Novel aminophosphinic derivatives as aminopeptidase a inhibitors

A technology of amino and group, which is applied in the field of preparation of the compound, can solve problems such as increased activity and adverse reactions

Pending Publication Date: 2021-07-23
QUANTUM GENOMICS +3
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, the activity of the renin-angiotensin-aldosterone system (RAAS) is increased in patients with HF, and its maladaptive mechanisms may lead to adverse effects such as cardiac remodeling and sympathetic activation

Method used

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  • Novel aminophosphinic derivatives as aminopeptidase a inhibitors
  • Novel aminophosphinic derivatives as aminopeptidase a inhibitors
  • Novel aminophosphinic derivatives as aminopeptidase a inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0220] Example 1: 4-Amino-4-[hydroxy(3-methylbutyl)phosphoryl]butanoic acid

[0221] Step 1: (3-Methylbutyl)phosphinic acid

[0222] According to protocol A from anhydrous Et 2 Diethyl chlorophosphite (1.90 mL, 17.4 mmol, 1.0 eq.) in O (6 mL), followed by addition from anhydrous Et 2 The title compound (1.40 g, 59%) was prepared from freshly prepared Grignard reagent in 1-bromo-3-methylbutane (2.76 g, 18.3 mmol, 1.05 eq.) in O (9 mL).

[0223] MS (ESI + ): [M+H] + =137.2; [(Mx2)+H] + =273.2

[0224] 1 H NMR (MeOD, 500MHz) δ (ppm): 7.02 (dt, J=536.2, 2.0Hz, 1H); 1.85-1.71 (m, 2H); 1.71-1.59 (m, 1H); 1.55-1.42 (m, 2H); 0.96(d, J=6.7Hz, 6H)

[0225] 31 P NMR (CD 3 OD, 202MHz) δ (ppm): 36.32

[0226] Step 2: [4-(Benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl](3-methylbutyl)phosphinic acid

[0227] From the previous product (800 mg, 5.88 mmol, 1.0 eq.) and NH in AcOH (10 mL) and AcCl (1.2 mL) according to Protocol B of multicomponent reactions 2 Cbz (977mg, 6.46m...

Embodiment 2

[0237] Example 2: 4-Amino-4-[hydroxy(4-methylpentyl)phosphoryl]butanoic acid

[0238] Step 1: (4-Methylpentyl)phosphinic acid

[0239] According to protocol A from anhydrous Et 2 Diethyl chlorophosphite (1.26 mL, 11.5 mmol, 1.0 eq.) in O (6 mL), followed by addition of 2 1-Bromo-4-methylpentane (2.0 g, 12.1 mmol, 1.05 eq.) in O (6 mL) freshly prepared Grignard reagent to prepare the title compound (740 mg, 43%).

[0240] MS (ESI + ): [M+H] + =151.2; [(Mx2)+H] + =301.2

[0241] 1 H NMR (500MHz, MeOD) δ (ppm): 7.01 (dt, J = 536.1, 2Hz, 1H); 1.78-1.67 (m, 2H); 1.67-1.53 ​​(m, 3H); 1.35-1.27 (m, 2H ); 0.91 (d, J=6.6Hz, 6H)

[0242] 31 P NMR (CD 3 OD, 202MHz) δ (ppm): 35.69

[0243] Step 2: [4-(Benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl](4-methylpentyl)phosphinic acid

[0244] From the previous product (300 mg, 2.0 mmol, 1.0 eq.) and NH in AcOH (5 mL) and AcCl (428 μL) according to Protocol B of the multicomponent reaction 2 Cbz (362 mg, 2.4 mmol, 1.2 eq.), f...

Embodiment 3

[0255] Example 3: 4-Amino-4-[hydroxy(5-methylhexyl)phosphoryl]butanoic acid

[0256] Step 1: (5-Methylhexyl)phosphinic acid

[0257] According to protocol A from anhydrous Et 2 Diethyl chlorophosphite (1.15mL, 10.54mmol, 1.0eq.) in O (6mL) was subsequently added from anhydrous Et 2 1-Bromo-5-methylhexane (2.0 g, 11.17 mmol, 1.05 eq.) in O (5 mL) freshly prepared Grignard reagent to prepare the title compound (797 mg, 46%).

[0258] MS (ESI + ): [M+H] + =165.2; [(Mx2)+H] + =329.2

[0259] 1 H NMR (500MHz, MeOD) δ (ppm): 7.00 (dt, J = 533.5, 1.99Hz, 1H); 1.73 (s, 2H); 1.62-1.51 (m, 3H); 1.43 (dd, J = 8.6, 7.5Hz, 2H); 1.23(dd, J=8.6, 7.0Hz, 2H); 0.90(d, J=6.6Hz, 6H)

[0260] 31 P NMR (CD 3 OD, 202MHz) δ (ppm): 35.5

[0261] Step 2: [4-(Benzyloxy)-1-{[(benzyloxy)carbonyl]amino}-4-oxobutyl](5-methylhexyl)phosphinic acid

[0262] From the previous product (300 mg, 1.83 mmol, 1.0 eq.) and NH in AcOH (4 mL) and AcCl (391 μL) according to Protocol B of the multicomponent re...

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Abstract

The present invention relates to a novel compound, to a composition comprising the same, to methods for preparing the compound, and the use of this compound in therapy. In particular, the present invention relates to compound that is useful in the treatment and prevention of primary and secondary arterial hypertension, ictus, myocardial ischaemia, cardiac and renal insufficiency, myocardial infarction, peripheral vascular disease, diabetic proteinuria, Syndrome X and glaucoma.

Description

[0001] field of invention [0002] The present invention relates to novel compounds, to compositions comprising the compounds, to processes for the preparation of the compounds, and to the use of these compounds in therapy. In particular, the present invention relates to drugs useful in the treatment and prevention of primary and secondary arterial hypertension, sudden onset, myocardial ischemia, cardiac and renal insufficiency, myocardial infarction, peripheral vascular disease, diabetic proteinuria, syndrome X and glaucoma compounds. [0003] Background of the invention [0004] Essential Hypertension (HTN) and heart failure (HF) are two major pathologies of cardiovascular disease. HTN affects approximately 1 billion individuals worldwide. It is a major risk factor for coronary heart disease, HF, stroke and renal insufficiency. Despite the availability of effective and safe medications, HTN and its associated risk factors remain uncontrolled in many patients. In Western c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/30A61K31/662A61P9/10A61P9/12
CPCC07F9/301A61P9/10A61P9/12C07F9/303A61K31/662
Inventor F.巴拉沃伊内D.康佩尔C.洛伦斯科特斯
Owner QUANTUM GENOMICS
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