モノクロタリン誘発ラット肺高血圧モデルは原発性肺高血圧に特徴的なモデルである。
７週齢の雄性ＳＤラットにモノクロタリン（Ｓｉｇｍａ社より購入）６０ｍｇ／ｋｇを皮下投与した。３週間後に右心室収縮期圧を測定した。さらに肺動脈標本を作製し中膜の肥厚を測定した。
被験液（下記一般式（Ｉ）式中Ｒ１は水素原子）は、３０ｍｇ／ｋｇ／ｄａｙの割合で、モノクロタリン投与日より３週間経口投与した。
モノクロタリン投与３週間後の右心室収縮期圧および、肺動脈の中膜肥厚の程度を測定した。右心室収縮期圧および、肺動脈の中膜肥厚の程度を表１に示した。
＜実施例２＞
モノクロタリン誘発ラット原発性肺高血圧モデルを用いて、一般式（Ｉ）（式中Ｒ１は水素原子）と、プロスタサイクリン誘導体であるベラプロストナトリウムの併用効果を検討した。
７週齢の雄性ＳＤラットにモノクロタリン（Ｓｉｇｍａ社より購入）６０ｍｇ／ｋｇを皮下投与した。３週間後に肺動脈標本を作製し中膜の肥厚を測定した。
被験液（下記一般式（Ｉ）式中Ｒ１は水素原子）は、３ｍｇ／ｋｇ／ｄａｙおよび６ｍｇ／ｋｇ／ｄａｙの割合で、ベラプロストナトリウムは、３μｇ／ｋｇ／ｄａｙおよび１０μｇ／ｋｇ／ｄａｙの割合で、モノクロタリン投与日より３週間経口投与した。モノクロタリン投与３週間後に、肺動脈の中膜肥厚が発生しており、一般式（Ｉ）の化合物（式中Ｒ１は水素原子）３ｍｇ／ｋｇ／ｄａｙ，６ｍｇ／ｋｇ／ｄａｙ、あるいはベラプロストナトリウムの３μｇ／ｋｇ／ｄａｙ，１０μｇ／ｋｇ／ｄａｙ単独では、肺動脈の中膜肥厚を抑制しなかった。
一方、一般式（Ｉ）の化合物（式中Ｒ１は水素原子）３ｍｇ／ｋｇ／ｄａｙとベラプロストナトリウム３μｇ／ｋｇ／ｄａｙとを併用して、同じ試験をしたところ、中膜肥厚が抑制され、各々、単独では中膜肥厚の抑制が認められない用量を、併用することにより、中膜肥厚抑制効果が認められた。
一般式（Ｉ）（式中Ｒ１は水素原子）とベラプロストナトリウムとの併用において、相乗効果が認められた。
＜実施例３＞
本発明の化合物の急性毒性試験を、ラット（Ｊｃｌ：Ｗｉｓｔａｒ，５週齢）およびマウス（Ｓｌｃ：ｄｄＹ，５週齢）を用いて実施した結果、低毒性であることが確認された。その結果を表２に示す。
製剤例（無菌注射剤）
下記表３の成分を注射用蒸留水に溶解し、その後、注射用蒸留水を添加し、必要な最終重量とし、この溶液２ｍｌをアンプルに密封し、加熱滅菌した。
製剤例（錠剤）
下記表４の成分を含む錠剤を常法により調整した。
本発明によれば、肺高血圧症予防治療剤、特に原発性肺高気圧症に有効な予防治療剤が提供できるので、産業上有用である。[Technical field]
The present invention relates to an agent for preventing and treating pulmonary hypertension.
[Conventional technology]
Pulmonary hypertension is a serious disease that occurs secondary to various cardiopulmonary diseases and abnormally increases pulmonary venous pressure. Among them, pulmonary hypertension, the cause of which cannot be determined clinically, is called primary pulmonary hypertension, and it is common among young women, mainly 30 years old. It is a life-threatening disease. Prostacyclin derivatives may be used as prophylactic and therapeutic agents for pulmonary hypertension, especially primary pulmonary hypertension, but may not be used in severe cases. Long-term administration is required. There are problems such as danger, and satisfactory results have not been obtained. On the other hand, the compound represented by the general formula (I) has kinase inhibitory activities such as Rho kinase, myosin light chain phosphorylase, protein kinase C, vascular smooth muscle relaxing action, blood flow increasing action, blood pressure reducing action, brain It is already known that it is an effective substance in vasodilators (especially angina pectoris), hypertension, brain, cardioprotective, arteriosclerosis, etc. (For example, refer to Patent Documents 1 to 9 and Non-Patent Documents 1 to 4.)
However, hypertension and pulmonary hypertension have different mechanisms of development, and drugs applicable to hypertension cannot be said to be useful for pulmonary hypertension as well. Moreover, it cannot be said that a drug applicable to arteriosclerosis is also useful for pulmonary hypertension. The compound represented by the general formula (I) is useful for the prevention and treatment of pulmonary hypertension, and the compound represented by the general formula (I), one or more selected from prostacyclin derivatives and endothelin antagonists There is no indication that a therapeutic agent for pulmonary hypertension combined with a therapeutic agent is useful for pulmonary hypertension, or a statement suggesting it.
Non-Patent Document 5 describes that there is pulmonary hypertension induced by hypoxia, and that hypoxia suppresses nitric oxide synthase (ecNOS) and causes vasoconstriction. ) Is associated with ecNOS suppression and thus may be effective in pulmonary hypertension induced by hypoxia. However, Non-Patent Document 5 merely estimates the effectiveness of the compound of general formula (I) against pulmonary hypertension induced by hypoxia, and the effectiveness is not actually confirmed. . In addition, drugs that are effective in a pulmonary hypertension model due to hypoxia may not be effective in other pulmonary hypertension models that have lesions in the pulmonary blood vessels (see Non-Patent Document 6). Document 5 does not suggest that the compound of general formula (I) is useful for pulmonary hypertension, particularly primary pulmonary hypertension.
<Document name>
Patent Document 1: Japanese Patent Laid-Open No. 61-152658 Patent Document 2: Japanese Patent Laid-Open No. 61-227581 Patent Document 3: Japanese Patent Laid-Open No. 2-256617 Patent Document 4: Japanese Patent Laid-Open No. 4-264030 Patent Document 5: Japanese Patent Application Laid-Open No. 6-056668 Patent Document 6: Japanese Patent Application Laid-Open No. 6-080569 Patent Document 7: Japanese Patent Application Laid-Open No. 7-80854 Patent Document 8: International Publication No. 98/06433 Pamphlet Patent Document 9: International Publication No. 00/03746 Pamphlet Non-Patent Document 1: Br. J. et al. Pharmacol. , 98, p1091 (1989),
Non Patent Literature 2: J. Org. Pharmacol. Exp. Ther. , 259, p738 (1991)
Non-Patent Document 3: Circulation, 96, p4357 (1997)
Non-Patent Document 4: Cardiovasc. Res. , 43, p1029 (1999)
Non-Patent Document 5: Sample. Circ. 104, No17, 1001 (2001.10.23)
Non-patent document 6: Japanese clinical 59, No6, p1076-1080, (2001)
Non-Patent Document 7: Chem. Phram. Bull. , 40, (3) p770-773 (1992)
[Disclosure of the Invention]
Under the circumstances as described above, it has been desired to provide a medicine that is useful and has no side effects for preventing or treating pulmonary hypertension, particularly primary pulmonary hypertension.
As a result of intensive studies on the compound represented by the general formula (I), or an acid addition salt or hydrate thereof, the present inventors have found that the compound exhibits the above-mentioned vascular smooth muscle relaxing action, blood flow increasing action, We have found prevention and treatment effects for pulmonary hypertension that are totally unpredictable from the actions known in the art, such as blood pressure lowering action, brain and cardioprotective action. Furthermore, by combining the compound represented by the general formula (I) with at least one pharmaceutically acceptable therapeutic agent from the prostacyclin derivative and the endothelin antagonist, it is surprising that each of them is compared with the use of each compound alone. As a result, the present inventors have found that the effect of preventing and treating pulmonary hypertension dramatically increases and completed the present invention.
That is, the present invention provides the following general formula (I)
The compound represented by the general formula (I) of the present invention can be synthesized according to a known method, for example, a method described in Non-Patent Document 7, Patent Document 1, and the like. The acid addition salt is preferably a pharmaceutically acceptable non-toxic salt, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, Mention may be made of organic acid salts such as fumaric acid, maleic acid and methanesulfonic acid. Examples of hydrates include 1/2 hydrate, monohydrate, and trihydrate.
Examples of the prostacyclin derivative used in combination with the pharmaceutically acceptable compound (a) of the present invention include beraprost sodium and epoprostenol sodium, and the endothelin antagonist includes bosentan.
In preparing the pulmonary hypertension preventive or therapeutic agent of the present invention as a preparation suitable for administration, the compound represented by the above general formula (I) or an acid addition salt or hydrate thereof is publicly known. An example is mixing with a pharmaceutically acceptable carrier. Examples of the carrier include gelatin; sugars such as lactose and glucose; starches such as wheat, rice and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc; vegetable oil; stearic alcohol And alcohol such as benzyl alcohol; gum; polyalkylene glycol and the like.
The liquid carrier generally includes water, physiological saline, dextrose or a similar sugar solution, glycols such as ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. When preparing a capsule, it is preferable to prepare the capsule using gelatin.
The lower limit of the active ingredient contained in the pulmonary hypertension preventive / therapeutic agent of the present invention comprising the above carrier and the compound represented by the general formula (I) or an acid addition salt or hydrate thereof is 0.01% by weight. The upper limit is preferably 80% by weight or less, more preferably 60% by weight or less.
Examples of the administration method include oral administration and parenteral administration. Examples of dosage forms suitable for oral administration include tablets, capsules, powders, granules, liquids, elixirs, and the like, and dosage forms suitable for parenteral administration include liquids. When administered parenterally, for example, by intramuscular injection, intravenous injection, or subcutaneous injection, in order to make the compound of general formula (I) or an acid addition salt or hydrate thereof isotonic, sodium chloride or glucose It is administered as a sterile solution to which other solutes are added.
Examples of the solution for administration by injection include sterilized water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, intravenous injection solution, electrolyte solution (for intravenous injection) and the like. The The lower limit of the active ingredient when dissolved in this way is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, and the upper limit is preferably 20% by weight or less, more preferably 10% by weight or less. To contain the active ingredients. In the case of a solution for oral administration, a preferred example is a suspension or syrup containing 0.01 to 20% by weight of the active ingredient. Examples of the carrier in this case include aqueous excipients such as fragrances, syrups, and pharmaceutical micelles.
The dose of the compound represented by the general formula (I) of the pulmonary hypertension preventive / therapeutic agent of the present invention is the age, health status, body weight, degree of symptom of the recipient, type of treatment if there is simultaneous treatment, treatment frequency, Depending on the nature of the desired effect, administration route, administration schedule, etc., it is 0.01-20 mg / kg · day, preferably 0.05-10 mg / kg · day, more preferably 0.1- An example is 10 mg / kg · day. Examples of oral administration include 0.02 to 100 mg / kg · day, preferably 0.05 to 20 mg / kg · day, and more preferably 0.1 to 10 mg / kg · day.
In the case of co-administration, the dose ratio of the compound represented by the general formula (I) or its acid addition salt or hydrate to the prostacyclin derivative is 1: 1 to 1,000,000: 1, and the general formula (I ) Or an acid addition salt or hydrate thereof and the endothelin antagonist can be administered at a dose ratio of 1000: 1 to 1: 5000. The compound represented by the general formula (I) or the acid addition salt or hydrate thereof, the prostacyclin derivative and the endothelin antagonist may be combined as one mixture, but they are not mixed but used together by simultaneous administration or sequential administration. May be. And also when using together without mixing in this way, it includes as a concept of the pulmonary hypertension treatment preventive agent in this invention.
In the case of simultaneous or sequential administration, the same administration route may be used, or different administration routes such as one being oral and the other parenteral. Examples of the administration method of the prostacyclin derivative and the endothelin antagonist include parenteral administration and oral administration.
[Best Mode for Carrying Out the Invention]
Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.
<Example 1>
Using monocrotaline-induced rat primary pulmonary hypertension model, the effect of general formula (I) (wherein R1 is a hydrogen atom) was examined. In monocrotaline-induced rat pulmonary hypertension, pathologically, early monocrotaline administration showed damage of pulmonary artery endothelial cells and infiltration of inflammatory cells around the blood vessels, followed by thickening of the media. The condition is thought to be similar to primary pulmonary hypertension. It should be noted that drugs that are effective in a hypoxic pulmonary hypertension model, such as an angiotensin converting enzyme inhibitor, may not be effective in this monocrotaline-induced rat pulmonary hypertension model (Non-patent Document 6). The monocrotaline-induced rat pulmonary hypertension model is a characteristic model of primary pulmonary hypertension (see “Monocrothaline-induced pulmonary hypertension animal model”).
Monocrotaline (purchased from Sigma) 60 mg / kg was subcutaneously administered to 7-week-old male SD rats. The right ventricular systolic pressure was measured after 3 weeks. Furthermore, a pulmonary artery specimen was prepared and the thickness of the media was measured.
The test solution (R1 in formula (I) below is a hydrogen atom) was orally administered at a rate of 30 mg / kg / day for 3 weeks from the day of monocrotaline administration.
The right ventricular systolic pressure and the degree of medial thickness of the pulmonary artery were measured 3 weeks after administration of monocrotaline. Table 1 shows the right ventricular systolic pressure and the degree of medial thickness of the pulmonary artery.
<Example 2>
Using a monocrotaline-induced rat primary pulmonary hypertension model, the combined effect of general formula (I) (wherein R1 is a hydrogen atom) and beraprost sodium, a prostacyclin derivative, was examined.
Monocrotaline (purchased from Sigma) 60 mg / kg was subcutaneously administered to 7-week-old male SD rats. Three weeks later, a pulmonary artery specimen was prepared and the thickness of the media was measured.
The test solution (wherein R1 in formula (I) is a hydrogen atom) is a ratio of 3 mg / kg / day and 6 mg / kg / day, and beraprost sodium is a ratio of 3 μg / kg / day and 10 μg / kg / day Then, it was orally administered for 3 weeks from the day of monocrotaline administration. Three weeks after administration of monocrotaline, media thickening of the pulmonary artery occurred, and the compound of general formula (I) (wherein R1 is a hydrogen atom) 3 mg / kg / day, 6 mg / kg / day, or 3 μg of beraprost sodium / Kg / day, 10 μg / kg / day alone did not suppress tunica media thickening.
On the other hand, when a compound of general formula (I) (wherein R1 is a hydrogen atom) 3 mg / kg / day and beraprost sodium 3 μg / kg / day were subjected to the same test, medial thickness was suppressed, In combination with a dose that alone did not inhibit the medial thickening, the medial thickening inhibitory effect was observed.
A synergistic effect was observed in the combined use of general formula (I) (wherein R1 is a hydrogen atom) and beraprost sodium.
<Example 3>
An acute toxicity test of the compound of the present invention was carried out using rats (Jcl: Wistar, 5 weeks old) and mice (Slc: ddY, 5 weeks old), and as a result, it was confirmed that the toxicity was low. The results are shown in Table 2.
Formulation example (sterile injection)
The components in Table 3 below were dissolved in distilled water for injection, and then distilled water for injection was added to the required final weight, and 2 ml of this solution was sealed in an ampoule and sterilized by heating.
Formulation example (tablet)
Tablets containing the components shown in Table 4 below were prepared by a conventional method.
According to the present invention, a prophylactic / therapeutic agent for pulmonary hypertension, particularly a prophylactic / therapeutic agent effective for primary pulmonary hypertension can be provided, which is industrially useful.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001367144 | 2001-11-30 | ||
| JP2001367144 | 2001-11-30 | ||
| PCT/JP2002/012154 WO2003047591A1 (en) | 2001-11-30 | 2002-11-21 | Remedies for primary pulmonary hypertension |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2003047591A1 JPWO2003047591A1 (en) | 2005-04-14 |
| JP4525964B2 true JP4525964B2 (en) | 2010-08-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003548846A Expired - Lifetime JP4525964B2 (en) | 2001-11-30 | 2002-11-21 | Pulmonary hypertension preventive and therapeutic agent |
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| Country | Link |
|---|---|
| JP (1) | JP4525964B2 (en) |
| AU (1) | AU2002349411A1 (en) |
| WO (1) | WO2003047591A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2111863B1 (en) | 2005-10-26 | 2012-03-28 | Asahi Kasei Pharma Corporation | Fasudil in combination with bosentan for the treament of pulmonary arterial hypertension |
| WO2008049000A2 (en) * | 2006-10-18 | 2008-04-24 | United Therapeutics Corporation | Combination therapy for pulmonary arterial hypertension |
| CN106461677B (en) * | 2014-04-22 | 2018-09-11 | 国立大学法人东北大学 | The inspection method of pulmonary hypertension disease |
| CN105085478B (en) * | 2014-04-28 | 2019-04-12 | 南京明德新药研发股份有限公司 | Isoquinolin sulphone amide derivative and its pharmaceutical composition and pharmaceutical applications |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06141894A (en) * | 1992-11-11 | 1994-05-24 | Asahi Chem Ind Co Ltd | Method for measuring activity of myosin light chain phosphate |
| WO1998006433A1 (en) * | 1996-08-12 | 1998-02-19 | Yoshitomi Pharmaceutical Industries, Ltd. | MEDICINES COMPRISING Rho KINASE INHIBITOR |
| WO1999047153A2 (en) * | 1998-03-19 | 1999-09-23 | Brigham & Women's Hospital, Inc. | UPREGULATION OF TYPE III ENDOTHELIAL CELL NITRIC OXIDE SYNTHASE BY rho GTPase FUNCTION INHIBITORS |
| WO2000003746A2 (en) * | 1998-07-14 | 2000-01-27 | The Brigham And Women's Hospital, Inc. | Upregulation of type iii endothelial cell nitric oxide synthase by agents that disrupt actin cytoskeletal organization |
| US6228843B1 (en) * | 1999-04-23 | 2001-05-08 | University Technology Corporation | Method of using PKC inhibiting compounds to treat vascular disease |
| JP2001172182A (en) * | 1999-11-02 | 2001-06-26 | Pfizer Inc | Method for treating pulmonary hypertension |
-
2002
- 2002-11-21 WO PCT/JP2002/012154 patent/WO2003047591A1/en active Application Filing
- 2002-11-21 JP JP2003548846A patent/JP4525964B2/en not_active Expired - Lifetime
- 2002-11-21 AU AU2002349411A patent/AU2002349411A1/en not_active Abandoned
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06141894A (en) * | 1992-11-11 | 1994-05-24 | Asahi Chem Ind Co Ltd | Method for measuring activity of myosin light chain phosphate |
| WO1998006433A1 (en) * | 1996-08-12 | 1998-02-19 | Yoshitomi Pharmaceutical Industries, Ltd. | MEDICINES COMPRISING Rho KINASE INHIBITOR |
| WO1999047153A2 (en) * | 1998-03-19 | 1999-09-23 | Brigham & Women's Hospital, Inc. | UPREGULATION OF TYPE III ENDOTHELIAL CELL NITRIC OXIDE SYNTHASE BY rho GTPase FUNCTION INHIBITORS |
| WO2000003746A2 (en) * | 1998-07-14 | 2000-01-27 | The Brigham And Women's Hospital, Inc. | Upregulation of type iii endothelial cell nitric oxide synthase by agents that disrupt actin cytoskeletal organization |
| US6228843B1 (en) * | 1999-04-23 | 2001-05-08 | University Technology Corporation | Method of using PKC inhibiting compounds to treat vascular disease |
| JP2001172182A (en) * | 1999-11-02 | 2001-06-26 | Pfizer Inc | Method for treating pulmonary hypertension |
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| Publication number | Publication date |
|---|---|
| JPWO2003047591A1 (en) | 2005-04-14 |
| AU2002349411A1 (en) | 2003-06-17 |
| WO2003047591A1 (en) | 2003-06-12 |
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