JP2011529022A - 中枢神経系疾患および障害の治療に有効な新規化合物 - Google Patents
中枢神経系疾患および障害の治療に有効な新規化合物 Download PDFInfo
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- JP2011529022A JP2011529022A JP2011500935A JP2011500935A JP2011529022A JP 2011529022 A JP2011529022 A JP 2011529022A JP 2011500935 A JP2011500935 A JP 2011500935A JP 2011500935 A JP2011500935 A JP 2011500935A JP 2011529022 A JP2011529022 A JP 2011529022A
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Abstract
Description
本出願は2008年3月19日に出願の米国特許仮出願番号 61/037,987 の「中枢神経系疾患および障害の治療に有効な新規化合物」の利益を主張し、当該出願の内容を引用することによりその全てがここに組み込まれることとする。
1. 発明の技術分野
本発明は、実験動物の中枢神経系(CNS)に作用を示す新規化合物に関連する。さらに具体的には、本発明は、現存する中枢神経系(CNS)治療薬に比べて、同等あるいはより優れた生物学的作用(すなわち有効性)を発揮しながら、毒性学的安全性の増大/改善(すなわち毒性の低減)、代謝安定性の増大/改善、半減期の延長および/または優れた副作用プロファイルと抗痙攣作用を示す新規化合物に関連する。
数多くの病理学的症状(例えば、癲癇、脳卒中、双極性感情障害、片頭痛、不安、抑鬱、不眠、統合失調症、慢性または神経因性疼痛、痙性、脊椎損傷および慢性神経変性障害など)および疾患(例えば、パーキンソン病、ハンチントン病およびアルツハイマー病など)は、中枢神経系(CNS)の正常な機能の異常として特徴づけられる。これらの症状や疾患は、一般的にはCNSの正常な機能を調節する化合物や物質による薬理学的治療に対して反応する。そのような活性を有する化合物には、癲癇などのCNSの異常を治療するために本明細書に開示される本発明の化合物が含まれる。現在利用できる治療薬はしばしば良好なCNS活性を有するが、慢性毒性、重度の、および/または不快な副作用、短い薬理学的半減期のような不十分な薬物動態特性などその他の好ましくない特性を示すものが多い。例えば、CNS治療薬の短い半減期は、有害事象を発現させずに治療濃度を維持するためには、頻回の入院を必要とし、頻繁な投与スケジュールが必要となり治療コストが増加する可能性がある。さらに、必要とされる投与回数が増加すると患者の服薬コンプライアンスが低下する傾向がある。従って、現在利用できる治療薬に比べて、例えば半減期の延長、活性の増大(すなわち有効性の改善)および/または代謝安定性の向上(例えば、毒性代謝物の低減など)などの優れた特性を有し、CNS活性を調節できる新たな化合物の提供が望まれている。さらに、より幅広く多くの患者人口に本発明の有効な化合物の提供を可能にする、改善された、より簡単な/簡略化された、合成および化学的製造工程を開発することも可能である。
本明細書では、抗痙攣作用を有する一連の新規アミド類を開示するが、その多くは、短い、多様に分岐/置換された脂肪族リンカーを介してフェニル基がアミド部分へ結合している。本発明のその他の化合物(以下に示す)は、アラニン (Z = CH3 以下)、バリン [Z = CH(CH3)2]、ロイシン [Z = CH2CH(CH3)2]、イソロイシン [Z = CH(CH3)CH2CH3]またはフェニルアラニン (Z = CH2C6H5)などの光学的に活性なアミノ酸(例えば、 DまたはL)の、あるいはグリシン(Z=H)またはタウリン [R2 = (CH2)2SO3H、 以下に示す] などの光学的に不活性なアミノ酸の誘導体であるアミド類である。そのような化合物は以下の式で例示される:
式Iを有するCNS活性化合物:
別の実施態様では、R1は H であり、R2 は(CH2)2SO3HまたはCHZCOOHであり、Zは、H、 CH3、CH(CH3)2、CH2C6H5、CH2CH(CH3)2および CH(CH3)CH2CH3からなる群から独立して選択される。任意に、R1 および R2が共にシクロアルキルである。
式Iにおいて、R3は、ヒドロキシ、置換されたあるいは置換されていないアルキル、置換されたあるいは置換されていないシクロアルキルのいずれかであるか、あるいはR4も共にシクロアルキルである。任意に、R3 が OHの場合には R4 はエチルではない。
式IIを有するCNS活性化合物:
実施態様の一つにおいては、本発明は以下の式のうちの一つを有するCNS活性化合物を含む:
実施態様の一つにおいては、式1〜8のいずれも以下の特長を有しても良い:R1 は H、CH3、(CH2)2SO3Hまたは CHZCOOHのうちの一つであり、ここでZは、H、CH3、CH(CH3)2、CH2C6H5、CH2CH(CH3)2および CH(CH3)CH2CH3、これらの組み合わせまたはこれらの誘導体からなる群のうちの一つであり;R2、R3およびR4 は、独立してH、CH3、置換または未置換のアルキル、OH、OCH3、置換または未置換のアルコキシ、それらの組み合わせまたはそれらの誘導体のうちの一つであり;R5は、H、Cl、F、CF3、CN、C1-C5 置換または未置換のアルキル、C1-C5 置換または未置換のアルコキシ、OCF3CONR1R2、またはこれらの組み合わせあるいはこれらの誘導体のうちの一つであり;nは1〜5、好ましくは1〜3であり;および X は、O、NR1、無置換、C=O、S、SO2、これらの組み合わせまたはこれらの誘導体のうちの一つである。
1. 概観
本発明者は、本発明の化合物および薬理学活性のある化合物類似体および同類のあるものは、in vivoの投与によってCNS活性の調節に有効であることを発見した。すなわち、これらの薬剤は神経系の活性の全てを完全に抑制することなく、中枢神経系の神経伝達の抑制の増強または興奮の抑制によってCNS活性を調節する。従って、本発明に準じて、この薬剤を投与される患者は、例えば、癲癇発作の緩和(無麻酔で)、筋緊張の緩和(麻痺を起こさないで)、静穏化作用(鎮静作用なしで)または痙性のような歩行系症状の改善(虚弱化、あるいは弛緩状態にすることなく)のような状況下において、過度な鎮静、麻酔、あるいは麻痺をもたらされない。
痙攣:癲癇は、多くの原因による一般的な疾患であり、臨床上の管理が非常に困難な場合があり、発作を管理するために何年もの治療を必要とすることが多い。研究者達は、現時点では、患者の多くにとって有効な癲癇の治療法は存在しないと述べている。臨床試験において、患者が同様な種類の癲癇を有し、薬剤が同様な作用機序を有していても、他の薬剤よりもある薬剤に良好に反応する患者があることが示された。副作用の頻度及び重症度にも大きな差が存在する。このように癲癇の治療には、癲癇の治癒が可能となるか、あるいは、広範な活性を持った強力で安全な新薬が発見および開発されるまで、異なる作用機序と異なる副作用を持った複数の薬剤による治療が必要であろう。Dichter ら、 Drug Therapy 334:1583 (1996)。
痙性:痙性は、伸張反射の過剰興奮による過剰な腱反射を伴う緊張性反射(筋緊張)の増強を特長とする障害である。Lance、シンポジウム抄録、「痙性-運動制御障害」(SPASTICITY--DISORDERED MOTOR CONTROL)、Feldman ら(Eds.)(1980). 痙性に付随する主要な疾患及び症状には、多発性硬化症、脳性麻痺、脳卒中、脊髄の外傷または損傷および頭部外傷がある。痙性に起こる症状には疼痛を伴う屈筋および伸筋痙攣、亢進したあるいは過剰の深部腱反射、クローヌス、筋肉の虚弱化、疲労、器用さの損失、全般的な運動機能の様々な程度の損失、麻痺及び睡眠障害などが含まれる。
情緒障害:情緒障害には、例えば、躁病、総合失調感情障害、脳外傷性攻撃性、心的外傷後ストレス障害、双極性感情障害、パニック症状および行動調整不良症候群のような抑鬱症から不機嫌躁病まで含まれる。「J.感情障害」(J. Affective Disorders) 8:243-250 (1985)、 Emrich ら、 および 「感情性障害における抗痙攣剤(ANTICONVULSANTS IN AFFECTIVE DISORDERS)」 14-32 ページ、Bernasconi ら (Excerpta Medica 1984)。本発明による新規化合物および医薬製剤処方および組成は、これらの疾患、障害及び症状の治療に有効であり、またこの治療薬分類における現存の治療薬に比較して改善された副作用プロフィールを示す。
頭痛:片頭痛 [Hering と Kuritzky, Cephalagia 12: 81-84 (1992)]、群発性頭痛 [Hering とKuritzky, loc. cit. 9:195-198 (1989)]および慢性頭痛といった頭痛 [Mathew とSabiha, Headache 31: 71-74 (1991)] は抗痙攣剤によって治療されてきた。従って本発明の組成物および医薬製剤処方は、これらのタイプの頭痛の症状の緩和に、現存の治療にみられる有害な副作用なしで使用することが可能である。
「神経障害または疾患」とは、これらに限定されないが、癲癇、不安症、多発性硬化症、脳卒中、頭部外傷、脊髄傷害およびパーキンソン病およびハンチントン病、アルツハイマー病および筋萎縮性側索硬化症のような慢性神経変性疾患を含む神経系の障害および疾患を意味する。さらに「神経障害または疾患とは、抗痙性剤または抗痙攣剤による治療が適用され、有効性を示し、推奨されるおよび/または処方される疾患または症状を意味する。
「抗痙攣剤」とは全身性強直・間代発作、欠神発作、単純部分発作、複雑部分発作、二次性全般性部分発作、癲癇重積状態および頭部外傷や外科手術後の外傷起因性痙攣などの症状に発症し、観察され、見られる痙攣の重症度、回数や期間を軽減することのできる化合物を意味する。
実施例1 化合物A[3−(4−クロロフェニル)−3−メチルブチルアミド]の調製。
白色沈殿物を濾過しTHF(100mL)で洗浄した。濾過物および洗浄液を合わせて減圧下で蒸発させた。その結果入手した白色固体をジエチルエーテル中で再溶解させた(300mL)。エーテル層をH2O、1.0M HCL、炭酸水素ナトリウム飽和溶液および塩水で洗浄した。次にエーテル溶液を硫酸マグネシウム上で乾燥させ、濾過し、減圧下で蒸発させた。その結果得られた白色固体を冷却したジエチルエーテルおよびヘキサン(50:50)溶液を加えて粉末とした。この結果5.46gの白色の剥片[3−(4−クロロフェニル)−3,N−ジメチルブチルアミド]が得られた(収率86%)。 GC/MS分析によりこの物質は100%純粋であった。 1H NMR 分光法によって生成物の構造と一致するシグナルが得られ、98%以上の純度が示された。
対応するアセトフェノン(以下の表1)から上述の実施例4の化合物Dの調製方法を使って化合物E−Nを調製した。さらに、化合物M(実施例13)および化合物N(実施例14)を対応するアミン、すなわち各々メチルアミンおよびジメチルアミン、から調製した。すべての最終生成物はGC/MS分析により100%純粋であった。1H−NMR 分光法によって各々の最終生成物の構造と一致するシグナルが得られ98%以上の純度が示された。
[1−(4−メトキシ−フェニル)シクロプロピル)アセトニトリル(60.4mmol)のDMSO(75mL)溶液をH2O2(50%w/w)(434mmol)および炭酸カリウム(121mmol)を使って0°Cで処理する。反応混合液を室温で週末中、撹拌する。反応混合液を水(100mL)およびCH2Cl2(200mL)を使用して分液ロートへ移す。反応混合液を平衡化しCH2Cl2層を除去する。水層をさらに2回CH2Cl2(2x300mL)で抽出する。CH2Cl2抽出液を合わせて、水で5回連続して洗浄した後(5x200mL)、塩水(500mL)で洗浄し、無水硫酸マグネシウム上で乾燥させ、濾過し、減圧下で濃縮して、2−[1−(4−メトキシフェニル)−シクロプロピル]―アセトアミドを入手する。
(3−(4−クロロフェノキシ)−3−メチルブチロニトリル(60.4mmol)のDMSO(75mL)溶液をH2O2(50%w/w)(434mmol)および炭酸カリウム(121mmol)を使って0°Cで処理する。反応混合液を室温で週末の間、撹拌する。反応混合液を水(100mL)およびCH2Cl2(200mL)を使用して分液ロートへ移す。反応混合液を平衡化しCH2Cl2層を除去する。さらに水層を2回CH2Cl2(2x300mL)を使って抽出する。CH2Cl2抽出液を合わせて水で5回連続して洗浄した後(5x200mL)、塩水(500mL)で洗浄し、無水硫酸マグネシウム上で乾燥させ、濾過し、減圧下で濃縮し、3−(4−クロロフェノキシ)−3−メチルブチルアミドを入手する。
本発明の多様な化合物の抗痙攣作用は、多種の齧歯類(マウスおよびラット)癲癇モデルにおいてin vivoで証明された。動物実験をWhite ら、「抗癲癇薬の発見と非臨床試験による開発」(Discovery and preclinical development of antiepileptic drugs), in Antiepileptic Drugs, 5th ed., Levy et al.(Eds.), Lippincott Williams and Wilkins, Philadelphia, PA, 2002 (968 pp.), pp. 36-48 の記載に従って実施し、参照により その全体が本明細書に組み込まれる。化合物A、G、H、IおよびFの結果を以下の表2および3に要約して示す。
本発明のさまざまな化合物の抗痙攣活性はまた、2つのラットの癲癇重積状態モデルにおいてin vivoで証明された。米国国立衛生研究所(NIH)の米国国立神経疾患脳卒中研究所(NINDS)の抗痙攣剤スクリーニングプログラム(ASP)で開発されたプロトコルに従って動物実験を実施した。表4に結果の要約を示す。
化合物A、I、HおよびFについてStem Cell Innovations, Inc. (Houston, TX) のヒト肝細胞に基づくアッセイACTIVTox(R)(C3A肝細胞を使用)で試験を実施した。 具体的には、試験化合物を多種類の濃度で、乳酸脱水素酵素LDHの放出を測るLDH放出アッセイ(細胞死の指標)で試験した。
Claims (16)
- 式Iを有するCNS活性化合物であって、
該任意に置換された芳香環系は、フェニル、フェノキシ、およびヘテロサイクリックアリルからなる群から選択され、ここで5個までの置換基が任意に芳香環上にあってもよく、各置換基は水素、アルキル、シクロアルキル、ハロゲン、アルコキシ、チオアルキル、スルホキシアルキル、 スルホニルアルキル、アルキレンジオキシ、ハロアルキル、ハロアルコキシ、OH、CH2OH、CONH2、CN、アセトキシ、N(アルキル)2、NO2、CHO、CH3CH(OH)、アセチル、およびOCH2COOHからなる群から独立して選択され
R1およびR2は各々独立して、H、任意に置換されたアルキル、任意に置換されたシクロアルキル、または任意に置換されたCW2フェニルであり、ここで各Wは両方のWがエチルでないという条件で、H、メチルおよびエチルからからなる群から独立して選択され、さらにここで、フェニル基またはシクロアルキル基には5個までの置換基が任意に含まれ、各置換基は独立してハロゲン、アルコキシ、チオアルキル、スルホキシアルキル、スルホニルアルキル、ハロアルキル、ハロアルコキシ、CONH2、CN、アセトキシ、N(アルキル)2、NO2およびアセチルからなる群から選択され、R1 または R2の一方がHの場合には、他方のR1またはR2は、(CH2)2SO3Hまたは CHZCOOHであり、ここでZはH、CH3、CH(CH3)2、CH2C6H5、CH2CH(CH3)2およびCH(CH3)CH2CH3からなる群の一つであり、またはR1およびR2が共にシクロアルキル基であり、
R3は、ヒドロキシ、アルキル、シクロアルキルのうちの一つであるか、またはR4も共に、R3またはR4の一方がOHの場合には他方のR3またはR4がエチルでないという条件で、シクロアルキルであり、
R4がアルキル、シクロアルキルのうちのひとつであり、またはR3も共にシクロアルキルであり、そして
Xが、無置換、メチレン、ケトン、CHOH、酸素、NR1、硫黄、スルホンまたはスルホキシドのうちの1つである化合物。 - 式IIを有するCNS活性化合物であって、
R4およびR5は、各々独立して任意に置換されたフェニルまたは任意に置換されたヘテロサイクリックアリル基であり、ここで5個までの置換基を含んでも良く、各置換基はハロゲン、アルコキシ、チオアルキル、スルホキシアルキル、 スルホニルアルキル、ハロアルコキシ、CH2OH、CONH2、CN、アセトキシ、N(アルキル)2、NO2、アセチルおよびOCH2COOHからなる群から独立して選択され、
Yは無置換またはメチレンのいずれかである化合物。 - 式1〜9のうちの一つを有するCNS活性化合物であって
Zは、H、CH3、CH(CH3)2、CH2C6H5、CH2CH(CH3)2またはCH(CH3)CH2CH3のうちの一つであり、
R2およびR3は、独立してHまたはCH3のうちの一つであり、
R4は、H、CH3、OH、またはOCH3のうちの一つであり、
R5は、H、Cl、F、CF3、CN、C1-C5 アルキル、C1-C5アルコキシ、OCF3または CONR1R2のうちの1つであり、
n=1〜5、
Q=O、NR2、C=O、S、SO、またはSO2であり、そして
X = O、NR2、または無置換、C=O、S、SO、またはSO2である化合物。 - CNS活性を調節する医薬組成物であって、該組成物が、
医薬上許容できる担体および
前記担体と結合させた請求項1〜4のうちの一つに記載されたCNSに活性のある化合物を含む医薬組成物。 - さらに医薬品添加物を含む請求項5に記載の医薬組成物。
- 請求項5に記載の医薬組成物であって、CNS活性化合物のCNS活性調節の治療有効量を含む医薬組成物。
- 請求項7に記載の医薬組成物であって、
患者に抗痙攣作用を提供する、
患者の痙攣を治療および/または予防する、
患者のてんかん発作を治療および/または予防する、
患者の痙性を治療および/または予防する、
患者の感情障害を治療および/または予防する、
患者の双極性感情障害を治療および/または予防する、
患者の慢性頭痛を治療および/または予防する、
患者の群発性頭痛を治療および/または予防する、
患者の片頭痛を治療および/または予防する、
患者の静止不能症候群を治療および/または予防する、
患者の神経因性疼痛を治療および/または予防する、あるいは
患者の運動障害を治療および/または予防する、
ための治療の少なくとも一つに充分な治療有効量を含む医薬組成物。 - CNS活性を調節する方法であって
請求項1〜4のいずれか一つに記載のCNS活性化合物を患者に投与することを含む方法。 - CNS活性化合物が医薬上許容できる担体に結合された、請求項9に記載の方法。
- CNS活性化合物の、患者のCNS活性を調節する治療有効量が患者に投与される請求項9に記載の方法。
- 請求項11に記載の方法であって、
患者に抗痙攣作用を提供する、
患者の痙攣を治療および/または予防する、
患者の癲癇発作を治療および/または予防する、
患者の痙性を治療および/または予防する、
患者の感情障害を治療および/または予防する、
患者の双極性感情障害を治療および/または予防する、
患者の慢性頭痛を治療および/または予防する、
患者の群発性頭痛を治療および/または予防する、
患者の片頭痛を治療および/または予防する、
患者の静止不能症候群を治療および/または予防する、
患者の神経因性疼痛を治療および/または予防する、あるいは
患者の運動障害を治療および/または予防する、
治療のうちの少なくとも一つについて十分な治療有効量が患者に投与される請求項11に記載の方法。 - 請求項11に記載の方法であって、前記の治療有効量が不安、抑鬱、不眠、片頭痛、統合失調症、パーキンソン病、痙性、アルツハイマー病、双極性障害、慢性または神経因性疼痛、脳卒中、慢性神経変性疾患、ハンチントン病、脳損傷、脊髄損傷または癲癇重積状態の少なくとも1つの治療および/または予防に十分である方法。
- 請求項11に記載の方法であって、前記の治療有効量が化学的対応策として十分な方法。
- 請求項15に記載の方法であって、さらに、
塩基性溶液中で4−シアノフェノ−ルを還流しながら加熱する方法と、
β-ブチロラクトンを還流溶液へ添加する方法と、
該溶液を室温に冷却する方法と、
水およびジエチルエ―テルを添加して該溶液の二相混合液を調製する方法と、
形成後にジエチルエーテル相を除去する方法と、
形成後に水相にpH〜2のHCl溶液を添加して酸性化する方法と、
酸性化した水相をエチルアセテートで抽出する方法と、
エチルアセテート層を乾燥させ3−(4−シアノフェノキシ)酪酸を生成する方法と、
有機溶媒で3−(4−シアノフェノキシ)酪酸の溶液を調製する方法と、
塩化オキサリルで該溶液を処理して[3−(4−シアノフェノキシ)ブチリルクロライド]を得る方法と、
3−(4−シアノフェノキシ)ブチリルクロライド溶液へアンモニアガスを発泡により通す方法と、そして
該溶液から[3−(4−シアノフェノキシ)ブチルアミド]を入手する方法
を含む製造方法。
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Cited By (4)
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US9206143B2 (en) | 2008-03-19 | 2015-12-08 | Aurimmed Pharma, Inc. | Compounds advantageous in the treatment of central nervous system diseases and disorders |
US9212155B2 (en) | 2008-03-19 | 2015-12-15 | Aurimmed Pharma, Inc. | Compounds advantageous in the treatment of central nervous system diseases and disorders |
JP2017214399A (ja) * | 2008-03-19 | 2017-12-07 | オーリムメッド・ファルマ・インコーポレーテッド | 中枢神経系疾患および障害の治療に有効な新規化合物 |
US10793515B2 (en) | 2008-03-19 | 2020-10-06 | Aurimmed Pharma, Inc. | Compounds advantageous in the treatment of central nervous system diseases and disorders |
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KR101672884B1 (ko) | 2016-11-04 |
US9206143B2 (en) | 2015-12-08 |
WO2009117515A3 (en) | 2010-03-04 |
AU2009225647C1 (en) | 2015-11-19 |
KR20110025734A (ko) | 2011-03-11 |
JP2020055824A (ja) | 2020-04-09 |
KR20160129112A (ko) | 2016-11-08 |
CA2718723A1 (en) | 2009-09-24 |
IL208180B (en) | 2020-07-30 |
CN102164488A (zh) | 2011-08-24 |
EP2268140B1 (en) | 2020-11-11 |
RU2010142655A (ru) | 2012-04-27 |
JP2017214399A (ja) | 2017-12-07 |
US20110046138A1 (en) | 2011-02-24 |
EP2268140A4 (en) | 2012-03-21 |
JP5746612B2 (ja) | 2015-07-08 |
EP2268140A2 (en) | 2011-01-05 |
JP2015166370A (ja) | 2015-09-24 |
AU2009225647A2 (en) | 2010-12-23 |
IL208180A0 (en) | 2010-12-30 |
WO2009117515A2 (en) | 2009-09-24 |
CA2718723C (en) | 2018-05-08 |
AU2009225647B2 (en) | 2015-01-29 |
CN102164488B (zh) | 2015-02-25 |
AU2009225647A1 (en) | 2009-09-24 |
KR101922949B1 (ko) | 2018-11-28 |
WO2009117515A8 (en) | 2010-10-28 |
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