JP2020517707A - Sestrin−GATOR2相互座用のモジュレーターおよびその使用 - Google Patents
Sestrin−GATOR2相互座用のモジュレーターおよびその使用 Download PDFInfo
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Abstract
Description
本発明は、Sestrin−GATOR2の相互作用をモジュレートし、それによって、間接的に、mTORC1活性を選択的にモジュレートするのに有用な化合物および方法に関する。本発明は、本発明の化合物を含む薬学的に許容される組成物および種々の障害の処置において前記組成物を使用する方法も提供する。
ラパマイシン標的タンパク質複合体1(mTORC1)タンパク質キナーゼは、増殖因子、細胞ストレス、ならびに栄養およびエネルギーレベルなどの多様な環境要因を感知する主な増殖調節因子である。活性化されると、mTORC1は、mRNAの翻訳および脂質合成などの同化作用プロセスを増強する基質をリン酸化し、オートファジーなどの異化作用プロセスを制限する。mTORC1の調節不全は、とりわけ、糖尿病、てんかん、神経変性、免疫応答、骨格筋増殖の抑制、およびがんを含む広範囲の疾患において生じる(Howellら、(2013年) Biochemical Society transactions 41巻、906〜912頁;Kimら、(2013年) Molecules and cells 35巻、463〜473頁;LaplanteおよびSabatini、(2012年) Cell 149巻、274〜293頁)。
Sestrin−GATOR2複合体のモジュレーションは、間接的に、mTORC1活性を選択的にモジュレートする潜在的治療標的を表す。
1.本発明のある特定の実施形態についての一般的説明:
本発明の化合物、およびその組成物は、Sestrin−GATOR2モジュレーターとして有用である。ある特定の実施形態では、本発明は、式I:
R1は、HまたはC1〜6アルキルであり;
R2は、R、−(CH2)n−フェニル、−C(O)R、−SO2R、または−C(O)N(R)2であり;
nは、0、1、または2であり;
各Rは、独立して、水素、−CN、あるいは飽和もしくは不飽和C1〜6脂肪族、フェニル、4〜7員の飽和もしくは部分的不飽和の単環式炭素環式環、1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環、または窒素、酸素、もしくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜8員の飽和もしくは部分的飽和の複素環式環から選択される必要に応じて置換された基であり;
R3は、環A、−C(O)R、−C(O)OR、−C(O)N(R)2、−SO3H、−SO2N(R)2、−S(O)R、−S(O)環A、−ORまたは−B(OR)2(式中、同一のホウ素上の2つのOR基はそれらの介在原子と一緒になって5〜8員の単環式飽和もしくは部分的に不飽和の、ホウ素および2つの酸素に加えて、窒素、酸素、もしくは硫黄から独立して選択される0〜3個のヘテロ原子を有する環を形成するか、またはR3およびR4は一緒になって、窒素、酸素もしくは硫黄から選択される0〜1個のヘテロ原子を有する必要に応じて置換された5〜6員の環を形成する)であり;
Lは、共有結合または1〜9個のフルオロ基で必要に応じて置換された直鎖状もしくは分枝鎖状のC1〜6アルキレン鎖であり;
環Aは、フェニル、または窒素、酸素もしくは硫黄から独立して選択される1〜4個のヘテロ原子を有する必要に応じて置換された5〜6員のヘテロアリール環から選択される必要に応じて置換された環であり;
R4は、R、−CF3、−OR、−N(R)2、−Si(R)3、もしくは−SRであるか、またはR3およびR4は一緒になって、窒素、酸素もしくは硫黄から選択される0〜1個のヘテロ原子を有する必要に応じて置換された5〜6員の環を形成し;
R5は、HまたはC1〜4アルキルである]の化合物またはその薬学的に許容される塩を提供する。
本発明の化合物は、本明細書で一般的に記載されるものを含み、本明細書に開示されるクラス、サブクラス、および種によってさらに例示される。本明細書で使用する場合、別段示されなければ、以下の定義が適用されるものとする。この発明の目的として、化学元素は、元素周期表、CAS版、Handbook of Chemistry and Physics、第75版に従って同定される。さらに、有機化学の一般的原理が、その全内容が参照により本明細書に組み込まれる、「Organic Chemistry」、Thomas Sorrell、University Science Books、Sausalito:1999年、および「March's Advanced Organic Chemistry」、第5版:Smith,M.B.およびMarch,J.、John Wiley & Sons、New York:2001年に記載されている。
ある特定の実施形態では、本発明は、式I:
R1は、HまたはC1〜6アルキルであり;
R2は、R、−(CH2)n−フェニル、−C(O)R、−SO2R、または−C(O)N(R)2であり;
nは、0、1、または2であり;
各Rは、独立して、水素、−CN、あるいは飽和もしくは不飽和C1〜6脂肪族、フェニル、4〜7員の飽和もしくは部分的不飽和の単環式炭素環式環、1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環、または窒素、酸素、もしくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜8員の飽和もしくは部分的飽和の複素環式環から選択される必要に応じて置換された基であり;
R3は、環A、−C(O)R、−C(O)OR、−C(O)N(R)2、−SO3H、−SO2N(R)2、−S(O)R、−S(O)環A、−ORまたは−B(OR)2(式中、同一のホウ素上の2つのOR基はそれらの介在原子と一緒になって5〜8員の単環式飽和もしくは部分的に不飽和の、ホウ素および2つの酸素に加えて、窒素、酸素、もしくは硫黄から独立して選択される0〜3個のヘテロ原子を有する環を形成するか、またはR3およびR4は一緒になって、窒素、酸素もしくは硫黄から選択される0〜1個のヘテロ原子を有する必要に応じて置換された5〜6員の環を形成する)であり;
Lは、共有結合または1〜9個のフルオロ基で必要に応じて置換された直鎖状もしくは分枝鎖状のC1〜6アルキレン鎖であり;
環Aは、フェニル、または窒素、酸素もしくは硫黄から独立して選択される1〜4個のヘテロ原子を有する必要に応じて置換された5〜6員のヘテロアリール環から選択される必要に応じて置換された環であり;
R4は、R、−CF3、−OR、−N(R)2、−Si(R)3、もしくは−SRであるか、またはR3およびR4は一緒になって、窒素、酸素もしくは硫黄から選択される0〜1個のヘテロ原子を有する必要に応じて置換された5〜6員の環を形成し;
R5は、HまたはC1〜4アルキルである]の化合物またはその薬学的に許容される塩を提供する。
Qは、−C(R’)2−または−NH−であり;
RxおよびRyのそれぞれは、水素であるか、またはRxおよびRyは一緒になって=Oを形成し;
各Rは、独立して、水素、−CN、あるいはC1〜6脂肪族、フェニル、4〜7員の飽和もしくは部分的不飽和の単環式炭素環式環、1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環、または窒素、酸素、もしくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜8員の飽和もしくは部分的飽和の複素環式環から選択される必要に応じて置換された基であり;
各R’は、独立して、水素、ハロゲン、−CN、あるいはC1〜6脂肪族、フェニル、4〜7員の飽和もしくは部分的不飽和の単環式炭素環式環、1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環、または窒素、酸素、もしくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜8員の飽和もしくは部分的飽和の複素環式環から選択される必要に応じて置換された基であり;
Lは、共有結合または1〜9個のフルオロ基で必要に応じて置換された直鎖状もしくは分枝鎖状のC1〜6アルキレン鎖であり;
R4’は、R、−CF3、−OR、−N(R)2、−Si(R)3、または−SRであり;
R5’は、H、−OR、またはC1〜4アルキルである]の化合物またはその薬学的に許容される塩を提供する。
R1は、HまたはC1〜6アルキルであり;
R2は、R、−(CH2)n−フェニル、−C(O)R、−SO2R、または−C(O)N(R)2であり;
各R4’’は、独立して、R、ハロゲン、または−CF3であり;
各Rは、独立して、水素、−CN、あるいは飽和もしくは不飽和C1〜6脂肪族、フェニル、4〜7員の飽和もしくは部分的不飽和の単環式炭素環式環、1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環、または窒素、酸素、もしくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜8員の飽和もしくは部分的飽和の複素環式環から選択される必要に応じて置換された基であり;
L1は、共有結合または1〜9個のフルオロ基で必要に応じて置換された直鎖状もしくは分枝鎖状のC1〜6アルキレン鎖である]の化合物またはその薬学的に許容される塩を提供する。
4.使用、製剤化および投与
薬学的に許容される組成物
本明細書に記載の化合物および組成物は、一般的に、Sestrin−GATOR2の相互作用の阻害または活性化に有用である。一部の実施形態では、提供される化合物、またはその組成物は、Sestrin−GATOR2の相互作用のアクチベーターである。
4A MS:4Å分子篩
AcOH:酢酸
ACN:アセトニトリル
Anhyd:無水の
Aq:水性の
Bn:ベンジル
Boc:tert−ブトキシカルボニル
CbzCl:クロロギ酸ベンジル
Cbz−OSU:N−(ベンジルオキシカルボニルオキシ)スクシンイミド
Cu(OAc)2:酢酸銅(II)
d:日数
DAST:ジエチルアミノ硫黄トリフルオリド
DBU:1,8−ジアゾビシクロ[5.4.0]ウンデカ−7−エン
DCE:1,2−ジクロロエタン
DCM:ジクロロメタン
DEA:ジエチルアミン
DIBAL−H:水素化ジイソブチルアルミニウム
DIPEA:N,N−ジイソプロピルエチルアミン
DMA:N,N−ジメチルアセトアミド
DMAP:4−ジメチルアミノピリジン
DMF:N,N−ジメチルホルムアミド
DMSO−ジメチルスルホキシド
DPPA:ジフェニルホスホリルアジド
EDC:1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩
ee:鏡像異性体過剰率
ESI:エレクトロスプレーイオン化
Et3N:トリエチルアミン
Et2O:ジエチルエーテル
EtOAc:酢酸エチル
EtOH:エタノール
Fmoc:フルオレニルメチルオキシカルボニル
Fmoc−OSu:N−(9−フルオレニルメトキシカルボニルオキシ)スクシンイミド
h:時間
HATU:1−[Bis(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシドヘキサフルオロホスフェート
HCOONH4:ギ酸アンモニウム
HPLC:高速液体クロマトグラフィー
IBX:2−ヨードキシ安息香酸
IPA:イソプロピルアルコール
KOAc:酢酸カリウム
M:モル濃度
Me:メチル
MeOH:メタノール
mins:分
mL:ミリリットル
mM:ミリモル濃度
mmol:ミリモル
MTBE:メチルtert−ブチルエーテル
NaBH3CN:シアノ水素化ホウ素ナトリウム
Na2CO3:炭酸ナトリウム
NaHCO3:炭酸水素ナトリウム
NMP:N−メチルピロリジン
NMR:核磁気共鳴
℃:セルシウス度
PBS:リン酸緩衝生理食塩水
Pd/C:パラジウム炭素
Pd(OH)2/C:パールマン触媒
PE:石油エーテル
PhNH2:アニリン
PPh3:トリフェニルホスフィン
Rel:相対的な
rt:室温
sat:飽和
SFC:超臨界流体クロマトグラフィー
SOCl2:塩化チオニル
TBAB:テトラ−n−ブチルアンモニウムブロミド
tBuOK:カリウムtert−ブトキシド
TEA:トリエチルアミン
Tf:トリフルオロメタンスルホネート
TfAA:トリフルオロメタンスルホン酸無水物
TFA:トリフルオロ酢酸
TIPS:トリイソプロピルシリル
THF:テトラヒドロフラン
TMSCN:トリメチルシリルシアニド
pTSA:パラトルエンスルホン酸
TsOH:p−トルエンスルホン酸
(S)−2−(ジメチルアミノ)−4−メチルペンタン酸[I−1]
ステップ1:(S)−2−(ジメチルアミノ)−4−メチルペンタン酸:
(S)−2−アミノ−7,7,7−トリフルオロヘプタン酸塩酸塩[I−2]および(R)−2−アミノ−7,7,7−トリフルオロヘプタン酸塩酸塩[I−3]。
ステップ1:1,1,1−トリフルオロ−5−ヨードペンタン:
tert−ブチル2−(ジフェニルメチレンアミノ)アセテート(2.0g、6.78mmol)およびTBAB(109mg、0.339mmol)のトルエン(35mL)およびDCM(15mL)中溶液に、−10℃で、KOH(50%、20mL)を添加し、5分後に、1,1,1−トリフルオロ−5−ヨードペンタンのEt2O(30mL)中上記溶液を5分かけて滴下添加し、得られた混合物を、−10℃〜0℃で1時間撹拌した。溶液を水(200mL)で希釈し、EA(100mL)で抽出した。有機相を水(100mL×2)およびブライン(100mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、真空中で濃縮し、粗生成物をクロマトグラフィー(シリカ、酢酸エチル/石油エーテル=1/10)、次いで、キラル分取HPLC[カラム、R,R−whelk−ol 4.6*250mm 5um;溶媒、MeOH(0.2%のメタノール アンモニア)]で精製して、(S)−tert−ブチル2−(ジフェニルメチレンアミノ)−7,7,7−トリフルオロヘプタノエート(200mg、0.48mmol、7.1%)および(R)−tert−ブチル2−(ジフェニルメチレンアミノ)−7,7,7−トリフルオロヘプタノエート(200mg、0.48mmol、7.1%)を得た。
(S)−2−アミノ−4,4,4−トリフルオロブタン酸[I−4]および(R)−2−アミノ−4,4,4−トリフルオロブタン酸[I−5]。
(S)−2−アミノ−5,5,5−トリフルオロペンタン酸[I−6]および(R)−2−アミノ−5,5,5−トリフルオロペンタン酸[I−7]。
ステップ1:4,4,4−トリフルオロブタナール:
(S)−2−アミノ−6,6,6−トリフルオロヘキサン酸[I−8]および(R)−2−アミノ−6,6,6−トリフルオロヘキサン酸[I−9]。
(S)−2−(ベンジルアミノ)−4−メチルペンタン酸[I−11]。
(S)−4−メチル−2−(2−フェニルアセトアミド)ペンタン酸[I−12]:
(S)−2−(イソプロピルアミノ)−4−メチルペンタン酸[I−13]:
(S)−2−(イソブチルアミノ)−4−メチルペンタン酸[I−14]:
(S)−2−ベンズアミド−4−メチルペンタン酸[I−15]:
(S)−2−イソブチルアミド−4−メチルペンタン酸[I−16]:
(S)−2−(シクロヘキサンスルホンアミド)−4−メチルペンタン酸[I−17]:
(S)−4−メチル−2−(フェニルメチルスルホンアミド)ペンタン酸[I−18]:
(S)−4−メチル−2−(メチルスルホンアミド)ペンタン酸[I−19]:
(S)−2−アミノ−4−メチル−N−フェニルペンタンアミド[I−20]:
(S)−2−アミノ−N,4−ジメチルペンタンアミド[I−21]:
(S)−4−メチル−2−(フェニルアミノ)ペンタン酸[I−22]:
(S)−4−メチル−2−(フェニルスルホンアミド)ペンタン酸[I−25]:
(S)−4−メチル−2−(フェニルアミノ)ペンタン酸[I−26]:
(S)−2−アセトアミド−4−メチルペンタン酸[I−36]:
(S,E)−2−(4−メトキシ−4−オキソブタ−2−エンアミド)−4−メチルペンタン酸[I−45]:
(R)−2−アミノ−3,3−ジフルオロ−4−メチルペンタン酸[I−46]および(S)−2−アミノ−3,3−ジフルオロ−4−メチルペンタン酸[I−47]:
(S)−2−アミノ−4−メチル−N−(メチルスルホニル)ペンタンアミド塩酸塩[I−147]。
ステップ1:(S)−tert−ブチル4−メチル−1−(メチルスルホンアミド)−1−オキソペンタン−2−イルカルバメート:
(S)−tert−ブチル4−メチル−1−(メチルスルホンアミド)−1−オキソペンタン−2−イルカルバメート(130mg、0.42mmol)のEt2O(15mL)中溶液に、4MのHCl/ジオキサン(5mL)を添加し、室温で3時間撹拌した。固体を濾過して、(S)−2−アミノ−4−メチル−N−(メチルスルホニル)ペンタンアミド塩酸塩[I−147]を白色固体(32mg、0.13mmol、31%)として得た。ESI-MS (EI+, m/z): 209.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 3.96 (t, J = 3.0 Hz, 1H), 3.32 (s, 3H), 1.74-1.79 (m, 3H), 1.02-1.05 (m, 6H).
(S)−2−アミノ−N,4,4−トリメチル−N−(メチルスルホニル)ペンタンアミド塩酸塩[I−193]。
ステップ1:(S)−tert−ブチル4,4−ジメチル−1−(N−メチルメチルスルホンアミド)−1−オキソペンタン−2−イルカルバメート:
(S)−tert−ブチル4,4−ジメチル−1−(N−メチルメチルスルホンアミド)−1−オキソペンタン−2−イルカルバメート(420mg、1.25mmol)のEt2O(20mL)中溶液に、4MのHCl/ジオキサン(10mL)を添加し、室温で17時間撹拌した。固体を濾過して、(S)−2−アミノ−N,4,4−トリメチル−N−(メチルスルホニル)ペンタンアミド塩酸塩[I−193]を白色固体(250mg、0.13mmol、71%)として得た。ESI-MS (EI+, m/z): 237.1 [M+H]+. 1H NMR (500 MHz, DMSO) δ 8.55 (s, 3H), 4.59 (s, 1H), 3.50 (s, 3H), 3.26 (s, 3H), 1.81-1.85 (m, 1H), 1.63-1.67 (m, 1H), 0.95 (s, 9H).
2−アミノ−4−フルオロ−4−メチル−N−(メチルスルホニル)ペンタンアミド塩酸塩[I−192]。
ステップ1:tert−ブチル4−フルオロ−4−メチル−1−(メチルスルホンアミド)−1−オキソペンタン−2−イルカルバメート:
(S)−tert−ブチル4,4−ジメチル−1−(N−メチルメチルスルホンアミド)−1−オキソペンタン−2−イルカルバメート(200mg、0.6mmol)のEt2O(20mL)中溶液に、4MのHCl/ジオキサン(10mL)を添加し、室温で17時間撹拌した。固体を濾過して、2−アミノ−4−フルオロ−4−メチル−N−(メチルスルホニル)ペンタンアミド塩酸塩[I−192]を白色固体(89.8mg、0.34mmol、57%)として得た。ESI-MS (EI+, m/z): 227.1 [M+H]+. 1H NMR (500 MHz, DMSO) δ 8.44 (s, 3H), 4.02 (s, 1H), 3.25 (s, 3H), 2.16-2.25 (m, 1H), 2.03-2.10 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H).
(S)−メチル2−((S)−2−アミノ−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート塩酸塩[I−190]。
ステップ1:(S)−メチル2−((S)−2−(tert−ブトキシカルボニルアミノ)−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート:
(S)−メチル2−((S)−2−(tert−ブトキシカルボニルアミノ)−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート(500mg、1.34mmol)のEt2O(20mL)中溶液に、4MのHCl/ジオキサン(10mL)を添加し、室温で17時間撹拌した。固体を濾過して、(S)−メチル2−(S)−2−アミノ−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート塩酸塩[I−190]を白色固体(300mg、0.97mmol、73%)として得た。ESI-MS (EI+, m/z): 273.2 [M+H]+. 1H NMR (500 MHz, DMSO) δ 9.07-9.09 (d, J = 7.5 Hz, 1H), 8.42 (s, 3H), 4.29-4.34 (m, 1H), 3.82 (m, 1H), 3.60 (s, 3H), 1.72-1.83 (m, 2H), 1.50-1.62 (m, 3H), 0.86-0.91 (m, 15H).
(S)−メチル2−アミノ−4,4−ジメチルペンタノエート塩酸塩[I−122]。
ステップ1:(S)−メチル2−アミノ−4,4−ジメチルペンタノエート塩酸塩[I−122]:
(R)−メチル2−アミノ−4,4−ジメチルペンタノエート塩酸塩[I−123]。
ステップ1:(R)−メチル2−アミノ−4,4−ジメチルペンタノエート塩酸塩[I−123]:
2−アミノ−N−シアノ−5,5,5−トリフルオロ−4−メチルペンタンアミド塩酸塩[I−205]。
ステップ1:2−(tert−ブトキシカルボニルアミノ)−5,5,5−トリフルオロ−4−メチルペンタン酸:
2−(tert−ブトキシカルボニルアミノ)−5,5,5−トリフルオロ−4−メチルペンタン酸(385mg、1.35mmol)、1−ヒドロキシピロリジン−2,5−ジオン(197mg、1.71mmol)、DCC(353mg、1.71mmol)の混合物をDCM(15mL)中に溶解した。混合物を室温で17時間撹拌した。濾過し、濾液をブライン(20mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、濃縮して、粗製の2,5−ジオキソピロリジン−1−イル2−(tert−ブトキシカルボニルアミノ)−5,5,5−トリフルオロ−4−メチルペンタノエート(400mg)を白色固体として得た。ESI-MS (EI+, m/z): 282.9 [M-100]+.
2,5−ジオキソピロリジン−1−イル2−(tert−ブトキシカルボニルアミノ)−5,5,5−トリフルオロ−4−メチルペンタノエート(300mg、0.78mmol)、シアナミド(66mg、1.57mmol)、NaOH(156mg、3.9mmol)の混合物をTHF(16mL)中に溶解した。混合物を0℃で0.5時間および室温で17時間撹拌した。溶液を分取HPLC(Boston C18 21*250mm 10μm、移動相:A:0.1%のトリフルオロ酢酸;B:アセトニトリル)で精製して、tert−ブチル1−シアナミド−5,5,5−トリフルオロ−4−メチル−1−オキソペンタン−2−イルカルバメート(45mg、0.14mmol)を白色固体として得た。MS (EI+, m/z): 310.3 [M+H]+.
tert−ブチル1−シアナミド−5,5,5−トリフルオロ−4−メチル−1−オキソペンタン−2−イルカルバメート(45mg、0.14mmol)のEt2O(20mL)中溶液に、4MのHCl/ジオキサン(10mL)を添加し、室温で24時間撹拌した。溶液を分取HPLC(Boston C18 21*250mm 10μm、移動相:A:0.1%のトリフルオロ酢酸;B:アセトニトリル)で精製して、2−アミノ−N−シアノ−5,5,5−トリフルオロ−4−メチルペンタンアミド塩酸塩[I−205](12.3mg、0.05mmol、27%)を白色固体として得た。MS(EI+、m/z):210.1[M+H]+。1H NMR (500 MHz, CD3OD) δ 4.06-4.09 (m, 1H), 2.43-2.65 (m, 1H), 1.67-1.85 (m, 2H), 1.18-1.22 (m, 3H).
2−アミノ−3−(1−メチルシクロブチル)プロパン酸[I−206]。
ステップ1:N−メトキシ−N,1−ジメチルシクロブタンカルボキサミド:
N−メトキシ−N,1−ジメチルシクロブタンカルボキサミド(2.0g、12.7mmol)の乾燥THF(20mL)中溶液に、0℃にてN2下で、1MのLiAlH4(19mL、19mmol)を滴下添加した。混合物を室温まで温め、2時間撹拌した。溶液を飽和セニエット塩でゆっくりとクエンチし、Et2O(100mL)で抽出し、有機相を水(100mL×2)およびブライン(100mL)で洗浄し、乾燥させ(Na2SO4)、濾過して、次のステップに使用した。
witting試薬(2.15g、5.86mmol)の乾燥THF(80mL)中溶液に、0℃で、t−BuONa(844mg、8.79mmol)を添加し、1時間撹拌した。次いで、1−メチルシクロブタンカルバルデヒドの溶液を添加し、室温で17時間撹拌した。溶液をEtOAc(100mL×2)で抽出した。有機相をブライン(100mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、真空中で濃縮した。粗生成物をクロマトグラフィー(シリカ、酢酸エチル/石油エーテル=1/30)で精製して、(Z)−tert−ブチル2−(tert−ブトキシカルボニルアミノ)−3−(1−メチルシクロブチル)アクリレート(700mg、2.2mmol)を無色油として得た。ESI-MS (EI+, m/z): 200.2 [M-56*2]+.
(Z)−tert−ブチル2−(tert−ブトキシカルボニルアミノ)−3−(1−メチルシクロブチル)アクリレート(700mg、2.2mmol)およびPd/C(10%、100mg)のMeOH(100mL)中混合物を30℃で17時間撹拌した。混合物を濾過し、濾液を濃縮乾固して、tert−ブチル2−(tert−ブトキシカルボニルアミノ)−3−(1−メチルシクロブチル)プロパノエート(600mg、粗製)を無色油として得た。ESI-MS (EI+, m/z): 158.2 [M-156]+.
tert−ブチル2−(tert−ブトキシカルボニルアミノ)−3−(1−メチルシクロブチル)プロパノエート(600mg、粗製)のEt2O(20mL)中溶液に、4MのHCl/ジオキサン(10mL)を添加し、室温で17時間撹拌した。溶液を濃縮して、2−アミノ−3−(1−メチルシクロブチル)プロパン酸を得た。MS(EI+、m/z):158.0[M+H]+。1H NMR (500 MHz, D2O) δ 3.91 (t, J = 7.5 Hz, 1H), 2.06-2.02 (m, 1H), 1.88-1.64 (m, 7H), 1.15 (s, 3H).
S−2−アミノ−3−(1−メチルシクロブチル)プロパン酸[I−93]。
2−アミノ−3−(1−メチルシクロブチル)プロパン酸に関する手順は、実施例8と同一であった。
2−アミノ−3−(1−メチルシクロブチル)プロパン酸(300mg、粗製)、CbzOSu(714mg、2.8mmol)のアセトン(10mL)および飽和NaHCO3(3mL)中混合物を室温で5時間撹拌した。溶液を分取HPLC(Boston C18 21*250mm 10μm、移動相:A:0.1%のトリフルオロ酢酸;B:アセトニトリル)で精製して、2−(ベンジルオキシカルボニルアミノ)−3−(1−メチルシクロブチル)プロパン酸(160mg、0.54mmol)を白色固体として得た。MS (EI+, m/z): 292.0[M+H]+.
2−(ベンジルオキシカルボニルアミノ)−3−(1−メチルシクロブチル)プロパン酸(160mg、0.54mmol)をキラルHPLCで精製して、(S)−2−(ベンジルオキシカルボニルアミノ)−3−(1−メチルシクロブチル)プロパン酸(50mg、0.17mmol)を白色固体として得た。MS (EI+, m/z): 292.0[M+H]+.
(S)−2−(ベンジルオキシカルボニルアミノ)−3−(1−メチルシクロブチル)プロパン酸(50mg、0.17mmol)およびPd/C(10%、10mg)のMeOH(10mL)中混合物を室温で1時間撹拌した。溶液を分取HPLC(Boston C18 21*250mm 10μm、移動相:A:0.1%のトリフルオロ酢酸;B:アセトニトリル)で精製して、(S)−2−アミノ−3−(1−メチルシクロブチル)プロパン酸[I−93](2mg、0.01mmol)を白色固体として得た。MS(EI+、m/z):292.0[M+H]+。1H NMR (500 MHz, D2O) δ 3.76-3.79 (t, 1H), 1.96-2.00 (m, 1H), 1.61-1.86 (m, 7H), 1.11 (s, 3H).
2−アミノ−3−(トリメチルシリル)プロパン酸塩酸塩[I−204]
ステップ1:tert−ブチル2−(ジフェニルメチレンアミノ)−3−(トリメチルシリル)プロパノエート:
tert−ブチル2−(ジフェニルメチレンアミノ)−3−(トリメチルシリル)プロパノエート(500mg、1.31mmol)の4MのHCl/ジオキサン(6mL)中溶液を室温で17時間撹拌した。DCM(80mL)を添加した。固体を濾過して、2−アミノ−3−(トリメチルシリル)プロパン酸塩酸塩[I−204]を白色固体(113mg、0.57mmol、44%)として得た。ESI-MS (EI+, m/z): 162.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 13.78 (br, 1H), 8.33 (br, 1H), 3.75 (m, 1H), 1.00-1.14 (m, 2H), 0.06 (s, 9H).
(S)−2−アミノ−3−(トリメチルシリル)プロパン酸塩酸塩[I−201]。
ステップ1:(S)−2−アミノ−3−(トリメチルシリル)プロパン酸塩酸塩[I−201]:
(R)−2−アミノ−3−(トリメチルシリル)プロパン酸塩酸塩[I−200]。
ステップ1:(R)−2−アミノ−3−(トリメチルシリル)プロパン酸塩酸塩[I−200]:
(S)−2−アミノ−4−フルオロ−4−メチルペンタン酸[I−194]。
ステップ1:(S)−2−アミノ−4−フルオロ−4−メチルペンタン酸[I−194]:
(S)−3,3−ジメチル−1−(2H−テトラゾール−5−イル)ブタン−1−アミン[I−94]。
ステップ1:(S)−tert−ブチル1−シアノ−3,3−ジメチルブチルカルバメート:
(S)−tert−ブチル1−シアノ−3,3−ジメチルブチルカルバメート(粗製の500mg)、ZnBr2(900mg、4.0mmol)、NaN3(260mg、4.0mmol)のDMF(20mL)中混合物を100℃で17時間撹拌した。混合物を、次いで、ブライン(200mL)で希釈し、酢酸エチル(60mL)で抽出し、乾燥させ(Na2SO4)、濃縮して、粗製の(S)−tert−ブチル3,3−ジメチル−1−(2H−テトラゾール−5−イル)ブチルカルバメート(400mg)を黄色ドープとして得た。ESI-MS (EI+, m/z): 214.3 [M+H-56]+.
(S)−tert−ブチル3,3−ジメチル−1−(2H−テトラゾール−5−イル)ブチルカルバメート(粗製300mg)の4MのHCl/ジオキサン(3.5mL)中溶液を室温で17時間撹拌した。次いで、溶液を濃縮し、逆相HPLC(Boston C18 21*250mm 10μm、移動相:A:0.1%のトリフルオロ酢酸;B:アセトニトリル)で直接精製して、(S)−3,3−ジメチル−1−(2H−テトラゾール−5−イル)ブタン−1−アミン2,2,2−トリフルオロ酢酸塩[I−94](3ステップで30mg、0.11mmol、9%)を白色固体として得た。MS (EI+, m/z): 170.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.18 (br, 3H), 4.48 (m, 1H), 2.14 (m, 1H), 1.73 (dd, Jz=3.5, 16.5 Hz 1H), 0.72 (s, 9H).
2−アミノ−5,5,5−トリフルオロ−4−メトキシペンタン酸[I−175]の合成:
1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 7.36-7.26 (m, 5H), 4.53 (s, 2 H), 3.8-3.83 (m, 2H), 2.71-2.68 (m, 2H).
1H NMR (500 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 4.51 (t, J= 12 Hz, 2 H), 4.23-4.19 (m, 1H), 3.59-3.57 (m, 2H), 2.04-2.01 (m, 1H), 1.78-1.73 (m, 1H), 0.13 (s, 9H).
1H NMR (500 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 4.53 (t, J= 12 Hz, 2 H), 3.78-3.74 (m, 1H), 3.66-3.57 (m, 2H), 3.5 (s, 3H), 2.03-1.96 (m, 1H), 1.78-1.57 (m, 1H).
1H NMR (500 MHz, メタノール-d4) δ 4.23-4.19 (m, 1H), 3.96-3.88 (m, 1H), 3.64-3.6 (m, 3H), 2.29-2.22 (m, 1H), 2.04-1.97 (m, 1H).
2−アミノ−4,4,5−トリメチルヘキサン酸[I−176]:
2−アミノ−4,4−ジメチルヘプタン酸[I−178]
2−アミノ−4,4−ジメチルヘキサン酸[I−195]、(S)−2−アミノ−4,4−ジメチルヘキサン酸[I−120]、(R)−2−アミノ−4,4−ジメチルヘキサン酸[I−191]。
2−アミノ−6,6,6−トリフルオロ−4−メチルヘキサン酸[I−177]:
(S)−2−アミノ−5−フルオロ−4−(フルオロメチル)ペンタン酸[I−179]
ステップ1:5−(ベンジルオキシメチル)−2,2−ジメチル−1,3−ジオキサン:
5−(ベンジルオキシメチル)−2,2−ジメチル−1,3−ジオキサン(930mg、3.94mmol)のMeOH(20mL)中溶液に、3Nの水性HCl(2mL)を添加した。混合物を50℃で2時間撹拌した。反応混合物を濃縮し、DCM(20mL)で希釈し、ブライン(15mL)で洗浄し、乾燥および蒸発させて、粗製の無色油(780mg、100%)を得た。ESI-MS (EI+, m/z): 197 [M+H]+.
予め冷却した、2−(ベンジルオキシメチル)プロパン−1,3−ジオール(780mg、3.94mmol)のDCM(20mL)中溶液に、−78℃で、DAST(1.9g、11.8mmol)を滴下添加した。混合物を20℃で24時間撹拌した。反応混合物を、−78℃にて、飽和NaHCO3水溶液(10mL)でクエンチした。DCM相を分離し、ブラインで洗浄し、MgSO4で乾燥させ、短いシリカゲルパッドを通して濾過し、次いで、濃縮して、粗製の無色油(800mg、100%)を得た。ESI-MS (EI+, m/z): 223 [M+Na]+. 1H NMR (500 MHz, CDCl3) δ 7.37 - 7.28 (m, 5H), 4.65 - 4.57 (m, 2H), 4.55 - 4.48 (m, 4H), 3.57 (d, J = 6.2 Hz, 2H), 2.50 - 2.34 (m, 1H).
予め冷却した、((3−フルオロ−2−(フルオロメチル)プロポキシ)メチル)ベンゼン(800mg、3.94mmol)のDCM(20mL)中溶液に、−78℃で、BCl3/トルエン(1M、6mL、6.0mmol)を滴下添加した。混合物を−78〜0℃で2時間撹拌した。反応混合物を、−78℃にて、H2O(0.5mL)でクエンチした。DCM相をMgSO4で乾燥させ、濾過し、溶液(約20mL)を次のステップに直接使用した。
予め冷却した、3−フルオロ−2−(フルオロメチル)プロパン−1−オール(ステップ4由来の8mLの溶液、1.6mmol)の溶液に、−40℃で、py(380mg、4.8mmol)次いで、Tf2O(1.36g、4.8mmol)を滴下添加した。混合物を−30℃で1時間撹拌した。反応混合物を、−40℃にて、ブライン(20mL)でクエンチした。DCM相を分離し、MgSO4で乾燥させ、濾過し、次いで、濃縮して、粗製の黄褐色油(200mg、51%)を得て、これを次のステップに直接使用した。
予め冷却した、tert−ブチル2−(ジフェニルメチレンアミノ)アセテート(944mg、3.2mmol)のTHF(20mL)中溶液に、−78℃にて25分で、LDA(THF/トルエン/ヘキサン中2.5M、1.28mL、3.2mmol)を添加した。混合物をこの温度で10分間撹拌した。3−フルオロ−2−(フルオロメチル)プロピルトリフルオロメタンスルホネート(200mg、0.82mmol)のTHF(2mL)中溶液を−78℃で滴下添加した。反応混合物を冷却浴のちょうど上に置き、さらに1時間撹拌した。反応混合物を飽和NH4Cl水溶液(20mL)でクエンチし、MTBE(30mL*2)で抽出し、H2O、ブライン(それぞれ50mL)で洗浄し、乾燥させ、濃縮して、粗製物を得て、これをクロマトグラフィー(シリカゲル、PEから5%EA/PE)で2回精製して、所望の生成物(22mg、6.9%)を白色固体として得た。ESI-MS (EI+, m/z): 388 [M+H]+ .1H NMR (500 MHz, DMSO) δ 7.56 - 7.45 (m, 6H), 7.41 (t, J = 7.4 Hz, 2H), 7.18 (d, J = 6.3 Hz, 2H), 4.50 - 4.17 (m, 4H), 3.91 (dd, J = 7.7, 5.5 Hz, 1H), 2.11 - 1.97 (m, 1H), 1.87 (dd, J = 12.7, 5.5 Hz, 2H), 1.38 (s, 9H).
tert−ブチル2−(ジフェニルメチレンアミノ)−5−フルオロ−4−(フルオロメチル)ペンタノエート(55mg、0.14mmol)の3NのHCl/MeOH(2mL)中溶液を室温で20時間撹拌した。反応混合物を濃縮し、Et2Oで洗浄して、粗製の固体を得て、これを、DCM/TFA(1:1、2mL)に溶解して、室温で20時間撹拌した。反応混合物を蒸発させ、Et2Oで洗浄して、粗製の固体を得て、これを、6NのHCl(1mL)に溶解し、80℃で2時間撹拌した。反応混合物を蒸発させ、凍結乾燥させて、粗生成物を得て、これを、3mMのHCl/H2Oを使用するRP−biotageで精製して、所望の生成物(8.3mg、29%)を白色固体として得た。ESI-MS (EI+, m/z): 168 [M+H]+. 1H NMR (500 MHz, DMSO) δ 7.85 (bs, 3H), 4.48 (dd, J = 48.3, 14.2 Hz, 4H), 3.46 - 3.36 (m, 1H), 2.47 - 2.26 (m, 1H), 1.78 (dt, J = 14.3, 7.3 Hz, 1H), 1.63 - 1.53 (m, 1H).
(S)−3−アミノ−5,5−ジメチル−ジヒドロフラン−2(3H)−オン[I−187]:
ステップ1:(S)−3−アミノ−5,5−ジメチル−ジヒドロフラン−2(3H)−オン[I−187]:
(S)−2−アミノ−5,5−ジフルオロ−4,4−ジメチルペンタン酸[I−90]の合成:
(S)−2−アミノ−5,5−ジフルオロ−4,4−ジメチルペンタン酸[I−88]の合成):
(S)−メチル2−((S)−2−アミノ−5,5−ジフルオロ−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート[I−185]の合成:
1H-NMR (500 MHz, DMSO-d6): 9.11 (d, J = 7 Hz, 1H), 8.41 (s, 3H), 5.81 (t, J = 56.5 Hz, 1H), 4.34-4.31 (m, 1H), 3.89-3.81 (m, 1H), 3.62 (s, 3H), 1.98-1.93 (m, 1H), 1.76-1.73 (m, 1H), 1.65-1.54 (m, 3H), 0.93-0.81 (m, 12H).
(S)−メチル2−((R)−2−アミノ−5,5−ジフルオロ−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート[I−184]の合成:
1H-NMR (500 MHz, DMSO-d6): 9.18 (d, J = 7 Hz, 1H), 8.38 (s, 3H), 5.79 (t, J = 56.5 Hz, 1H), 4.37-4.32 (m, 1H), 3.85-3.78 (m, 1H), 3.58 (s, 3H), 1.97-1.92 (m, 1H), 1.77-1.72 (m, 1H), 1.61-1.51 (m, 3H), 0.94-0.82 (m, 12H).
(2S,4R)−2−アミノ−5,5,5−トリフルオロ−4−メチルペンタン酸、(2R,4S)−2−アミノ−5,5,5−トリフルオロ−4−メチルペンタン酸、(2R,4R)−2−アミノ−5,5,5−トリフルオロ−4−メチルペンタン酸および(2S,4S)−2−アミノ−5,5,5−トリフルオロ−4−メチルペンタン酸:[3d;I−145];[3c;I−146];[3a;I−167];[3b;I−250]の合成
(S)−2−アミノ−5,5,5−トリフルオロ−4,4−ジメチルペンタン酸(I−128):
使用した手順は、実施例187で使用したのと同一であった。
(S)−メチル2−((R)−2−アミノ−5,5,5−トリフルオロ−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート[I−188]:
1H-NMR (500 MHz, MeOD-d4): 4.47 (t, J = 7.5 Hz, 1H), 3.99-3.97 (m, 1H), 3.77 (s, 3H), 2.33-2.28 (m, 1H), 1.95-1.91 (m, 1H), 1.69-1.68 (m, 3H), 1.24-1.17 (m, 6H), 1.00-0.94 (m, 6H).
(S)−メチル2−((S)−2−アミノ−5,5,5−トリフルオロ−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート[I−189]:
使用した手順は、実施例188で使用したのと同一であった。
手順および特徴付け:
(実施例189)
(S)−メチル2−((S)−2−アミノ−5,5,5−トリフルオロ−4,4−ジメチルペンタンアミド)−4−メチルペンタノエート[I−189]:1H-NMR (500 MHz, MeOD-d4): 4.52 (t, J = 7.5 Hz, 1H), 4.02-3.99 (m, 1H), 3.73 (s, 3H), 2.35-2.30 (m, 1H), 1.95-1.91 (m, 1H), 1.78-1.67 (m, 3H), 1.25 (s, 3H), 1.17 (s, 3H), 1.01-0.97 (m, 6H).
(S)−2−アミノ−6−フルオロヘキサン酸[I−108]。
(R)−2−アミノ−6−フルオロヘキサン酸[I−109]。
ステップ1:tert−ブチル2−(ジフェニルメチレンアミノ)−6−フルオロヘキサノエート:
(S)−tert−ブチル2−(ジフェニルメチレンアミノ)−6−フルオロヘキサノエート(360mg、0.97mmol)のジオキサン(10mL)およびHCl(水溶液 6M)中溶液を室温で16時間撹拌した。混合物をエーテルおよび水で抽出した。水層を、pHを3〜4に調整した後、EAで抽出した。有機層を濃縮して、(S)−2−アミノ−6−フルオロヘキサン酸[I−108]を白色固体(125mg、0.84mmol、86%)として得た。ESI-MS (EI+, m/z): 150.3 [M+H]+. 1H NMR (500 MHz, D2O) δ 4.469 (t, J = 6.0 Hz, 1H), 4.351 (t, J = 6.0 Hz, 1H), 3.950 (t, J = 6.0 Hz, 1H), 1.904-1.820 (m, 2H), 1.690-1.588 (m, 2H) , 1.456-1.388 (m, 2H).
(R)−tert−ブチル2−(ジフェニルメチレンアミノ)−6−フルオロヘキサノエート(300mg、0.81mmol)のジオキサン(10mL)およびHCl(水溶液 6M)中溶液を室温で16時間撹拌した。混合物をエーテルおよび水で抽出した。水層を、pHを3〜4に調整した後、EAで抽出した。有機層をHPLCで精製して(R)−2−アミノ−6−フルオロヘキサン酸[I−109]を白色固体(35mg、0.23mmol、29%)として得た。ESI-MS (EI+, m/z): 150.2 [M+H]+. 1H NMR (500 MHz, D2O) δ 4.505 (t, J = 6.0 Hz, 1H), 4.410 (t, J = 6.0 Hz, 1H), 3.823 (t, J = 6.0 Hz, 1H), 1.906-1.827 (m, 2H), 1.722-1.639 (m, 2H) , 1.485-1.399 (m, 2H).
メチル2−アミノ−5,5,5−トリフルオロ−4−(トリフルオロメチル)ペンタノエート(I−198):
(S)−2−アミノ−5,5,5−トリフルオロ−4−(トリフルオロメチル)ペンタン酸(I−164):
2−アミノ−4−シクロペンチルブタン酸[I−203]:
2−アミノ−5−シクロペンチルペンタン酸[I−202]:
2−アミノ−N−シクロペンチル−3,3−ジフルオロ−N,4−ジメチルペンタンアミド[I−197]の合成:
2−アミノ−5−フルオロ−4,4−ジメチルペンタン酸[I−196]。
ステップ1:3−ヒドロキシ−N−メトキシ−N,2,2−トリメチルプロパンアミド:
−78℃まで冷却した、3−ヒドロキシ−N−メトキシ−N,2,2−トリメチルプロパンアミド(4.5g、27.9mmol)のDCM(40mL)中混合物に、DAST(7.4mL、55.9mmol)を滴下添加した。次いで、室温で1〜2時間撹拌し、−78℃まで再度冷却し、DAST(4mL、27.9mmol)を滴下添加した。反応混合物を室温でさらに1時間撹拌した。反応混合物を−78℃まで冷却し、飽和NH4Cl(15mL)をゆっくりと添加し、DCM(50mL)を添加し、有機層を分離し、飽和NH4Cl(30mL)、ブライン(30mL×2)で洗浄し、乾燥させ、濃縮して、残留物を得て、これをクロマトグラフィー(シリカ、酢酸エチル/石油エーテル=1/4)で精製して、3−フルオロ−N−メトキシ−N,2,2−トリメチルプロパンアミド(1.9g、28%)を無色油として得た。ESI-MS (EI+, m/z): 164.2 [M+H]+.
0℃に冷却した、3−フルオロ−N−メトキシ−N,2,2−トリメチルプロパンアミド(1.0g、61.3mmol)のTHF(10mL)中混合物に、LiAlH4(6.1mL、61.3mmol、THF中1M)を滴下添加した。次いで、この温度で0.5〜1時間撹拌した。飽和NH4Cl(10mL)をゆっくりと添加し、Et2O(20mL×3)で抽出し、水(15mL×2)およびブライン(15mL)で洗浄し、乾燥させて、次のステップに直接使用した。ESI-MS (EI+, m/z):MSなし。
3−フルオロ−2,2−ジメチルプロパナール(約630mg、6.1mmol、上記ステップに由来するEt2O溶液)、tert−ブチル2−(tert−ブトキシカルボニルアミノ)−2−ジエトキシホスホリル−アセテート(2.25g、6.1mmol)およびt−BuONa(1.2g、12.3mmol)のTHF(15mL)中混合物を室温で16時間撹拌した。飽和NH4Cl(15mL)を添加し、EA(30mL×3)で抽出し、有機層と合わせ、水(15mL)およびブライン(15mL)で洗浄し、乾燥させ、濃縮して、残留物を得て、これをクロマトグラフィー(シリカ、石油エーテルからDCM)で精製して、(Z)−tert−ブチル2−(tert−ブトキシカルボニルアミノ)−5−フルオロ−4,4−ジメチルペンタ−2−エノエート(190mg、0.60mmol、8%)を白色固体として得た。ESI-MS (EI+, m/z): 206 [M-111]+.
ステップ5:tert−ブチル2−(tert−ブトキシカルボニルアミノ)−5−フルオロ−4,4−ジメチルペンタノエート:
(Z)−tert−ブチル2−(tert−ブトキシカルボニルアミノ)−5−フルオロ−4,4−ジメチルペンタ−2−エノエート(190mg、0.60mmol)およびPd/C(10%、30mg)のIPA(15mL)中混合物を、室温にて、水素下で17時間撹拌した。混合物を濾過し、濃縮して、tert−ブチル2−(tert−ブトキシカルボニルアミノ)−5−フルオロ−4,4−ジメチルペンタノエート(200mg、粗製)を無色の液体として得た。ESI-MS (EI+, m/z): 342.2 [M+Na]+.
ステップ6:2−アミノ−5−フルオロ−4,4−ジメチルペンタン酸トリフルオロ酢酸:
tert−ブチル2−(tert−ブトキシカルボニルアミノ)−5−フルオロ−4,4−ジメチルペンタノエート(200mg、粗製)の6MのHCl(20mL)およびジオキサン(10mL)中溶液を50℃に17時間加熱した。混合物を真空中で濃縮し、水(30mL)で希釈し、Et2O(20mL×2)で抽出し、濾液を真空中で濃縮し、逆相シリカゲルクロマトグラフィーで精製して、2−アミノ−5−シクロペンチルペンタン酸トリフルオロ酢酸(31.7mg、0.11mmol、19%)を白色固体として得た。ESI-MS (EI+, m/z): 164.2 [M+H]+. 1H-NMR (500 MHz, D2O): δ 4.16 (d, J = 47.5 Hz, 1H), 3.97 (t, J = 5.5 Hz, 1H), 2.03 (dd, J = 15.5 Hz, J = 5.5 Hz, 1H), 1.71 (dd, J = 15.5 Hz, J = 6.0 Hz, 1H), 0.91 (dd, J = 15.0 Hz, J = 2.0 Hz, 6H).
2,4−ジアミノ−4−メチルペンタン酸[I−186]の合成:
4,4,4−トリフルオロ−3−メチル−1−(2H−テトラゾール−5−イル)ブタン−1−アミン[I−199]の合成:
ウエスタンブロットアッセイ
Sestrin2およびSestrin2/GATOR2相互作用に関するロイシンの活性を模倣するかまたはアンタゴナイズする化合物を特定する方法。
動物の使用:175〜200gの体重の雄のスプラーグドーリーラット(Charles River Laboratories、Wilmington、MA)を到着してすぐに(Yale University、New Haven CT)群で飼育し、実験研究を開始する前に5日間順化させた。プロトコールで指定された絶食期間を除いて、ラットには食餌と水を自由に与えた。動物は、臨床徴候について毎日モニタリングした。資格を有する獣医師が、すべてのげっ歯類の手順について監督した。すべての職員が、エール動物飼育利用委員会(Yale animal care and use committee)(IACUC)からの訓練を受けた。すべての動物の手順は、国立衛生研究所(National Institutes of Health)のIACUCに厳格に従って、エール大学で行い、エール動物飼育利用委員会によって承認された。
化合物またはケタミンの単回投与後の新規性抑制食餌および雌の尿のにおいかぎ試験における行動変化
研究設計:175〜200gの体重の雄のスプラーグドーリーラット32頭を、4つの研究群(n=8/処置群)へと無作為化し、続いて、5日間順化させた。研究0日目に、群1および2のラットは、それぞれ、生理食塩水(Sal)またはケタミン(Ket)のいずれかの単回投与を腹腔内注射(i.p.)によって受けた。群3および4のラットは、それぞれ、NV−5138のビヒクル(Veh、0.5%のメチルセルロース/0.1%のTween−80)またはNV−5138(160mg/kg)の単回投与を経口胃管栄養法によって受けた。すべてのラットを、1日目の投与の24時間後に、FUSTに供した。2日目の投与の48時間後に、すべてのラットのLMAをオープンフィールドで測定した。次いで、ラットを20時間絶食させ、投与の72時間後にNSFTに供した。研究設計を表6に表す。試験物投与と3回の行動試験のタイムラインは、図1にまとめる。
ラット前頭前野に由来するシナプトソーム調製物におけるmTORC1シグナル伝達経路およびシナプスタンパク質発現についてのNV−5138およびケタミン投与の単回投与の比較作用
研究設計:175〜200gの体重の雄のスプラーグドーリーラット48頭を、8つの研究群(n=6/群)へと無作為化し、続いて、5日間順化させた。研究0日目に、群3および7のラットは、それぞれ、i.p.注射で、Salの単回投与を受け、一方、群4および8のラットはKet(10mg/kg)の単回投与を受けた。群1および5のラットは、それぞれ、経口胃管栄養法によって、Vehの単回投与を受け、一方、群2および6のラットはNV−5138(160mg/kg)の単回投与を受けた。投与の1時間後に、群1〜4のラットを、無麻酔断頭によって屠殺し、続いて、PFCを回収した。粗製のシナプトソームをPFCから調製し、3つのmTORC1基質、pmTOR、pp70S6Kおよびp4E−BP1、ならびに対応する総タンパク質ローディング対照(mTOR、p70S6K、およびGAPDH)をWBによって定量した。投与の24時間後に、群5〜8のラットを、無麻酔断頭によって屠殺し、PFCを回収した。粗製のシナプトソームをPFCから調製し、シナプスタンパク質(GluR1およびPSD95)、および総タンパク質ローディング対照(GAPDH)をWBによって定量した。研究設計を表7に表す。試験物投与とWBのためのラットの屠殺のタイムラインは、図5に提供する。
ラットの脳の複数領域におけるmTORC1シグナル伝達経路に対するNV−5138の単回経口投与の効果
研究設計:175〜200gの体重の雄のラット10頭を、2つの研究群(n=5/群)へと無作為化し、続いて、5日間順化させた。群1は、Vehの単回投与を経口胃管栄養法によって受け、群2は、NV−5138(Vehにおいて調製した160mg/kg)の単回投与を経口胃管栄養法によって受けた。投与の1時間後に、ラットを無麻酔断頭によって屠殺し、顕微解剖によるPFC、海馬、線条体、新皮質および小脳の単離に加えて、NV−5138曝露の分析のために、血漿を回収した。総タンパク質抽出物は、採取した組織から調製し、WB分析、続いて、選択したmTORC1基質の定量分析に提出した。研究設計を表8に表す。試験物投与、およびWBのためのラットの屠殺のタイムラインは、図9に提供する。
・ Phenomenex LUX Celluloseカラム(4.6×150mm、5μm)
・ 移動相A−水中0.1%のギ酸
・ 移動相B−アセトニトリル中0.1%のギ酸
・ 勾配:
○ 初期−40%のA
○ 2分−40%のA
○ 2.1分−2%のA
○ 3分−2%のA
○ 3.1分−40%のA
○ 4分−40%のA
・ 流速0.8mL/分
・ カラム温度摂氏40度
・ Sciex 5500 Triple Quad Mass Spec
ラットの脳および選択した周辺器官におけるmTORC1シグナル伝達経路に対するNV−5138またはロイシンの単回経口投与の効果
研究設計:175〜200gの体重の雄のラット30頭を、3つの研究群(n=10)へと無作為化し、続いて、5日間順化させた。試験物を、表9に示した投与および図12に示したタイムラインのように、経口胃管栄養法によって投与した。投与の1時間後に、ラットを無麻酔断頭によって屠殺し、化合物レベルおよびWB分析のために、血漿、脳および選択した周辺組織を採取した。組織は、WBのために調製し、mTORC1活性の尺度として、mTORC1基質であるpS6を定量した。
・ Phenomenex LUX Celluloseカラム(4.6×150mm、5μm)
・ 移動相A−水中0.1%のギ酸
・ 移動相B−アセトニトリル中0.1%のギ酸
・ 勾配:
○ 初期−40%のA
○ 2分−40%のA
○ 2.1分−2%のA
○ 3分−2%のA
○ 3.1分−40%のA
○ 4分−40%のA
・ 流速0.8mL/分
・ カラム温度摂氏40度
・ Sciex 5500 Triple Quad Mass Spec
ショ糖嗜好性および新規性抑制食餌試験ならびにシナプスタンパク質発現に対するNV−5138の単回投与の効果
研究設計:175〜200gの体重の雄のラット56頭を、4つの研究群(n=14/群)へと無作為化し、続いて、5日間順化させた。研究のマイナス20日目に、2つの群のラットを25日間CUSに供し、2つの群のラットを正常に飼育し、NS群としての役割を果たした。CUSプロトコールの21日目に、ラットは、VehまたはNV−5138(160mg/kg)のいずれかの単回投与を経口胃管栄養法によって受けた(0日目)。SPTおよびNSFTを、それぞれ、投与の24および48時間後(1日目および2日目)に実施した。行動試験が完了したら、CUSプロトコールの25日後に、NV−5138またはVehの第2の投与を5日目に投与し、ラットを24時間後に無麻酔断頭によって屠殺した。粗製のシナプトソームをPFCから調製し、シナプスタンパク質、GluR1およびPSD95をWBによって定量した。研究設計を表10に表す。試験物投与、行動試験、およびWBのためのラットの屠殺のタイムラインは、図14に提供する。
ラットにおける単回経口投与後の強制水泳および新規性抑制食餌試験におけるNV−5138の薬理学活性のmTORC1活性化への依存性
研究設計:175〜200gの体重の雄のラット20頭を、3つの研究群(n=6〜7/群)へと無作為化し、続いて、5日間順化させた。投与の2週間前に、すべてのラットのPFCに、両側のITカニューレを外科的に移植した。投与の日に、すべての処置群は、mTORC1活性を完全に阻害することが以前に示されたラパマイシン(R)ビヒクル(Veh−R、10%のDMSO)またはラパマイシン(R、0.01nmol/μL)のいずれかを含有する両側のIT注入液(0.5μL/片側)を受けた。髄腔内注入の30分後に、NV−5138ビヒクル(Veh−NV、0.5%のメチルセルロース/0.1%のTween−80)またはNV−5138(160mg/kg)を経口胃管栄養法によって投与した。各処置群を、経口投与後の指定した時間に評価した:FSTは24時間(1日目) LMAは48時間(2日目)およびNSFTは72時間(20時間の絶食後の3日目)。一般的な自発運動活性における全体的変化を除外するために、LMAを測定した。研究設計は表11に表され、外科的手順、試験物投与および行動試験のタイムラインは図20に提供する。
NV−5138またはケタミンの単回投与後の強制水泳試験および新規性抑制食餌試験における行動変化の持続
研究設計:175〜200gの体重の雄のラット48頭を、6つの研究群(n=8/群)へと無作為化し、続いて、5日間順化させた。すべての試験物の単回投与を0日目に投与し、3、7および10日後に行動試験を実施した。0日目に、群1および2に、それぞれ、NV−5138(経口胃管栄養法によって160mg/kg)およびKet(i.p.注射によって10mg/kg)を投与し、3日目にFSTに供した。群3および4のラットは、0日目に、経口胃管栄養法によって、それぞれ、NV−5138ビヒクル(Veh)またはNV−5138(160mg/kg)の単回投与を受けた。群5および6のラットは、0日目に、i.p.注射によって、それぞれ、Ketビヒクル(Sal)またはKet(10mg/kg)の単回投与を受けた。群3〜6のラットを、7日目にFST、10日目にNSFTに供した。群3〜6のすべてのラットは、NSFTの前の夜に20時間絶食させた。研究設計を表12に表す。試験物投与および行動試験のタイムラインは図24に提供する。
NV−5138の単回投与後の層Vの錐体ニューロンにおける生理学的変化
研究設計:175〜200gの体重の雄のラット16頭を、2つの研究群(n=8)へと無作為化し、続いて、5日間順化させた。研究の0日目に、ラットは、経口胃管栄養法によって、NVビヒクル(Veh、0.5%のメチルセルロース/0.1%のTween−80)またはNV−5138(160mg/kg)のいずれかの単回投与を受けた。1日目、投与の24時間後に、ラットを屠殺し、脳のスライスを調製し、PFCの層Vの錐体ニューロンの全細胞パッチクランプ記録に供した。研究設計を表13に表す。試験物投与および生理学的分析のタイムラインを図27にまとめる。
化合物を毎日投与するかまたはケタミンを1日おきに投与した後の強制水泳および新規性抑制食餌試験における行動変化
研究設計:175〜200gの体重の雄のスプラーグドーリーラット24頭を、4つの研究群(n=6/群)へと無作為化し、続いて、5日間順化させた。研究のマイナス1日目に、ラットを事前水泳に供した。研究0日目に開始して、群2のラットは、1日おきに(0、2、4、および6日目)、それぞれ、i.p.注射によってKet(10mg/kg)の投与を受けた。群1のラットは、7日間(0〜6日目)、経口胃管栄養法によって毎日Vehの投与を受けた。群3および4のラットは、7日間(0〜6日目)、それぞれ、経口胃管栄養法によって毎日NV−5138の投与(40または80mg/kg)の投与を受けた。すべてのラットを、7日目の最終投与の24時間後にFSTに供した。8日目の最終投与の48時間後に、すべてのラットのLMAをオープンフィールドで測定した。次いで、ラットを20時間絶食させ、9日目(最終投与の72時間後)にNSFTに供した。研究設計を表14に表す。試験物投与および行動試験のタイムラインは、図32にまとめる。
マーモセットのヒト脅威試験
研究設計:36頭のマーモセット(Callithrix jacchus)をペアにして、無作為に処置群に分けた。ヒト脅威試験(HTT)の24時間前に、動物を、ビヒクル、ケタミン(0.3mg/kg;i.m.)またはNV−5138(160mg/kg;p.o.)で処置した。次の日に、同じ動物を、ビヒクル(s.c.)またはクロルジアゼポキシド(chloriazepoxide)(1mg/kg;s.c.)で処置した。次いで、動物を、ヒト観察者の存在により、2分の期間にわたって、脅威姿勢の数についてモニタリングした。自発運動活性は、観察されたジャンプの数によって測定して、同じ期間にわたってモニタリングした。
Claims (20)
- 疾患、障害、または状態を処置することを必要とする患者において疾患、障害、または状態を処置する方法であって、前記疾患、障害、または状態は、処置抵抗性の鬱、リソソーム蓄積障害、JNCL、シスチン症、ファブリー病、MLIV、精神遅滞または遺伝子型の自閉症から選択され、前記方法は、式I:
式中、
R1は、HまたはC1〜6アルキルであり;
R2は、R、−(CH2)n−フェニル、−C(O)R、−SO2R、または−C(O)N(R)2であり;
nは、0、1、または2であり;
各Rは、独立して、水素、−CN、あるいは飽和もしくは不飽和C1〜6脂肪族、フェニル、4〜7員の飽和もしくは部分的不飽和の単環式炭素環、1〜4個のヘテロ原子を有する5〜6員の単環式ヘテロアリール環、または窒素、酸素、もしくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜8員の飽和もしくは部分的飽和の複素環式環から選択される必要に応じて置換された基であり;
R3は、環A、−C(O)R、−C(O)OR、−C(O)N(R)2、−SO3H、−SO2N(R)2、−S(O)R、−S(O)環A、−ORまたは−B(OR)2(式中、同一のホウ素上の2つのOR基は介在原子と一緒になって5〜8員の単環式飽和もしくは部分的に不飽和の、ホウ素および2つの酸素に加えて、窒素、酸素、もしくは硫黄から独立して選択される0〜3個のヘテロ原子を有する環を形成するか、またはR3およびR4は一緒になって、窒素、酸素もしくは硫黄から選択される0〜1個のヘテロ原子を有する必要に応じて置換された5〜6員の環を形成する)であり;
Lは、共有結合または1〜9個のフルオロ基で必要に応じて置換された直鎖状もしくは分枝鎖状のC1〜6アルキレン鎖であり;
環Aは、フェニル、または窒素、酸素もしくは硫黄から独立して選択される1〜4個のヘテロ原子を有する必要に応じて置換された5〜6員のヘテロアリール環から選択される必要に応じて置換された環であり;
R4は、R、−CF3、−OR、−N(R)2、−Si(R)3、もしくは−SRであるか、またはR3およびR4は一緒になって、窒素、酸素もしくは硫黄から選択される0〜1個のヘテロ原子を有する必要に応じて置換された5〜6員の環を形成し;
R5は、HまたはC1〜4アルキルであり、
式Iの前記化合物は、表2に示されるもの以外である、方法。 - R1が、Hである、請求項1に記載の方法。
- R1が、C1〜6アルキルである、請求項1に記載の方法。
- R2が、−(CH2)n−フェニルである、請求項1に記載の方法。
- R2が、−C(O)R、−SO2R、または−C(O)N(R)2である、請求項1に記載の方法。
- R2が、メチル、−(CH2)−フェニル、または−C(O)CH3である、請求項1に記載の方法。
- R3が、−C(O)R、−C(O)OR、−C(O)N(R)2、−SO3H、−SO2N(R)2、−S(O)R、−S(O)環A、−ORまたは−B(OR)2である、請求項1から6のいずれかに記載の方法。
- 前記化合物が、式II:
- 環Aが、必要に応じて置換されたフェニルである、請求項8に記載の方法。
- 環Aが、窒素、酸素または硫黄から独立して選択される1〜4個のヘテロ原子を有する必要に応じて置換された5員のヘテロアリール環である、請求項8に記載の方法。
- 環Aが、1〜2個の窒素原子を有する必要に応じて置換された6員のヘテロアリール環である、請求項8に記載の方法。
- 環Aが、イミダゾリル、イソキサゾリル、1H−ピロリル、ピラゾリル、オキサゾリル、テトラゾリル、チアゾリル、トリアゾリル.ピリジル、またはピリミジニルから選択される、必要に応じて置換された環である、請求項8に記載の方法。
- Lが、共有結合である、請求項1から12のいずれか一項に記載の方法。
- Lが、1〜4個のフルオロ基で必要に応じて置換された直鎖状または分枝鎖状のC1〜6アルキレン鎖である、請求項1から12のいずれか一項に記載の方法。
- Lが、メチレン、n−ブチレニル.エチレニル、またはn−プロピレニルである、請求項14に記載の方法。
- R4が、−CF3、−OR、または−SRである、請求項1から15のいずれか一項に記載の方法。
- R4が、イソプロピル、tert−ブチル、シクロプロピル、シクロブチル、sec−ブチル、メトキシル、またはメチルチオイルである、請求項16に記載の方法。
- R5が、Hである、請求項1から17のいずれか一項に記載の方法。
- R5が、メチルである、請求項1から17のいずれか一項に記載の方法。
- 追加の治療剤または療法を前記患者に投与することをさらに含む、請求項1から19のいずれか一項に記載の方法。
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