JP4369924B2 - ジアミン誘導体、製造法及び抗酸化薬 - Google Patents
ジアミン誘導体、製造法及び抗酸化薬 Download PDFInfo
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- JP4369924B2 JP4369924B2 JP2005505402A JP2005505402A JP4369924B2 JP 4369924 B2 JP4369924 B2 JP 4369924B2 JP 2005505402 A JP2005505402 A JP 2005505402A JP 2005505402 A JP2005505402 A JP 2005505402A JP 4369924 B2 JP4369924 B2 JP 4369924B2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000005944 tissue migration Effects 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P35/00—Antineoplastic agents
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Anti-Oxidant Or Stabilizer Compositions (AREA)
- Furan Compounds (AREA)
Description
1.式(1)
2.式(2)
3.式(1)
4.3記載の抗酸化薬を含有することを特徴とする腎疾患、脳血管又は循環器疾患治療薬
5.3記載の抗酸化薬を含有することを特徴とする脳梗塞治療薬
6.3記載の抗酸化薬を含有することを特徴とする網膜の酸化障害抑制薬。
7.加齢性黄斑変性症あるいは糖尿病性網膜症に対する6記載の網膜の障害抑制薬。
8.3記載の抗酸化薬を含有することを特徴とするリポキシゲナーゼ阻害薬。
である。
本発明化合物である前記式(1)で表される化合物は、例えば、次のようにして製造することができるが、本発明化合物は一般的に知られる方法によっても合成することができ、この方法に限定されるものではない。
製造工程1
製造工程2
Me:メチル
本発明のジアミン誘導体は、抗酸化作用を有することから、低比重リボ蛋白(Low density lipoprotein、以下LDLと略記する。)の酸化的変性を防ぐことによって動脈硬化病変の発生、進展を阻止することができ、動脈硬化の治療薬に適用することができると共に、酸化作用に基づく各種疾病、例えば、老化痴呆性疾患、心臓病、癌、糖尿病、消化器疾患、熱傷、眼疾患、腎疾患等の治療薬としても有用である。更に、脳卒中や心筋梗塞等の虚血性臓器疾患では、虚血部位の血液再潅流時に種々の活性酸素が発生し、脂質過酸化反応による細胞膜破壊等により組織障害が増悪されるが、本発明のジアミン誘導体は、その抗酸化活性により種々の活性酸素や過酸化脂質を除去し、虚血病変部の組織障害を防ぐことができ、虚血臓器障害の治療薬に適用することができる。また、本発明のジアミン誘導体は、リポキシゲナーゼ阻害作用を有し、リポキシゲナーゼの作用を阻害することによりアラキドン酸をHPETEに変換するのを抑制することができる。
本発明の抗酸化薬は、上記抗酸化作用を有する本発明のジアミン誘導体又はその薬学的に許容される塩の1種又は2種以上を有効成分として含有するものであれば、特に限定されるものではなく、上記疾病の医薬として、任意の様式で投与することができる。例えば、経口、経鼻、非経口、局所、経皮又は経直腸で投与することができ、その形態も、固体、半固体、凍結乾燥粉末又は液体の剤形、例えば、錠剤、坐薬、丸薬、軟質及び硬質カプセル、散薬、液剤、注射剤、懸濁剤、エアゾル剤、持続放出製剤等とすることができ、正確な投与量を処方でき、かつ、簡便に投与することができる適当な剤形とすることができる。
本発明の網膜の光酸化障害抑制薬は、上記抗酸化作用を有する本発明のジアミン誘導体又はその薬学的に許容される塩の1種又は2種以上を有効成分として含有する抗酸化薬を含有するものであれば、特に限定されるものではなく、投与様式、投与形態、投与量も上記抗酸化薬と同様の様式、形態、投与量とすることができ、また、上記抗酸化薬と同様の製剤用成分、担体、アジュバント等を包含させることができ、賦形剤、崩壊剤、結合剤等や、有効成分と反応しない他の網膜酸化障害抑制薬の1種又は2種以上を適宜加えてもよく、また、上記の他に、他の薬効を有する成分を適宜含有させてもよい。また、投与形態としては、上記抗酸化薬における場合と同様の投与形態の他、点眼剤、眼軟膏剤とすることができる。
はこれらの実施例に限定されるものではない。
本発明化合物を含有する製剤を以下の方法により調製した。
経口剤(有効成分10mg錠)
本発明化合物 10mg
乳糖 81.4mg
コーンスターチ 20mg
ヒドロキシプロピルセルロース 4mg
カルボキシメチルセルロースカルシウム 4mg
ステアリン酸マグネシウム 0.6mg
合計 120mg
本発明化合物のin vitro抗酸化脂質作用を、Malvyらの方法(Malvy,c.,et al.,)バイオケミカル・アンド・バイオフィジカル・リサーチ・コミュニケーションズ(Biochemical and Biophysical Research Communications、1980年、第95巻、p.734−737)に準じて、ラット脳ホモジネートでの過酸化脂質活性の測定により評価した。即ち、ラット脳を摘出し、水冷下、脳に5倍量のリン酸緩衝−生理食塩水溶液(pH7.4)(以下PBSと略記する。)を加え、テフロン(登録商標)ホモジナイザーでホモジナイズし、10,000gで20分間遠心分離し、上清の脳ホモジネートを調製した。調製した脳ホモジネートに500μMシステイン及び5μM硫酸第一鉄及び100mM KClを加え、37℃で30分間インキュベートし、過酸化脂質の分解で生じたマロンジアルデヒドをチオバルビツール酸法で測定した。測定値から本発明化合物の50%阻害濃度(以下IC50と略記する。)を求めた。結果を表3に示す。本発明化合物はin vitro抗酸化脂質作用を有していることが分かった。
対照薬−1は下記化合物である。
本発明化合物の組織移行性は、ex vivo抗過酸化脂質作用を測定することにより評価した。生理食塩水溶液或いは1%ポリエチレン硬化ヒマシ油(日光ケミカルズ社製:NIKKOL HCO−60)生理食塩水溶液に溶解又は懸濁した試験化合物を、一群3匹のSD系雄性ラット(6週齢)(日本SLC株式会社より入手)に100mg/kgの割合で腹腔内投与した。投与30分後に頚動脈を切断して放血死させ、脳、心臓、腎臓を摘出した。実施例4に記載した方法で、各組織ホモジネートの過酸化脂質活性を測定した。本発明化合物の各組織における阻害率は対照群(生理食塩水投与群)と試験化合物投与群の過酸化脂質生成量から求めた。結果を表4に示す。結果から、本発明化合物は組織移行性が高いことが明かである。
本発明化合物のin vivo抗酸化作用をジャーナル・オブ・メディシナル・ケミスリー(J.Med.Chem.、1997年、第40巻、P.559−573)記載の方法に準じて、塩化第一鉄のマウス脊髄くも膜下腔内投与による異常行動や死亡率の抑制効果から評価した。Slc:ICR系雄性マウス(5週)(日光SLC株式会社より入手)、一群3〜7匹を用い、50mM塩化第一鉄の生理食塩水溶液をマウスの第5一第6腰椎間より脊柱管に5μl投与した。症状観察は、塩化第一鉄投与20分から60分行い、表5に示す症状から60分後のスコアを求めた。試験化合物は生理食塩水溶液又は1%ポリエチレン硬化ヒマシ油(日光ケミカルズ社製NIKKOL HCO−60)生理食塩水溶液に溶解又は懸濁し、塩化第一鉄投与30分前に腹腔内或いは経口投与した。本発明化合物の50%阻害用量(以下ID50と略記する)は対照群(生理食塩水投与群)のスコアと試験化合物投与群のスコアから求めた。結果を表6に示す。結果から、本発明化合物はin vivo抗酸化作用を有することが分かった。
本発明化合物の網膜移行性を評価した。一群3匹のSD系雄性ラット(6適齢)に、0.1N塩酸溶液或いは1%ポリエチレン硬化ヒマシ油(NIKKOL HCO−60)溶液に溶解或いは懸濁した試験化合物を経口投与し、30分後に両眼を摘出し、氷冷下で網膜を分離した。網膜を氷冷下、0.1Mトリス一塩酸緩衝液(pH7.4)中、ポリトロン微量ホモジナイザー(NS−310E:日音医理科器機社製)で、5%ホモジネート液を調製し、37℃で、1時間自動酸化させ、生成した過酸化脂質量をチオバルビツール酸法(真杉ら、ビタミン51、21−29、1977)で定量した。各投与量における阻害率から30%阻害する投与量(ID30)を求めた。その結果を表7に示す。結果から、本発明化合物はex vivo網膜過酸化脂質生成抑制作用を有し、網膜移行性が高いことが分かった。
本発明化合物の紫外線照射ラット網膜中の66kDaタンパク質の増加抑制作用を評価した。Wistar系雄性ラット(7〜9週齢)に、試験化合物を0.1N塩酸溶液或いは1%ポリエチレン硬化ヒマシ油(NIKKOL HCO−60)溶液に溶解或いは懸濁して経口投与し、30分後に右眼にUVスポット光源を用いて、UV−A(12mW/cm2)を30分間照射した。また、左眼は照射せずにコントロールとした。UV−A照射中及び前後2時間以内は、室内光を遮断した環境でラットを飼育した。照射48時間後に網膜を分離し、実施例4記載したと同様の方法で、5%ホモジネート液を調製した。網膜タンパク質の変化は、Lammliの方法(Nature,277,680−685,1970)に準じ、SDS−ポリアクリルアミド電気泳動を行った。即ち、濃縮ゲルは4.5%ゲル(pH6.8)を、分離ゲルは、10%(pH8.8)を用いて泳動用緩衝液(25mMトリス、192mMグリシン0.1%SDS)、20mM定電流(limit 300V)で泳動した。泳動後、ゲル15%TCA、次いでエタノール:酢酸:水(25:8:65)で固定し、0.25%クマシープリリアントブルーR−250を含むエタノール:酢酸:水(9:2:9)で染色した。その後、エタノール:酢酸:水(25:8:65)で脱色し、泳動後の66kDaタンパク質をデンシトグラフにより解析した。試料中のタンパク質量は、Lowry法で求めた。結果を表8に示す。結果から、本発明化合物は66kDaタンパク質の増加を顕著に抑制することが分かった。
用]
5−LO阻害活性はCarterら(Carter G.W,et al,J.Pharmacol.Exp,Ther.:256,929−37、1991)の方法を一部改変して測定した。即ち、ハンクス溶液中でヒト末梢血単核細胞とDMSO(最終濃度は1%)に溶解した試験化合物をプレインキュベーション(37℃、15分)した後、さらに30μM A23187を加えインキュベーション(37℃、30分)した。その結果生成するロイコトリエンB4をエンザイムイムノアッセイによって定量し、その値から試験化合物の5−LOに対する50%生成抑制濃度(μM)を算出した。結果を表9に示す。
雄性マウスに本発明化合物の一回用量を経口投与した後、7日間観察し死亡率を求めた。結果を表10に示す。対照薬−2は下記化合物であり、
Claims (8)
- 請求項3記載の抗酸化薬を含有することを特徴とする腎疾患、脳血管又は循環器疾患治療薬。
- 請求項3記載の抗酸化薬を含有することを特徴とする脳梗塞治療薬。
- 請求項3記載の抗酸化薬を含有することを特徴とする網膜の酸化障害抑制薬。
- 加齢性黄斑変性症あるいは糖尿病性網膜症に対する請求項6記載の網膜の障害抑制薬。
- 請求項3記載の抗酸化薬を含有することを特徴とするリポキシゲナーゼ阻害薬。
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