JP6864070B2 - モルフィナン化合物 - Google Patents
モルフィナン化合物 Download PDFInfo
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- JP6864070B2 JP6864070B2 JP2019232665A JP2019232665A JP6864070B2 JP 6864070 B2 JP6864070 B2 JP 6864070B2 JP 2019232665 A JP2019232665 A JP 2019232665A JP 2019232665 A JP2019232665 A JP 2019232665A JP 6864070 B2 JP6864070 B2 JP 6864070B2
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- dextromethorphan
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Description
本出願は、35 U.S.C. §119のもとで、米国仮特許出願Nos.60/915,130、2007年5月1日出願;60/916,662、2007年5月8日出願;および60/976,004、2007年9月28日出願に基づく優先権を主張し、それらの内容全体をすべて本明細書に援用する。
。デキストロメトルファンの向精神作用に関する1研究により、高メタボライザー(extensive metabolizer)(EM)には低メタボライザー(poor metabolizer)(PM)と比較してより高い中毒が報告されることが見いだされ、これはデキストロルファンがデキストロメトルファン中毒潜在性に関与することの証拠を提供する(Zawertailo LA, et al., J Clin Psychopharmacol, 1998 Aug, 18(4): 332-7)。
用語“改善する”および“処置する”は互換性をもって用いられ、治療処置および/または予防処置を含む。両用語とも、疾患(たとえば本明細書に記載する疾患または障害)の発現または進行を低下、抑制、軽減、減少、制止、または安定化することを意味する。
または“水素”と具体的に指定した場合、その位置は自然界に存在する同位体組成の水素をもつと理解される。
本発明は、式Iの化合物を提供し、これにはその医薬的に許容できる塩類、溶媒和物および水和物が含まれる:
R1は、CH3、CH2D、CHD2、CD3、CHF2、およびCF3から選択され;
R2は、CH3、CH2D、CHD2、およびCD3から選択される。
ある態様において、R1がCH3である場合はR2はCH3またはCD3ではない。他の態様において、R1がCD3である場合はR2はCH3ではない。
式Iの化合物を合成するための好都合な方法は、デキストロメトルファンの製造に用いる合成法において、適切なジュウテリウム化された中間体および試薬を代わりに用いる。式Iの化合物は、下記に示す既知の中間体X、XIおよびXIIのいずれか1つから、および既知の方法で容易に入手できる関連中間体から製造できる。
本発明は、発熱物質を含まない組成物であって、有効量の式I(たとえば、本明細書中のいずれかの式を含む)の化合物、またはその化合物の医薬的に許容できる塩、溶媒和物もしくは水和物;および許容できるキャリヤーを含む組成物をも提供する。好ましくは、本発明の組成物は医薬用として配合され(“医薬組成物”)、その際、キャリヤーは医薬的に許容できるキャリヤーである。キャリヤー(1以上)は、配合物の他の成分と適合性であり、かつ医薬的に許容できるキャリヤーの場合には医薬中に使用する量でレシピエントに対して有害でないという意味で、“許容できる”。
他の態様において、本発明は、細胞におけるσ2受容体、N−メチル−D−アスパラギン酸(NDMA)の活性、またはα3β4ニコチン酸受容体の活性を調節する方法であって、細胞を1種類以上の式Iの化合物と接触させることを含む方法を提供する。
本発明の化合物および組成物は、溶液または生体試料(たとえば血漿)中のデキストロメトルファンの濃度を測定する方法、デキストロメトルファンの代謝を調べる方法、および他の分析試験における、試薬としても有用である。
a)既知濃度の式Iの化合物を溶液または生体試料に添加し;
b)デキストロメトルファンを式Iの化合物から識別する測定機器に溶液または生体試料を装入し;
c)式Iの化合物の検出量が生体試料または溶液に添加した式Iの化合物の既知濃度と相関するように測定機器を校正し;そして
d)校正した測定機器で生体試料中のデキストロメトルファンの量を測定し;そして
e)検出量と式Iの化合物について得られた濃度との相関関係を用いて溶液または生体試料中のデキストロメトルファンの濃度を判定する。
a)既知量の式Iの化合物を溶液または生体試料に添加し;
b)式Iの化合物についての少なくとも1つの信号およびデキストロメトルファンについての少なくとも1つの信号を、これら2種類の化合物を識別しうる測定機器で検出し; c)式Iの化合物についての少なくとも1つの信号と溶液または生体試料に添加した式Iの化合物の既知量との相関関係を求め;そして
d)式Iの化合物について検出した少なくとも1つの信号と溶液または生体試料に添加した式Iの化合物の量との相関関係を用いて溶液または生体試料中のデキストロメトルファンの量を判定する。
分間撹拌した(この時点で、20%酢酸エチル/ヘキサン中のtlcは反応が完了したことを示した)。氷中の27% NH4OH溶液を、撹拌バーを入れたビーカーに装入し、撹拌しながら反応混合物を徐々に添加した。得られた混合物を20分間撹拌し、次いで4:1 CHCl3/CH3OH(200mL)で抽出した。有機層をNa2SO4で乾燥させ、濾過し、次いでロータリーエバポレーターで濃縮した。粗製物質を自動フラッシュカラムクロマトグラフィー(CH3OH、1% NH4OH含有/CHCl3,0−10%)により精製した。純粋な画分をロータリーエバポレーターで濃縮して、1.48gの13を白色固体として得た。
配法5−95% ACN;波長: 280 nm):保持時間: 6.91分. MS (M+H+): 275.7.
謝速度が低下する。0.5mg/mLに30分間曝露した後、ほぼ75%の化合物101および71%の化合物100が元のままであった。デキストロメトルファンはより高い不安定さを示し、30分間のインキュベーション後に約65%が元のままであったにすぎない。
* 各被験品を2mg/mLの濃度に溶解し、1mg/kgで投与した
** 配合物は、D5W中の10%ジメチルイソソルビド(DMI)、15%エタノール(ETOH)、35%プロピレングリコール(PG)(v:v:v)からなる
本明細書は以下の発明の開示を包含する:
[1]式Iの化合物:
[式中:
R1は、CH3、CH2D、CHD2、CD3、CHF2、およびCF3から選択され;R2は、CH3、CH2D、CHD2、およびCD3から選択され;
ただし、R1がCH3である場合はR2はCH3またはCD3ではなく、
さらに、R1がCD3である場合はR2はCH3ではない]。
[2]R1は、CH2D、CHD2、CD3、CHF2、およびCF3から選択される、[1]に記載の化合物。
[3]R1は、CH2D、CHD2、およびCD3から選択される、[2]に記載の化合物。
[4]R1はCD3である、[3]に記載の化合物。
[5]R2は、CH3、CHD2、またはCD3である、[1]〜[4]のいずれか1項に記載の化合物。
[6]R2はCH3である、[5]に記載の化合物。
[7]R2はCD3である、[5]に記載の化合物。
[8]R1はCF3である、[2]に記載の化合物。
[9]R1はCHF2である、[2]に記載の化合物。
[10]R2は、CH3、CHD2、およびCD3から選択される、[8]に記載の化合物。
[11]下記のものから選択される式Iの化合物:
[13][1]に記載の化合物および許容できるキャリヤーを含む、発熱物質を含まない組成物。
[14]医薬の投与のために配合され、キャリヤーが医薬的に許容できるキャリヤーである、[13]に記載の組成物。
[15]さらに、情動不安定;偽性延髄性情動;自閉症;神経障害;神経変性性疾患;脳傷害;意識異常障害;心血管疾患;緑内障;遅発性ジスキネジー;糖尿病性神経障害;網膜障害性疾患;ホモシステイン誘発性アポトーシスにより起きる疾患または障害;ホモシステインレベルの上昇により起きる疾患または障害;慢性疼痛;難治性疼痛;神経障害性疼痛;交感神経仲介疼痛;消化器機能障害に関連する疼痛;てんかん性発作;耳鳴;性的機能障害;難治性咳;皮膚炎;耽溺性障害;レット症候群(RTT);喉頭筋痙攣の無調節による音声障害;メトトレキセート神経毒性;および癌により起きる疲労から選択される疾患または状態の治療または予防に有用な第2の療法薬を含む、[13]または[14]に記載の組成物。
[16]第2の療法薬がキニジン、硫酸キニジン、オキシコドン、およびガバペンチンから選択される、[15]に記載の組成物。
[17]情動不安定;偽性延髄性情動;自閉症;神経障害;神経変性性疾患;脳傷害;意識異常障害;心血管疾患;緑内障;遅発性ジスキネジー;糖尿病性神経障害;網膜障害性疾患;ホモシステイン誘発性アポトーシスにより起きる疾患または障害;ホモシステインレベルの上昇により起きる疾患または障害;慢性疼痛;難治性疼痛;神経障害性疼痛;交感神経仲介疼痛;消化器機能障害に関連する疼痛;てんかん性発作;耳鳴;性的機能障害;難治性咳;皮膚炎;耽溺性障害;レット症候群(RTT);喉頭筋痙攣の無調節による音声障害;メトトレキセート神経毒性;および癌により起きる疲労から選択される疾患または状態に罹患しているかまたは罹患しやすい対象を処置する方法であって、それを必要とする対象に、下記を含む療法有効量の医薬組成物を投与する段階を含む方法:
a.式Iの化合物:
[式中:
R1は、CH3、CH2D、CHD2、CD3、CHF2、およびCF3から選択され;R2は、CH3、CH2D、CHD2、およびCD3から選択され;
ただし、R1がCH3である場合はR2はCH3ではない]。
b.医薬的に許容できるキャリヤー。
[18]対象が糖尿病性神経障害性疼痛に罹患しているかまたは罹患しやすい、[17]に記載の方法。
[19]それを必要とする対象に、キニジン、硫酸キニジン、オキシコドン、およびガバペンチンから選択される第2の療法薬を投与する追加段階を含む、[17]または[18]に記載の方法。
[20]対象が糖尿病性神経障害に罹患しているかまたは罹患しやすく、第2の療法薬が硫酸キニジンである、[19]に記載の方法。
[21]組成物を神経障害性疼痛の処置に使用する、[14]に記載の組成物。
Claims (7)
- R1がCD3である、請求項1の医薬組成物。
- R2がCD3である、請求項2の医薬組成物。
- 医薬的に許容できる塩がHBr塩である、請求項1〜3のいずれかの医薬組成物。
- 重水素として示されていない原子はいずれも、その原子の自然界での同位体存在比率で存在する、請求項1〜4のいずれかの医薬組成物。
- 各重水素原子の同位体純度が少なくとも95%である、請求項1〜5のいずれかの医薬組成物。
- 各重水素原子の同位体純度が少なくとも97%である、請求項1〜5のいずれかの医薬組成物。
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