JP6208751B2 - 炎症及び疼痛を治療するための医薬組成物 - Google Patents
炎症及び疼痛を治療するための医薬組成物 Download PDFInfo
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- JP6208751B2 JP6208751B2 JP2015516148A JP2015516148A JP6208751B2 JP 6208751 B2 JP6208751 B2 JP 6208751B2 JP 2015516148 A JP2015516148 A JP 2015516148A JP 2015516148 A JP2015516148 A JP 2015516148A JP 6208751 B2 JP6208751 B2 JP 6208751B2
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Description
本発明は、医薬的に許容される担体、及びω−(アリールスルホニル)アルキルニトリル化合物、又はその医薬的許容される塩を含んで成る医薬組成物に関する。本発明はまた、炎症又は炎症関連障害及び疼痛を治療するための前記化合物の使用方法にも関する。
炎症は、微生物又は組織損傷が、高められた血管透過性、内皮受容体のアップレギュレーション、及び周囲組織に侵入し、そして炎症の従来の状況、すなわち発赤、腫脹、発熱及び疼痛を強く生成する先天性及び適応性免疫系の種々の細胞のそれによる増大された放出を生成する種々の細胞型からのサイトカイン及びケモカインの放出を誘発する工程である。
本発明は、医薬的に許容される担体、及び3−(アリールスルホニル)プロパンニトリル化合物、又はその医薬的許容される塩又は溶媒和物を含んで成る医薬組成物に向けられる。化合物は、少なくとも90%の鈍度(w/w)である。
定義
「アルキル」とは、1〜12個の炭素原子、好ましくは1〜8個の炭素原子、及びより好ましくは、1〜6個の炭素原子の直鎖又は分枝鎖の基を言及する。
「アリールアルキル」とは、アルキル部分に1〜6個の炭素原子及びアリール部分に6〜10個の炭素原子を有するアリール−アルキル−基を言及する。そのようなアリールアルキル基は、ベンジル、フェネチル及び同様のものにより例示される。
「シクロアルキル」とは、1〜3個のアルキル基により任意に置換される単環又は複数の縮合環を有する、3〜12個の炭素原子の環状アルキル基を言及する。そのようなシクロアルキル基は、例によれば、単環構造体、例えばシクロプロピル、シクロブチル、シクロペンチル、シクロオクチル、1−メチルシクロプロピル、2−メチルシクロペンチル、2−メチルシクロオクチル、及び同様のもの、又は複数の環構造体、例えばアダマンチル及び同様のものを包含する。
本発明者は、下記式I:
R2−R6は、H、C1-6アルキル(例えば、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、i−ブチル、sec−ブチル、t−ブチル)、シクロアルキル(例えば、シクロペンチル、シクロヘキシル)、フェニル、置換フェニル、アリールアルキル(例えば、ベンジル)、ハロゲン(例えば、フルオロ、クロロ、ブロモ、ヨード)、シアノ、カルボキシ、カルボキシアミド、アセチル、ヒドロキシル、C1-6アルコキシ(例えば、メトキシ)、トリフルオロメトキシ、チオ、メチルチオ、メチルスルフィニル、メチルスルホニル、ニトロ、アミノ、C1-6アルキルアミノ(例えば、メチルアミノ、ジメチルアミノ)、アセトアミド、フルオロメチル、クロロメチル、ブロモメチル、ヨードメチル、トリフルオロメチル、トリフルオロメトキシ、シアノメチル、カルボキシメチル、ヒドロキシメチル、メトキシメチル、チオメチル、アミノメチル、ニトロメチル、アセトアミドから成る群から、独立して選択され;又は
R2及びR3は、融合された、二環式環構造、例えばナフチルを生成するために連結され;又は
R3及びR4は、融合された、二環式環構造、例えばナフチルを生成するために連結され;又は
R4及びR5は、融合された、二環式環構造、例えばナフチルを生成するために連結され;又は
R2−R6は独立して、誘導的に又は共鳴を通して、電子放出効果により、芳香族環の電子密度を増大する置換基である}
で表わされるω−(アリールスルホニル)アルキルニトリル(又はω−(アリールスルホニル)アルカンニトリル)、又は医薬的に許容されるその塩又は溶媒和物が、炎症、炎症−関連障害、及び疼痛の治療のために有効であることを発見した。
本発明は、1又は2以上の医薬的に許容される担体、及び活性化合物3−(アリールスルホニル)プロパンニトリル、又は医薬的に許容されるその塩又は溶媒和物を含んで成る医薬組成物を提供する。医薬組成物中の活性化合物又はその医薬的に許容される塩又は溶媒和物は一般的に、局所製剤のためには、約0.01−20%、又は0.05−20%、又は0.1−20%、又は0.2−15%、又は0.5−10%、又は1−5%(w/w);注射用製剤のためには、約0.1−5%;パッチ製剤のためには0.1−5%;錠剤製剤のためには約1−90%;及びカプセル製剤のためには1−100%の量で存在する。
炎症は、免疫系の先天性及び獲得された成分の活性化及び継続に起因する組織病理学の工程及び状態である。細胞対細胞相互作用におけるアラキドン酸カスケード及びサイトカイン生成及び作用は、免疫活性化及び応答の決定的成分であり、これが炎症を誘発する。アラキドン酸は、多くの細胞膜に存在する。アラキドン酸が膜から切除される場合、それは前炎症性実体として知られる、既知エイコサノイド、例えばプロスタグランジン及びロイコトリエンの多くを生成することができる。
表1は、3−(アリールスルホニル)プロパンニトリル、例えば3−(フェニルスルホニル)プロピオニトリル、3−[(4−メチルフェニル)スルホニル]プロピオニトリル、3−(ナフタレン−2−スルホニル)−プロピオニトリル、及び3−[(4−クロロフェニル)スルホニル]プロピオニトリル(それらは、Aldrich Rare Chemical Collectionから購入された)を含む1つのゲル製剤を例示する。
表2は、3−(アリールスルホニル)プロパンニトリル、例えば3−(フェニルスルホニル)プロピオニトリル、3−[(4−メチルフェニル)スルホニル]プロピオニトリル、3−(ナフタレン−2−スルホニル)−プロピオニトリル、及び3−[(4−クロロフェニル)スルホニル]プロピオニトリルを含む別のゲル製剤を例示する。
3−(フェニルスルホニル)プロピオニトリル、3−[(4−メチルフェニル)スルホニル]プロピオニトリル、3−(ナフタレン−2−スルホニル)−プロピオニトリル、及び3−[(4−クロロフェニル)スルホニル]プロピオニトリルを、Aldrich Rare Chemical Collectionから購入し、そしてこの実験に使用した。
3−[(4−メチルフェニル)スルホニル]プロピオニトリルを、ビヒクル(水中、1%Tween80)に懸濁し、3mg/mlにした。試験化合物、デキサメタゾン(ビヒクル中、正の対照)、及びビヒクルを、マウスに経口投与し、そしてマウスにおける局所アラキドン酸−誘発された耳腫脹モデルにおいて抗−炎症活性について評価した。
活性化合物(3−(アリールスルホニル)プロパンニトリル)を、ヒト末梢包液単核細胞(PBMC)からのインビトロサイトカイン放出に対するそれらの阻害効果について試験した。PBMCによるサイトカインの分泌は、炎症応答において有意な役割を演じる。
この研究は、経口及び皮下経路によるラットへの投与の後、試験物質の全身性(血漿)暴露を決定するために行われる。
3−(アリールスルホニル)プロパンニトリルを、実施例3に従って、ゲル製剤に調製する。ゲル製剤における試験物質、3−(アリールスルホニル)プロパンニトリル、インドメタシン(正の対照)、及びビヒクル(活性化合物を有さないゲル製剤)を、ラットカラギーナン誘発された肢炎症モデルにおいて抗−炎症及び鎮痛活性について評価する。
3−(アリールスルホニル)プロパンニトリルを、実施例3に従ってゲル製剤に調製する。ゲル製剤中、活性化合物(1−5%)、モルヒネ(正の対照)及びビヒクル(活性化合物)を有さないゲル製剤を、ラットホットプレートにおける鎮痛活性について評価する。
CFA(完全フロイントアジュバント)は、炎症性疼痛を誘発することが知られている(Walker, et al.JPET. 304: 56-62, 2003)。
ホルマリン試験は、ホルマリン誘発された組織損傷に起因する持続性疼痛のモデルである。ホルマリンモデルは、侵害受容の炎症性、神経性及び中枢機構を包含する。下記に記載されるアッセイは、強力な中枢鎮痛剤及び弱い鎮痛/抗−炎症剤の両者に対して敏感な後期炎症発痛相に関する(Hunskaar, et al., J. Neuroscience Meth. 14: 69-76, 1985)。ホルマリン試験は、神経障害性疼痛を治療するための化合物を試験するための適切なモデルを表す(Benson, et al. Proceedings of Measuring Behavior, 2008, Eds. Spink, et al, 324-325)。
末梢神経病変は、自発的疼痛の他に、軽いタッチに対する誇張された応答(触覚異痛)を包含する症状を生成することができる。慢性狭窄損傷モデルは、神経障害性疼痛モデルである。
目的:標準的なNSAID治療の一時停止後、変形性関節症に関連する、軽度〜中等度の膝疼痛を有する患者において、ゲル製剤中の活性化合物の有効性を調べること。この研究の焦点は、疼痛を伴う関節炎により引き起こされる症状に対してである。臨床試験は、他の筋骨格系障害のために、十分に確立されたパラダイムとして変形性膝関節を利用している。
少なくとも2ヶ月間、標準的NSAID療法の安定した用量により制御される膝の疼痛を伴う変形性関節症を有する患者は、7日間の休薬期間のためにNSAIDの使用を中止する。次に、患者を、1:1:1の比率(1%活性ゲル、5%活性ゲル、プラシーボ)にランダム化する。合計150人までの患者が登録され、そして8、10、14及び21日で、引き続き、7日間、治療される。
安全性:
・研究を通しての有害事象(AE)。
・登録時の身体検査(−7日、NSAIDウォッシュアウト期間の開始)、ベースライン(1日目、治療の開始)、10日目及び21日目。
・登録時までの生命徴候(−7日目、NSAIDウォッシュアウト期間の開始)、ベースライン(1日目、治療の開始)、及び2、4、8、10、14及び21日目。
・ベースラインでの臨床実験室での測定(1日目)、8及び14日目。
一次臨床活性パラメーターは、VAS、及びWestern Ontario and McMaster University(WOMAC)スケールにより定量化されるような、適用の部位での疼痛の測定である。膝の腫脹、圧痛及び炎症に対する治療の効果が記録され、また、治療後の疼痛の低下又は根絶までの時間が記録される。
一次臨床活性エンドポイントは、以下である:
・WOMAC機能障害指数でのベースライン(1日目)から8日目までの変化:
−疼痛(尺度0−20)。
−凝り(尺度0−8)。
−身体機能(尺度0−68)。
・VAS疼痛尺度(1−100)でのベースライン(1日目)から8日目までの変化。
・毎日のベースライン(前治療1)から治療2の30分後までの変化により測定されるような、2及び3日目でのVAS疼痛尺度での日内変化。
・ベースライン(1日目)から1日目での最初の適用の30分及び60分後までの腫脹、圧痛及び炎症の研究者評価の変化。
・ベースライン(1日目)から8日目までの腫脹、圧痛及び炎症の研究者評価の変化。
・活性ゲル又はプラシーボゲルの各局所適用に続く疼痛の低下又は根絶までの時間。
・レスキュー薬(APAP)の使用。
目的:アトピー性皮膚炎を有する患者における3−(アリールスルホニル)プロパンニトリルゲルの有効性を調べるためである。
安全性:
安全性が、一般的病歴及び物理的徴候により、血液学、血清化学及び尿検査についての臨床検査により、及び「0」(ナシ)〜「3」(重度)の評価尺度を用いて、紅斑、スケーリング、乾燥、ピリピリした痛み/熱傷の局所適用部位許容性パラメーターの評価により評価される。
有効性は、下記を用いて評価する:
1.研究開始時まで、及び12週まで、及び続いて、研究投薬の中断の4週後で、2週間隔で、疾患重症度の総合評価。調査員の全体的評価(IGA)は、0〜4の評価尺度(0=なし又はなし(clear)、1=ほとんどなし、2=軽度の関与、3=中位の疾患関与、及び4=重度の疾患関与)に基づかれる。
目的:尋常性乾せんを有する患者における3−(アリールスルホニル)プロパンニトリルゲルの有効性を調べるためである。
安全性:
安全性が、一般的病歴及び物理的徴候により、血液学、血清化学及び尿検査についての臨床検査により、及び「0」(ナシ)〜「3」(重度)の評価尺度を用いて、紅斑、スケーリング、乾燥、ピリピリした痛み/熱傷の局所適用部位許容性パラメーターの評価により評価される。
有効性は、下記を用いて評価する:
1.研究開始時まで、及び12週まで、及び続いて、研究投薬の中断の4週後で、2週間隔で、疾患重症度の総合評価。調査員の全体的評価(IGA)は、0〜4の評価尺度(0=なし又はなし(clear)、1=ほとんどなし、2=軽度の関与、3=中位の疾患関与、及び4=重度の疾患関与)に基づかれる。
目的:尋常性ざ瘡を有する患者における3−(アリールスルホニル)プロパンニトリルゲルの有効性を調べるためである。
安全性:
安全性が、一般的病歴及び物理的徴候により、血液学、血清化学及び尿検査についての臨床検査により、及び「0」(ナシ)〜「3」(重度)の評価尺度を用いて、紅斑、スケーリング、乾燥、ピリピリした痛み/熱傷の局所適用部位許容性パラメーターの評価により評価される。
有効性は、下記を用いて評価する:
1.研究開始時まで、及び12週まで、及び続いて、研究投薬の中断の4週後で、2週間隔で、疾患重症度の総合評価。調査員の全体的評価(IGA)は、0〜4の評価尺度(0=なし又はなし(clear)、1=ほとんどなし、2=軽度の関与、3=中位の疾患関与、及び4=重度の疾患関与)に基づかれる。
Claims (15)
- 前記化合物が少なくとも90%(w/w)純度を有し、前記組成物がゲル、クリーム、ローション、軟膏、又はパッチの局所形態である、請求項1に記載の医薬組成物。
- 前記医薬的に許容される担体が、乳酸ラウリル、ジエチレングリコールモノエチルエーテル、トリカプリル酸/カプリン酸グリセリド、オクチサレート、シリコーン油、スクアレン、及びヒマワリ油、から成る群から選択される軟化薬である、請求項2に記載の医薬組成物。
- 前記医薬的に許容される担体が、乳酸エステル及びジエチレングリコールモノエチルエーテルから成る群から選択される浸透促進剤である、請求項2に記載の医薬組成物。
- アクリル酸塩/C10-30アルキル及びトリス(2-ヒドロキシエチル)アミンをさらに含んで成る、請求項4に記載の医薬組成物。
- 前記化合物が少なくとも90%(w/w)純度を有し、前記組成物が錠剤又はカプセルの経口形態である、請求項1に記載の医薬組成物。
- 急性又は慢性腫脹、疼痛、又は発赤を特徴とする、炎症の局在性症状の徴候を軽減又は緩和するための、請求項1に記載の医薬組成物。
- 経口製剤である、請求項1に記載の医薬組成物。
- 前記炎症及び/又は疼痛が、筋骨格捻挫、筋骨格ストレイン、腱障害(tendonopathy)、末梢神経根障害、変形性関節症、変性関節疾患、若年性関節炎、痛風、強直性脊椎炎、乾癬性関節炎、システムループスエリテマトーデス、肋軟骨炎、腱炎、滑液包炎、顎関節症候群、及び線維筋痛症、から成る群から選択される骨格又は筋疾患又は症状と関係がある、請求項1に記載の医薬組成物。
- 前記炎症及び/又は疼痛が、関節、靱帯、腱、骨、筋肉、又は筋膜と関係がある、請求項1に記載の医薬組成物。
- 前記炎症及び/又は疼痛が、皮膚炎又は乾せんと関係がある、請求項1に記載の医薬組成物。
- 炎症性皮膚疾患又は皮膚障害の治療のための請求項1に記載の医薬組成物であって、該炎症性皮膚疾患又は皮膚障害が、皮膚炎、乾せん、又はざ瘡である、医薬組成物。
- アトピー性皮膚炎を治療するため、並びに紅斑、硬結、苔癬化、スケーリング(scaling)、滲出及び痂皮から成る群から選択される1又は2以上の症状を緩和するための、請求項12に記載の医薬組成物。
- 乾せんを治療するため、並びに乾せん病変の紅斑、スケーリング(scaling)、及び/又は厚さから成る群から選択される1又は2以上の症状を緩和するための、請求項12に記載の医薬組成物。
- ざ瘡を治療するため、並びに閉鎖面疱、丘疹、膿疱、結節、及び嚢胞から成る群から選択されるざ瘡病変を緩和するための、請求項12に記載の医薬組成物。
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US201261655916P | 2012-06-05 | 2012-06-05 | |
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PCT/US2013/044157 WO2013184708A1 (en) | 2012-06-05 | 2013-06-04 | Pharmaceutical composition for treating inflammation and pain |
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WO2015081188A1 (en) * | 2013-11-27 | 2015-06-04 | Olatec Industries Llc | Pharmaceutical composition comprising omega-(arylsulfonyl)alkylnitrile |
EP3110412B1 (en) | 2014-02-25 | 2018-10-31 | Olatec Therapeutics LLC | 4-benzylsulfonyl-2-butenenitrile |
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US5175192A (en) * | 1984-03-19 | 1992-12-29 | The Rockefeller University | Inhibitors of the advanced glycosylation of proteins and methods of use therefor |
US4996193A (en) * | 1989-03-03 | 1991-02-26 | The Regents Of The University Of California | Combined topical and systemic method of administration of cyclosporine |
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WO2008101064A1 (en) * | 2007-02-14 | 2008-08-21 | Logical Therapeutics, Inc. | Method of treating arthritis, pain or inflammation with naproxen 2(methanesulfonyl)ethyl ester and an h2 receptor antagonist |
BRPI1014528A2 (pt) * | 2009-03-18 | 2016-04-05 | Olatec Ind Llc | compostos para tratamento de inflamação e dor |
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EP2854785A4 (en) | 2016-02-10 |
KR20150023570A (ko) | 2015-03-05 |
AU2013271778B2 (en) | 2018-03-01 |
US20130324601A1 (en) | 2013-12-05 |
BR112014030287A2 (pt) | 2017-06-27 |
WO2013184708A1 (en) | 2013-12-12 |
MX368640B (es) | 2019-10-09 |
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