JP4243701B2 - Rheumatoid therapeutics containing benzamide derivatives as active ingredients - Google Patents
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Description
本発明はベンズアミド誘導体を有効成分とするリウマチ治療薬に関するものである。 The present invention relates to a therapeutic agent for rheumatism comprising a benzamide derivative as an active ingredient.
リウマチは、関節滑膜を病変の主座とする難治性の慢性炎症性疾患であるが、その発症原因については不明なところも多く、また症状もさまざまである。このリウマチの病態の特徴の１つとして、滑膜の異常増殖およびそれに引き続く軟骨や骨の破壊がみられる。リウマチの治療は主として薬物療法によるが、その薬物として古くからステロイド剤や非ステロイド系抗炎症剤（ＮＳＡＩＤｓ）がリウマチの症状を改善する目的で用いられてきた。さらに、近年になってリウマチ患者には自己抗体産生を初めとする全身性の免疫異常が認められることがわかり、免疫抑制剤、免疫調節剤（ＤＭＡＲＤｓ）等も用いられている。 Rheumatoid arthritis is an intractable chronic inflammatory disease whose joint is the synovial membrane, but the cause of its onset is unknown and there are various symptoms. One of the characteristics of the pathological condition of rheumatism is abnormal growth of synovium and subsequent destruction of cartilage and bone. Treatment of rheumatism is mainly based on pharmacotherapy, but steroids and non-steroidal anti-inflammatory drugs (NSAIDs) have long been used as drugs for the purpose of improving rheumatic symptoms. Furthermore, it has recently been found that systemic immune abnormalities such as autoantibody production are observed in rheumatic patients, and immunosuppressants, immunomodulators (DMARDs), and the like are also used.
一方、本発明の有効成分であるベンズアミド誘導体は、分化誘導作用やヒストン脱アセチル化酵素阻害作用に基づく癌や自己免疫疾患等の治療剤として有用であることが開示されている（特許文献１および２参照）。これらの特許文献には、化学構造が多岐にわたる膨大な組み合わせのベンズアミド誘導体が開示されている。そしてこれらの特許文献に記載された発明は、癌疾患の治療を目的とするものである。また、これらの特許文献には適用可能性のある疾患として数多くの疾患名が羅列されているが、具体的な薬理効果を示す記載はなく、特にリウマチに対する具体的効果についての記載は全くない。 On the other hand, it is disclosed that the benzamide derivative, which is an active ingredient of the present invention, is useful as a therapeutic agent for cancer, autoimmune disease and the like based on differentiation inducing action and histone deacetylase inhibiting action (Patent Document 1 and 2). These patent documents disclose a vast number of combinations of benzamide derivatives with various chemical structures. The inventions described in these patent documents are intended to treat cancer diseases. In addition, in these patent documents, many disease names are listed as applicable diseases, but there is no description showing specific pharmacological effects, and there is no description regarding specific effects particularly on rheumatism.
また、どのような基本化学構造を有するベンズアミド誘導体がリウマチに対し有用であるかについては全く示唆もされていない。
したがって、これらの多数の公知ベンズアミド誘導体の中から、リウマチの治療薬として有用な化合物を見出すことは非常に興味のある課題である。 Therefore, finding a compound useful as a therapeutic agent for rheumatism among these many known benzamide derivatives is a very interesting subject.
そこで、本発明者等は、リウマチ治療におけるベンズアミド誘導体の効果を鋭意研究した。 Accordingly, the present inventors have intensively studied the effects of benzamide derivatives in the treatment of rheumatism.
リウマチに対する治療効果を動物モデルを用いて評価検討する方法は、種々報告されている。例えば、コラーゲン誘発関節炎モデルを用いる方法（Nature, 283, 666-668 (1980)）等がある。本発明では、この動物モデルに準じてリウマチに対するベンズアミド誘導体の効果を評価検討した。詳細な試験方法および結果は、後述の実施例（薬理試験の項）で説明するが、下記一般式［１］で表される基本化学構造を有する化合物群（以下、本化合物とする）は、顕著な関節炎抑制効果を示した。
この結果は、本化合物が、リウマチ治療薬として非常に有用であることを示すものである。 This result shows that this compound is very useful as a therapeutic agent for rheumatism.
本発明により、ベンズアミド誘導体を有効成分とするリウマチ治療剤を提供することができる。 According to the present invention, a therapeutic agent for rheumatism comprising a benzamide derivative as an active ingredient can be provided.
本発明は、下記一般式［１］で表される化合物またはその塩類（以下、本化合物とする）を有効成分とするリウマチ治療薬に関する。
［式中、Ｒ1 およびＲ 2 は水素原子、Ｒ 3 はアミノ基、Ｘはピリジル基、Ｙは−ＣＨ 2 Ｏ−または−ＣＨ 2 ＯＣＨ 2 −、Ｚは直接結合またはメチレン基をそれぞれ示す。以下、同じ］ [Wherein, R 1 and R 2 are hydrogen atoms, R 3 is an amino group, X is a pyridyl group, Y is —CH 2 O— or —CH 2 OCH 2 —, and Z is a direct bond or a methylene group , respectively. same as below]
前述のアミノ基は汎用される保護基で保護されていてもよい。この保護基の例としては、アセチル基等の低級アルカノイル基やベンゾイル基等のアシル基が挙げられる。 The aforementioned amino group may be protected with a commonly used protecting group. Examples of this protecting group include lower alkanoyl groups such as acetyl groups and acyl groups such as benzoyl groups.
本化合物の特に好ましい具体例として、下記化学式で示されるＮ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド［２］、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド［３］若しくはＮ−（２−アミノフェニル）−４−［（ピリジン−３−イル）メトキシアセチルアミノ］ベンズアミド［４］またはその塩類が挙げられる。
上記の塩類とは、医薬として許容される塩類であれば特に制限はなく、例えば、塩酸、硝酸、硫酸、臭化水素酸、リン酸等の無機酸との塩、酢酸、乳酸、リンゴ酸、コハク酸、クエン酸、安息香酸、フマル酸、マレイン酸、酒石酸、トリフルオロ酢酸、メタンスルホン酸、ｐ−トルエンスルホン酸等の有機酸との塩、ナトリウム、カリウム、カルシウム等のアルカリ金属もしくはアルカリ土類金属との塩、トリエチルアミン、ピリジン等の有機アミンとの塩が挙げられる。 The salts are not particularly limited as long as they are pharmaceutically acceptable salts. For example, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, lactic acid, malic acid, Salts with organic acids such as succinic acid, citric acid, benzoic acid, fumaric acid, maleic acid, tartaric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, alkali metals or alkaline earths such as sodium, potassium, calcium Examples thereof include salts with similar metals and salts with organic amines such as triethylamine and pyridine.
本化合物には光学異性体が存在する場合もあるが、それらも本発明に含まれる。さらに、本化合物は溶媒和物、例えば水和物の形態をとっていてもよい。 The compound may have optical isomers, and these are also included in the present invention. Furthermore, the present compounds may take the form of solvates, for example hydrates.
本化合物を投与するための製剤の調製には、特別な技術は必要でなく、汎用されている技術を用いて製剤を調製すればよい。剤形としては、注射剤、錠剤、カプセル剤、散剤、顆粒剤等の全身投与製剤、塗布剤、局所注入剤等の局所投与製剤が挙げられる。 The preparation of the preparation for administering the present compound does not require any special technique, and the preparation may be prepared using a widely used technique. Examples of the dosage form include systemic preparations such as injections, tablets, capsules, powders and granules, and local preparations such as coating agents and topical injections.
錠剤、カプセル剤、散剤、顆粒剤等の固形剤は、乳糖、結晶セルロース、デンプン等の増量剤、ステアリン酸マグネシウム、タルク等の滑沢剤、ヒドロキシプロピルセルロース、ポリビニルピロリドン等の結合剤、カルボキシメチルセルロース カルシウム、低置換ヒドロキシプロピルメチルセルロース等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂等のコーテイング剤を必要に応じて使用し、調製することができる。 Solid agents such as tablets, capsules, powders and granules are bulking agents such as lactose, crystalline cellulose and starch, lubricants such as magnesium stearate and talc, binders such as hydroxypropylcellulose and polyvinylpyrrolidone, carboxymethylcellulose Disintegrating agents such as calcium and low-substituted hydroxypropylmethylcellulose, and coating agents such as hydroxypropylmethylcellulose, macrogol, and silicone resin can be used as necessary.
注射剤、局所注入剤等の液剤は、注射用精製水、生理食塩水、リンゲル液、植物油等の溶剤、エタノール、プロピレングリコール、グリセリン等の溶解補助剤、ピロ亜硫酸ナトリウム、亜硫酸水素ナトリウム、アスコルビン酸ナトリウム、エチレンジアミン四酢酸等の安定化剤、カルボキシメチルセルロースナトリウム、モノステアリン酸アルミニウム、ポリソルベート８０等の懸濁化剤、ポリオキシエチレン硬化ヒマシ油、レシチン等の乳化剤、リン酸ナトリウム、酢酸ナトリウム等の緩衝剤、塩化ナトリウム、ブドウ糖等の等張化剤、塩酸プロカイン、ベンジルアルコール、クロロブタノール等の無痛化剤、パラオキシ安息香酸エステル等の保存剤を必要に応じて使用し、調製することができる。 Liquids such as injections and topical infusions include purified water for injection, physiological saline, Ringer's solution, solvents such as vegetable oil, solubilizers such as ethanol, propylene glycol, glycerin, sodium pyrosulfite, sodium bisulfite, sodium ascorbate , Stabilizers such as ethylenediaminetetraacetic acid, suspending agents such as sodium carboxymethylcellulose, aluminum monostearate, polysorbate 80, emulsifiers such as polyoxyethylene hydrogenated castor oil, lecithin, buffers such as sodium phosphate and sodium acetate In addition, an isotonic agent such as sodium chloride and glucose, a soothing agent such as procaine hydrochloride, benzyl alcohol, and chlorobutanol, and a preservative such as paraoxybenzoate can be used as necessary.
これらの製剤は、特開平１０−１５２４６２や特開平１１−３０２１７２に記載されたものであってもよいが、さらに後述の実施例（製剤例の項）のものであってもよい。無論、この製剤例は本発明の範囲を限定するものではない。 These preparations may be those described in JP-A-10-152462 and JP-A-11-302172, but may be those in Examples (formulation examples) described below. Of course, this formulation example does not limit the scope of the present invention.
本化合物の投与量は通常１日当り０．００１ｍｇ〜１０００ｍｇで１日１回または数回に分けて投与することが出来る。 The dosage of this compound is usually 0.001 mg to 1000 mg per day, and can be administered once or divided into several times a day.
これらの投与量、投与回数は患者の症状、年令、投与経路等に応じて適宜増減できる。 These doses and the number of doses can be appropriately increased or decreased according to the patient's symptoms, age, route of administration and the like.
以下に、実施例として薬理試験および製剤例を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 In the following, pharmacological tests and formulation examples will be shown as examples, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.
［薬理試験］
１）タイプIIコラーゲン誘発関節炎に対する作用
タイプIIコラーゲン誘発関節炎モデルは薬物のリウマチに対する効果を評価する動物モデルとして汎用されている（Nature, 283, 666-668 (1980)）。そこで、このモデルに準じて本化合物の関節炎抑制効果を評価検討した。
[Pharmacological test]
1) Action on type II collagen-induced arthritis The type II collagen-induced arthritis model is widely used as an animal model for evaluating the effect of drugs on rheumatism (Nature, 283, 666-668 (1980)). Thus, the arthritis inhibitory effect of this compound was evaluated and examined according to this model.
（実験方法）
ウシ関節軟骨由来タイプIIコラーゲンの０．０５Ｎ酢酸溶液（２ｍｇ／ｍｌ）と等量のフロインド不完全アジュバントを混合してエマルジョンを調製した（最終濃度：１ｍｇ／ｍｌ）。
(experimental method)
An emulsion was prepared by mixing 0.05N acetic acid solution of bovine articular cartilage-derived type II collagen (2 mg / ml) and an equal amount of Freund's incomplete adjuvant (final concentration: 1 mg / ml).
一次感作として、このエマルジョンをラット（雌、７週齢、体重約１３０〜１６０ｇ）背部皮内５箇所に各々１００μｌ（計５００μｌ：タイプIIコラーゲンとして５００μg／ラットに相当）注入した。一次感作から７日後、再びこのエマルジョンをラット尾根部皮内に１００μｌ注入した（二次感作）。 As a primary sensitization, 100 μl of each emulsion (total 500 μl: equivalent to 500 μg / rat as type II collagen) was injected into the rat skin (female, 7 weeks old, body weight about 130 to 160 g) at 5 sites in the back skin. Seven days after the primary sensitization, 100 μl of this emulsion was injected again into the rat ridge skin (secondary sensitization).
被験化合物溶液０．５ｍｌ／ｋｇ（被験化合物は基剤としての５％カルボキシメチルセルロース溶液に溶解）を１次感作の直前、７日目および１４日目に経口投与した。尚、各被験化合物の投与量は、夫々６ｍｇ／ｋｇとした。 A test compound solution 0.5 ml / kg (the test compound was dissolved in a 5% carboxymethylcellulose solution as a base) was orally administered immediately before the first sensitization, on the 7th and 14th days. The dose of each test compound was 6 mg / kg.
被験化合物としてＮ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド［化学式２，被験化合物１］、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド［化学式３，被験化合物２］またはＮ−（２−アミノフェニル）−４−［（ピリジン−３−イル）メトキシアセチルアミノ］ベンズアミド［化学式４，被験化合物３］を用いた。
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide [Chemical Formula 2 , Test Compound 1], N- (2-aminophenyl) -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide [Chemical Formula 3 , Test Compound 2] or N- (2-aminophenyl) -4-[(pyridin-3-yl) methoxyacetylamino] benzamide [ Chemical formula 4 , test compound 3] was used.
コントロールとして被験化合物を含まない基剤のみを上記と同様にして投与した。 As a control, only a base containing no test compound was administered in the same manner as described above.
（結果）
試験結果は、一群８例の平均値で図１に示す。図１から明らかなように、コントロール群においては、二次感作後、３日目（一次感作より１０日目）より後肢容積の増大が開始し、７日目（一次感作より１４日目）に後肢容積は最大に達した。
(result)
The test results are shown in FIG. As is apparent from FIG. 1, in the control group, the hindlimb volume started to increase on the third day (10 days after the primary sensitization) after the second sensitization, and on the seventh day (14 days after the primary sensitization). Eye) the hind limb volume reached a maximum.
一方、被験化合物投与群では、いずれもこの後肢容積の増大が顕著に抑制され、特に、被験化合物２を投与した場合、後肢容積の増大は全く見られず、正常ラット（無処置群）とほとんど同じであった。 On the other hand, in the test compound administration group, this increase in hind limb volume was remarkably suppressed. In particular, when test compound 2 was administered, no increase in hind limb volume was observed at all, which was almost the same as that of normal rats (no treatment group). It was the same.
［製剤例］
カプセル剤（１カプセル当りの成分量）
本化合物 １ｍｇ
乳糖 １４９ｍｇ
[Formulation example]
Capsule (component amount per capsule)
1 mg of this compound
Lactose 149mg
上記、本化合物の量およびその他の添加物の量の混合比を適宜変更することにより、所望の配合量のカプセル剤を調製することができる。 A capsule having a desired blending amount can be prepared by appropriately changing the mixing ratio of the amount of the present compound and the amount of other additives.
Claims (2)
A therapeutic agent for rheumatism comprising a compound represented by the following general formula [1] or a salt thereof as an active ingredient.
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