JP5266042B2 - 統合失調症前駆症の治療方法 - Google Patents
統合失調症前駆症の治療方法 Download PDFInfo
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- JP5266042B2 JP5266042B2 JP2008505637A JP2008505637A JP5266042B2 JP 5266042 B2 JP5266042 B2 JP 5266042B2 JP 2008505637 A JP2008505637 A JP 2008505637A JP 2008505637 A JP2008505637 A JP 2008505637A JP 5266042 B2 JP5266042 B2 JP 5266042B2
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
本出願は、2005.04.11に出願された米国仮出願s.n.US60/670,000の優先権主張であり、本明細書の全体に参照されることにより援用される。
統合失調症は異質(heterogeneous)であるけれども,大抵の患者は発病前期,前駆期および精神疾患期からなる過程が続くと見なされる(Woods and McGlashan,2005)。発病前期は,正常な無症候期間または生後から始まる比較的微妙で安定した機能障害が特徴である。前駆期は,第一症候期として概念化されており,持続期間は比較的短く,重症度が高まっている。患者が完全な精神症になると,我々が現在それを概念的に説明するように,患者は統合失調症の発症を経験してしまったと定義される。現在の治療剤のガイドラインは,疾患発症後の明らかな精神症期に適用しているだけである。
抗精神病剤の投与は,前駆症状の患者に対して最初に試行された。前駆症状の介入に関する一部の問題は,新しい非定型精神病剤でさえ体重増加および代謝症候群を含む厄介な副作用を有しうるということである。これらの副作用の多くは,大人よりも若者において目立つことがある(Woods et al.,2002)。抗精神病剤の投与が前駆症状の患者に最初に試行されることは理解できるが,前駆症は統合失調症の慢性期と関係する神経生物学とは異なる神経毒または退行変性過程を含むかもしれない。他の投薬は,おそらく慢性患者らには弱い効果のみであり,前駆期の潜在的に固有の神経細胞学に影響を及ぼすということもあり得,それによって前駆症状を改善する,および/または,統合失調症が進行するのを防ぐかもしれない。
統合失調症のNMDA機能低下モデル 統合失調症の従来のモデルは主にドパミンの役割に焦点を当ててきた。ドパミンモデルは,2つの主要な結果に基づかれている。1つ目は,統合失調症に酷似する精神病を促進するため、特に慢性投与後に続く,アンフェタミンおよび他のドパミン放出薬剤の効力である。2つ目は,特定の症状を回復に向かわせるドパミン(D2)受容体を遮断する薬剤の効力である。統合失調症の症状は,3つの症候群に分類されるのが通常である。動揺,妄想および偏執性妄想のような症状からなる陽性群;運動遅延,情動的な引きこもりおよび消極的/無感動の社会的引きこもりのような症状からなる陰性群;見当式障害または概念的解体のような症状からなる認知的(AKA自閉症又は解体)群である。ドパミンモデルの限界は,アンフェタミンは主に統合失調症の陽性症状に似ている症状を含むが,陰性又は認知的症状のどちらかに似ている症状を含まないということである。さらに,抗精神病治療剤は,統合失調症の陰性症状よりも,陽性症状の治療剤において,集団的にはるかに効果的であると判明してきた。
Kapur S, Remington G (2001) Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biological Psychiatry 50:873−883.
R2は,HまたはC1−C20の置換されてもよいアルキル基であり;
R3は,HまたはC2−C21の置換されてもよいアシル基であり;および
R4は,HまたはC2−C21の置換されてもよいアルキル基を示す。
R2aはOH,C1−C20の置換されてもよいアルコキシ基,置換されてもよいC1−C20のヒドロカルビル基又は置換されてもよい複素環又は芳香族複素環基であり;
R3aはCH3またはR3またはR1と一緒になって置換されてもよい複素環基若しくは芳香族複素環基を形成し;
R3はH,C2−C21の置換されてもよいアシル基,又は置換されてもよいC1−C20(好ましくは置換されてもよいC5−C20)のヒドロカルビル基,又は置換されてもよい複素環基もしくは芳香族複素環基を示す。
神経症の症状
不安
情動不安
怒り,興奮
心的状態関連症状
無快感症
憂鬱感
罪責感
自殺行為
気分変動
意欲の変化
無気力,活力の喪失
倦怠,興味の喪失
疲労,精力の喪失
認知変化
注意障害−集中力の欠如
空想への没頭
思考途絶
抽象概念の低下
身体的症状
身体的不調の訴え
食欲不振
睡眠障害
その他の症状
偏執強迫現象
解離現象
対人過敏症の増加
自己,他人または世界観の変化
異常な話し方
亜症候群性知覚異常
不信感
その他の亜症候群性思想内容
情動の変化
行動の変化
学業または日常役割機能の低下
引きこもり
衝動性
奇妙な行動
攻撃的または破壊的な行動
論派の1つは,前駆症は非特異的な神経症型の症状,続いて標準からいっそう著しく逸脱し,最終的には明らかな精神病になるというパターンからなると考えている。自覚症状は,通常,日常役割機能の多少の低下およびその他の行動の変化に付随して起こる。統合失調症前駆症の非特異的変化の2パターンは,「機能低下の変化」および「機能亢進の変化」である。機能低下パターンは,引きこもり,無力および内向的行動を特徴とする。機能亢進パターンは神経質,情動不安,緊張,不安,心配および懸念という病状を特徴とする。精神病が差し迫っていることを告げる「特異的な」症状が発症する前に,これらの非特異的な症状は数週間から数年続くかもしれない。これらは臨床的に認識できる統合失調症的性質の症状(p.569)であり,不信感,外部環境には親密感がなくなってしまったという感情,および「放心した」もしくは「困惑した」感情からなる。これらの症状は明らかな精神病の事象の弱化型であるかのように思える。患者が精神科に処置を受けに来る前に,初期の特異的変化はしばしば数ヶ月から数年続くと考えられている。
Thomas LE and Woods SW参照。統合失調症前駆症状:「A developmentally informed review and update for psychopharmacological treatment」Child and Adolescent Psychiatric Clinics of North America,2006;15:109−133
明らかな統合失調症において,
A.以下の症状が2つまたはそれ以上起こっている:
(1)妄想
(2)幻覚
(3)著しく解体した会話
(4)著しく解体した行動
(5)陰性症状,加えて,
B.社会的/職業的な機能不全,
C.その症状はこれまでのところ少なくとも6ヶ月間は断続的に続いている;および
D.その症状は統合失調症感情障害,気分障害,薬物乱用,または発育または内科的疾患が原因ではない。
参照,Diagnostic and Statistical Mannual of Mental Disorders,Fourth Edition.merican Psychiatric Association,Washington DC,1994,pp285−6。
R2はOH,C1−C20の置換されてもよいO−アルキル基,またはなく;
R3はH,またはC2−C21の置換されてもよいアシル基;そして
R4はH,C2−C21の置換されてもよいアルキル基,またはR2がなく,前記CO基に結合すると,五員複素環を形成する−N−基(D−サイクロセリンまたは誘導体を形成する)を示す。
以前の議論を以下に簡単に要約する:
1.NMDA機能低下モデルは,ドパミンモデルよりも慢性統合失調症において陰性および認知機能障害がわかりやすい。
2.陰性症状および認知機能障害は,統合失調症前駆症において陽性症状の出現より先に起こるように思われる。
3.先在するNMDA機能低下はドパミン枯渇(dopamine disruption)の出現の一因となりうる。
前駆NMDA機能低下の持続の次におこるドパミン枯渇(dopamine disruption)が現れることで,後になって慢性統合失調症の幻覚のようなもっと重大な陽性症状が現れることがわかるかもしれない。
R2aはOH,C1−C20の置換されてもよいアルコキシ基(エステルを形成する),置換されてもよいC1−C20のヒドロカルビル基または置換されてもよい複素環もしくは芳香族複素環基である;
R3aはCH3またはR3と同じであり,またはR1は任置換されてもよい複素環もしくは芳香族複素環基を形成する;
R3はH,C2−C21の置換されてもよいアシル基,または置換されてもよいC1−C20(好ましくは置換されてもよいC5−C20)のヒドロカルビル基,または置換されてもよい複素環もしくは芳香族複素環基を示す。
R2はOH,C1−C20の置換されてもよいO−アルキル基,またはない;
R3はH,またはC2−C21の置換されてもよいアシル基であり;
R4はH,C2−C21の置換されてもよいアルキル基,またはR2がないとき(D−サイクロセリンもしくは誘導体を形成する),前記CO基に結合して複素五員環基を形成する−N−基であり;または薬学的に許容される塩,溶媒和物(水和物を含む)もしくはその多形体を前記前駆統合失調症の症状を治療するため,および/または好ましくは患者の前駆症状の統合失調症が明らかな精神病になる可能性を予防するまたは少なくとも減少するために,前駆統合失調症(初期または再発)の症状を示す患者または被験者に,単独で投与される又は好ましくは薬学的に許容される担体,添加物もしくは賦形剤と併用して,およびグリシントランスポーター阻害剤と併用してもよい。NMDAグリシン部位アゴニストとして有用な好ましい化合物はグリシン,アラニンまたはセリンまたはそのいずれか1つもしくはそれ以上のプロドラックまたはその薬学的に許容される塩を含む。
R2aはOH,C1−C20の置換されてもよいアルコキシ基(エステルを形成する),置換されてもよいC1−C20のヒドロカルビル基または置換されてもよい複素環または芳香族複素環基であり;
R3aはCH3またはR3と同じであり,またはR1は置換されてもよい複素環もしくは芳香族複素環基を形成する;
R3はH,C2−C21の置換されてもよいアシル基,または置換されてもよいC1−C20(好ましくは置換されてもよいC5−C20)のヒドロカルビル基,または置換されてもよい複素環もしくは芳香族複素環基を示す。
当該化合物の個々の成分は,別々のまたは混合した薬剤剤形で,連続してまたは同時にのどちらで投与されてもよい。
本発明に記載の1つまたはそれ以上の化合物が第2治療活性剤と併用して使用されるとき,1つ1つの化合物の投与量は,化合物が単独で使用されるときと同じまたは異なってもどちらでもよい。適切な投与量は当業者には容易に分かるであろう。
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Claims (1)
- 必要とする患者での前駆統合失調症の治療のための薬剤の製造における、グリシン又は薬学的に許容されるその塩である少なくとも1つの化合物の使用。
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FR2842804B1 (fr) | 2002-07-29 | 2004-09-03 | Sanofi Synthelabo | Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique |
FR2861070B1 (fr) | 2003-10-17 | 2006-01-06 | Sanofi Synthelabo | Derives de n-[phenyl(pyrrolidin-2-yl)methyl]benzamide et n-[(azepan-2-yl)phenylmethyl]benzamide, leur preparation et leur application en therapeutique |
FR2861071B1 (fr) * | 2003-10-17 | 2006-01-06 | Sanofi Synthelabo | Derives de n-[phenyl(alkylpiperidin-2-yl) methyl]benzamide, leur prepartation et leur application en therapeutique |
JP2010539242A (ja) * | 2007-09-19 | 2010-12-16 | ビージー メディシン, インコーポレイテッド | サルコシンレベルを増大させる方法 |
US20150224120A1 (en) * | 2011-09-14 | 2015-08-13 | Catherine Clelland | Compositions and methods for treating hyperprolinemia-associated mental disorders |
US9040581B1 (en) | 2013-02-21 | 2015-05-26 | The Florida State University Research Foundation, Inc. | Methods of treatment using D-serine |
CN105814018B (zh) * | 2013-12-20 | 2018-03-20 | 中国人民解放军军事医学科学院毒物药物研究所 | 新型脲类化合物、制备方法及其用途 |
CN111491629A (zh) | 2017-11-22 | 2020-08-04 | 康塞特医药品公司 | D-丝氨酸的氘化类似物及其用途 |
US11484519B2 (en) | 2019-03-07 | 2022-11-01 | Florida State University Research Foundation, Inc. | D-serine inhibit neuroinflammation due to a brain injury |
CN112225728A (zh) * | 2020-08-18 | 2021-01-15 | 四川农业大学 | 一种多取代苯甲酰胺化合物及其制备方法和应用 |
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RU2355683C2 (ru) | 2003-09-09 | 2009-05-20 | Ф.Хоффманн-Ля Рош Аг | Производные 1-бензоилпиперазина в качестве ингибиторов поглощения глицина для лечения психозов |
WO2005040166A1 (en) * | 2003-10-23 | 2005-05-06 | F.Hoffmann-La Roche Ag | Triaza-spiropiperidine derivatives for use as glyt-1 inhibitors in the treatment of neurological and neuropsychiatric disorders |
WO2005058885A2 (en) * | 2003-12-18 | 2005-06-30 | Glaxo Group Limited | Piperidine derivatives and their use as glycine transporter inhibitors |
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JP2007528879A (ja) * | 2004-03-12 | 2007-10-18 | ハー・ルンドベック・アクチエゼルスカベット | フェニルインダン誘導体 |
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US8492418B2 (en) | 2013-07-23 |
JP2008535864A (ja) | 2008-09-04 |
WO2006110724A3 (en) | 2007-03-22 |
WO2006110724A2 (en) | 2006-10-19 |
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