JP2007516941A - 5ht2cレセプター関連疾患の処置に有用なベンズアゼピン誘導体 - Google Patents
5ht2cレセプター関連疾患の処置に有用なベンズアゼピン誘導体 Download PDFInfo
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Abstract
Description
本発明は、5HT2cレセプターの調節因子である、特定の置換−2,3,4,5−テトラヒドロ−3−ベンズアゼピン誘導体に関する。従って、本発明の化合物は、5HT2Cレセプターの関連の疾患、状態または障害(例えば、肥満および関連障害)の予防または処置のために有用である。
肥満は、合併症(例えば、II型糖尿病、高血圧症、脳卒中、特定の形態の癌および胆嚢疾患であるが、これらに限定されない)から起こる、罹患率および死亡率のリスクを増加させる生命にかかわる障害である。
(肥満度指数(BMI)による体重の分類)
ADにおいて有益な効果を有する薬剤についての必要性が存在する。従って、脳においてのみ発現されるセロトニン5HT2Cレセプターは、魅力的な標的である。
本発明は、5HT2Cレセプターに結合し、5HT2Cレセプターの活性を調節する化合物、およびそれらの用途を説明する。本明細書中で使用される場合、用語5HT2Cレセプターは、GeneBank受託番号AF498983に見出されるヒト配列、天然に存在する対立遺伝子改変体、哺乳動物オルソログ、およびこれらの組換え変異体を含む。
ここで、
R1は、HまたはC1〜8アルキルである;
R2は、C1〜4アルキル、−CH2−O−C1〜4アルキル、C1〜4ハロアルキル、またはCH2OHである;そして
R3、R4、R5、およびR6は、それぞれ独立にH、C1〜4アルキル、アミノ、シアノ、ハロゲン、C1〜4ハロアルキル、ニトロまたはOHである;または
これらの薬学的に受容可能な塩、水和物、および溶媒和物である;
ただし、R2が、C1〜4アルキル、−CH2−O−C1〜4アルキル、およびCH2OHである場合、R3およびR6は、両方とも水素ではない。
(定義)
明瞭さおよび一貫性のために、以下の定義が本特許文書全体にわたって使用される。
本明細書中で使用される場合、用語「アルキル」は、直鎖炭化水素、分枝炭化水素および環状炭化水素を含む炭化水素化合物を意味することが意図され、例えば、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、n−ブチル、sec−ブチル、tert−ブチル、シクロブチル、シクロプロピルメチル、n−ペンチル、イソペンチル、tert−ペンチル、シクロペンチル、シクロペンチルメチル、n−ヒキシル、シクロヘキシルなどが挙げられるが、これらに限定されない。用語「C1〜8アルキル」とは、1〜8個の炭素原子を含むアルキル基をいう。同様に、用語「C1〜4アルキル」とは、1〜4個の炭素原子を含むアルキル基をいう。本明細書全体にわたって、用語アルキルが、非環状炭化水素化合物および環状炭化水素化合物の両方を包含することが意図されることが理解される。本発明の化合物のいくつかの実施形態において、アルキル基は非環状である。さらなる実施形態において、アルキル基は環状であり、そしてさらなる実施形態において、アルキル基は環状および非環状の両方である。ここで、優先度は特定されず、用語「アルキル」は、環状および非環状の両方である基を意味することが意図される。
(1)疾患を予防すること;例えば、疾患、状態または障害にかかりやすい可能性があるが、まだその疾患の病状または総体症状が認められても示してもいない個体において、その疾患、状態または障害を予防すること、
(2)疾患を抑制すること;例えば、疾患、状態または障害の病状または総体症状が認められるかまたは示している個体において、その疾患、状態または障害を抑制すること(すなわち、病状および/または総体症状のさらなる進展を阻止すること)ならびに
(3)疾患を改善すること;例えば、疾患、状態または障害の病状または総体症状が認められるかまたは示している個体において、その疾患、状態または障害を改善すること(すなわち、病状および/または総体症状を後進させること)
(本発明の化合物)
本発明の1つの局面は、式(I):
ここで:
R1は、HまたはC1〜8アルキルであり;
R2は、C1〜4アルキル、−CH2−O−C1〜4アルキル、C1〜4ハロアルキルまたはCH2OH;そして
R3、R4、R5およびR6は、各々独立して、H、C1〜4アルキル、アミノ、シアノ、ハロゲン、C1〜4ハロアルキル、ニトロまたはOHであり;
ただし、R2がC1〜4アルキル、−CH2−O−C1〜4アルキルおよびCH2OHの場合、R3およびR6は両方とも水素ではない。
本発明の1つの局面は、5HT2cレセプターを調節する方法に関し、この方法は、このレセプターを治療有効量または治療有効用量の本明細書中に記載される化合物と接触させる工程を包含する。好ましくは、本発明の化合物は、5HT2Cレセプターのアゴニストである。
本発明の状況において、式(I)の化合物またはその薬学的組成物は、本明細書中に記載の5HT2Cレセプターに関連する疾患、状態および/または障害の活性を調節するために利用され得る。5HT2Cレセプター関連疾患の活性調節の例としては、食物摂取を減少させることによる肥満および/または過体重の予防または処置、満腹感(すなわち、十分な感覚)の誘発、体重増加の調節、体重の減少ならびに/またはレシピエントが体重を減少させるそして/または体重を維持するように代謝に影響することが挙げられる。従って、このような化合物および薬学的組成物は、体重増加が本明細書中に列挙されるような疾患および/または障害の構成要素である障害および/または疾患の状況において、使用され得る。さらに、本発明の化合物および組成物は、アルツハイマー病、勃起障害ならびに本明細書中に記載の他の5HT2Cレセプター関連疾患および/または障害の予防および/または処置のために使用され得る。
さらなる局面に従うと、本発明はまた、式(I)または本明細書中で開示される任意の式の1つ以上の化合物、および1つ以上の薬学的に受容可能なキャリアを含有する薬学的組成物に関する。
以下に概略される例示された合成において、上記標識置換基は、式(I)および、本明細書中に記載されるような亜属の式の、本発明の化合物の定義に示されるのと同一物である。
本発明の他の目的は、式(I)の放射標識化合物に関し、この化合物は、放射画像化において有用であるだけでなく、組織サンプル(ヒトを含む)における5HT2Cレセプターを局在決定し、定量するための、および放射標識化合物の結合を阻害することによって5HT2Cレセプターリガンドを同定するための、インビトロおよびインビボ両方のアッセイにおいても有用である。このような放射標識化合物を含む新規5HT2Cレセプターアッセイを開発することは、本発明のさらなる目的である。
A.トリチウムガスでの触媒的還元−この手順は、通常高い比放射能の生成物を生じ、ハロゲン化前駆体または不飽和前駆体を必要とする。
A.サンドマイヤーおよび類似の反応−この手順は、アリールアミンまたはヘテロアリールアミンをジアゾニウム塩(例えば、テトラフルオロホウ酸塩)に変換し、続いて、Na125Iを使用して、125I標識化合物に変換する。代表的な手順は、Zhu,D.−G. and co−workers、J.Org.Chem.2002,67,943−948によって報告される。
細胞内IP3蓄積アッセイ):
HEK293細胞を、25μlのリポフェクトアミンを使用して、16μgのヒト5HT2CレセプターcDNAを含むかまたは含まない15cm滅菌皿中にトランスフェクトした[例えば、Saltzman,A.G.,et al.Biochem.Biophys.Res.Commun.181,1469−1478(1991)を参照のこと]。次いで、細胞を、37℃/5%CO2で3〜4時間、インキュベートし、次いで、トランスフェクション培地を除去し、100μlのDMEMで置換した。次いで、細胞を100cm滅菌皿上にプレートした。次の日に、細胞を、55K/0.2mlの密度で、96ウェルPDLマイクロタイターウェルプレートにプレートした。6時間後、培地を、イノシトールを含まないDMEM中で、[3H]イノシトール(0.25uCi/ウェル)で交換し、プレートを37℃5%CO2で一晩インキュベートした。次の日に、ウェルをアスピレートし、試験化合物を含む200μlのDMEM、10μMパルギリン、および10mM LiClを適切なウェルに添加した。次いで、プレートを37℃/5%CO2で3時間インキュベートし、続いて、アスピレートし、新鮮な氷冷停止溶液(1M KOH、19mM Naボレート、3.8mM EDTA)を各ウェルに添加した。プレートを氷上で5〜10分間維持し、そしてウェルを、200μlの新鮮な氷冷中和溶液(7.5%HCl)の添加によって中和した。次いで、プレートをさらなる処理が望まれるまで、凍結させた。次いで、溶解物を1.5mlエッペンドルフ管中に移し、そして1mlのクロロホルム/メタノール(1:2)/チューブを添加した。この溶液を15秒間ボルテックスし、上相をBiorad AG1−X8TMアニオン交換樹脂(100〜200メッシュ)に適用した。最初に、樹脂を1:1.25W/Vの水で洗浄し、そして0.9mlの上相をカラムに充填した。次いで、カラムを10mlの5mMミオ−イノシトールおよび10mlの5mM Naボレート/60mM Naホルメートで洗浄した。イノシトールトリスホスフェートを、2mlの0.1Mギ酸/1Mギ酸アンモニウムを有する10mlのシンチレーションカクテルを含むシンチレーションバイアル中に溶出した。このカラムを、10mlの0.1Mギ酸・3Mギ酸アンモニウムで洗浄することによって再生し、そしてddH2Oで2回リンスし、水中4℃で保存した。
(食物を与えない(food−deprived)ラットにおける食物摂取の阻害)
雄性Sprague0Dawleyラット(250〜350g)を、試験の前の一晩、食物を与えない。食物を与えない前に、その動物の体重を量り、体重に従って、群のバランスを取るために処置群に分けた。試験の日に、動物を個々のケージ(敷きわら無し)中に、9:00amに、水に自由にアクセスさせて配置する。10:00amに、動物に、試験化合物を注射し(p.o.、i.p.、またはs.c.)、薬物投与の60分後(p.o.)または30分後(i.p.およびs.c.)のいずれかで、皿に予め秤量した量の食物を与える。異なる時点にわたる食物消費を、食物を与えてから、1時間後、2時間後、4時間後、および6時間後に、食物カップを秤量することによって決定する。従って、食物消費を、p.o.研究において、注射の2時間後、3時間後、5時間後および7時間後に測定し、i.p.研究およびs.c.研究において、注射の1.5時間後、2.5時間後、4.5時間後および6.5時間後に測定する。
(本発明の選択された化合物の合成)
(実施例3.1:(R,S)6,8−ジクロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアセピン(本明細書中において、化合物1とも呼ばれる)の調製)
ジクロロメタン(20mL)中の2,4−ジクロロフェネチルアミン(1.0g、5.3mmol)の溶液を、ジイソプロピルエチルアミン(0.82g、6.3mmol)および2−クロロプロピオニル(0.67mL、5.3mmol)で連続的に処理し、そして20℃で4時間撹拌した。この混合物を、ジクロロメタン(50mL)で希釈し、10%水性HCl、ブライン(20mL)で洗浄し、Na2SO4で乾燥し、そして濃縮し、1.5gの所望の生成物を褐色油状物として得た。MS C11H12Cl3NO+Hについての計算値:280観測値:280。
ニートな2−クロロ−N−[2−(2,4−ジクロロフェニル)エチル]プロピオンアミド(2.5g、9.1mmol)およびAlCl3(3.6g、27mmol)を、150℃で18時間、撹拌しながら加熱した。生成物混合物を、水(10ml)でクエンチし、ジクロロメタン(100mL)で希釈し、有機相を分離し、ブライン(50mL)で洗浄し、Na2SO4で乾燥し、濃縮し、1.9gの褐色油状物を得た。MS C11H11Cl2NO+Hについての計算値:244,観測値:244。
テトラヒドロフラン(50mL)中の6,8−ジクロロ−1−メチル−2−オキソ−2,3,5−トリヒドロ−1H−3ーベンズアゼピン(1.9g、7.8mmol)の溶液を、THF(20.0ml、20.0mmol)中の1M ボランで処理し、20℃で5時間撹拌した。この混合物をメタノール(10mL)でクエンチし、濃HCl(0.2mL)で酸性化し、メタノール(3×100mlL)で共沸し、濃縮した。フラッシュクロマトグラフィー(ジクロロメタン中、5%メタノール)は、1.0gの透明な油状物を生じた。1H NMR(400 MHz,CDCl3)δ7.20(s,1H),6.90(s,1H),4.30(bs,1H),3.92(m,1H),3.51(m,1H),3.37(m,2H),3.03(m,1H),2.77(m,2H),1.31(d,J=8 Hz,3H)。MS C11H13Cl2N+Hについての計算値:230,観測値:230。
1,2−ジクロロエタン(15mL)中のN−トリフルオロアセチル−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(2.5g、8.5mmol)の溶液を、Selectfluor(3.9g、11mmol)、トリフルオロメタンスルホン酸(8mL、90mmol)で処理し、60時間、75℃で撹拌した。生成物の混合物を水(200mL)中に注ぎ、EtOAc(200mL)で抽出し、有機相を飽和水性NaHCO3(2×100mL)、ブライン(100mL)で洗浄し、Na2SO4で乾燥し、濃縮した。粗生成物を、フラッシュクロマトグラフィー(ヘキサン中の6%EtOAc、シリカ)によって精製し、0.6gの白色固体を得た。C13H12ClF4NO+Hについての計算値:310,観測値:310。
メタノール(3mL)中のN−トリフルオロアセチル−8−クロロ−9−フルオロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(160mg、0.22mmol)の溶液を、15%水性NaOH(2mL)で処理し、3.5時間、25℃で撹拌した。生成物混合物を濃縮し、3回、CH2Cl2(5mL)で抽出し、Na2SO4で乾燥し、濃縮し、93mgの透明油状物を得た。1H NMR(400MHz,CDCl3)δ7.06(dd,J=8,8Hz,1H),6.75(d,J=8Hz,1H), 3.58(m,1H),3.25−3.15(m,3H),2.93(d,J=13Hz, 1H)2.75−2.60(m,3H),1.96(bs,1H),1.33(d,J=8Hz,3H)。MS C11H13ClFN+Hについての計算値:214,観測値:214。
(S)−N−トリフルオロアセチル−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンを、化合物7の調製について本明細書中で記載した手順と類似の手順を使用して、(S)−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンから調製した(1つの例外は、D−酒石酸を使用して、分割工程を行ったことである)。1H NMR(400MHz,CDCl3,回転異性体の混合物)δ7.27(m,1H),6.96(m,1H),4.26(bm,0.6H),4.19−4.03(m,1.7H),3.92−3.87(m,0.8H)3.75−3.69(m,0.8H),3.47−3.22(m,2H),2.91(m,1H), 1.28−1.25(m,3H)。MS C13H13ClF3NO+Hについての計算値:292,観測値:292。
ジクロロメタン(10mL)中の(S)−N−トリフルオロアセチル−9−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(0.62g、2.1mmol)の溶液を、N−クロロスクシイミド(0.284g、2.1mmol)およびトリフルオロメタンスルホン酸(0.639g、4.2mmol)で処理した。反応物を16時間、20℃で攪拌し、水(20mL)で希釈し、ジクロロメタン(25mL)で抽出した。有機物をMgSO4で乾燥し、濾過し、そして濃縮した。HPLC生成を行い、0.078gの白色固体を得た。1H NMR(400MHz,CDCl3,回転異性体の混合物)δ7.32−7.25(m,1H),6.97−6.93(m,1H),4.27−4.24(m,0.6H),4.19−4.13(m,1H),4.08−4.01(m,1H),3.91−3.86(0.8H,m),3.74−3.69(m,0.8H),3.45−3.37(m,1H),3.31−3.21(m,1H),2.96−2.80(m,1H),1.28−1.22(m,3H)。MS C13H12Cl2F3NO+Hについての計算値:326,観測値:326。
メタノール(10mL)中の(S)−N−トリフルオロアセチル−8,9−ジクロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(0.270g、1.2mmol)の溶液を、15%水性NaOH(10mL)で処理し、3.5時間、25℃で攪拌した。生成物混合物を濃縮し、3回、CH2Cl2(25mL)で抽出し、Na2SO4で乾燥し、濃縮して、0.270gの透明な油状物を得た。1H NMR(400MHz,CDCl3)δ7.40(d,J=8Hz,1H),7.16(d,J=8Hz, 1H),4.17(m,1H),3.55(m,2H),3.5−3.3(m,2H),3.2−3.0(m,2H),1.43(d,J=7Hz,3H)。MS C11H13Cl2N+Hについての計算値:230,観測値:230。
1,2−ジクロロエタン(15mL)中の(S)−N−トリフルオロアセチル−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(2.5g、8.5mmol)の溶液を、Selectfluor(3.9g、11mmol)、トリフルオロメタンスルホン酸(8mL、90mmol)で処理し、60時間、75℃で撹拌した。生成物の混合物を水(200mL)中に注ぎ、EtOAc(200mL)で抽出し、有機相を飽和水性NaHCO3(2×100mL)、ブライン(100mL)で洗浄し、Na2SO4で乾燥し、濃縮した。粗生成物を、フラッシュクロマトグラフィー(ヘキサン中の6%EtOAc、シリカ)によって精製し、0.6gの白色固体を得た。C13H12ClF4NO+Hについての計算値:310,観測値:310。
メタノール(3mL)中の(S)−N−トリフルオロアセチル−8−クロロ−9−フルオロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(160mg、0.22mmol)の溶液を、15%水性NaOH(2mL)で処理し、3.5時間、25℃で撹拌した。生成物混合物を濃縮し、3回、CH2Cl2(5mL)で抽出し、Na2SO4で乾燥し、濃縮し、93mgの透明油状物を得た。1H NMR(400MHz,CDCl3)δ7.06(dd,J=8,8Hz,1H),6.75(d,J=8Hz,1H),3.58(m,1H),3.25−3.15(m,3H),2.93(d,J=13Hz,1H)2.75−2.60(m,3H),1.96(bs,1H),1.33(d,J=8Hz,3H)。MS C11H13ClFN+Hについての計算値:214,観測値:214。
還流凝縮器および添加漏斗を備えた1リットル三ツ口丸底フラスコに、アルゴンバルーン下で、連続的に、2−(4−クロロフェニル)エチルアミン(30g、193mmol)、400mLアセトニトリル、トリエチルアミン(19.5g、193mmol)および80mLアセトニトリルを添加した。透明無色の溶液を攪拌し、0℃に冷却した。5mLアセトニトリル中の2−クロロプオピオニルクロリド(24.5g、193mmol、蒸留)を、20分にわたってゆっくり添加し、白色気体の発生、白色沈殿の形成、および反応混合物の薄い黄色への色の変化を生じた。さらに10mLのアセトニトリルを使用して、添加漏斗をリンスした。この混合物を0℃で30分間攪拌し、次いで、室温に温め、さらに1時間激しく攪拌した。黄色の反応混合物をロータリーエバポレーターで、トリエチルアミン塩酸塩を含む固体(76.36g)に濃縮した。この物質を100mLの酢酸エチルおよび200mL水にとり、激しく攪拌した。層を分離し、水層をさらに100mLの酢酸エチルで抽出した。合わせた有機層を25mLの飽和ブラインで洗浄し、硫酸マグネシウムで乾燥し、濾過し、そして淡い黄褐色の固体(41.6g、88%)に濃縮した。酢酸エチル−ヘキサン8:2のTLCは、プレートの経路の3分の2で主要なスポットを、そしてベースラインに小さなスポットを示した。ベースラインスポットを以下のように除去した:この物質を40mLの酢酸エチルにとり、溶液が曇るまでヘキサンを添加した。0℃に冷却し、白色結晶固体(40.2g、85%収率)を得た。この生成物は、既知の化合物である(Hasan et al.,Indian J.Chem.,1971,9(9),1022)、CAS Registry No.34164−14−2。LC/MSは、2.45分に生成物を与えた;246.1 M++H+。1H NMR(CDCl3):δ7.2(dd,4H,Ar),6.7(br S,1H,NH),4.38(q,1H,CHCH3),3.5(q,2H,ArCH2CH 2NH),2.8(t,2H,ArCH2),1.7(d,3H,CH3)。13C NMR(CDCl3):169(1C,C=O),136(1C,Ar−Cl),132(1C,Ar),130(2C,Ar),128(2C,Ar),56(1C,CHCl),40(1C,CHN),34(1C,CHAr), 22(1C,CH3)。
2−(4−クロロフェニル)エチル−N−2−クロロプロピオンアミド(10g、40.6mmol)および塩化アルミニウム(16g、119.9mmol)を、アルゴンバルーン、攪拌装置および加熱装置を備える乾燥100mL丸底フラスコに添加した。白色固体を91℃でバブリングしながら黄褐色油状物に溶融させた(注記:不純な開始物質を使用する場合、黒いタールが生じるが、清浄な生成物がなお単離され得る)。この混合物を加熱し、150℃で12時間攪拌した。反応をLC/MSで追いかけ、5分の反応時間で、5−95%w/0/01%TFA(水/MeCN(50:50)中)から、開始物質は、2.45分(246.M+H+)、生成物は、2.24分(209.6M+H+)である。室温に冷却した後、反応混合物を10mLのMeOH、続く、5mLの5%HCl水および5mLの酢酸エチルのゆっくりした添加でクエンチした。得られた層の分離後、水層を二回の10mL酢酸エチルで抽出した。合わせた有機層を硫酸マグネシウムで乾燥させ、濾過し、そして黄褐色固体(6.78g、80%収率)に濃縮した。LC/MSは、1つのピークを2.2分に209.6MIで示した。この物質を酢酸エチルでとり、セライトおよびKieselgel60(60mLブッフナー漏斗上の0.5インチプラグ)で濾過し、濾液をヘキサン/酢酸エチルで再結晶化させ、最終生成物を得た(4.61g、54%収率)。1H NMR(CDCl3):δ7.3−7.1(m,3H,Ar),5.6(br s,1H,NH),4.23(q,1H,CHCH3),3.8(m,1H,ArCH2CH 2NH),3.49(m,1H,ArCH2CH 2NH),3.48(m,1H,ArCH 2CH2NH),3.05(m,1H,ArCH 2CH2NH),1.6(d,3H,CH2)。13C NMR(CDCl3):178(1C,C=O),139(1C,Ar),135(1C,Ar),130,129(2C,Ar),126(2C,Ar),42(1C,C),40(1C,CHN),33(1C,CHAr),14(1C,CH3)。
8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン−2−オン(150mg、0.716mmol、HPLCまたは再結晶によって精製)を、2Mボラン−テトラヒドロフラン溶液(2mL、2.15mmol)を有する50mL丸底フラスコに添加した。この混合物を10時間室温で、アルゴンバルーン下で攪拌した。LC/MSは、主要ピークとして所望の生成物を示し、葯5%の開始物質がなお存在した。反応混合物を5mLメタノールでクエンチし、溶媒をロータリーエバポレーターで除去した。この手順を、メタノール添加およびエバポレーションで繰り返した。この混合物をロータリーエバポレーターでエバポレートさせ、2時間後、減圧し、白色固体として生成物を得た(117mg、70%収率)。1H NMR(CDCl3):δ10.2(br s,1H),9.8(br s,1H),7.14(dd,1H,J=2,8Hz),7.11(d,1H,J=2Hz),7.03(d,1H,J=8Hz),3.6(m,2H),3.5(m,2H),2.8−3.0(m,3H),1.5(d,3H,J=7Hz)。LC/MS:1.41分,196.1 M + H+および139主要フラグメント。
清浄な乾燥50mL丸底フラスコに、11.5g(0.06mol)の8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンを、2.23g(0.015mol)のL−(+)−酒石酸に対して添加した。懸濁液を56gのtert−ブタノールおよび6.5mLのH2Oで希釈した。この混合物を加熱還流(75〜78℃)し、10分間攪拌して、無色溶液を得た。この溶液をゆっくり室温に(1時間で)冷却し、3時間室温で攪拌した。懸濁液を濾過し、そして残留物を2回アセトン(10mL)で洗浄した。生成物を60℃で減圧(50mbar)で乾燥し、6.3gの酒石酸塩(ee=80)を得た。この酒石酸塩を56gのtert−ブタノールおよび6.5mLのH2Oに添加した。得られた懸濁液を加熱還流し、1〜2gのH2Oを添加して、無色溶液を得た。この溶液をゆっくり室温に冷却し(1時間にわたる)、そして3時間室温で攪拌した。懸濁液を濾過し、残留物を2回、アセトン(10mL)で洗浄した。生成物を、減圧(50mbar)下で60℃で乾燥させ4.9g(48%収率)の生成物(ee>98.9)を得た。
8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンのL−酒石酸塩(300mg、0.87mmol)を、50%水酸化ナトリウム溶液(114μL、2.17mmol)を有する25mLの丸底フラスコに追加の2mLの水とともに、添加した。この混合物を3分間室温で攪拌した。溶液を塩化メチレン(5mL)で2回抽出した。合わせた有機抽出物を水(5mL)で洗浄し、ポンプでエバポレートして乾固させ、遊離アミン(220mg粗製重量)を得た。LC/MS196(M+H)。
ジクロロメタン(50mL)中の(R)−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(1.0g、4.31mmol)の溶液を、0℃で、ピリジン(1.0mL)および無水トリフルオロ酢酸(1.35g、6.46mmol)で処理した。これを20℃に温め、3時間攪拌し、1M HCl(25mL)で希釈した。これを、ジクロロメタン(2×50mL)で抽出し、有機物をMgSO4で乾燥させ、濾過し、濃縮して、オフホワイト色の固体として1.7gを得た。1H NMR(400MHz,CDCl3,回転異性体の混合物)δ7.27(m,1H),6.96(m,1H),4.26(bm,0.6H),4.19−4.03(m,1.7H),3.92−3.87(m,0.8H),3.75−3.69(m,0.8H),3.47−3.22(m,2H),2.91(m,1H),1.28−1.25(m,3H)。MS C13H13ClF3NO+Hについての計算値:292,観測値:292。
化合物7を、(R)−N−トリフルオロアセチル−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンから、化合物5の調製について、本明細書中で記載された類似の2工程手順を利用して、調製した。1H NMR(400MHz,CDCl3)δ7.40(d,J=8Hz,1H),7.16(d,J=8Hz,1H),4.17(m,1H),3.55(m,2H),3.5−3.3(m,2H),3.2−3.0(m,2H),1.43(d,J=7Hz,3H)。MS C11H13Cl2N+Hについての計算値:230,観測値:230。
ジクロロエタン(7mL)中のジクロロエタン(7mL)中の(S)−N−トリフルオロアセチル−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン(0.875g、3.0mmol)の溶液を、N−ブロモスクシンイミド(0.284g、2.1mmol)およびトリフルオロメタンスルホン酸(0.639g、4.2mmol)で処理した。反応物を室温で16時間攪拌し、酢酸エチル(20mL)で希釈し、そして水(2×10mL)で抽出した。有機物をMgSO4で乾燥させ、濾過し、濃縮した。フラッシュクロマトグラフィー(ヘキサン中5%EtOAc、シリカ)によって、0.13gの無色油状物を得た。MS C13H12BrClF3NO+Hについての計算値:370,観測値:370。
化合物8を、(S)−N−トリフルオロアセチル−9−ブロモ−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンから、化合物5の調製について本明細書中に記載される類似の手順を使用して、調製した。(S)−9−ブロモ−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンを、(S)−N−トリフルオロアセチル−9−ブロモ−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンから得た。1H NMR(400 MHz, CDCl3)δ7.17(d,J=8Hz,1H),6.92(d,J=8Hz,1H), 3.92−3.87(m,1H),3.29−3.20(m,2H),3.11(dd,J=14,5Hz,1H),2.99(dd,J=14,2Hz,1H),2.74−2.65(m,2H),1.32(d,J=7Hz,3H)。MS C11H13BrClN+Hについての計算値: 274,観測値:274。
化合物10を、(S)−8,9−ジクロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンから、化合物9の調製ついての本明細書中に記載の類似の手順を使用して、調製した。1H NMR(400MHz,CDCl3)δ7.19(d,J=8Hz,1H),6.89(d,J=8Hz,1H),3.91−3.88(m,1H),3.28(ddd,J=15,12,2Hz,1H),2.99−2.88(m,2H),2.68(ddd,J=15,5,1Hz,1H),2.36−2.32(m,4H),2.13(t,J=11Hz,1H),1.27(d,J=7Hz,3H)。MS C12H15Cl2N+Hについての計算値:243,観測値:243。
本発明の化合物は、20mm×250mm Chiralcel ODキラルカラムを有するVarian ProStar HPLCシステムを使用して、種々の濃度のヘキサン中のイソプロパノール(IPA)(例えば、ヘキサン中5%IPA、ヘキサン中1%IPAなどの濃度)中の0.2%ジエチルアミンで溶出して、それぞれのエナンチオマーに分離され得る。
Claims (123)
- R1がHである、請求項1に記載の化合物。
- R1がC1〜8アルキルである、請求項1に記載の化合物。
- R1がメチルである、請求項3に記載の化合物。
- R1がエチルである、請求項3に記載の化合物。
- R1がn−プロピルである、請求項3に記載の化合物。
- R1がイソプロピルである、請求項3に記載の化合物。
- R1がn−ブチルである、請求項3に記載の化合物。
- R2がC1〜4アルキルである、請求項1〜8のいずれか1項に記載の化合物。
- R2がメチルである、請求項1〜8のいずれか1項に記載の化合物。
- R2がエチルである、請求項1〜8のいずれか1項に記載の化合物。
- R2がイソプロピルである、請求項1〜8のいずれか1項に記載の化合物。
- R2がn−プロピルである、請求項1〜8のいずれか1項に記載の化合物。
- R2がC1〜4ハロアルキルである、請求項1〜8のいずれか1項に記載の化合物。
- R2が−CF3である、請求項1〜8のいずれか1項に記載の化合物。
- R3がHである、請求項1〜15のいずれか1項に記載の化合物。
- R3がC1〜4アルキルである、請求項1〜15のいずれか1項に記載の化合物。
- R3が−CH3である、請求項1〜15のいずれか1項に記載の化合物。
- R3がアミノである、請求項1〜15のいずれか1項に記載の化合物。
- R3がシアノである、請求項1〜15のいずれか1項に記載の化合物。
- R3がハロゲンである、請求項1〜15のいずれか1項に記載の化合物。
- R3がフッ素原子である、請求項1〜15のいずれか1項に記載の化合物。
- R3が塩素原子である、請求項1〜15のいずれか1項に記載の化合物。
- R3が臭素原子である、請求項1〜15のいずれか1項に記載の化合物。
- R3がヨウ素原子である、請求項1〜15のいずれか1項に記載の化合物。
- R3がC1〜4ハロアルキルである、請求項1〜15のいずれか1項に記載の化合物。
- R3がCF3である、請求項1〜15のいずれか1項に記載の化合物。
- R3がニトロである、請求項1〜15のいずれか1項に記載の化合物。
- R3が−OHである、請求項1〜15のいずれか1項に記載の化合物。
- R4がHである、請求項1〜29のいずれか1項に記載の化合物。
- R4がC1〜4アルキルである、請求項1〜29のいずれか1項に記載の化合物。
- R4が−CH3である、請求項1〜29のいずれか1項に記載の化合物。
- R4がアミノである、請求項1〜29のいずれか1項に記載の化合物。
- R4がシアノである、請求項1〜29のいずれか1項に記載の化合物。
- R4がハロゲンである、請求項1〜29のいずれか1項に記載の化合物。
- R4がフッ素原子である、請求項1〜29のいずれか1項に記載の化合物。
- R4が塩素原子である、請求項1〜29のいずれか1項に記載の化合物。
- R4が臭素原子である、請求項1〜29のいずれか1項に記載の化合物。
- R4がヨウ素原子である、請求項1〜29のいずれか1項に記載の化合物。
- R4がC1〜4ハロアルキルである、請求項1〜29のいずれか1項に記載の化合物。
- R4がCF3である、請求項1〜29のいずれか1項に記載の化合物。
- R4がニトロである、請求項1〜29のいずれか1項に記載の化合物。
- R4が−OHである、請求項1〜29のいずれか1項に記載の化合物。
- R5がHである、請求項1〜43のいずれか1項に記載の化合物。
- R5がC1〜4アルキルである、請求項1〜43のいずれか1項に記載の化合物。
- R5が−CH3である、請求項1〜43のいずれか1項に記載の化合物。
- R5がアミノである、請求項1〜43のいずれか1項に記載の化合物。
- R5がシアノである、請求項1〜43のいずれか1項に記載の化合物。
- R5がハロゲンである、請求項1〜43のいずれか1項に記載の化合物。
- R5がフッ素原子である、請求項1〜43のいずれか1項に記載の化合物。
- R5が塩素原子である、請求項1〜43のいずれか1項に記載の化合物。
- R5が臭素原子である、請求項1〜43のいずれか1項に記載の化合物。
- R5がヨウ素原子である、請求項1〜43のいずれか1項に記載の化合物。
- R5がC1〜4ハロアルキルである、請求項1〜43のいずれか1項に記載の化合物。
- R5がCF3である、請求項1〜43のいずれか1項に記載の化合物。
- R5がニトロである、請求項1〜43のいずれか1項に記載の化合物。
- R5が−OHである、請求項1〜43のいずれか1項に記載の化合物。
- R6がHである、請求項1〜57のいずれか1項に記載の化合物。
- R6がC1〜4アルキルである、請求項1〜57のいずれか1項に記載の化合物。
- R6がCH3である、請求項1〜57のいずれか1項に記載の化合物。
- R6がアミノである、請求項1〜57のいずれか1項に記載の化合物。
- R6がシアノである、請求項1〜57のいずれか1項に記載の化合物。
- R6がハロゲンである、請求項1〜57のいずれか1項に記載の化合物。
- R6がフッ素原子である、請求項1〜57のいずれか1項に記載の化合物。
- R6が塩素原子である、請求項1〜57のいずれか1項に記載の化合物。
- R6が臭素原子である、請求項1〜57のいずれか1項に記載の化合物。
- R6がヨウ素原子である、請求項1〜57のいずれか1項に記載の化合物。
- R6がC1〜4ハロアルキルである、請求項1〜57のいずれか1項に記載の化合物。
- R6がCF3である、請求項1〜57のいずれか1項に記載の化合物。
- R6がニトロである、請求項1〜57のいずれか1項に記載の化合物。
- R6が−OHである、請求項1〜57のいずれか1項に記載の化合物。
- 6,8−ジクロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン;6−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピン;8−クロロ−9−フルオロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンおよび8,9−ジクロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンからなる群より選択される、請求項1に記載の化合物。
- 9−ブロモ−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンである、請求項1に記載の化合物。
- N−メチル−8,9−ジクロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンおよびN−メチル−9−ブロモ−8−クロロ−1−メチル−2,3,4,5−テトラヒドロ−1H−3−ベンズアゼピンからなる群より選択される、請求項1に記載の化合物。
- 前記化合物がR光学異性体である、請求項1〜74のいずれか1項に記載の化合物。
- 前記化合物がS光学異性体である、請求項1〜74のいずれか1項に記載の化合物。
- 請求項1〜76のいずれか1項に記載の化合物および薬学的に受容可能なキャリアを含有する、薬学的組成物。
- 5HT2Cレセプターを調節する方法であって、該方法は、該レセプターを、治療有効量の請求項1〜76のいずれか1項に記載の化合物と接触させる工程を包含する、方法。
- 前記化合物が、前記レセプターのアゴニストである、請求項78に記載の方法。
- 中枢神経系の障害;中枢神経系への損傷;心血管障害;胃腸障害;尿崩症または睡眠時無呼吸の予防または処置の方法であって、該方法はこのような予防または処置を必要としている個体に、治療有効量の請求項1〜76のいずれか1項に記載の化合物または請求項77に記載の薬学的組成物を投与する工程を包含する、方法。
- 前記中枢神経系の障害は、うつ病、異型うつ病、双極性障害、不安障害、強迫性障害、社会恐怖またはパニック状態、睡眠障害、性機能障害、精神病、精神分裂病、片頭痛、および頭痛または他の疼痛に関連する他の状態、頭蓋内圧上昇、てんかん、人格障害、アルツハイマー病、年齢関連性行動障害、痴呆に関連する行動障害、器質性精神障害、幼児期における精神障害、攻撃性、年齢関連性記憶障害、慢性疲労症候群、薬物嗜癖およびアルコール嗜癖、肥満、過食症、神経性食欲不振および月経前緊張からなる群より選択される、請求項80に記載の方法。
- 前記中枢神経系の障害が肥満である、請求項81に記載の方法。
- 前記中枢神経系の障害がアルツハイマー病である、請求項81に記載の方法。
- 前記性機能障害が男性の勃起障害である、請求項81に記載の方法。
- 前記中枢神経系への損傷が、外傷、脳卒中、神経変性疾患、中毒性CNS疾患または感染性CNS疾患によるものである、請求項80に記載の方法。
- 前記中枢神経系への損傷が、脳炎または髄膜炎によるものである、請求項80に記載の方法。
- 前記心血管障害が血栓症である、請求項80に記載の方法。
- 前記心血管障害が、胃腸運動性の機能障害である、請求項80に記載の方法。
- 前記個体が哺乳動物である、請求項80〜88の1項に記載の方法。
- 前記哺乳動物がヒトである、請求項89に記載の方法。
- 個体の食物摂取を減少させる方法であって、該方法は、該個体に治療有効量の請求項1〜76のいずれか1項に記載の化合物または請求項77に記載の薬学的組成物を投与する工程を包含する、方法。
- 前記個体が哺乳動物である、請求項91の1つに記載の方法。
- 前記哺乳動物がヒトである、請求項92に記載の方法。
- 個体における満腹感を誘発する方法であって、該方法は、該個体に治療有効量の請求項1〜76のいずれか1項に記載の化合物または請求項77に記載の薬学的組成物を投与する工程を包含する、方法。
- 前記個体が哺乳動物である、請求項94の1つに記載の方法。
- 前記哺乳動物はヒトである、請求項95に記載の方法。
- 個体の体重増加を調節する方法であって、該方法は、体重調節に苦しんでいる該個体に治療有効量の請求項1〜76のいずれか1項に記載の化合物または請求項77に記載の薬学的組成物を投与する工程を包含する、方法。
- 前記個体が哺乳動物である、請求項97の1つに記載の方法。
- 前記哺乳動物がヒトである、請求項98に記載の方法。
- 前記ヒトが約18.5〜約45の肥満度指数を有する、請求項93、96および99のいずれか1項に記載の方法。
- 前記ヒトが約25〜約45の肥満度指数を有する、請求項93、96および99のいずれか1項に記載の方法。
- 前記ヒトが約30〜約45の肥満度指数を有する、請求項93、96および99のいずれか1項に記載の方法。
- 前記ヒトが約35〜約45の肥満度指数を有する、請求項93、96および99のいずれか1項に記載の方法。
- 薬学的組成物を生成する方法であって、該方法は、請求項1〜76のいずれか1項に記載の少なくとも1つの化合物および薬学的に受容可能なキャリアを混合する工程を包含する、方法。
- 治療によるヒトまたは動物の身体の処置方法における使用のための、請求項1〜76のいずれか1項に記載の化合物。
- 治療によるヒトまたは動物の身体の中枢神経系の障害;中枢神経系への損傷;心血管障害;胃腸障害;尿崩症または睡眠時無呼吸の予防または処置の方法において使用するための、請求項1〜76のいずれか1項に記載の化合物。
- 請求項106に記載の化合物であって、ここで前記中枢神経系の障害が、うつ病、異型うつ病、双極性障害、不安障害、強迫性障害、社会恐怖またはパニック状態、睡眠障害、性機能障害、精神病、精神分裂病、片頭痛および頭痛または他の疼痛に関連する他の状態、頭蓋内圧上昇、てんかん、人格障害、アルツハイマー病、年齢関連性行動障害、痴呆に関連する行動障害、器質性精神障害、幼児期における精神障害、攻撃性、年齢関連性記憶障害、慢性疲労症候群、薬物嗜癖およびアルコール嗜癖、肥満、過食症、神経性食欲不振および月経前緊張からなる群より選択される、化合物。
- 前記中枢神経系の障害が肥満である、請求項107に記載の化合物。
- 前記中枢神経系の障害がアルツハイマー病である、請求項107に記載の化合物。
- 前記性機能障害が男性における勃起障害である、請求項107に記載の化合物。
- 前記中枢神経系への損傷が、外傷、脳卒中、神経変性疾患、中毒性CNS疾患または感染性CNS疾患によるものである、請求項106に記載の化合物。
- 前記中枢神経系への損傷が脳炎または髄膜炎によるものである、請求項106に記載の化合物。
- 前記心血管障害が血栓症である、請求項106に記載の化合物。
- 前記胃腸障害が胃腸運動性の機能障害である、請求項106に記載の化合物。
- 中枢神経系の障害;中枢神経系への損傷;心血管障害、胃腸障害;尿崩症または睡眠時無呼吸の処置または予防における使用のための医薬の製造のための、請求項1〜76のいずれか1項に記載の化合物の使用。
- 請求項115に記載の使用であって、ここで前記中枢神経系の障害が、うつ病、異型うつ病、双極性障害、不安障害、強迫性障害、社会恐怖またはパニック状態、睡眠障害、性機能障害、精神病、精神分裂病、片頭痛および頭痛または他の疼痛に関連する他の状態、頭蓋内圧上昇、てんかん、人格障害、アルツハイマー病、年齢関連性行動障害、痴呆に関連する行動障害、器質性精神障害、幼児期における精神障害、攻撃性、年齢関連性記憶障害、慢性疲労症候群、薬物嗜癖およびアルコール嗜癖、肥満、過食症、神経性食欲不振および月経前緊張からなる群より選択される、使用。
- 前記中枢神経系の障害が肥満である、請求項116に記載の使用。
- 前記中枢神経系の障害がアルツハイマー病である、請求項116に記載の使用。
- 前記性機能障害が男性における勃起障害である、請求項116に記載の使用。
- 前記中枢神経系への損傷が、外傷、脳卒中、神経変性疾患、中毒性CNS疾患または感染性CNS疾患によるものである、請求項115に記載の使用。
- 前記中枢神経系への損傷が、脳炎または髄膜炎によるものである、請求項115に記載の使用。
- 前記心血管障害が血栓症である、請求項115に記載の使用。
- 前記胃腸障害が胃腸運動性の機能障害である、請求項115に記載の使用。
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JP2013536858A (ja) * | 2010-09-01 | 2013-09-26 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 5−ht2cアゴニストの速く溶解する剤形 |
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JP2013539470A (ja) * | 2010-09-01 | 2013-10-24 | アリーナ ファーマシューティカルズ, インコーポレイテッド | ロルカセリンと光学活性な酸との塩 |
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