JP4064237B2 - 興奮性アミノ酸のプロドラッグ - Google Patents
興奮性アミノ酸のプロドラッグ Download PDFInfo
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- C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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Description
(B)R13およびR14が両方水素である式Iの化合物(二酸)に関しては、反応式2に記載のように、R13およびR14が両方ともは水素ではない式Iの化合物を脱保護する。
(C)R13およびR14が両方ともは水素でない化合物Iに関しては、式II:
により示される対応するアミノ酸を用いてアミド化する。
(D)R13およびR14が水素ではなく、R13およびR14がカルボキシ保護エステル基(ジエステル)でもよい式IIの化合物については、式II(式中、R13およびR14は両方とも水素である(二酸))の化合物をエステル化する。
(E)R13およびR14が水素ではない(ジエステル)式IIの化合物に関しては、製造例2に記載のように、式IV:
により表される化合物を脱保護する。
(F)R13およびR14が両方ともは水素ではない式IIの化合物(ジエステル)に関しては、製造例2に記載のように式IVの化合物をエステル化する。
(G)R13およびR14が両方水素である式IVの化合物(二酸)に関しては、製造例1に記載のように、式IIの化合物のアミン基を保護する。
LY354740と比較して、本発明の化合物が受容体結合に影響を与える能力を試験するために、ヒトmGluR2、ヒトmGluR3およびラット脳組織に由来する細胞膜に対し、高親和性のmGluR2アンタゴニスト放射性リガンド[3H]LY341495の置換を測定した(Ornstein P.L.,Arnold M.B.,Bleisch T.J.,Wright R.A.,Wheeler W.J.,and Schoepp D.D.,[3H]LY341495,a highly potent,selective and novel radioligand for labeling group II metabotropic receptors.Bioorg.Med.Chem.Lett.8:1919−1922(1998);およびJohnson B.G.,Wright R.A.,Arnold M.B.,Wheeler W.J.,Ornstein P.L.,and Schoepp D.D.,[3H]LY341495 as a novel rapid filtration antagonist radioligand for group II metabotropic receptors:Characterization of binding to membranes of mGlu receptor subtype expressing cells.Neuropharmacology 38:1519−1529(1999))。
mGlu2/3受容体関連治療動物モデルにおける、LY35740と比較しての、本発明の化合物の経口効力を試験するため、ラット恐怖増強驚愕アッセイで試験を行なった。このモデルは、LY354740および本発明の化合物のようなmGlu2/3アゴニストに非常に感度が高いので、特別に選択した(Helton D.R.,Tizzano J.P.,Monn J.A.,Schoepp D.D.,and Kallman M.J.,Anxiolytic and side−effect profile of LY354740:A potent,high selective,orally active agonist for group II metabotropic glutamate receptors,J.Pharmacol.Exp.Ther.284:651−660(1998)を参照のこと)。このモデルにおける式Iの化合物の作用がmGlu2/3受容体媒介性である事を実証するために、先にLY354740に関して実証されている(Tizzano,J.P.,Griffey K.I.,Ornstein P.L.,Monn J.A.,and Schoepp D.D.,Actions of mGlu receptor agonists on fear−conditioning versus fear−expression in rats,Neuropharmacology,38:A45(#144)(1999))ように、LY341495(mGlu2/3受容体アンタゴニスト)(Kingston A.E.,Ornstein P.L.,Wright R.A.,Johnson B.G.,Mayne N.G.,Burnett J.P.,Belagaje R.,Wu S.,and Schoepp D.D.,LY341495 is a nanomolar potent and selective antagonist for group II metabotropic glutamate receptors,Neuropharmacology,37:112(1998)を参照のこと)の化合物媒介性恐怖増強驚愕の抑制を遮断する能力もまた、測定した。各実験のポジティブコントロールとして、ジアゼパム(0.6mg/kg、腹腔内)を用いた。全ての実験は、食餌供給ラット(fed rat)で行なった。
本発明の化合物の経口投薬の後のLY354740へのインビボ暴露をLY354740と比較して試験するために、ラットにおけるLY354740の血漿濃度測定試験を行なった。
Ac=アセチル
Anal.=元素分析
BnまたはBzl=ベンジル
Bu=ブチル
BOC=ブトキシカルボニル
calcd=計算値
D2O=酸化ジューテリウム
DCC=ジシクロヘキシルカルボジイミド
DIBAL−H=ジイソブチルアルミニウム水素化物
DMAP=ジメチルアミノピリジン
DMF=ジメチルホルムアミド
DMSO=ジメチルスルホキシド
EDC=N−エチル−N’N’−ジメチルアミノプロピルカルボジイミド
Et=エチル
EtOH=エタノール
FAB=高速原子衝撃(質量分析)
FDMS=電解離脱質量分析法
HOAt=1−ヒドロキシ−7−アザベンゾトリアゾール
HOBt=1−ヒドロキシベンゾトリアゾール
HPLC=高性能液体クロマトグラフィー
HRMS=高分解質量スペクトル
i−PrOH=イソプロパノール
IR=赤外線スペクトル
L=リットル
Me=メチル
MeOH=メタノール
MPLC=中圧液体クロマトグラフィー
Mp=融点
MTBE=t−ブチルメチルエーテル
NBS=N−ブロモスクシンイミド
NMR=核磁気共鳴
Ph=フェニル
p.o.=経口投与
i−Pr=イソプロピル
ロッシェル塩(Rochelle’s Salt)=酒石酸カリウムナトリウム
SM=出発物質
TBS=tert−ブチルジメチルシリル
TEA=トリエチルアミン
Temp.=温度
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
TLC=薄層クロマトグラフィー
t−BOC=tert−ブトキシカルボニル。
(1S,2S,5R,6S)−2−tert−ブトキシカルボニルアミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸の合成
収率77%;mp100〜101℃。
[α]D 25=−41.1°(c=1.0,MeOH)。
1H NMR(メタノール−d4)δ:4.98(brs,1H),2.44(dd,1H,J=6.2,2.6Hz),2.19−1.92(m,4H),1.62(t,1H,J=2.8Hz),1.43(s,9H),1.29(m,1H)。
13C NMR(メタノール−d4)δ:175.6,175.2,158.2,60.1,34.6,31.9,28.4,27.2,25.6,20.6。
MS(エレクトロスプレー):285.12。
(1S,2S,5R,6S)−2−アミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジメチルエステル塩酸塩の合成
収率73%;mp193〜194℃。
[α]D 25=+22.2。(c=1.0,MeOH)。
1H NMR(D2O)δ:3.86(s,3H),3.67(s,3H),2.31〜2.04(m,6H),1.57(m,1H)。
13C NMR(メタノール−d4)δ:171.9,170.2,65.6,52.8,51.2,32.4,29.9,28.5,26.2,20.7。
(C10H16NO4Clについて)計算値:C,48.10;H,6.46;N,5.61;Cl,14.20。実測値:C,47.88;H,6.25;N,5.57;Cl,14.52。
出発ジメチルエステル塩酸塩(1.0当量)(製造例2の生成物)を窒素下で乾燥ジクロロメタン(0.1M溶液)に懸濁した。対応するN−BOC−アミノ酸(1.5当量)、N−エチル−N’,N’−ジメチルアミノプロピルカルボジイミド(EDC,1.5当量)および1−ヒドロキシベンゾトリアゾール(HOBt,1.5当量)を1度に加え、続いてシリンジを介してトリエチルアミン(1.0当量)を加え、最後にジメチルアミノピリジン(DMAP,0.1当量)を加えた。反応混合物を室温で一晩攪拌し、次いで1N塩酸(20ml/mmol)を加えることにより加水分解し、塩化メチレンで希釈した(10ml/mmol)。水層を塩化メチレン(5ml/mmol)で抽出し、合わせた有機層を1N塩酸(10ml/mmol)で2回洗浄し、最終的に水およびブライン(各10ml/mmol)で洗浄した。硫酸ナトリウムで乾燥させ、減圧下でエバポレーションした後、粗残渣を適切な溶離剤(代表的には、混合物ヘキサン/酢酸エチル)を用いるシリカゲルによるクロマトグラフィーにより精製した。
ジシクロヘキシルカルボジイミド(DCC)(1.1当量)の塩化メチレン(4.0M溶液)溶液を製造例2の生成物(1.0当量)、トリエチルアミン(1.0当量)およびN−t−ブトキシカルボニル−L−アラニン(1.1当量)の塩化メチレン(1.0M溶液)中の混合物に加え、約1.5時間、攪拌する。得られた混合物を1〜12時間攪拌し、次いでろ過する。ろ過ケーク(ジシクロヘキシルウレア)を塩化メチレンでリンスし、ろ過物を0.1M NaHCO3、続いて1.0N塩酸で洗浄した。有機相を乾燥させ(Na2SO4)、ろ過し、濃縮して表題化合物を油状物として得た。
(1S,2S,5R,6S)−2−[(2’S)−(2’−tert−ブトキシカルボニルアミノ)−プロピオニル]アミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸ジメチルエステルの合成
収率50%。泡状白色固体。mp51〜52℃。
[α]D 25=−27.7(c=0.52,CHCl3)。
1H NMR(CDCl3)δ:7.28(brs,1H),5.04(brd,1H,J=7.6Hz),4.16(m,1H),3.74(s,3H),3.66(s,3H),2.49(dd,1H,J=13.9,8.3Hz)2.42(dd,1H,J=6.3,2.8Hz),2.18−1.89(m,3H),1.70(t,1H,J=2.9Hz),1.45(s,9H),1.33(d,3H,J=7.0Hz),1.19(m,1H)。
13C NMR(CDCl3)δ:172.8,172.6,172.6,155.7,80.2,66.3,52.6,51.8,49.5,34.4,32.0,28.2,28.1,26.6,21.1,17.6。
ジシクロヘキシルカルボジイミド(DCC)(1.1当量)の塩化メチレン(4.0M溶液)溶液を製造例2の生成物(1.0当量)、トリエチルアミン(1.0当量)およびN−t−ブトキシカルボニル−L−アラニン(1.1当量)の塩化メチレン(1.0M溶液)中の混合物に、約1.5時間攪拌しながら加えた。得られた混合物を1〜12時間攪拌し、次いでろ過した。ろ過ケーク(ジシクロヘキシルウレア)を塩化メチレンでリンスし、ろ液を0.1M NaHCO3、続いて1.0N塩酸で洗浄した。有機相を乾燥させ(Na2SO4)、ろ過し、濃縮して表題化合物を油状物として得た。
(1S,2S,5R,6S)−2−[(2’S)−(2’−tert−ブトキシカルボニルアミノ)−プロピオニル]アミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸の合成
収率1.36kg(84%)、白色固体として回転異性体のおよそ85:15混合物
[α]D25−24.8(C1.0,MeOH)
1H NMR(DMSO−d6)δ12.20(s,2H),8.40(s,0.85H),8.36(s,0.15H),6.69(d,J=8.2Hz,0.85H),6.33(br d,0.15H),3.99(五重項、J=7.2Hz,0.85H),3.84(br m,0.15H),2.18−2.13(m,2H),1.91−1.84(m,1H),1.82−1.75(m,2H),1.46(br s,0.85H),1.43(br s,0.15H),1.35(s,9H),1.23−1.15(m,1H),1.13(d,J=6.9Hz,3H)。
13C NMR(CD3OD)δ176.4,176.0(2 C),157.5,80.5,67.3(量の少い回転異性体),67.2(量の多い回転異性体),50.9,35.6,32.8,29.3,28.7,27.4,22.1,18.5。
MS(EI)(C16H28N3O7(M+NH4 +)について)計算値374.20、実測値374.24 m/z。
(1S,2S,5R,6S)−2−[(2’S)−(2’−アミノ)−プロピオニル]アミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩の合成
収率72%。白色結晶固体。mp>250℃(分解)。
[α]D 25=−7.80(c=1.0,MeOH)。
1H NMR(メタノール−d4)δ:3.96(q,1H,J=7.0Hz),2.47(dd,1H,J=6.3,2.7Hz),2.37(dd,1H,J=13.6,8.2Hz),2.18−1.92(m,3H),1.66(t,1H,J=3.0Hz),1.53(d,3H,J=7.0Hz),1.46−1.34(m,1H)。
13C NMR(メタノール−d4)δ:175.2,174.7,170.2,66.4,49.0,36.6,32.0,28.5,26.3,21.2,16.6。
収率80%。白色固体。
(1S,2S,5R,6S)−2−[(2’S)−(2’−アミノ)−プロピオニル]アミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸メタンスルホネートの合成
収率78%
1H NMR(CD3OD)δ3.96(q,J=7.1Hz,1H),2.71(s,3H),2.45(dd,J=6.4,2.7Hz,1H),2.38(dd,J=13.9,8.4Hz,1H),2.20−2.08(m,1H),2.01−1.93(m,2H),1.67(t,J=2.9Hz,1H),1.52(d,J=7.0Hz,3H),1.46−1.3(m,1H)13C NMR(CD3OD)δ176.3,175.7,171.2,67.4,50.0,39.5,35.7,33.1,29.5,27.4,22.2,17.6。
(C12H20N2O8Sについて)
計算値:C,40.90;H,5.72;N,7.95。
実測値:C,40.81;H,5.69;N,7.83。
(1S,2S,5R,6S)−2−[(2’S)−(2’−アミノ)−プロピオニルアミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸の合成
収率72%
1H NMR(CD3OD)δ3.93(q,J=7.1Hz,1H),2.48(dd,,J=6.6,2.9Hz,1H),2.32(dd,,J=13.5,8.4Hz,1H),2.20−2.08(m,1H),2.01−1.90(m,2H),1.61(t,,J=2.9Hz,1H),1.51(d,,J=7.0Hz,3H),1.48−1.33(m,1H)13C NMR(CD3OD)δ176.9(2C),171.1,68.0,50.1,35.9,33.2,29.7,27.3,22.5,17.6。
Claims (8)
- (1S,2S,5R,6S)−2−[(2’S)−(2’−アミノ)−プロピオニル]アミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸塩酸塩である、請求項1に記載の式Iの化合物の製薬上許容される塩。
- (1S,2S,5R,6S)−2−[(2’S)−(2’−アミノ)−プロピオニル]アミノ−ビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸メタンスルホン酸塩である、請求項1に記載の式Iの化合物の製薬上許容される塩。
- 製薬上許容されるキャリア、希釈剤または賦形剤と組合せて、請求項1〜3のいずれか1項に記載の式Iの化合物またはその製薬上許容される塩を含有する医薬製剤。
- 心臓バイパス手術および移植の結果として生じる大脳欠損、大脳虚血、脊髄外傷、頭部外傷、アルツハイマー病、ハンティングトン舞踏病、筋萎縮性側索硬化症、AIDS誘発性痴呆、周産期低酸素症、低血糖性神経損傷、目の損傷および網膜症、認知障害、特発性および薬物誘発性パーキンソン病、筋肉痙攣、偏頭痛、尿失禁、薬物耐性、退薬症状および薬物停止、喫煙停止、嘔吐、脳浮腫、慢性疼痛、睡眠障害、痙攣、トゥーレット症候群、注意欠損障害、または遅発性ジスキネジアから選ばれる神経学的な障害を治療するための医薬製剤であって、請求項1〜3のいずれか1項に記載の化合物を薬学的に有効な量で含む医薬製剤。
- 精神分裂病、不安および関連障害、うつ病、双極性障害、精神病または強迫性障害から選ばれる精神医学的障害を治療するための医薬製剤であって、請求項1〜3のいずれか1項に記載の化合物を薬学的に有効な量で含む医薬製剤。
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