JP2016535098A - Nmdaアンタゴニストプロドラッグ - Google Patents
Nmdaアンタゴニストプロドラッグ Download PDFInfo
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- JP2016535098A JP2016535098A JP2016551069A JP2016551069A JP2016535098A JP 2016535098 A JP2016535098 A JP 2016535098A JP 2016551069 A JP2016551069 A JP 2016551069A JP 2016551069 A JP2016551069 A JP 2016551069A JP 2016535098 A JP2016535098 A JP 2016535098A
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- JP
- Japan
- Prior art keywords
- phenyl
- pyridin
- compound
- pharmaceutically acceptable
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 claims description 15
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06147—Dipeptides with the first amino acid being heterocyclic and His-amino acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Description
AAは、ペプチド結合で結合された天然アミノ酸である)
の化合物またはその薬学的に許容される塩を提供する。
一態様において、本発明は、式(I)(式中、R1はC1−6アルキルC(O)O(C1−6アルコキシ)であり、例えば、それはC1−4アルキルC(O)O(C1−4アルコキシ)である)の化合物を提供する。例としては、(CH3)2CHC(O)OCH2O、(CH3)2CHC(O)OCH(CH(CH3)2)O、CH3C(O)OCH(CH3)Oまたは(CH3)2CHC(O)OCH(CH3)Oが挙げられる。
(S)−(1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)メチルイソブチレート;
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレート;
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレートジアステレオマー1;
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレートジアステレオマー2;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテート;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテートジアステレオマー1;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテートジアステレオマー2;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレート;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレートジアステレオマー1;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレートジアステレオマー2;
(S)−1−((S)−2−アミノ−3−メチルブタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
(S)−1−((S)−2,6−ジアミノヘキサノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
(S)−1−(−2−アミノ−3−(1H−イミダゾール−4−イル)プロパノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
2−((S)−2−((S)−1−(−2−アミノ−3−(4−ヒドロキシフェニル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジン;
2−((S)−2−((S)−1−(−2−アミノ−3−(1H−インドール−3−イル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジン;
(S)−1−((S)−2−アミノ−3−フェニルプロパノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;もしくは
(S)−1−((S)−2−アミノ−4−メチルペンタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
または上記のいずれか1つの薬学的に許容される塩。
またはMilliQ H2O中の0.1%NH3、またはMilliQ H2O中の10mM NH4OAcおよび5%CH3CN、またはMilliQ H2O中の0.05%トリフルオロ酸(trifluoric acid)、またはMilliQ H2O中のNH4HCO3(10mM))およびB(CH3OHまたはCH3CN)を用いて適用した。質量分析計(MS)分析は、エレクトロスプレーイオン化(ESI+/−)、大気圧光イオン化(APPI+/−)および/または大気圧化学イオン化(APCI+/−)を用いて陽および/または陰イオンモードで実施した。
DBU 1,8-ジアザビシクロ[5.4.0]ウンデカ−7−エンDCM
ジクロロメタン
DEA ジエチルアミン
DIPEA ジイソプロピルエチルアミン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EtOAc 酢酸エチル
HATU 2−(1H−7−アザベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェートメタナミニウム
IPA イソプロパノール
MTBE メチルtert−ブチルエーテル
rt 室温または周囲温度、約20〜25℃
sat 飽和
T3P プロパンホスホン酸無水物
クロロメチルイソブチレート
1H NMR (500 MHz, CDCl3) δ ppm 1.17 (m, 6 H), 2.62 (m, 1 H), 5.72 (s, 2 H).
(S)−(1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)メチルイソブチレート
1H NMR (500 MHz, DMSO-d6) δ ppm 1.00 (m, 6 H), 2.46 (m, 1 H, DMSO-d6に一部隠れた), 3.09 (m, 2 H), 5.04 (m, 1 H), 5.52 (m, 2 H), 7.17 - 7.24 (m, 3 H), 7.27 -
7.34 (m, 4 H), 7.65 (td, 1 H), 8.24 (d, 1 H), 8.49 (m, 1 H).
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレート
*で特定された炭素原子の2つの可能な立体配置のため、実施例2には2つの異なるジアステレオマーがある。これらを、実施例2ジアステレオマー1および実施例2ジアステレオマー2と称する。それらの絶対配置は、決定されていない。
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレート
キラル分離によって最初に溶出するジアステレオマーとして105mgのジアステレオマー1を光学純度99%で得た。
1H NMR (500 MHz, DMSO-d6) δ ppm 0.66 - 1.07 (m), 1.86 (m), 2.39 (m), 2.98 - 3.21 (m), 5.01 (m), 6.31 (m), 7.10 - 7.26 (m), 7.26 - 7.37 (m), 7.56 - 7.73 (m), 8.10 (d), 8.43 - 8.55 (m). スペクトルのプロトンの総数:28 回転異性体メジャー/マイナー(major/minor)比:1/0.15
MS(ES+APCI+)m/z 385(M+H)+
2番目に溶出するジアステレオマーとして104mgのジアステレオマー2を得た。
1H NMR (500 MHz, DMSO-d6) δ ppm 0.48 - 0.69 (m), 0.75 - 0.87 (m), 0.87 - 1.07
(m), 1.73 (m), 1.85 (m), 2.40 (m), 2.98 (m), 3.03 - 3.18 (m), 4.97 (m), 6.22 - 6.38 (m), 7.13 - 7.26 (m), 7.26 - 7.37 (m), 7.65 (m), 7.78 (d), 8.06 (d), 8.48 (m). スペクトル中のプロトンの総数:28 回転異性体メジャー/マイナー比:1/0.17
MS(ES+APCI+)m/z 385(M+H)+
光学純度=99%
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテート
*で特定された炭素原子で2つの可能な立体配置のため、実施例3には2つの異なるジアステレオマーがある。これらを、実施例3ジアステレオマー1および実施例3ジアステレオマー2と称する。それらの絶対配置は、決定されていない。
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテート
キラル分離によって最初に溶出するジアステレオマーとして29mgのジアステレオマー1を光学純度99%で得た。
1H NMR (500 MHz, DMSO-d6) δ ppm 1.31 (d, 3 H), 1.92 (s, 3 H), 3.00 - 3.16 (m, 2
H), 5.00 (td, 1 H), 6.52 (q, 1 H), 7.14 - 7.25 (m, 3 H), 7.30 (d, 4 H), 7.65 (t, 1 H), 8.13 (d, 1 H), 8.50 (d, 1 H). スペクトルのシグナルは広がっており、DMSO−シグナルの分裂を認めることができなかった。
13C NMR (126 MHz, DMSO-d6) δ 19.6, 20.7, 44.6, 54.9, 88.7, 121.6, 123.8, 126.4, 126.9, 128.3, 136.2, 143.0, 149.0, 153.2, 158.0, 168.6 ppm. MS(ES+)m/z 328(M+H)+
2番目に溶出するジアステレオマーとして39mgのジアステレオマー2を得た。
1H NMR (500 MHz, DMSO-d6) δ ppm 1.32 (d, 3 H), 1.95 (s, 3 H), 3.01 - 3.18 (m,
2 H), 5.00 (td, 1 H), 6.53 (q, 1 H), 7.13 - 7.24 (m, 3 H), 7.29 (d, 4 H), 7.65 (t, 1 H), 8.17 (d, 1 H), 8.49 (d, 1 H). スペクトルのシグナルは広がっており、DMSO−シグナルの分裂を認めることができなかった。
13C NMR (126 MHz, DMSO-d6) δ 19.6, 20.7, 44.4, 54.9, 88.6, 121.6, 123.7, 126.4, 126.9, 128.3, 136.2, 143.0, 149.0, 153.1, 158.0, 168.5. MS(ES+)m/z 329(M+H)+
光学純度98%。
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレート
*で特定された炭素原子の2つの可能な立体配置のため、実施例4には2つの異なるジアステレオマーがある。これらを、実施例4ジアステレオマー1および実施例4ジアステレオマー2と称する。それらの絶対配置は、決定されていない。
物1.16gを得、これをさらに精製することなく次のステップに用いた。
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレート
キラル分離によって最初に溶出するジアステレオマーとして25mgのジアステレオマー1を光学的純度99%で得た。
1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 - 1.05 (m), 1.19 (d), 1.32 (d), 2.31 - 2.44 (m), 2.98 - 3.20 (m), 4.94 - 5.07 (m), 6.48 (d), 6.52 (q), 7.15 - 7.25 (m), 7.25 - 7.34 (m), 7.60 - 7.70 (m), 7.77 (d), 8.06 - 8.18 (m), 8.44 - 8.55 (m). スペクトル中のプロトンの総数:24 メジャー/マイナー比:1:0.07
MS(ES+APCI+)m/z 357(M+H)+
UV純度=100%
2番目に溶出する異性体として25mgのジアステレオマー2を得た。
1H NMR (500 MHz, DMSO-d6) d ppm 0.82 - 0.94 (m), 0.94 - 1.04 (m), 1.25 (d), 1.32 (d), 2.24 - 2.32 (m), 2.34 - 2.44 (m), 3.00 - 3.17 (m), 5.02 (td), 6.48 (d), 6.52 (q), 7.15 - 7.25 (m), 7.25 - 7.38 (m), 7.55 - 7.77 (m), 8.16 (d), 8.44 - 8.57 (m). スペクトル中のプロトンの総数:24 メジャー/マイナー比:1:0.08
MS(ES+APCI+)m/z 357(M+H)+
UV純度=100%
光学純度=99%
2−((S)−2−フェニル−2−((S)−ピロリジン−2−イウムカルボキサミド)エチル)ピリジニウムジクロリド(それは(S)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド二塩酸塩と称することもできる)
(S)−tert−ブチル2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−カルボキシレート
1H NMR (300 MHz, CDCl3): ppm 1.35 (s, 9 H), 1.70 - 1.90 (m, 2 H), 2.05 - 2.19 (m, 2 H), 3.13 (dd, 1 H), 3.29 - 3.39 (m, 1 H), 3.46 - 3.62 (m, 2 H), 4.20 - 4.29 (m, 2 H), 5.39 (q, 1 H), 6.91 (d, 1 H), 7.09 - 7.14 (m, 1 H), 7.16 - 7.23 (m, 5 H), 7.49 (td, 1 H), 8.45 - 8.59 (m, 1 H).
Boc−L−Pro−OH(2.0g、9.29mmol)を無水DMF(15mL)に溶解した。HATU(3.7g、9.76mmol)およびヒューニッヒ塩基(5.3mL、30.66mmol)を加え、そして混合物を室温で30分間撹拌した。次いで、2−[(2S)−2−アザニウウムイル(azaniumyl)−2−フェニルエチル]ピリジン−1−イウムジクロリド(2.5g、9.29mmol)を溶液に加え、そして混合物を室温で3時間30分間撹拌した。水を加え、そして混合物をEtOAcで3×抽出した。有機相をブラインで洗浄し、Na2SO4で乾燥させ、濾過し、そして減圧下で濃縮した。生成物を、SiO2カラムにおいて勾配(0%MeOH/50%EtOAc/50%ヘプタン→0%MeOH/100%EtOAc/0%ヘプタン→10%MeOH/90%EtOAc/0%ヘプタン)で溶離し、次いでC−18カラムにおいてMeOHおよび水(0〜100%MeOH)の勾配で溶離して精製し、表題化合物2.9g(78%)を得た。
1H NMR (300 MHz, CDCl3): ppm 1.35 (s, 9 H), 1.70 - 1.90 (m, 2 H), 2.05 - 2.19 (m, 2 H), 3.13 (dd, J = 13.8, 7.1 Hz, 1 H), 3.29 - 3.39 (m, 1 H), 3.46 - 3.62 (m, 2 H), 4.20 - 4.29 (m, 1 H), 5.39 (q, J = 6.8 Hz, 1 H), 6.91 (d, J = 7.3 Hz, 1 H), 7.09 - 7.14 (m, 1 H), 7.16 - 7.23 (m, 5 H), 7.49 (td, J = 7.63, 1.8 Hz, 1 H), 8.45 - 8.59 (m, 1 H).
(S)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド二塩酸塩
1H NMR (300 MHz, DMSO-d6): ppm 1.61 - 1.84 (m, 3 H), 2.30 - 2.36 (m, 1 H), 3.05 - 3.11 (m, 2 H), 3.39 - 3.47 (m, 2 H), 4.05 - 4.20 (m, 2 H), 5.34 (q, 1 H), 7.17 - 7.41 (m, 5 H), 8.20 - 8.42 (m, 1 H), 8.67 - 8.75 (m, 1 H), 9.45 - 9.62 (m, 2 H).
tert−ブチル(2S)−2−{[(1S)−1−フェニル−2−(ピリジン−2−イル)エチル]カルバモイル}ピロリジン−1−カルボキシレート(2.9g、7.33mmol)を1,4−ジオキサン中の4M HCl溶液(73mL、293.31mmol)に溶解した。反応混合物を室温で3時間撹拌した。揮発性物質を真空下で除去し、そして生成物をMTBEで摩砕した。固形物をブーフナー漏斗上の濾過によって回収し、MTBEで洗浄し、そして真空下で乾燥させ、(2S)−2−{[(1S)−1−フェニル−2−(ピリジン−1−イウム−2−イル)エチル]カルバモイル}ピロリジン−1−イウム2.7g(100%)を得た。
1H NMR (300 MHz, D2O): ppm 1.66 - 1.83 (m, 3 H), 2.20 - 2.26 (m, 1 H), 3.14 (t, J = 6.9 Hz, 2 H), 3.34 (dd, J = 14.1, 8.2 Hz, 1 H), 3.51 (dd, J = 14.4, 7.3 Hz, 1 H), 4.18 (dd, J = 8.5, 6.2 Hz, 1 H), 5.11 (t, J = 7.9 Hz, 1 H), 7.06 - 7.10 (m, 2 H), 7.15 - 7.21 (m, 3 H), 7.61 - 7.70 (m, 2 H), 8.23 (dt, J = 7.9, 1.5 Hz, 1 H), 8.37 (d, J = 5.8 Hz, 1 H).
(S)−1−((S)−2−アミノ−3−メチルブタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド
tert−ブチル(S)−3−メチル−1−オキソ−1−((S)−2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−イル)ブタン−2−イルカルバメート
1H NMR (300 MHz, CDCl3): ppm 0.91 (d, 3 H), 1.00 (d, 3 H), 1.43 (s, 9 H), 1.85 - 1.99 (m, 2 H), 2.00 - 2.16 (m, 1 H), 2.17 - 2.21 (m, 1 H), 3.12 - 3.27 (m, 2 H), 3.47 - 3.62 (m, 1 H), 3.63 - 3.78 (m, 1 H), 4.32 (dd, 1 H), 4.58 (d, 1 H), 5.23 - 5.35 (m, 2 H), 6.97 (d, 1 H), 7.10 (dd, 1 H), 7.14 - 7.30 (m, 5 H), 7.50 (td, 1 H), 7.84 (d, 1 H), 8.48 (dd, 1 H).
(S)−1−((S)−2−アミノ−3−メチルブタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド二塩酸塩
1H NMR (300 MHz, CD3OD): ppm 0.97 (d, 3 H), 1.04 (d, 3 H), 1.68 - 1.79 (m, 1 H), 1.86 - 2.05 (m, 2 H), 2.13 - 2.27 (m, 2 H), 3.50 - 3.61 (m, 3 H), 3.68 - 3.75 (m, 1 H), 4.02 (d, 1 H), 4.45 (dd, 1 H), 5.40 (dd, 1 H), 7.31 - 7.43 (m, 5 H), 7.90 (t, 1 H), 8.02 (d, 1 H), 8.51 (td, 1 H), 8.75 (d, 1 H).
[M+H]+=395.27
(S)−1−((S)−2,6−ジアミノヘキサノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド
tert−ブチル(S)−6−オキソ−6−((S)−2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−イル)ヘキサン−1,5−ジイルジカルバメート
1H NMR (300 MHz, CDCl3): ppm 1.34 - 1.39 (m, 2 H), 1.41 (s, 9 H), 1.43 (s, 9 H
), 1.52 - 1.64 (m, 3 H), 1.68 - 2.02 (m, 4 H), 2.08 - 2.22 (m, 2 H), 3.02 - 3.16
(m, 3 H), 3.20 - 3.28 (m, 1 H), 3.48 - 3.57 (m, 1 H), 3.60 - 3.70 (m, 1 H), 4.40 - 4.51 (m, 1 H), 4.54 - 4.57 (m, 1 H), 4.97 - 5.08 (m, 1 H), 5,29 - 5.39 (m, 2 H), 7.00 (d, 1 H), 7.10 - 7.32 (m, 6 H), 7.52 (td, 1 H), 7.86 (d, 1 H), 8.49 (d, 1 H).
2−[(2S)−2−{[(2S)−1−[(2S)−2,5−ジアザニウムイルヘキサノイル]ピロリジン−2−イル]ホルムアミド}−2−フェニルエチル]ピリジン−1−イウムトリクロリドの合成
1H NMR (300 MHz, D2O): ppm 1.23 - 1.35 (m, 2 H), 1.46 - 1.59 (m, 3 H), 1.65 - 1.80 (m, 4 H), 2.04 - 2.13 (m, 1 H), 2.80 (t, 2 H), 3.31 - 3.43 (m, 2 H), 3.47 -
3.57 (m, 2 H), 4.16 (t, 1 H), 4.28 (t, 1 H), 5.11 (t, 1 H), 7.10 - 7.13 (m, 2 H), 7.16 - 7.26 (m, 3 H), 7.68 - 7.73 (m, 2 H), 8.31 (td, 1 H), 8.42 (dd, 1 H);
[M+H]+=424.2
(S)−1−(−2−アミノ−3−(1H−イミダゾール−4−イル)プロパノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド
tert−ブチル(S)−3−(1H−イミダゾール−4−イル)−1−オキソ−1−((S)−2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−イル)プロパン−2−イルカルバメート
1H NMR (300 MHz, CDCl3): ppm 1.44 (s, 9 H), 1.77 - 2.00 (m, 3 H), 2.05 - 2.19 (m, 1 H), 3.03 - 3.14 (m, 2 H), 3.23 (dd, 1 H), 3.40 (dd, 1 H), 3.52 - 3.58 (m, 1 ), 4.50 - 4.62 (m, 2 H), 5,43 - 5.50 (m, 2 H), 6.91 - 6.97 (m, 2 H), 7.13 - 7.27 (m, 5 H), 7.53 (t, 1 H), 7.65 (s, 1 H), 8.53 (d, 1 H), 8.67 (d, 1 H).
2−((S)−2−((S)−1−((S)−2−アンモニオ−3−(1H−イミダゾール−1−イウム−4−イル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジニウムトリクロリド
1H NMR (300 MHz, D2O): ppm 1.50 - 1.58 (m, 1 H), 1.69 - 1.76 (m, 2 H), 2.07 - 2.14 (m, 1 H), 3.12 - 3.21 (m, 3 H), 3.38 (dd, 7.3 Hz, 1 H), 3.48 - 3.56 (m, 2 H), 4.32 (t, 1 H), 4.43 (t, 1 H), 5.14 (t, 1 H), 7.08 - 7.12 (m, 2 H), 7.15 - 7.23 (m, 3 H), 7.26 (s, 1 H), 7.65 - 7.70 (m, 2 H), 8.26 (td, 1 H), 8.39 (d, 1 H), 8.49 (d, 1 H);
[M+H]+=433.2;
[M+Na]+=455.1
2−((S)−2−((S)−1−(−2−アミノ−3−(4−ヒドロキシフェニル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジン二塩酸塩
tert−ブチル(S)−3−(4−ヒドロキシフェニル)−1−オキソ−1−((S)−2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−イル)プロパン−2−イルカルバメート
1H NMR (300 MHz, CDCl3): ppm 1.44 (s, 9 H), 1.73 - 2.02 (m, 3 H), 2.16 - 2.22 (m, 1 H), 2.92 - 3.09 (m, 4 H), 3.35 - 3.42 (m, 1 H), 3.48 - 3.51 (m, 1 H), 3.53 - 3.68 (m, 1 H), 4.48 - 4.51 (m, 1 H), 4.65 - 4.73 (m, 1 H), 5.06 - 5.14 (m, 1 H), 5.43 (d, 1 H), 6.61 (d, 1 H), 6.86 (d,, 2 H), 6.94 - 6.99 (m, 2 H), 7.08 - 7.26 (m, 6 H), 7.42 (dd, 1 H), 8.49 (d, 1 H), 8.63 (s, 1 H).
2−((S)−2−((S)−1−((S)−2−アンモニオ−3−(4−ヒドロキシフェニル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジニウムジクロリド
1H NMR (300 MHz, D2O): ppm 1.48 - 1.57 (m, 1 H), 1.68 - 1.73 (m, 2 H), 1.98 - 2.05 (m, 1 H), 2.68 - 2.76 (m, 1 H), 2.93 - 3.00 (m, 1 H), 3.10 - 3.19 (m, 1 H),
3.40 - 3.63 (m, 3 H), 4.20 - 4.28 (m, 2 H), 5.14 (t, 1 H), 6.65 (d, 2 H), 6.96 (d, 2 H), 7.13 - 7.22 (m, 5 H), 7.63 - 7.66 (m, 2 H), 8.19 - 8.22 (m, 1 H), 8.40
(d, 1 H);
[M+H]+=459.2
2−((S)−2−((S)−1−(−2−アミノ−3−(1H−インドール−3−イル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジン二塩酸塩
tert−ブチル(S)−3−(1H−インドール−3−イル)−1−オキソ−1−((S)−2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−イル)プロパン−2−イルカルバメート
1H NMR (300 MHz, CDCl3): ppm 1.44 (s, 9 H), 1.77 - 1.89 (m, 3 H), 2.14 - 2.24 (m, 1 H), 3.03 - 3.24 (m, 4 H), 3.28 - 3.36 (m, 2 H), 3.54 - 3.65 (m, 1 H), 4.52 - 4.58 (m, 1 H), 4.79 - 4.88 (m, 1 H), 5,12 - 5.27 (m, 1 H), 5.34 - 5.41 (m, 1 H), 6.63 (d, 1 H), 6.94 - 7.31 (m, 8 H), 7.38 - 7.53 (m, 3 H), 7.62 - 7.67 (m, 1 H), 8.59 (d, 1 H), 9.87 (s, 1 H).
2−((S)−2−((S)−1−((S)−2−アンモニオ−3−(1H−インドール−3−イル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジニウムジクロリド
1H NMR (300 MHz, D2O): ppm 1.41 - 1.53 (m, 1 H), 1.63 - 1.72 (m, 2 H), 1.93 - 2.04 (m, 1 H), 2.85 (dd, 1 H), 2.94 - 3.55 (m, 5 H), 4.19 - 4.31 (m, 2 H), 5.08 (t, 1 H), 6.90 - 7.31 (m, 9 H), 7.38 (d, 1 H), 7.55 - 7.58 (m, 2 H), 8.15 (t, 1 H), 8.31 (d, 1 H);
[M+H]+=482.2、
[M+Na]+=504.1
(S)−1−((S)−2−アミノ−3−フェニルプロパノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド
tert−ブチル(S)−1−オキソ−3−フェニル−1−((S)−2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−イル)プロパン−2−イルカルバメート
1H NMR (300 MHz, CDCl3): ppm 1.44 (s, 9 H), 1.73 - 1.91 (m, 3 H), 2.10 - 2.19 (m, 1 H), 3.10 - 3.40 (m, 3 H), 3.45 - 3.61 (m, 2 H), 4.27 - 4.35 (m, 1 H), 4.50 - 4.56 (m, 1 H), 4.60 - 4.69 (m, 1 H), 5,17 - 5.41 (m, 3 H), 6.93 - 7.03 (m, 2 H), 7.06 - 7.32 (m, 9 H), 7.47 - 7.56 (m, 1 H), 7.82 (d, 1 H), 8.48 (d, 1 H).
2−((S)−2−((S)−1−((S)−2−アンモニオ−3−フェニルプロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジニウムジクロリド
1H NMR (300 MHz, D2O): ppm 1.39 - 1.48 (m, 1 H), 1.58 - 1.65 (m, 2 H), 1.92 - 1.99 (m, 1 H), 2.66 - 2.74 (m, 1 H), 2.95 - 3.10 (m, 2 H), 3.29 - 3.45 (m, 3 H),
4.15 - 4.27 (m, 2 H), 5.09 (t, 1 H), 6.97 - 7.17 (m, 10 H), 7.59 - 7.64 (m, 2 H
), 8.18 (t, 1 H), 8.35 (d, 1 H);
[M+H]+=443.3、
[M+Na]+=465.2
(S)−1−((S)−2−アミノ−4−メチルペンタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド
tert−ブチル(S)−4−メチル−1−オキソ−1−((S)−2−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイル)ピロリジン−1−イル)ペンタン−2−イルカルバメート
1H NMR (300 MHz, CDCl3): ppm 0.91 (d, 3 H), 0.98 (d, 3 H), 1.34 - 1.52 (m, 1 H), 1.41 (s, 9 H), 1.70 - 1.84 (m, 2 H), 1.85 - 1.96 (m, 3 H), 2.11 - 2.18 (m, 1 H), 3.07 - 3.27 (m, 2 H), 3.47 - 3.56 (m, 1 H), 3.61 - 3.71 (m, 1 H), 4.43 - 4.5
6 (m, 2 H), 5.14 - 5.18 (m, 1 H), 5,26 - 5.34 (m, 1 H), 6.98 (d, J = 7.7 Hz, 1 H), 7.08 - 7.25 (m, 5 H), 7.52 (t, 1 H), 7.83 (d, 1 H), 8.48 (d, 1 H).
2−((S)−2−((S)−1−((S)−2−アンモニオ−4−メチルペンタノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジニウムジクロリド
1H NMR (300 MHz, D2O): ppm 0.72 (d, 6 H), 1.31 - 1.49 (m, 4 H), 1.65 - 1.74 (m, 2 H), 1.93 - 2.02 (m, 1 H), 3.23 - 3.49 (m, 4 H), 3.99 - 4.04 (m, 1 H), 4.16 - 4.21 (m, 1 H), 5.07 (t, 1 H), 7.08 - 7.20 (m, 5 H), 7.63 - 7.67 (m, 2 H), 8.22 (td, 1 H), 8.37 (dd, 1 H);
[M+H]+=409.2、
[M+Na]+=431.2
2−[(2S)−2−{[(2S)−1−[(2S)−2−アザニウムイル−5−{[アザニウムイル(イミニウムイル)メチル]アミノ}ペンタノイル]−ピロリジン−2−イル]ホルムアミド}−2−フェニルエチル]ピリジン−1−イウムテトラクロリド
tert−ブチルN−[(1Z)−{[(4S)−4−{[(tert−ブトキシ)カルボニル]アミノ}−5−オキソ−5−[(2S)−2−{[(1S)−1−フェニル−2−(ピリジン−2−イル)エチル]カルバモイル}ピロリジン−1−イル]ペンチル]アミノ}({[(tert−ブトキシ)カルボニル]イミノ})メチル]カルバメート
1H NMR (300 MHz, CDCl3): ppm 1.43 (s, 9 H), 1.46 (s, 9 H), 1.51 (s, 9 H), 1.57 - 1.76 (m, 4 H), 1.86 - 1.99 (m, 3 H), 2.12 - 2.25 (m, 1 H), 3.11 (dd, 1 H), 3.23 - 3.30 (m, 1 H), 3.58 - 3.95 (m, 4 H), 4.42 (t,, 1 H), 4.56 (d, 1 H), 5,31 - 5.38 (m, 2 H), 6.98 (d, 1 H), 7.17 - 7.33 (m, 5 H), 7.54 (t, 1 H), 7.93 (d, 1 H), 8.56 (d, 1 H).
2−[(2S)−2−{[(2S)−1−[(2S)−2−アザニウムイル−5−{[アザニウムイル(イミニウムイル)メチル]アミノ}ペンタノイル]ピロリジン−2−イル]ホルムアミド}−2−フェニルエチル]ピリジン−1−イウムテトラクロリド
1H NMR (300 MHz, D2O): ppm 1.31 - 1.57 (m, 3 H), 1.66 - 1.78 (m, 4 H), 2.00 - 2.10 (m, 1 H), 2.99 (t, 2 H), 3.28 - 3.40 (m, 4 H), 4.16 (t, 1 H), 4.26 (t, 1 H)
, 5.09 (t, 1 H), 7.10 - 7.13 (m, 2 H), 7.16 - 7.21 (m, 3 H), 7.67 - 7.71 (m, 2 H), 8.27 (t, 1 H), 8.40 (d, 1 H);
[M+H]+=452.2
本明細書に記載されたプロドラッグは、うつ病または疼痛を患っている対象に経口投与することが企図されている。
この実施例は、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンへの異なる変換速度(すなわち、遅いまたは急速な)を達成して適したPKプロファイルを確認するため、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミン(式中、R1はC1−6アルキルC(O)O(C1−6アルコキシ)である)の異なるプロドラッグを用いてもよいことを示している。したがって、異なるプロドラッグを製造するためにR1を変えることにより、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンの異なる薬物動態プロファイルが得られる。さらに、この実施例は、プロドラッグが遊離塩基に変換されるときに、経口曝露において予想される損失がないことを示している。プロドラッグ(式中、R1は、C1−6アルキルC(O)O(C1−6アルコキシ)である)の(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンへの変換は、エステルのような官能基の最初の酵素的加水分解を介して起こり、続いて(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンへの自然変換が起こることが予想される。含まれる酵素は、いくつかの非特異的な高い能力のエステラーゼであるのことが予想され、それは非選択的エステラーゼ阻害剤による変換を阻害するが、選択的阻害剤を用いた変換を阻害しないことによって示すことができる。このようなエステラーゼは、人体の至るところに分布することが予想される。(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンのプロドラッグの薬物動態的性質ならびに異なる身体区画における(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンの形成速度および形成度を試験するため、ヒト腸液(HIF)、ヒト肝臓S9画分およびヒト全血を用いている。表1に示すように、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンの異なるプロドラッグからの(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンの形成速度は、試験したすべてのアッセイにおいて著しく異なる。
この実施例は、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンへの変換(すなわち、遅いまたは急速な)異なる速度を達成して適したPKプロファイルを確認するため、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミン(式中、R1は、
したがって、異なるプロドラッグの使用によって(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンの異なる薬物動態プロファイルを達成することができる。
この実施例は、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンのプロドラッグの経口投与が、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンの1時間の静脈内注入と類似した薬物動態プロファイルを有することを示している。
この実施例は、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミン二塩酸塩のプロドラッグ(実施例5)および(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミン二塩酸塩の用量をイヌに投与したときに、プロドラッグでは、NOELおよびLOELによって表されるような発作のリスクが、より少なかったことを示している。
この実施例は、図1aおよび図1bに示すように、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンのプロドラッグ、実施例5の用量増加によるヒト腸液中の(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンの濃度の増加が、比例するよりも少ないことを示している。結果として、それにより、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンを直接投与することに比べて、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンのプロドラッグを投与することで高濃度の(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンを得ることが困難となり、そのことは、薬物乱用に求められている。理論によって拘束されることを望むわけではないが、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンのプロドラッグ(式中、R1がある)は、主にDPPIVによって切断される。プロドラッグの(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンへの変換に影響を及ぼすDPPIVの内因性および/または外因性の調整の可能性がある。
実施例17のインビトロ観察と一致して、ラットにおけるインビボ研究(下の実施例18)は、上記のような(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンのCmax曝露が、(S)−1−フェニル−2−(ピリジン−2−イル)エタンアミンのプロドラッグの治療用量と治療超過用量との間の移行に比例するほどには増加しないことを示している。これらのインビボ研究の結果を表5に作表した。
Claims (18)
- 以下からなる群から選択される請求項1に記載の化合物:
(S)−(1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)メチルイソブチレート;
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレート;
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレートジアステレオマー1;
2−メチル−1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)プロピルイソブチレートジアステレオマー2;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテート;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテートジアステレオマー1;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルアセテートジアステレオマー2;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレート;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレートジアステレオマー1;
1−((S)−1−フェニル−2−(ピリジン−2−イル)エチルカルバモイルオキシ)エチルイソブチレートジアステレオマー2;
(S)−1−((S)−2−アミノ−3−メチルブタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
(S)−1−((S)−2,6−ジアミノヘキサノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
(S)−1−(−2−アミノ−3−(1H−イミダゾール−4−イル)プロパノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
2−((S)−2−((S)−1−(−2−アミノ−3−(4−ヒドロキシフェニル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジン;
2−((S)−2−((S)−1−(−2−アミノ−3−(1H−インドール−3−イル)プロパノイル)ピロリジン−2−カルボキサミド)−2−フェニルエチル)ピリジン;
(S)−1−((S)−2−アミノ−3−フェニルプロパノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;もしくは
(S)−1−((S)−2−アミノ−4−メチルペンタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミド;
または上記のいずれか1つの薬学的に許容される塩。 - 化合物(S)−1−((S)−2−アミノ−3−メチルブタノイル)−N−((S)−1−フェニル−2−(ピリジン−2−イル)エチル)ピロリジン−2−カルボキサミドまたはその薬学的に許容される塩。
- 請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩を、薬学的に許容される補助剤、賦形剤または担体と共に含む医薬組成物。
- 治療に使用するための、請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩。
- うつ病の処置のための薬剤の製造における請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の使用。
- うつ病の処置のための請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の使用。
- うつ病障害が大うつ病性障害である、請求項6または7に記載の使用。
- うつ病の処置を必要とする患者に請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の治療有効量を投与することを含む、うつ病を処置する方法。
- うつ病障害が大うつ病性障害である、請求項9に記載の方法。
- 疼痛の処置のための薬剤の製造における請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の使用。
- 疼痛の処置のための請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の使用。
- 疼痛の処置を必要とする患者に請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の治療有効量を投与することを含む、疼痛を処置する方法。
- レット症候群、自殺念慮、双極性障害、強迫性障害、サリンガス中毒またはてんかん重積状態の処置のための薬剤の製造における、請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の使用。
- レット症候群、自殺念慮、双極性障害、強迫性障害、サリンガス中毒またはてんかん重積状態の処置のための請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の使用。
- レット症候群、自殺念慮、双極性障害、強迫性障害、サリンガス中毒またはてんかん重積状態を処置する方法であって、処置を必要とする患者に請求項1、2または3に記載された式(I)の化合物またはその薬学的に許容される塩の治療有効量を投与することを含む方法。
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US11358935B2 (en) | 2016-11-28 | 2022-06-14 | Biohaven Pharmaceutical Holding Company Ltd. | Prodrugs of lanicemine and their method of use |
CN107578281B (zh) * | 2017-08-31 | 2021-03-30 | 湖南大学 | 电子商务环境下用户优惠券行为预测方法及模型构建方法 |
IL299308A (en) * | 2020-06-23 | 2023-02-01 | Biohaven Therapeutics Ltd | Cutaneous formulations of (1S)-1-PHENYL-2-PYRIDIN-2-YLETHANAMINE |
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