JPH01265027A - Remedy for hepatopathy - Google Patents
Remedy for hepatopathyInfo
- Publication number
- JPH01265027A JPH01265027A JP9235588A JP9235588A JPH01265027A JP H01265027 A JPH01265027 A JP H01265027A JP 9235588 A JP9235588 A JP 9235588A JP 9235588 A JP9235588 A JP 9235588A JP H01265027 A JPH01265027 A JP H01265027A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- liver
- group
- administered
- 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
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- 235000019423 pullulan Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000019512 sardine Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000000000 tetracarboxylic acids Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は３−アミノピラゾロ［３，４−ｄ］ピリミジン
誘導体を含有してなる肝疾患治療剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a therapeutic agent for liver diseases containing a 3-aminopyrazolo[3,4-d]pyrimidine derivative.
［従来の技術］
肝疾患の治療または予防には種々の薬剤が試みられてい
るが、急性肝不全、劇症肝炎などに対して有効な治療ま
たは予防効果を示す薬剤はまだ見出されていない。[Prior Art] Various drugs have been tried to treat or prevent liver diseases, but no drug has yet been found that exhibits effective therapeutic or preventive effects on acute liver failure, fulminant hepatitis, etc. .
一方、利尿、降圧、鎮痛、抗炎症等の作用を有する３−
アミノピラゾロ［３，４−ｄ］ピリミジン誘導体につい
ては、例えば特開昭５３−３１６９４号公報、特開昭６
０−１２６２８５号公報、特開昭６１−５０８２号公報
などに開示されているが、３−アミノピラゾロ［３，４
−ｄ］ピリミジン誘導体が急性肝不全のモデル実験に対
して有効性を示したとする報告例は見当たらない。On the other hand, 3-
Regarding aminopyrazolo[3,4-d]pyrimidine derivatives, for example, JP-A-53-31694, JP-A-6
0-126285, JP-A-61-5082, etc., 3-aminopyrazolo[3,4
-d] There have been no reports that pyrimidine derivatives have been shown to be effective in model experiments of acute liver failure.
［発明が解決しようとする課題］
本発明は種々の肝疾ルの治療作用を有する肝疾患治療剤
を提供するものである。[Problems to be Solved by the Invention] The present invention provides a therapeutic agent for liver diseases that has therapeutic effects on various liver diseases.
［課題を解決するための手段］
Ｒｔ
［式中、Ｒ１およびＲ１はそれぞれ脂肪族炭化水素基を
、Ｒ３およびＲ４はそれぞれ水素、アルキル基またはア
シル基を、Ｉｔｓは水素、アルキル基またはアシル基を
示し、破線はピラゾール環に二重結合が２個存在するこ
とを示し、Ｒ５は１位または２位のいずれかに結合して
いる］で表わされる３−アミノピラゾロ［３，４〜ｄ］
ピリミジン誘導体またはその塩を有効成分として含有し
てなる肝疾患治療剤である。[Means for Solving the Problems] Rt [In the formula, R1 and R1 each represent an aliphatic hydrocarbon group, R3 and R4 each represent hydrogen, an alkyl group, or an acyl group, and Its represents hydrogen, an alkyl group, or an acyl group. 3-aminopyrazolo[3,4-d]
This is a liver disease therapeutic agent containing a pyrimidine derivative or a salt thereof as an active ingredient.
上記一般式（１）に関し、ＲＩまたはＲ７で示される脂
肪族炭化水素基としては炭素数１〜６程度のアルキル基
（例、メチル、エチル、プロピル、イソプロピル、ブチ
ル、イソブチル。ペンチル、イソペンデル、ヘキシルな
ど）、炭素数２〜６程度のアルケニル基（例、ビニル、
アリル（ＡｕｙＲ）、Ｉ−プロペニル。Regarding the above general formula (1), the aliphatic hydrocarbon group represented by RI or R7 is an alkyl group having about 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopendel, hexyl etc.), alkenyl groups having about 2 to 6 carbon atoms (e.g., vinyl,
Allyl (AuyR), I-propenyl.
イソプロペニル、２−ブテニル、ｌ、３−ブタジェニル
、２−ペンテニルなど）があげられる。なかでも炭素数
２〜５程度の脂肪族炭化水素基が好ましく、炭素数２〜
４程度の脂肪族炭化水素基がより好ましい。isopropenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, etc.). Among these, aliphatic hydrocarbon groups having about 2 to 5 carbon atoms are preferable, and those having about 2 to 5 carbon atoms are preferable.
An aliphatic hydrocarbon group of about 4 is more preferred.
Ｒ３またはＲ４で示されるアルキル基としては炭素数１
〜４程度のアルキル基（例、メチル、エチル。The alkyl group represented by R3 or R4 has 1 carbon number
~4 alkyl groups (e.g. methyl, ethyl.
プロピル、イソプロピル、ブチル、イソブチルなど）が
好ましい。Ｒ３またはＲ６で示されるアシル基としては
カルボン酸由来のもの（例、アルカノイル基、芳香族カ
ルボニル基など）、アルコキシカルボニル基（例、メト
キシカルボニル、エトキシカルボニルなどの低級（ｃ
１−４）アルコキシカルボニル基）などがあげられるが
、カルボン酸由来のもの、すなわちアルカノイル基なか
でも炭素数７以下のもの（例、アセチル、トリフルオロ
アセチル、プロピオニル、ブチリル、バレリル、シクロ
ヘキサンカルボニルなど）または芳香族カルボニル基（
例、ベンゾイルなど）が好ましい。(propyl, isopropyl, butyl, isobutyl, etc.) are preferred. Examples of the acyl group represented by R3 or R6 include those derived from carboxylic acids (e.g., alkanoyl groups, aromatic carbonyl groups, etc.), alkoxycarbonyl groups (e.g., lower (c) groups such as methoxycarbonyl, ethoxycarbonyl, etc.
1-4) alkoxycarbonyl group), but those derived from carboxylic acids, that is, alkanoyl groups with 7 or fewer carbon atoms (e.g., acetyl, trifluoroacetyl, propionyl, butyryl, valeryl, cyclohexanecarbonyl, etc.) or aromatic carbonyl group (
Examples, benzoyl, etc.) are preferred.
Ｒ６で示されるアルキル基としては、ハロゲンまたは水
酸基で置換されていてらよい低級アルキル基、特に炭素
数１〜４程度のらの（例、メチル。The alkyl group represented by R6 is a lower alkyl group optionally substituted with a halogen or hydroxyl group, particularly a carbon atom having about 1 to 4 carbon atoms (eg, methyl).
エチル、プロピル、ブチル、Ｌ−ブチルなど）が好まし
い。 Ｒ６で示されるアシル基としてはカルボン酸由来
のらの（例、アルカノイル基、芳香族カルボニル基（例
、ベンゾイルなど）など）、アルコキンカルボニル基な
どが挙げられ、アルカノイル基としては炭素数７以下の
もの（例、アセチル、トリフルオロアセチル、プロピオ
ニル、ブチリル、バレリル。(ethyl, propyl, butyl, L-butyl, etc.) are preferred. Examples of the acyl group represented by R6 include carbonyl groups derived from carboxylic acids (e.g., alkanoyl groups, aromatic carbonyl groups (e.g., benzoyl), etc.), alkoxycarbonyl groups, etc. The alkanoyl group has 7 or less carbon atoms. (e.g., acetyl, trifluoroacetyl, propionyl, butyryl, valeryl).
シクロヘキサンカルボニルなど）が好ましく、アルコキ
ンカルボニル基としては低級（Ｃ、−、）アルコキシカ
ルボニル基（例、メトキシカルボニル、エトキシカルボ
ニルなど）が好ましい。cyclohexanecarbonyl, etc.) are preferred, and as the alkoxycarbonyl group, lower (C, -,) alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, etc.) are preferred.
上記一般式（１）で表わされる化合物（化合物（■））
の中でも式
［式中、Ｒ２およびＲ７はそれぞれ炭素数２〜４の脂肪
族炭化水素基を、Ｒ３およびＲ４はそれぞれ水素、アル
キル基またはアシル基を、Ｒ６は水素、アルキル基また
はアシル基を示す］で表わされる化合物がより好ましい
。 式（Ｉ′）中、Ｒ３およびＲ４がそれぞれ水素、メ
チル基またはアセチル基であり、かつＲ６が水素、メチ
ル基、アセチル基またはメトキシカルボニル基である化
合物がさらに好ましい。Compound represented by the above general formula (1) (compound (■))
Among the formulas [wherein R2 and R7 each represent an aliphatic hydrocarbon group having 2 to 4 carbon atoms, R3 and R4 each represent hydrogen, an alkyl group or an acyl group, and R6 represents hydrogen, an alkyl group or an acyl group] ] More preferred are compounds represented by the following. In formula (I'), compounds in which R3 and R4 are each hydrogen, a methyl group, or an acetyl group, and R6 is hydrogen, a methyl group, an acetyl group, or a methoxycarbonyl group are more preferred.
化合物（１）の塩としては例えば塩酸塩、臭化水素酸塩
、硫酸塩、硝酸塩、燐酸塩などの無機酸塩、例えば酢酸
塩、酒石酸塩、クエン酸塩、フマール酸塩、マレイン酸
塩などの有機酸塩などの薬理学的に許容されうる塩があ
げられる。Examples of the salt of compound (1) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; for example, acetate, tartrate, citrate, fumarate, maleate, etc. Examples include pharmacologically acceptable salts such as organic acid salts of.
化合物（１）はいずれも公知化合物であり、例えば特開
昭５３−３１６９４号公報、特開昭６０−１２６２８５
号公報、特開昭６１−５０８２号公報、ヨーロッパ公開
第０１６６０５４号公報、特開昭６２−２２７１７号公
報などに記載された方法またはそれに準する方法によっ
て製造することができろ。Compound (1) is a known compound, for example, JP-A-53-31694, JP-A-60-126285.
It can be produced by the method described in JP-A-61-5082, European Publication No. 0166054, JP-A-62-22717, etc., or a method analogous thereto.
化合物（Ｉ）は１位または２位においてグルクロン酸と
結合したグルクロニド（グルクロン酸抱合体）であって
もよい。該グルクロニドは、化合物（１）を例えば哺乳
動物（例、マウス、ラット、サルなど）に経口あるいは
非経口投与して、尿、胆汁などから公知の分離精製手段
（例、抽出、ａ縮、中和。Compound (I) may be a glucuronide (glucuronide conjugate) bound to glucuronic acid at the 1st or 2nd position. The glucuronide can be obtained by oral or parenteral administration of Compound (1) to mammals (e.g., mice, rats, monkeys, etc.), and then separated and purified from urine, bile, etc. using known separation and purification methods (e.g., extraction, adenosis, and medialization). sum.
ろ過、再結晶、カラムクロマトグラフィー、薄層クロマ
トグラフィーなど）を用いて製造することができる。filtration, recrystallization, column chromatography, thin layer chromatography, etc.).
化合物（１）は免疫反応の関与している急性肝不全実験
モデルおよびＤ−ガラクトサミン、四塩化炭素、エンド
トキシン等により惹起される肝障害モデルにおいて著効
を示す。 肝疾患の発症または病態の形成には種々の免
疫反応が関与しており、急性または劇症肝炎の発症にも
免疫機構が関与する可能性が示されている。化合物（１
）につきＰｒｏｐｉｏｎｉｂａｃｔｅｒｉｕｍ ａｃ
ｎｅｓ（Ｐ、 ａｃｎｅｓ）の加熱死菌とＬｉｐｏｐｏ
ｌｙｓａｃｃｈａｒｉｄｅ（Ｌ Ｐ Ｓ ）を用いたマ
ウスの急性肝不全実験モデルに対する効果を調べた。Compound (1) exhibits remarkable efficacy in experimental models of acute liver failure involving immune reactions and models of liver damage induced by D-galactosamine, carbon tetrachloride, endotoxin, and the like. Various immune reactions are involved in the onset of liver diseases or the formation of pathological conditions, and it has been shown that the immune system may also be involved in the onset of acute or fulminant hepatitis. Compound (1
) per Propionibacterium ac
heat-killed bacteria of nes (P, acnes) and Lipopo
The effect of lysaccharide (L P S ) on an experimental model of acute liver failure in mice was investigated.
Ｐ、ａｃｎｅｓの加熱死菌を実験動物に静注して肝内に
単核細胞浸潤を誘起し、その後に微量のダラム陰性菌由
来のＬＰＳを追加静注すると、はとんどの実験動物は２
４時間以内に死亡し、それらの肝臓には広範囲な壊死巣
が認められたが、化合物（１）を用いると用量依存的に
惣性肝不全を抑制した。When heat-killed P. acnes bacteria were intravenously injected into experimental animals to induce mononuclear cell infiltration in the liver, and then a trace amount of LPS derived from Durham-negative bacteria was further intravenously injected, most experimental animals
The mice died within 4 hours, and extensive necrotic foci were observed in their livers; however, when compound (1) was used, the liver failure was suppressed in a dose-dependent manner.
本急性肝不全動物実験モデルはヒトの急性肝炎や劇症肝
炎に類似する病理学的経過を示す。下式で示される化合
物（Ａ）は本動物実験モデルに対して顕著な致死抑制効
果を示し、また上記の各種肝障害モデルにおいて血中ト
ランスアミナーゼ値の上昇を抑制するなど浸れた効果を
示した。This animal experimental model of acute liver failure exhibits a pathological course similar to acute hepatitis and fulminant hepatitis in humans. Compound (A) represented by the following formula exhibited a remarkable effect of suppressing lethality in the present animal experimental model, and also exhibited significant effects such as suppressing the increase in blood transaminase levels in the various liver injury models mentioned above.
ｕ
以上の動物における薬効試験成績より、化合物（Ｉ）は
各種原因による肝障害に対して肝保護作用を有すること
から各種急性および慢性肝炎、肝障害、劇症肝炎等の治
療に有用であり、またこれらの結果生じる肝線維症およ
び肝硬変の予防作用をら併有するしのと考えられる。Based on the drug efficacy test results in animals described above, Compound (I) has a hepatoprotective effect against liver damage caused by various causes, and is therefore useful for the treatment of various acute and chronic hepatitis, liver damage, fulminant hepatitis, etc. It is also thought to have a preventive effect on liver fibrosis and cirrhosis that result from these conditions.
化合物（１）は低毒性であり、例えば慢性肝炎、劇症肝
炎、肝線維症、肝硬変、アルコール肝炎などの予防、治
療に有用である。Compound (1) has low toxicity and is useful, for example, in the prevention and treatment of chronic hepatitis, fulminant hepatitis, liver fibrosis, liver cirrhosis, alcoholic hepatitis, and the like.
本発明の肝疾患治療剤は、その有効成分である式（１）
で示される化合物自体をそのまま投与することもできる
が、一般にはこれに増量剤、希釈剤。The liver disease therapeutic agent of the present invention has the formula (1) as its active ingredient.
Although the compound represented by can be administered as it is, it is generally combined with a filler or diluent.
賦形剤などを混合し、種々の医薬組成物として投与され
る。このような医薬組成物の剤形の例としては、例えば
カプセル剤、顆粒剤、散剤１錠剤、火剤。It is mixed with excipients and administered as various pharmaceutical compositions. Examples of dosage forms of such pharmaceutical compositions include capsules, granules, powder tablets, and gunpowder.
シロップ剤、注射剤、廃剤等が挙げられる。Examples include syrups, injections, and waste drugs.
また医薬組成物に使用されるものとしては、例えば白糖
、乳糖、ブドウ糖、でん粉、マンニット、ソルビット微
結晶セルロース、タルク、シクロデキストリン等の賦形
剤、ヒドロキシプロピルセルロース、ヒドロキシプロピ
ルメチルセルロース、カルボキシメチルセルロース、プ
ルラン、メチルセルロース、ポリビニルピロリドン、ゼ
ラチン、アラビヤゴム、ポリエチレングリコール、白糖
、でん粉等の結合剤、でん粉、カルボキシメチルセルロ
ース、カルボキシメチルセルロースのカルシウム塩、低
置換度ヒドロキシプロピルセルロース等の崩壊剤、タル
ク、ステアリン酸マグネシウム等の滑沢剤、ヒドロキシ
プロピルメチルセルロース、エチルセルロース、ヒドロ
キシメチルセルロース、ヒドロキシプロピルメチルセル
ロースフタレート、オイドラギット［ローム社製（西ド
イツ）；メタアクリル酸・アクリル酸共重合物］および
酸化チタン、ベンガラ等の色素、安息香酸ナトリウム、
亜硫酸水素ナトリウム等の保存剤、メチルセルロース、
ステアリン酸アルミニウム等の懸濁化剤、ポリソルベー
ト８０．エマルゲル４０８．エマゾール３１０等の分散
剤、水等の溶剤、カカオ脂、ポリエチレングリコール、
ライテップゾール、白色ワセリン等の基剤等が挙げられ
、これらは製剤の種類に応じて適宜選択される。Examples of substances used in pharmaceutical compositions include excipients such as white sugar, lactose, glucose, starch, mannitol, sorbitol microcrystalline cellulose, talc, cyclodextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, Binders such as pullulan, methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, white sugar, starch, disintegrants such as starch, carboxymethylcellulose, calcium salts of carboxymethylcellulose, low-substituted hydroxypropylcellulose, talc, magnesium stearate, etc. Lubricants, hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose phthalate, Eudragit [manufactured by Rohm (West Germany); methacrylic acid/acrylic acid copolymer], pigments such as titanium oxide, red iron oxide, sodium benzoate ,
Preservatives such as sodium bisulfite, methylcellulose,
Suspending agents such as aluminum stearate, polysorbate 80. Emulgel 408. Dispersants such as Emazol 310, solvents such as water, cacao butter, polyethylene glycol,
Examples include bases such as Lytepsol and white petrolatum, and these are appropriately selected depending on the type of formulation.
本発明の肝疾患治療剤は経口的または非経口的（例、注
射、廃剤等）に人間を含む哺乳動物に投与することがで
きる。なお、化合物（１）がグルクロニドである場合に
は経口的に投与するのが好ましい。The therapeutic agent for liver diseases of the present invention can be administered to mammals including humans orally or parenterally (eg, injection, waste medicine, etc.). In addition, when compound (1) is a glucuronide, it is preferable to administer it orally.
投与量は投与対象、投与ルート、症状などにより異なる
が、例えば成人の肝障害患者に対して経口投与する場合
、通常薬効成分［化合物（１）１１回量として約ｏ 、
ｔ ｍｇ／ ｋｇ 〜３０ ｍｇ／ ｋｇ体重程度、
好ましくは０ 、５ ｍｇ／ｋｇ−１０ｍｇ／ｋｇ体重
程度を１日１回〜３回程度投与するのか好都合である。The dosage varies depending on the subject, route of administration, symptoms, etc., but for example, when orally administered to adult patients with liver failure, the amount of the medicinal active ingredient [Compound (1), approximately
t mg/kg ~ 30 mg/kg body weight,
Preferably, it is convenient to administer about 0.5 mg/kg to 10 mg/kg body weight once to three times a day.
［実施例］
以下に実施例、実験例、参考例を挙げて本発明をさらに
具体的に説明するが、これらは本発明を限定するもので
はない。[Example] The present invention will be described in more detail below with reference to Examples, Experimental Examples, and Reference Examples, but these do not limit the present invention.
本明細書において用いる略号の例を表１に挙げる。Table 1 lists examples of abbreviations used in this specification.
表 １
Ｍｅ：メチル ｌＩＣ：アリル
Ｅｔ：エチル ＡＣニアセチル
Ｐｒ：プロピル ＧＯＴ：グルタミンオキザルＢｕニ
ブチル 酢酸
トランスアミナーゼ
ＧｌｃＵ： グルクロン酸
実施例 １
下記の組成のうち、化合物（Ａ）、乳糖９ヒドロキンプ
ロピルセルロース、低置換度ヒドロキシプロピルセルロ
ースを混合し、それに水を加え練合をおこなったのち４
０°Ｃ，１６時間真空乾燥し、乳鉢で粉砕し、１６メツ
シユの篩を通し顆粒とした。Table 1 Me: Methyl IC: Allyl Et: Ethyl AC Niacetyl Pr: Propyl GOT: Glutamine oxal Bu Nibutyl Acetate transaminase GlcU: Glucuronic acid Example 1 Among the following compositions, compound (A), lactose 9-hydroxypropyl cellulose, After mixing low-substituted hydroxypropyl cellulose and adding water to it and kneading it, 4
The mixture was vacuum dried at 0°C for 16 hours, ground in a mortar, and passed through a 16-mesh sieve to form granules.
これにステアリン酸マグネシウムを加え、ロータリー弐
打錠機（菊水製作所製）で１錠当り１５０ｍｇの錠剤を
製造した。Magnesium stearate was added to this, and tablets of 150 mg each were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho).
錠剤１錠中の組成
化合物（Ａ） ２５ ｍｇ乳糖
８０．５ｍｇ
ヒドロキシプロピルセルロース ４ 、５ｍｇ低置換
度ヒドロキシプロピル
セルロース ３９ ｍｇステア
リン酸マグネンウム １ ｍｇ（水
０．０５Ｍ１）
計 １５０ ｍｇ実施例 ２
実施例Ｉで得た錠剤に下記処方の水性フィルムコーテイ
ング液をフィルムコーティング装置（ハイコーター、フ
ロイント産業株式会社製）を用いてコーティングし、フ
ィルム錠を得た。Composition in one tablet Compound (A) 25 mg Lactose 80.5 mg Hydroxypropyl cellulose 4,5 mg Low substituted hydroxypropyl cellulose 39 mg Magnenium stearate 1 mg (water)
0.05M1) Total 150 mg Example 2 The tablets obtained in Example I were coated with an aqueous film coating liquid of the following formulation using a film coating device (Hi-Coater, manufactured by Freund Sangyo Co., Ltd.) to obtain film tablets. .
フィルム錠１錠中の組成
実施例１で得た錠剤 １５０ ｍｇヒドロ
キシプロピルメチル
セルロース ７．１２ ｍｇ酸化
チタン ０．．８ ｍｇ黄色三
二酸化鉄 ０．０８ ＋ｎｇ仁＊−−−
−−−−−−−−−ム町ハＱ計
１５８ ｍｇ実施例 ３
下記組成割合の物質をよく混合したのら、水を加えて練
合し、押出し造粒機（菊水製作所製、スクリーンＢ！１
．Ｏｍｍφ）で造粒し、ただちにマルメライザ−（富士
パラダル社製、 １０１０００ｒｐで顆粒としたのち４
０℃１６時間真空乾燥し、丸面で篩過し、１２〜４２メ
ツシユの顆粒を得た。Composition of one film tablet Tablet obtained in Example 1 150 mg Hydroxypropyl methyl cellulose 7.12 mg Titanium oxide 0. ．． 8 mg yellow iron sesquioxide 0.08 +ng kernel*---
−−−−−−−−Mu Town HaQ Meter
158 mg Example 3 After thoroughly mixing the substances with the following composition ratios, water was added and kneaded, and the extrusion granulator (manufactured by Kikusui Seisakusho, Screen B!1) was used.
．． 0mmφ), immediately granulated with Marmerizer (manufactured by Fuji Paradal Co., Ltd., 101,000 rpm, and then
The mixture was vacuum dried at 0°C for 16 hours and passed through a round sieve to obtain 12 to 42 mesh granules.
顆粒５００ｍｇ中の組成
化合物（Ａ） １００ ｍｇ
コーンスターチ ２００ ｍｇ微結
晶セルロース ５０ ｍｇカルボキシ
メチルセルロース
カルシウム ２５ ｍｇヒドロ
キシプロピルセルロース ２５ ｍｇプルロニ−ｔ
りＦ６８ １０ｍｇ乳糖
９０ ｍｇ（水 ０
．２成）
計 ５００ ｍｇ実験
例 １
７週齢の雄性Ｂ Ａ Ｌ Ｂ ／ ｃマウス１群ｌＯ匹
を用いて、それぞれのマウス尾静脈からＩｍｇ／マウス
量のＰ、ａｃｎｅｓ加熱死菌を静注し、７日後にＳａｌ
ｍｏｎｅｌｌａ ｅｎｔｅｒｉｔｉｄｉｓ由来のＬＰ
Ｓ（ｌμｇ／マウス）を追加静注して急性肝不全を惹起
した。Composition Compound (A) 100 mg in 500 mg of granules
Corn starch 200 mg Microcrystalline cellulose 50 mg Carboxymethyl cellulose Calcium 25 mg Hydroxypropyl cellulose 25 mg Plurony-t
RiF68 10mg lactose
90 mg (water 0
．． Experimental Example 1 Using 10 7-week-old male BAL B/c mice in one group, Img/mouse of P. acnes heat-killed bacteria was intravenously injected into the tail vein of each mouse. , after 7 days Sal
LP derived from monella enteritidis
Acute liver failure was induced by additional intravenous injection of S (1 μg/mouse).
通常、ＬＰＳ静注群では２４時間以内に９０％から１０
０％のマウスが死亡する。同条件下に表２の化合物（１
）の０．３．１あるいは３ｍｇ／ｋｇを５％アラビアゴ
ム液に懸濁し、ＬＰＳの投与１時間前に経口投与し、４
８時間後におけるマウスの死亡数を観察した。なお、対
照群には５％アラビアゴム液（Ｖｅｈｉｃｌｅ）のみを
、Ｉ、ＰＳの投与１時間前に経口投与した。結果は表２
に示すとおりとなった。Usually, within 24 hours, 90% to 10% of patients in the intravenous LPS group
0% of mice die. Under the same conditions, the compounds in Table 2 (1
0.3.1 or 3 mg/kg of ) was suspended in 5% gum arabic solution and orally administered 1 hour before administration of LPS.
The number of mouse deaths after 8 hours was observed. In addition, to the control group, only 5% gum arabic solution (vehicle) was orally administered 1 hour before the administration of I and PS. The results are in Table 2
The result is as shown in .
表２から明らかなように、化合物（１）は急性肝不全に
よる致死を有色に抑制した。As is clear from Table 2, compound (1) significantly suppressed mortality due to acute liver failure.
（以下余白）
【
丸験例 ２
７週令のＳＤ系雄性ラうトＩＰ３７匹を用いて、ガラク
トサミン（Ｉｇ／ｋｇ、腹腔内投与）、四基化炭な（１
ｍｅ／ｋｇ、腹腔内投与）又はＥ、Ｃｏ（ｉ由来のＬ
Ｐ Ｓ （３ｍｇ／ ｋｇ、静脈内投与）を投与して肝
障害を惹起させた。肝障害の程度は肝障害物質投与２４
時間後の血中トランスアミナーゼ値（ＧＯＴ）を指標と
して測定した。被検化合物（化合物（Ａ））；よ５％ア
ラビアゴム液に懸濁し、肝障害物質投与１時間前に経口
投与した。なお、対照群には５％アラビアゴム液（Ｊｅ
ｈｉｃｌｅ）のみをｆｉｆ障害物質投与１時間前に経口
投与した。(Left below) [Example 2: Using 37 7-week-old SD male rats IP, galactosamine (Ig/kg, intraperitoneal administration), charcoal tetracarbonate (1 g/kg, intraperitoneal administration)
me/kg, intraperitoneal administration) or E, Co (L derived from i
PS (3 mg/kg, intravenous administration) was administered to induce liver damage. The degree of liver damage is determined by the administration of liver-damaging substances24
The blood transaminase level (GOT) after hours was measured as an index. Test compound (compound (A)): It was suspended in 5% gum arabic solution and orally administered 1 hour before administration of the liver-damaging substance. The control group received 5% gum arabic solution (Je
hicle) alone was orally administered 1 hour before administration of the fif-inhibiting substance.
化合物（Ａ）はｌ ＝ ｌ Ｏｍｇ／ ｋｇの投与によ
り、血中トランスアミナーゼ値の上昇を明らかに抑制し
た（表３）。Compound (A) clearly suppressed the increase in blood transaminase levels when administered at l = l Omg/kg (Table 3).
表３ ラットにおけるガラクトサミン、四基化炭る作用
処 置 用 ｆｉ Ｇ Ｏ
Ｔ （Ｕ／Ｑ、）（ｍｇ／ｌｔｇ 、 ガラクト 四
塩化 エンド対 照 ２２５３
３４０２ １６６３化合物（八）
ｌ Ｎ、Ｔ、 ２０１２ １１５４３
９５１’ １０１３” ５６０”１０
９４９″’ Ｎ、Ｔ、 ２０９”
！１．Ｔ、 ：未検討
” ： ｐ＜０．０５． ” ： ｐ＜Ｑ、０１
ｖｓ対照群実験例 ３
化合物（Ａ）の急性毒性をＪＣρ：［ＣＲマウスおよび
Ｊ Ｇ（１： Ｗｉｓｔａｒラットを用いて検討した。Table 3 Galactosamine, tetracarboxylic acid treatment in rats
T (U/Q,) (mg/ltg, galactotetrachloride endo control 2253
3402 1663 Compound (8)
l N, T, 2012 11543
951'1013"560"10
949″' N, T, 209″
! 1. T, : Not examined" : p<0.05. " : p<Q, 01
Versus Control Group Experimental Example 3 The acute toxicity of compound (A) was investigated using JCρ:[CR mice and JG(1: Wistar rats).
腹腔内、皮下および経口投与した場合の急性毒性を表４
に示す。表４から化合物（Ａ）は、低毒性であり、安全
に投与できろことが明らかである。Table 4 shows the acute toxicity when administered intraperitoneally, subcutaneously, and orally.
Shown below. It is clear from Table 4 that compound (A) has low toxicity and can be administered safely.
表４ 化合物（Ａ）の急性毒性
参考例 ｌ
化合物（Ａ）をサルに２週間、ｌ ｇ／ ｋｇ／日経口
投与し尿（約４Ｃ）を集め、尿を水冷下６Ｎ−塩酸でり
１−１６に調整した後、塩化ナトリウム（６００ｇ）を
加え、酢酸エチル（Ｉρ×６回）で抽出した。酢酸エチ
ル抽出液を乾燥、ａ縮して褐色シラツブ（２０ｇ）を得
た。少量のクロロホルムに溶解し、シリカゲルクロマト
グラフィー（３００ｇ、溶出液５％〜３０％のメタノー
ル／クロロホルム）で分離精製し、２つの溶出部から１
−グルクロン酸抱合体（１ａ）および２−グルクロン酸
抱合体（ｌｂ）を得た。それぞれを含水アルコールより
再結晶して、無色結晶を得た。Table 4 Reference example of acute toxicity of compound (A) Compound (A) was orally administered to monkeys at 1 g/kg/day for 2 weeks, urine (approximately 4C) was collected, and the urine was soaked in 6N-hydrochloric acid under water cooling.1-16 After the mixture was adjusted to 50%, sodium chloride (600 g) was added, and the mixture was extracted with ethyl acetate (Iρ x 6 times). The ethyl acetate extract was dried and condensed to obtain brown sardines (20 g). Dissolved in a small amount of chloroform and purified by silica gel chromatography (300 g, eluent 5% to 30% methanol/chloroform).
-Glucuronide conjugate (1a) and 2-glucuronide conjugate (lb) were obtained. Each was recrystallized from hydroalcohol to obtain colorless crystals.
■−グルクロン酸抱合体（１ａ）
収量１ 、１ ｇ、融点２０２−２０５℃（分解）ＮＭ
Ｒ（ｄ、−ＤＭＳＯ）δ： ｌ’−１１，５，１３（Ｉ
Ｈ，ｄ、９１１ｚ）
ｔＯＨ
ＵＶ λ ｎｍ： ２８０（ｓｈ）、 ２５５（ｓ
ｈ）、 ２２８ａＸ
２−グルクロン酸抱合体（Ｉｂ）
収量１．０ｇ、融点１８２−１８６°ＣＮＭＲ（ｄ８−
ＤＭＳＯ）δ： １’−１１，５，６１（１１１，ｄ、
９Ｈｚ）
ｔ０１１
ＵＶ λ ｎｍ： ２８２．２５５．２２２１１８
Ｘ
［発明の効果］
本発明にかかわる３−アミノピラゾロ［３，４−ｄ］ピ
リミジン誘導体（化合物（Ｉ））は、マウス急性肝不全
による致死を減少させ、さらに各種肝障害時に生じる血
中トランスアミナーゼ値の上昇を抑制し、肝保護作用を
有することから、各種急性肝炎、慢性肝炎、劇症肝炎、
肝線維症、肝硬変等の予防または治療改善効果が期待さ
れ、医薬品として有用である。■-Glucuronide conjugate (1a) Yield 1.1 g, melting point 202-205°C (decomposed) NM
R(d,-DMSO)δ: l'-11,5,13(I
H, d, 911z) tOH UV λ nm: 280 (sh), 255 (s
h), 228aX 2-glucuronide conjugate (Ib) Yield 1.0 g, melting point 182-186° CNMR (d8-
DMSO) δ: 1'-11,5,61(111,d,
9Hz) t011 UV λ nm: 282.255.222118
X [Effect of the invention] The 3-aminopyrazolo[3,4-d]pyrimidine derivative (compound (I)) according to the present invention reduces mortality caused by acute liver failure in mice, and further reduces blood transaminase levels that occur during various liver disorders. It suppresses the increase in hepatitis and has a hepatoprotective effect, so it is effective against various types of acute hepatitis, chronic hepatitis, fulminant hepatitis,
It is expected to be effective in preventing or improving treatment of liver fibrosis, liver cirrhosis, etc., and is useful as a pharmaceutical.
代理人 弁理士 岩 １） 弘Agent Patent Attorney Iwa 1) Hiroshi
Claims (1)
基を、Ｒ＿３およびＲ＿４はそれぞれ水素、アルキル基
またはアシル基を、Ｒ＿５は水素、アルキル基またはア
シル基を示し、破線はピラゾール環に二重結合が２個存
在することを示し、Ｒ＿５は１位または２位のいずれか
に結合している］で表わされる化合物またはその塩を含
有してなる肝疾患治療剤。[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 each represent an aliphatic hydrocarbon group, R_3 and R_4 each represent hydrogen, an alkyl group, or an acyl group, and R_5 represents hydrogen. , represents an alkyl group or an acyl group, the broken line represents the presence of two double bonds in the pyrazole ring, and R_5 is bonded to either the 1st or 2nd position] or a salt thereof. A therapeutic agent for liver disease comprising:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9235588A JPH01265027A (en) | 1988-04-14 | 1988-04-14 | Remedy for hepatopathy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9235588A JPH01265027A (en) | 1988-04-14 | 1988-04-14 | Remedy for hepatopathy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01265027A true JPH01265027A (en) | 1989-10-23 |
Family
ID=14052093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9235588A Pending JPH01265027A (en) | 1988-04-14 | 1988-04-14 | Remedy for hepatopathy |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01265027A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8697710B2 (en) | 2008-12-06 | 2014-04-15 | Intra-Cellular Therapies, Inc. | Optionally substituted 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo [3,4-d]pyrimidin-6(7H)-ones |
| US8846693B2 (en) | 2007-12-06 | 2014-09-30 | Intra-Cellular Therapies, Inc. | Optionally substituted pyrazolo[3,4-d]pyrimidine-4,6-diones |
| US8859564B2 (en) | 2008-12-06 | 2014-10-14 | Intra-Cellular Therapies, Inc. | Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives useful as inhibitors of phosphodiesterase 1 |
| US8927556B2 (en) | 2008-12-06 | 2015-01-06 | Intra-Cellular Therapies, Inc. | 1H-pyrrolo[3,4-D]pyrimidin-2(6H)-one compounds |
| US9255099B2 (en) | 2006-06-06 | 2016-02-09 | Intra-Cellular Therapies, Inc. | Pyrazolo[3,4-D]pyrimidine-4,6(5H,7H)-diones as phosphodiesterase 1 inhibitors |
| US9371327B2 (en) | 2010-05-31 | 2016-06-21 | Intra-Cellular Therapies, Inc. | PDE1 inhibitor compounds |
| US9434730B2 (en) | 2010-05-31 | 2016-09-06 | Intra-Cellular Therapies, Inc. | PDE1 inhibitor compounds |
| US9546175B2 (en) | 2014-08-07 | 2017-01-17 | Intra-Cellular Therapies, Inc. | Organic compounds |
-
1988
- 1988-04-14 JP JP9235588A patent/JPH01265027A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9255099B2 (en) | 2006-06-06 | 2016-02-09 | Intra-Cellular Therapies, Inc. | Pyrazolo[3,4-D]pyrimidine-4,6(5H,7H)-diones as phosphodiesterase 1 inhibitors |
| US8846693B2 (en) | 2007-12-06 | 2014-09-30 | Intra-Cellular Therapies, Inc. | Optionally substituted pyrazolo[3,4-d]pyrimidine-4,6-diones |
| US8697710B2 (en) | 2008-12-06 | 2014-04-15 | Intra-Cellular Therapies, Inc. | Optionally substituted 3-amino-4-(thioxo or imino)-4,5-dihydro-2H-pyrazolo [3,4-d]pyrimidin-6(7H)-ones |
| US8859564B2 (en) | 2008-12-06 | 2014-10-14 | Intra-Cellular Therapies, Inc. | Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives useful as inhibitors of phosphodiesterase 1 |
| US8927556B2 (en) | 2008-12-06 | 2015-01-06 | Intra-Cellular Therapies, Inc. | 1H-pyrrolo[3,4-D]pyrimidin-2(6H)-one compounds |
| US9487527B2 (en) | 2008-12-06 | 2016-11-08 | Intra-Cellular Therapies, Inc. | Pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives useful as inhibitors of phosphodiesterase I |
| US9371327B2 (en) | 2010-05-31 | 2016-06-21 | Intra-Cellular Therapies, Inc. | PDE1 inhibitor compounds |
| US9434730B2 (en) | 2010-05-31 | 2016-09-06 | Intra-Cellular Therapies, Inc. | PDE1 inhibitor compounds |
| US9546175B2 (en) | 2014-08-07 | 2017-01-17 | Intra-Cellular Therapies, Inc. | Organic compounds |
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