JP7137010B2 - アミノペプチダーゼa阻害剤としての新規なアミノホスフィン酸誘導体 - Google Patents
アミノペプチダーゼa阻害剤としての新規なアミノホスフィン酸誘導体 Download PDFInfo
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- JP7137010B2 JP7137010B2 JP2021523633A JP2021523633A JP7137010B2 JP 7137010 B2 JP7137010 B2 JP 7137010B2 JP 2021523633 A JP2021523633 A JP 2021523633A JP 2021523633 A JP2021523633 A JP 2021523633A JP 7137010 B2 JP7137010 B2 JP 7137010B2
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- Prior art keywords
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- amino
- phosphoryl
- hydroxy
- butanoic acid
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/303—Cycloaliphatic acids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
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Description
(式中、
AHは、-CO2H、-SO3H、-PO3H2を表し;
lは2又は3であり;
mは、0、1、2又は3であり;
R1は、ハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、O-シクロアルキル基、O-アリール基、O-アリールアルキル基、ヘテロアルキル基、任意選択でアルキル基によりモノ置換又はジ置換されたアミノ基、ハロアルキル基、シクロアルキル基、アシル基、アリール基、又はアリールアルキル基を表し;
R2とR3は、独立に、水素原子、ハロゲン原子、アルキル基、ハロアルキル基を表すか、又は図(I)若しくは(II)に描かれた隣接炭素原子と一緒になってシクロアルキル基を形成することができる);
それらの薬学的塩、溶媒和物、双性イオン形態又はプロドラッグ
を提供する。
(式中、
AHは、-CO2H、-SO3H、-PO3H2を表し;
1は2又は3であり;
mは、0、1、2又は3であり;
R1は、ハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、O-シクロアルキル基、O-アリール基、O-アリールアルキル基、ヘテロアルキル基、任意選択でアルキル基によりモノ置換又はジ置換されたアミノ基、ハロアルキル基、シクロアルキル基、アシル基、アリール基又はアリールアルキル基を表し;
R2及びR3は、独立に、水素原子、ハロゲン原子、アルキル基、ハロアルキル基を表すか、又は式(I)若しくは(II)に描かれた隣接炭素原子と一緒になってシクロアルキル基を形成することができる)
に関する。
用語「アルキル」又は「Alk」は、1価の又は2価の、直鎖状又は分岐した、1から8個の炭素原子を有する飽和炭化水素鎖((C1~C8)アルキルとも名付けられる)、例えば、メチル、エチル、プロピル、イソプロピル、n-ブチル、iso-ブチル、sec-ブチル、tert-ブチル、tert-ブチル-メチル、n-ペンチル、n-ヘキシル、n-ヘプチル、又はn-オクチル基等を意味する。
- mは0若しくはlであり; 及び/又は
- AHは、CO2H若しくはSO3H若しくはPO3H2であり; 及び/又は
- R1は、ハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、O-シクロアルキル基、O-アリール基、O-アリールアルキル基、ヘテロアルキル基、ハロアルキル基、シクロアルキル基、アシル基、アリール基若しくはアリールアルキル基を表す。
(式中、
1、m、R1、R2、R3は、上に規定の通りであり;
Aは、-SO3Z-CO2Z又は-P(O)(OZ)2を表し、Zは、水素原子、アルキル及びアリールアルキル基からなる群から選択され;
Xは、水素原子、-(CO)-アルキル、-(CO)-アルコキシ、-(CO)-ベンジルオキシ、
Rは、アルキル基を表し、R'及びR"は、独立に、水素原子又はアルキル基を表し;
Yは、水素原子、アルキル、アリール、アリールアルキル又は
R、R'及びR"は上に規定の通りであり、
ここで、Z、X、及びYの少なくとも1つは、水素原子と異なる)
であり得る。
4-アミノ-4-[ヒドロキシ(3-メチルブチル)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(4-メチルペンチル)ホスホリル]ブタン酸;
4-アミノ-4-[(2-シクロヘキシルエチル)(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(ペンチル)ホスホリル]ブタン酸;
4-アミノ-4-[ヘキシル(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[(シクロブチルメチル)(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[(シクロペンチルメチル)(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(5-メチルヘキシル)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(4,4,4-トリフルオロブチル)ホスホリル]ブタン酸;
4-アミノ-4-[(シクロヘキシルメチル)(ヒドロキシ)ホスホリル]ブタン酸;及び
4-アミノ-4-[ヒドロキシ({[(プロパン-2-イル)アミノ]メチル})ホスホリル]ブタン酸;
からなる群から選択される。
上で特に言及した成分に加えて、製剤は、問題の製剤のタイプに関係を有する技術で従来の他の薬剤を含むことができ、例えば、経口投与のために適当なものは、香味剤を含むことができる。
本発明の目的の式(I)の化合物は、以下の式(V)、(VI)及び(VII)の前駆体を使用することにより、後で記載される合成経路に従って調製することができる
AIBN: アゾビスイソブチロニトリル
(Boc)2O: ジ-tert-ブチルジカーボネート
(n-Bu)4NBr: 臭化テトラ-n-ブチルアンモニウム
(n-Bu)4NI: ヨウ化テトラ-n-ブチルアンモニウム
AcCl: 塩化アセチル
AcOH: 酢酸
BTSP: ビス(トリメチルシリル)ホスホネート
Cbz: カルボキシベンジル
CH2Cl2又はDCM: ジクロロメタン
CHCl3: クロロホルム
cHex: シクロヘキサン
CuSO4: 硫酸銅
DCC: N,N'-ジシクロヘキシルカルボジイミド
DTAD: ジ-tert-ブチルアゾジカルボキシレート
EDCI: 1-エチル-3-(3-ジメチルアミノプロピル)エチルカルボジイミド
Et2O: ジエチルエーテル
EtOAc: 酢酸エチル
HBF4.Et2O: テトラフルオロホウ酸ジエチルエーテル複合体
HCl: 塩酸
HMDS: 1,1,1,3,3,3-ヘキサメチルジシラザン
I2: ヨウ素
i-PrOH: イソプロパノール
K2CO3: 炭酸カリウム
KOtBu: カリウムtert-ブトキシド
LiAlH4: 水素化リチウムアルミニウム
LiHMDS: リチウムビス(トリメチルシリル)アミド
LiOH.H2O: 水酸化リチウム一水和物(リチン)
MeOH: メタノール
Mg: マグネシウム
Na2S2O3: チオ硫酸ナトリウム
Na2SO4: 硫酸ナトリウム
NaBH4: 水素化ホウ素ナトリウム
NaHCO3: 重炭酸ナトリウム
NEt3: トリエチルアミン
NH2Cbz: ベンジルカルバメート
NH4Cl: 塩化アンモニウム
Pd(PPh3)4: テトラキス(トリフェニルホスフィン)パラジウム(0)
TFA: トリフルオロ酢酸
Eq.: 当量
ESI: エレクトロスプレーイオン化
HPLC: 高速液体クロマトグラフィー
NMR: 核磁気共鳴
PTFEフィルター: ポリテトラフルオロエチレンフィルター
工程1:ベンジル4-ヒドロキシブタノエートの合成
γ-ブチロラクトン(20mL、255mmol、1.0当量)及びNaOH(10.2g、255mmol、1.0当量)を水(170mL)に溶解し、温度を70℃に上げた。12時間後、水を蒸発させ、白色糊状物をトルエンと共に蒸発させた(3回)。白色固体を真空下に置き、70℃に2時間加熱した。固体をトルエンで再度溶解して痕跡量の水を除去した。得られた白色固体をアセトン(280mL)に懸濁した。テトラブチルアンモニウムヨージド(4.72g、12.8mmol、0.05当量)及び塩化ベンジル(29.4mL、255mmol、1.0当量)を懸濁液に加えた。溶液を6時間還流し、次いで室温で終夜戻した。次いで反応混合物を6時間再度還流させた。室温で、混合物を濾過し、濾液を蒸発させて粗製物を得、これをシリカゲル上でのクロマトグラフィーにより精製した。期待する生成物を含むフラクションを合わせ、真空で濃縮して、表題生成物(36.5g、74%)を得た。
1H NMR (CDCl3, 500 MHz) δ (ppm): 7.39-7.31 (m, 5H); 5.13 (s, 2H); 3.69 (t, 2H, J = 6.0 Hz); 2.50 (t, 2H, J = 7.0 Hz); 1.93-1.88 (m, 2H)
ベンジル4-ヒドロキシブタノエート(10g、51.49mmol、1.0当量)をジクロロメタン(1.7L)に溶解し、0℃に冷却した。デス-マーチンペルヨージナン(33g、77.23mmol、1.5当量)を加え、混合物を室温で2時間30分撹拌した。混合物を濃縮し、粗製物をシリカゲル上でのフラッシュクロマトグラフィーにより精製した。期待する生成物を含むフラクションを合わせ、真空で濃縮して、表題化合物(8.0g、81%)を薄黄色油状物として得た。
1H NMR (CDCl3, 500 MHz) δ (ppm): 9.82 (s, 1H); 7.39-7.31 (m, 5H); 5.14 (s, 2H); 2.82 (t, 2H, J = 7.0 Hz); 2.71-2.67 (m, 2H)
4-アミノ-4-[ヒドロキシ(3-メチルブチル)ホスホリル]ブタン酸
工程1: (3-メチルブチル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.90mL、17.4mmol、1.0当量)から、続いて無水Et2O(9mL)中のl-ブロモ-3-メチルブタン(2.76g、18.3mmol、1.05当量)からの新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(1.40g、59%)を調製した。
MS (ESI+): [M+H]+ = 137.2; [(Mx2)+H]+ = 273.2
1H NMR (MeOD, 500 MHz) δ (ppm): 7.02 (dt, J = 536.2, 2.0 Hz, 1H); 1.85-1.71 (m, 2H); 1.71-1.59 (m, 1H); 1.55-1.42 (m, 2H); 0.96 (d, J = 6.7 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 36.32
AcOH(10mL)及びAcCl(1.2mL)中の前段生成物(800mg、5.88mmol、1.0当量)及びNH2Cbz(977mg、6.46mmol、1.1当量)からの多成分反応、続いてベンジル4-オキソブタノエート(1.36g、7.05mmol、1.2当量)の添加についての手順Bに従って、白色固体として得られる表題化合物(1.75g、65%)を調製した。
MS (ESI+): [M+H]+ = 462.2; [(Mx2)+H]+ = 923.6
1H NMR (CD3OD, 500 MHz) δ (ppm): 7.54-7.22 (m, 10H); 5.23-5.02 (m, 4H); 4.05-3.89 (m, 1H); 2.54-2.43 (m, 1H); 2.31-2.17 (m, 1H); 1.95-1.79 (m, 1H); 1.78-1.59 (m, 2H); 1.59-1.40 (m, 3H); 1.40-1.24 (m, 1H); 1.06-0.80 (m, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 51.31
EtOH/AcOH混合物(1: 1、18mL)中の前段生成物(500mg、1.08mmol、1.0当量)から、水素化分解についての手順Eに従って、白色粉体として得られる表題化合物(164mg、76%)を調製した。
期待純度: >95%(LCMS及びNMRに基づいて)
MS (ESI+): [(M-H2O)+H]+ = 220.2; [M+H]+ = 238.2; [(Mx2)+H]+ = 475.2; [(Mx3)+H]+ = 712.4
1H NMR (CD3OD, 500 MHz) δ (ppm): 3.17-3.04 (m, 1H); 2.62 (t, J = 7.5 Hz, 2H); 2.30-2.13 (m, 1H); 2.05-1.83 (m, 1H); 1.74-1.39 (m, 5H); 0.96 (d, J = 6.6 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 33.08
4-アミノ-4-[ヒドロキシ(4-メチルペンチル)ホスホリル]ブタン酸
工程1: (4-メチルペンチル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.26mL、11.5mmol、1.0当量)から、続いて無水Et2O(6mL)中の1-ブロモ-4-メチルペンタン(2.0g、12.1mmol、1.05当量)からの新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(740mg、43%)を調製した。
MS (ESI+): [M+H]+ = 151.2; [(Mx2)+H]+ = 301.2
1H NMR (500 MHz, MeOD) δ (ppm): 7.01 (dt, J = 536.1, 2 Hz, 1H); 1.78-1.67 (m, 2H); 1.67-1.53 (m, 3H); 1.35-1.27 (m, 2H); 0.91 (d, J = 6.6 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 35.69
AcOH(5mL)及びAcCl(428μL)中の前段生成物(300mg、2.0mmol、1.0当量)及びNH2Cbz(362mg、2.4mmol、1.2当量)からの多成分反応、続いてAcOH(5mL)中のベンジル4-オキソブタノエート(460.8mg、2.4mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(416mg、44%)を調製した。
MS (ESI-): [M-H]- = 474.2
1H NMR (500 MHz, MeOD) δ (ppm): 7.39-7.23 (m, 10H); 5.20-5.00 (m, 4H); 3.96 (m, 1H); 2.57-2.43 (m, 2H); 2.27-2.13 (m, 1H); 1.85 (m, 1H); 1.71-1.45 (m, 5H); 1.21 (m, 2H); 0.88 (d, J = 6.7 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 50.75
EtOH/AcOH混合物(1: 1、7mL)中の前段生成物(200mg、420μmmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの粉体として得られる表題化合物(45mg、42%)を調製した。
期待純度: 95%(LCMS及びNMRに基づいて)
MS (ESI-): [M-H]- = 250.2; [(Mx2)-H]- = 501.3; [(Mx3)-H]- = 752.5
MS (ESI+): [(M-H2O)+H]+ = 234.2; [M+H]+ = 252.2; [(Mx2)+H]+ = 503.3; [(Mx3)+H]+ = 754.6
1H NMR (500 MHz, MeOD) δ (ppm): 3.13-3.05 (m, 1H); 2.64-2.56 (m, 2H); 2.27-2.13 (m, 1H); 2.01-1.87 (m, 1H); 1.67-1.51 (m, 5H); 1.29 (q, J = 6.9 Hz, 2H); 0.91 (d, J = 6.6 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 32.67
4-アミノ-4-[ヒドロキシ(S-メチルヘキシル)ホスホリル]ブタン酸
工程1: (5-メチルヘキシル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.15mL、10.54mmol、1.0当量)から、続いて無水Et2O(5mL)中の1-ブロモ-5-メチルヘキサン(2.0g、11.17mmol、1.05当量)からの新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(797mg、46%)を調製した。
MS (ESI+): [M+H]+ = 165.2; [(Mx2)+H]+ = 329.2
1H NMR (500 MHz, MeOD) δ (ppm): 7.00 (dt, J = 533.5, 1.99 Hz, 1H); 1.73 (s, 2H); 1.62-1.51 (m, 3H); 1.43 (dd, J = 8.6, 7.5 Hz, 2H); 1.23 (dd, J = 8.6, 7.0 Hz, 2H); 0.90 (d, J = 6.6 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 35.5
AcOH(4mL)及びAcCl(391μL)中の前段生成物(300mg、1.83mmol、1.0当量)及びNH2Cbz(331mg、2.19mmol、1.2当量)からの多成分反応、続いてAcOH(3mL)中のベンジル4-オキソブタノエート(421mg、2.19mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(521mg、58%)を調製した。
MS (ESI+): [M+H]+ = 490.2; [(Mx2)+H]+ = 979.7
1H NMR (500 MHz, MeOD) δ (ppm): 7.32 (dt, J = 20.9, 6.2 Hz, 10H); 5.23-4.90 (m, 4H); 4.08-3.84 (m, 1H); 2.72-2.34 (m, 2H); 2.21 (d, J = 13.5 Hz, 1H); 1.86 (tt, J = 14.0, 7.2 Hz, 1H); 1.72-1.38 (m, 5H); 1.37-1.07 (m, 4H); 0.88 (d, J = 6.8 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 50.6
EtOH/AcOH混合物(1: 1、9mL)中で、前段生成物(250mg、510μmmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの粉体として得られる表題化合物(32mg、23%)を調製した。
期待純度: 95%(LCMS及びNMRに基づいて)
MS (ESI-): [M-H]- = 264.2; [(Mx2)-H]- = 529.3; [(Mx3)-H]- = 794.6
MS (ESI+): [(M-H2O)+H]+ = 248.2; [M+H]+ = 266.3; [(Mx2)+H]+ = 531.3; [(Mx3)+H]+ = 796.6
1H NMR (500 MHz, MeOD) δ (ppm): 3.13-3.04 (m, 1H); 2.64-2.57 (m, 2H); 2.26-2.14 (m, 1H); 2.00-1.87 (m, 1H); 1.66-1.54 (m, 5H); 1.47-1.36 (m, 2H); 1.27-1.18 (m, 2H); 0.89 (d, J = 6.6 Hz, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 32.7
4-アミノ-4-[ヒドロキシ(ペンチル)ホスホリル]ブタン酸
工程1: ペンチルホスフィン酸
表題化合物(715mg、55%)を、手順Aに従って、無水Et2O(5mL)中でジエチルクロロ亜リン酸(1.05mL、9.58mmol、1.0当量)から、臭化ペンチルマグネシウム(Et2O中2.0M溶液、5.03mL、1.05当量)を添加することによって調製した。
MS (ESI-): [M-H]- = 135.0
MS (ESI+): [M+H]+ = 137.1; [(Mx2)+H]+ = 273.1
1H NMR (500 MHz, MeOD) δ (ppm): 7.01 (dt, J = 535.4, 2.0 Hz, 1H); 1.80-1.67 (m, 2H), 1.66-1.53 (m, 2H), 1.49-1.30 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 35.8
AcOH(9mL)及びAcCl(472μL)中の前段生成物(300mg、2.2mmol、1.0当量)及びNH2Cbz(400mg、2.64mmol、1.2当量)からの多成分反応、続いてAcOH(5mL)中のベンジル4-オキソブタノエート(508mg、2.64mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(560mg、55%)を調製した。
MS (ESI-): [M-H]- = 460.1; [(Mx2)-H]- = 921.5
MS (ESI+): [M+H]+ = 462.1; [(Mx2)+H]+ = 923.5
1H NMR (CD3OD, 500 MHz) δ (ppm): 7.40-7.22 (m, 10H); 5.16-5.02 (m, 4H); 3.96 (m, 1H); 2.57-2.42 (m, 2H); 2.22 (m, 1H); 1.85 (m, 1H); 1.73-1.47 (m, 4H); 1.30 (m, 4H); 0.90 (t, J = 5.2, 3.8 Hz, 3H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 50.8
EtOH/AcOH混合物(1: 1、9mL)中の前段生成物(250mg、540μmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの粉体として得られる表題化合物(65mg、50%)を調製した。
期待純度: 95%(LCMSに基づいて)及び92%(NMRに基づいて)
MS (ESI-): [M-H]- = 236.2; [(Mx2)-H]- = 473.3; [(Mx3)-H]- = 710.5
MS (ESI+): [(M-H2O)+H]+ = 220.2; [M+H]+ = 238.2; [(Mx2)+H]+ = 475.3; [(Mx3)+H]+ = 712.5
1H NMR (500 MHz, MeOD) δ (ppm): 3.12-3.07 (m, 1H), 2.63-2.56 (m, 2H), 2.28-2.14 (m, 1H), 2.00-1.87 (m, 1H), 1.68-1.52 (m, 4H), 1.46-1.31 (m, 4H), 0.99-0.85 (m, 3H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 32.7
4-アミノ-4-[ヘキシル(ヒドロキシ)ホスホリル]ブタン酸
工程1: ヘキシルホスフィン酸
表題化合物(1.21g、63%)を、手順Aに従って、無水Et2O(7mL)中で、ジエチルクロロ亜リン酸(1.40mL、12.78mmol、1.0当量)に、臭化ヘキシルマグネシウム(Et2O中2.0M溶液、6.71mL、1.05当量)を添加することによって調製した。
MS (ESI-): [M-H]- = 149.1
MS (ESI+): [M+H]+ = 151.2; [(Mx2)+H]+ = 301.2
1H NMR (500 MHz, MeOD) δ (ppm): 7.01 (dt, J = 535.4, 2.0 Hz, 1H); 1.79-1.67 (m, 2H), 1.65-1.52 (m, 2H); 1.50-1.40 (m, 2H); 1.40-1.27 (m, 4H); 0.96-0.87 (m, 3H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 35.8
AcOH(9mL)及びAcCl(428μL)中の前段生成物(300mg、2.0mmol、1.0当量)及びNH2Cbz(362mg、2.4mmol、1.2当量)からの多成分反応、続いてAcOH(5mL)中のベンジル4-オキソブタノエート(460mg、2.4mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(572mg、60%)を調製した。
1H NMR (500 MHz, MeOD) δ (ppm): 7.41-7.21 (m, 10H); 5.17-5.02 (m, 4H); 4.01-3.91 (m, 1H); 2.57-2.40 (m, 2H); 2.28-2.15 (m, 1H); 1.85 (m, 1H); 1.74-1.46 (m, 4H); 1.38-1.21 (m, 6H); 0.90 (t, J = 7.0 Hz, 3H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 50.7
EtOH/AcOH混合物(1: 1、9mL)中の前段生成物(250mg、0.520mmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの固体として得られる表題化合物(54mg、41%)を調製した。
期待純度: 97%(LCMSに基づいて)及び95%(NMRに基づいて)
MS (ESI-): [M-H]- = 250.2; [(Mx2)-H]- = 501.3; [(Mx3)-H]- = 752.6
MS (ESI+): [(M-H2O)+H]+ = 234.2; [M+H]+ = 252.2; [(Mx2)+H]+ = 503.3; [(Mx3)+H]+ = 754.6
1H NMR (500 MHz, MeOD) δ (ppm): 3.13-3.04 (m, 1H); 2.64-2.56 (m, 2H); 2.27-2.14 (m, 1H); 2.00-1.86 (m, 1H); 1.69-1.52 (m, 4H); 1.47-1.27 (m, 6H); 0.97-0.86 (m, 3H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 30.7
4-アミノ-4-[ヒドロキシ(4,4,4-トリフルオロブチル)ホスホリル]ブタン酸
工程1: (4,4,4-トリフルオロブチル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.12mL、10.2mmol、1.0当量)から、続いて無水Et2O(5mL)中の4-ブロモ-1,1,1-トリフルオロブタン(2.0g、10.0mmol、1.05当量)からの新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(1g、56%)を調製した。
MS (ESI-): [M-H]- = 175.1
MS (ESI+): [M+H]+ = 177.1; [(Mx2)+H]+ = 353.0
1H NMR (500 MHz, MeOD) δ (ppm): 7.05 (dt, J = 537.3, 1.8 Hz, 1H); 2.38-2.24 (m, 2H), 1.90-1.77 (m, 4H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 33.5
AcOH(9mL)及びAcCl(425μL)中の前段生成物(350mg、1.99mmol、1.0当量)及びNH2Cbz(360mg、2.39mmol、1.2当量)からの多成分反応、続いてAcOH(5mL)中のベンジル4-オキソブタノエート(458mg、2.38mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(595mg、60%)を調製した。
MS (ESI+): [M+H]+ = 502.1
1H NMR (500 MHz, MeOD) δ (ppm): 7.43-7.20 (m, 10H); 5.18-5.00 (m, 4H); 4.02-3.91 (m, 1H); 2.60-2.42 (m, 2H); 2.30-2.08 (m, 3H); 1.96-1.64 (m, 5H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 49.1
EtOH/AcOH混合物(1: 1、9mL)中の前段生成物(250mg、0.498mmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの固体として得られる表題化合物(29mg、21%)を調製した。
期待純度: 95%(LCMS及びNMRに基づいて)
MS (ESI-): [M-H]- = 276.2; [(Mx2)-H]- = 553.2; [(Mx3)-H]- = 830.4
MS (ESI+): [(M-H2O)+H]+ = 260.1; [M+H]+ = 278.2; [(Mx2)+H]+ = 555.2; [(Mx3)+H]+ = 832.4
1H NMR (500 MHz, MeOD) δ (ppm): 3.15-3.06 (m, 1H); 2.61 (t, J = 7.3 Hz, 2H); 2.36-2.14 (m, 3H); 2.01-1.80 (m, 3H); 1.72-1.58 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 30.9
4-アミノ-4-[(2-シクロヘキシルエチル)(ヒドロキシ)ホスホリル]ブタン酸
工程1: (2-シクロヘキシルエチル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.29mL、11.8mmol、1.0当量)から、続いて無水Et2O(6mL)中の(2-ブロモエチル)シクロヘキサン(2.4g、12.6mmol、1.05当量)からの新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(1.2g、58%)を調製した。
MS (ESI+): [M+H]+ = 177.2; [(Mx2)+H]+ = 353.2
1H NMR (500 MHz, MeOD) δ (ppm): 7.01 (dt, J = 535.8, 1.9 Hz, 1H); 1.82-1.63 (m, 7H); 1.52-1.40 (m, 2H); 1.39-1.13 (m, 4H); 1.02-0.86 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 36.5
AcOH(9mL)及びAcCl(425μL)中の前段生成物(350mg、1.99mmol、1.0当量)及びNH2Cbz(360mg、2.39mmol、1.2当量)からの多成分反応、続いてAcOH(5mL)中のベンジル4-オキソブタノエート(458mg、2.38mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(654mg、66%)を調製した。
MS (ESI-): [M-H]- = 474.2
MS (ESI+): [M+H]+ = 476.2
1H NMR (500 MHz, MeOD) δ (ppm): 7.41-7.21 (m, 10H); 5.23-4.97 (m, 4H); 3.96 (m, 1H); 2.60-2.42 (m, 2H); 2.32-2.14 (m, 1H); 1.86 (m, 1H); 1.73-1.60 (m, 7H); 1.44 (m, 2H); 1.28-1.10 (m, 4H); 0.85 (p, J = 11.6 Hz, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 51.4
EtOH/AcOH混合物(1: 1、9mL)中の前段生成物(250mg、0.498mmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの固体として得られる表題化合物(63mg、46%)を調製した。
期待純度: 95%(LCMS及びNMRに基づいて)
MS (ESI-): [M-H]- = 276.2; [(Mx2)-H]- = 553.3; [(Mx3)-H]- = 830.6
MS (ESI+): [(M-H2O)+H]+ = 260.2; [M+H]+ = 278.2; [(Mx2)+H]+ = 555.3; [(Mx3)+H]+ = 832.7
1H NMR (500 MHz, MeOD) δ (ppm): 3.14-3.04 (m, 1H); 2.64-2.57 (m, 2H); 2.27-2.14 (m, 1H); 2.00-1.86 (m, 1H); 1.82-1.45 (m, 9H); 1.33-1.13 (m, 4H); 1.01-0.86 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 33.1
4-アミノ-4-[(シクロブチルメチル)(ヒドロキシ)ホスホリル]ブタン酸
工程1: (シクロブチルメチル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.26mL、11.5mmol、1.0当量)から、無水Et2O(6mL)中の(ブロモメチル)シクロブタン(1.4g、9.4mmol、1.05当量)からの新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(290mg、24%)を調製した。
MS (ESI+): [M+H]+ = 177
1H NMR (500 MHz, MeOD) δ (ppm): 6.97 (dt, J = 533.5, 2.1 Hz, 1H), 2.76-2.58 (m, 1H); 2.25-2.13 (m, 2H), 1.99-1.76 (m, 6H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 33.1
AcOH(5mL)及びAcCl(463μL)中の前段生成物(290mg、2.16mmol、1.0当量)及びNH2Cbz(392mg、2.59mmol、1.2当量)からの多成分反応、続いてAcOH(4mL)中のベンジル4-オキソブタノエート(498mg、2.59mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(707mg、71%)を調製した。
MS (ESI+): [M+H]+ = 458
1H NMR (500 MHz, MeOD) δ (ppm): 7.39-7.21 (m, 10H); 5.17-5.01 (m, 4H); 3.89 (s, 1H); 2.64 (m, 1H); 2.48 (m, 2H); 2.26-1.96 (m, 3H); 1.95-1.60 (m, 7H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 49.4
EtOH/AcOH混合物(1: 1、9mL)中の前段生成物(250mg、0.544mmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの固体として得られる表題化合物(45mg、35%)を調製した。
期待純度: 97%(LCMSに基づいて)及び95%(NMRに基づいて)
MS (ESI-): [M-H]- = 234.1; [(Mx2)-H]- = 469.2; [(Mx3)-H]- = 704.5
MS (ESI+): [(M-H2O)+H]+ = 218.2; [M+H]+ = 236.2; [(Mx2)+H]+ = 471.2; [(Mx3)+H]+ = 706.4
1H NMR (500 MHz, MeOD) δ (ppm): 3.02-2.96 (m, 1H); 2.75-2.65 (m, 1H); 2.62-2.56 (m, 2H); 2.22-2.14 (m, 3H); 1.97-1.85 (m, 2H); 1.85-1.77 (m, 3H); 1.74 (dd, J = 12.9, 7.4 Hz, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 31.1
4-アミノ-4-[(シクロペンチルメチル)(ヒドロキシ)ホスホリル]ブタン酸
工程1: (シクロペンチルメチル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.26mL、11.5mmol、1.0当量)から、続いて無水Et2O(6mL)中で(ブロモメチル)シクロペンタン(2.0g、12.3mmol、1.05当量)からの新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(607mg、36%)を調製した。
1H NMR (500 MHz, MeOD) δ (ppm): 7.06 (dt, J = 534.5, 2.1 Hz, 1H); 2.20-2.08 (m, 1H), 1.98-1.89 (m, 2H), 1.82 (mm, 2H), 1.73-1.65 (m, 2H), 1.63-1.54 (m, 2H), 1.33-1.21 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 34.4
AcOH(5mL)及びAcCl(433μL)中の前段生成物(300mg、2.03mmol、1.0当量)及びNH2Cbz(367mg、2.43mmol、1.2当量)からの多成分反応、続いてAcOH(4mL)中のベンジル4-オキソブタノエート(467mg、2.43mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(541mg、56%)を調製した。
MS (ESI-): [M-H]- = 472.2
MS (ESI+): [M+H]+ = 274.1
1H NMR (500 MHz, MeOD) δ (ppm): 7.44-7.18 (m, 10H); 5.21-4.97 (m, 4H); 3.93 (m, 1H); 2.57-2.42 (m, 2H); 2.28-2.17 (m, 1H); 2.12 (m, 1H); 1.84 (m, 3H); 1.79-1.69 (m, 2H); 1.67-1.57 (m, 2H); 1.53 (m, 2H); 1.17 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 49.8
EtOH/AcOH混合物(1: 1、9mL)中の前段生成物(250mg、0.528mmol、1.0当量)から、水素化分解についての手順Eに従って、ベージュの固体として得られる表題化合物(62mg、47%)を調製した。
期待純度: 95%(LCMSに基づいて)及び93%(NMRに基づいて)
MS (ESI-): [M-H]- = 248.2; [(Mx2)-H]- = 497.2; [(Mx3)-H]- = 746.5
MS (ESI+): [(M-H2O)+H]+ = 232.2; [M+H]+ = 250.2; [(Mx2)+H]+ = 499.3; [(Mx3)+H]+ = 748.5
1H NMR (500 MHz, MeOD) δ (ppm): 3.10-3.01 (m, 1H); 2.64-2.55 (m, 2H); 2.27-2.12 (m, 2H); 2.02-1.87 (m, 3H); 1.72-1.61 (m, 4H); 1.61-1.51 (m, 2H); 1.31-1.19 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 31.6
4-アミノ-4-[(シクロヘキシルメチル)(ヒドロキシ)ホスホリル]ブタン酸
工程1: (シクロヘキシルメチル)ホスフィン酸
無水Et2O(6mL)中のジエチルクロロ亜リン酸(1.15mL、10.5mmol、1.0当量)から、続いて無水Et2O(5mL)中の(ブロモメチル)シクロヘキサン(2.0g、11.0mmol、1.05当量) の新鮮に調製されたグリニャール試薬の添加からの手順Aに従って表題化合物(475mg、28%)を調製した。
MS (ESI+): [M+H]+ = 163.2; [(Mx2)+H]+ = 325.2
1H NMR (500 MHz, MeOD) δ (ppm): 7.01 (dt, J = 533.6, 2.2 Hz, 1H); 1.90-1.82 (m, 2H); 1.75-1.62 (m, 6H); 1.34-1.27 (m, 2H); 1.24-1.17 (m, 1H); 1.15-1.04 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 33.7
AcOH(4mL)及びAcCl(396μL)中の前段生成物(300mg、1.85mmol、1.0当量)及びNH2Cbz(335mg、2.22mmol、1.2当量)からの多成分反応、続いてAcOH(3mL)中のベンジル4-オキソブタノエート(426mg、2.22mmol、1.2当量)の溶液の添加についての手順Bに従って、白色固体として得られる表題化合物(501mg、55%)を調製した。
MS (ESI+): [M+H]+ = 488.2; [(Mx2)+H]+ = 975.6
1H NMR (500 MHz, MeOD) δ (ppm): 7.40-7.23 (m, 10H); 5.17-5.01 (m, 4H); 3.90 (t, J = 9.4 Hz, 1H); 2.56-2.41 (m, 2H); 1.96-1.45 (m, 10H); 1.35-1.20 (m, 3H); 1.06-0.93 (m, 2H)
LiOH.H2O(43mg、1.03mmol、2.0当量)の存在でTHF/水の混合物(2/1、5mL)中の前段生成物(250mg、0.513mmol、1.0当量)から、手順Cに従って、白色固体として得られる表題化合物(205mg、100%)を調製した。
MS (ESI-): [M-H]- = 396.2; [(Mx2)-H]- = 793.4
MS (ESI+): [M+H]+ = 398.2; [(Mx2)+H]+ = 795.4
1H NMR (500 MHz, MeOD) δ (ppm): 7.42-7.22 (m, 5H); 5.22-5.03 (m, 2H); 3.97-3.86 (m, 1H); 2.51-2.33 (m, 2H); 2.26-2.13 (m, 1H); 1.92-1.53 (m, 9H); 1.35-1.11 (m, 3H); 1.07-0.93 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 33.1
TFA/アニソール(1.5mL/355μL)中の前段生成物(205mg、510μmol、1.0当量)から、手順Dに従って、ベージュの固体として得られる表題化合物(27mg、20%)を調製した。
推定純度: 90%(NMRに基づいて)
MS (ESI-): [M-H]- = 262.2; [(Mx2)-H]- = 525.3; [(Mx3)-H]- = 788.6
MS (ESI+): [(M-H2O)+H]+ = 246.2; [M+H]+ = 264.2
1H NMR (400 MHz, MeOD) δ (ppm): 3.07-2.97 (m, 1H), 2.59 (t, J = 7.6 Hz, 2H); 2.28-2.12 (m, 1H); 1.99-1.60 (m, 7H); 1.55-1.46 (m, 2H); 1.40-1.26 (m, 2H); 1.26-1.14 (m, 1H); 1.12-0.99 (m, 2H)
31P NMR (CD3OD, 202 MHz) δ (ppm): 31.8
インビトロにおけるAPA活性の測定
インビトロにおけるAPA活性の測定は、マイクロプレート上におけるアッセイの尺度にされたGoldbargのプロトコルに基づく(Pro Bind TM3915)(Chauvel et al.、1994)。インビトロにおいて、カルシウムイオンの存在下で、APAは、合成基質α-L-グルタミル-β-ナフチルアミド(GluβNa)をグルタメート及びβ-ナフチルアミン(βNa)に加水分解する。酸性媒体中におけるジアゾ化反応は、紫に着色した錯体の形成により、β-ナフチルアミンを明示することを可能にする: 次に、分光学的測定が、β-ナフチルアミンの増大する濃度で生じる標準曲線を参照することにより、形成された複合体の量を知ること、及び、試料の酵素活性を導き出すことを可能にする。
Glu-βNa基質(Bachem社)及びβ-ナフチルアミン(Sigma社)を50%DMSO(ジメチルスルホキシド)及び0.1N HClにそれぞれ溶解して、-20℃、10-2Mの濃度で保存した。ジアゾ化反応は、亜硝酸ナトリウム(87mM)、スルファミン酸アンモニウム(130mM)及びN-(1-ナフチル)-エチレンジアミン二塩酸塩(95%エタノール中23mM)の存在下で実施した。
反応は、50mMトリス-HCl緩衝剤中pH7.4で、カルシウム(4mM CaCl2)の存在下で起こり、組換えマウスAPAを、100μLの最終体積で、37℃で基質(200μM Glu-βNa)の存在下、及び種々の濃度の試験されるべき阻害剤の存在又は非存在下で、インキュベートする。反応を、10μLの3N HClを添加することにより停止させる。β-ナフチルアミンの標準曲線は、0.1N HCl中で増大する濃度(0.2mMまで)の2-ナフチルアミンをジアゾ化することにより、平行して準備した。
以下のものを各ウェルに添加する: 25μLの亜硝酸ナトリウム(NaNO2)(室温で混合して、5分待つ)、50μLのスルファミン酸アンモニウム(室温で混合して、5分待つ)、次に25μLのN-(1-ナフチル)エチレンジアミン二塩酸塩(37℃で混合して、紫色の安定化する間およそ30分間待つ)を添加する。
Claims (11)
- 以下の式(I):
(式中、
AHは、-CO2H、-SO3H、又は-PO3H2を表し;
1は2又は3であり;
mは0、1、2又は3であり;
R1は、ハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、O-シクロアルキル基、O-アリール基、O-アリールアルキル基、ヘテロアルキル基、任意選択でアルキル基によりモノ置換又はジ置換されたアミノ基、ハロアルキル基、シクロアルキル基、アシル基、アリール基又はアリールアルキル基を表し;
R2及びR3は、水素原子、ハロゲン原子、アルキル基、ハロアルキル基を独立に表すか、又は式(I)に描かれた隣接炭素原子と一緒になってシクロアルキル基を形成することができる);
それらの薬学的塩、溶媒和物、又は双性イオン。 - - mは0若しくは1であり;及び/又は
- AHは、CO2H若しくはSO3H若しくはPO3H2であり; 及び/又は
- R1は、ハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、O-シクロアルキル基、O-アリール基、O-アリールアルキル基、ヘテロアルキル基、ハロアルキル基、シクロアルキル基、アシル基、アリール基若しくはアリールアルキル基を表す、請求項1又は2に記載の化合物。 - 以下の式(III):
(式中、
1は2又は3であり;
mは0、1、2又は3であり;
R1は、ハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、O-シクロアルキル基、O-アリール基、O-アリールアルキル基、ヘテロアルキル基、任意選択でアルキル基によりモノ置換又はジ置換されたアミノ基、ハロアルキル基、シクロアルキル基、アシル基、アリール基又はアリールアルキル基を表し;
R2及びR3は、水素原子、ハロゲン原子、アルキル基、ハロアルキル基を独立に表すか、又は式(III)に描かれた隣接炭素原子と一緒になってシクロアルキル基を形成することができ;
Aは、-SO3Z、-CO2Z又は-P(O)(OZ)2を表し、Zは、水素原子、アルキル及びアリールアルキル基からなる群から選択され、
Xは、水素原子、-(CO)-アルキル、-(CO)-アルコキシ、-(CO)-ベンジルオキシ、
Rは、アルキル基を表し、R'及びR"は、水素原子又はアルキル基を独立に表し、
Yは、水素原子、アルキル、アリール、アリールアルキル基又は
Z、X及びYの少なくとも1つは、水素原子と異なる)。 - 4-アミノ-4-[ヒドロキシ(3-メチルブチル)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(4-メチルペンチル)ホスホリル]ブタン酸;
4-アミノ-4-[(2-シクロヘキシルエチル)(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(ペンチル)ホスホリル]ブタン酸;
4-アミノ-4-[ヘキシル(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[(シクロブチルメチル)(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[(シクロヘキシルメチル)(ヒドロキシ)ホスホリル]ブタン酸
4-アミノ-4-[(シクロペンチルメチル)(ヒドロキシ)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(5-メチルヘキシル)ホスホリル]ブタン酸;
4-アミノ-4-[ヒドロキシ(4,4,4-トリフルオロブチル)ホスホリル]ブタン酸;及び
4-アミノ-4-[ヒドロキシ({[(プロパン-2-イル)アミノ]メチル})ホスホリル]ブタン酸からなる群から選択される、請求項1又は2に記載の化合物。 - 請求項1から6のいずれか一項に記載の化合物を含む医薬組成物。
- 請求項1から6のいずれか一項に記載の少なくとも1種の化合物を、薬学的に許容される希釈剤又は担体と共に含む医薬組成物。
- 動脈高血圧症及び直接又は間接的に関係する疾患の処置における使用のための、請求項7又は8に記載の医薬組成物。
- 心臓疾患、心不全、脳卒中、末梢及び/又は大脳の血管系疾患、脳、眼及び/又は腎臓の疾患からなる群において選択される動脈高血圧症に直接又は間接的に関係する障害の処置における使用のための、請求項9に記載の医薬組成物。
- 原発性及び/又は続発性動脈高血圧症、発作、心筋虚血、心臓機能不全、腎臓機能不全、心筋梗塞、末梢血管疾患、糖尿病性タンパク尿、X症候群、緑内障、神経変性疾患及び記憶障害からなる群において選択される障害の処置における使用のための、請求項9に記載の医薬組成物。
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PCT/EP2019/079288 WO2020084147A1 (en) | 2018-10-26 | 2019-10-25 | Novel aminophosphinic derivatives as aminopeptidase a inhibitors |
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TW202207917A (zh) * | 2020-05-06 | 2022-03-01 | 法商量子基因科技有限公司 | 包含腦胺肽酶抑制劑、利尿劑及全身性腎素-血管收縮素系統阻斷劑之醫藥組合物 |
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Title |
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GEORGIADIS,D. et al,Potent and Selective Inhibition of Zinc Aminopeptidase A (EC 3.4.11.7, APA) by Glutamyl Aminophosphinic Peptides: Importance of Glutamyl Aminophosphinic Residue in the P1 Position,Biochemistry,2000年,Vol.39, No.5,p.1152-1155 |
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US20210309677A1 (en) | 2021-10-07 |
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TW202029965A (zh) | 2020-08-16 |
ZA202103581B (en) | 2022-08-31 |
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IL282484A (en) | 2021-06-30 |
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