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Highly substituted alpha-amino phosphonate derivative as well as preparation method and medical application thereof

A technology of monoethyl methylphosphonate and diethyl methylphosphonate, which is applied in the fields of highly substituted α-aminophosphonic acid derivatives, their preparation and their medical application, and can solve the lack of prevention of autoimmune diseases and/or treatments, immunocompromised, Cushing's syndrome, etc.

Active Publication Date: 2014-12-03
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the long-term application of hormone drugs and immunosuppressive drugs can easily lead to low immune function, such as Cushing's syndrome, and even serious side effects such as infection and tumor
Therefore, autoimmune diseases currently lack effective means of prevention and / or treatment

Method used

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  • Highly substituted alpha-amino phosphonate derivative as well as preparation method and medical application thereof
  • Highly substituted alpha-amino phosphonate derivative as well as preparation method and medical application thereof
  • Highly substituted alpha-amino phosphonate derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1: Preparation of α-[3-(cyclohexylamino)propylamino]-α-(2-hydroxy-5-nitrophenyl)methylphosphonic acid monoethyl ester-compound 1

[0100] Take by weighing 9.60g (0.052mol) 5-nitrosalicylaldehyde i.e. 2-hydroxyl-5-nitrobenzaldehyde, 7.85g (0.050mol) N-(3-aminopropyl) cyclohexylamine i.e. [3-( Cyclohexylamino) propylamine] and 7.80g (0.056mol) of diethyl phosphite were dissolved in 50ml of absolute ethanol, stirred at a bath temperature of about 60°C for 2.5 days, cooled, yellow crystals were precipitated, dried to obtain 19.20g, and Yield 92.4%, mp 192-194°C (dec.).

[0101] 1 H-NMR (D 2 O, ppm) 0.922(t, J=7.00Hz, 3H), 0.92-1.22(m, 5H), 1.430(m→d, J=11.76Hz, 1H), 1.588(br-s, 2H), 1.795( m, 4H), 2.60-2.70(m, 1H), 2.70-2.80(m, 1H), 2.82-2.92(m→d, J=9.38Hz, 3H), 3.563(m, 2H), 4.204(d, J=17.85Hz, 1H), 6.548(d, J=8.96Hz, 1H), 7.995(dd, J1=8.96Hz, J2=2.94Hz, 1H), 7.970(d, J=2.94Hz, 1H).

Embodiment 2

[0102] Example 2: Preparation of α-[3-(cyclohexylamino)propylamino]-α-(2,4-dihydroxyphenyl)methylphosphonic acid monoethyl ester-compound 2

[0103] According to the method of Example 1, 2,4-dihydroxybenzaldehyde was used instead of 5-nitrosalicylaldehyde to obtain yellow needle-like crystals with a yield of 91.9%, and mp>300°C.

[0104] 1 H-NMR (D 2O, ppm) 0.916(t, J=7.00Hz, 3H), 0.92-1.14(m, 5H), 1.423(m→d, J=12.32Hz, 1H), 1.52-1.68(m, 4H), 1.791( br-s, 2H), 2.40-2.49(m, 1H), 2.50-2.59(m, 1H), 2.75-2.90(m, 3H), 3.515(m, 2H), 3.821(d, J=18.21Hz, 1H), 6.17(d, J=2.52Hz, 1H), 6.220(dd, J 1 =8.40Hz,J 2 =2.52Hz, 1H), 6.840(dd, J 1 =8.40Hz,J 2 = 1.96Hz, 1H).

Embodiment 3

[0105] Example 3: Preparation of monomethyl α-[2-(dimethylamino)ethylamino]-α-(2-hydroxy-5-nitrophenyl)methylphosphonate-compound 3

[0106] According to the method of Example 1, 2-dimethylaminoethylamine is used to replace N-(3-aminopropyl) cyclohexylamine, and dimethyl phosphite is used to replace diethyl phosphite for reaction to obtain yellow cluster needles Like crystals, yield 93.1%, mp 176-178°C.

[0107] 1 H-NMR (D 2 O, ppm) 2.070(m, 2H), 2.753(s, 6H), 2.84-2.96(m, 2H), 3.325(d, J=10.08Hz, 3H), 3.937(d, J=20.59Hz, 1H) , 6.869(d, J=8.96Hz, 1H), 7.985(dd, J 1 =8.96Hz,J 2 =2.66Hz, 1H), 8.305(d, J=2.66Hz, 1H).

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Abstract

The invention relates to a highly substituted alpha-amino phosphonate derivative as well as a preparation method and a medical application thereof. Particularly, the invention provides a compound expressed by the general formula I, a derivative, a tautomera, a despinner or an optical isomer, a medical salt or a solvent compound, a medicament combination, a preparation method and an application of the compound to preparing a medicament for preventing or treating autoimmune diseases which are relevant to immune system dysfunction, such as chronic nephritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, chronic infectious arthritis, insulin-dependent diabetes, chronic toxic thyroiditis, myasthenia gravis, ankylosing spondylitis, pemphigus, and the like and organ transplantation and anaphylaxis diseases or an application of the compound used as a tool medicament for researching diseases which are relevant to the immune system function or dysfunction.

Description

Technical field: [0001] The present invention relates to the preparation of α-aminophosphonic acid with immunomodulatory activity as shown in general formula I, its derivatives, its stereoisomers, its pharmaceutically acceptable salts and its solvates, and its role in the prevention or treatment of immune Autoimmune diseases related to system dysfunction such as chronic nephritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes mellitus, chronic toxic thyroiditis, myasthenia gravis, ankylosing spondylitis , pemphigus, etc., and the application in organ transplantation and allergic diseases, or as a tool drug for the study of immune system function or diseases related to its dysfunction, and the pharmaceutical composition containing these compounds. Background technique: [0002] Autoimmune disease is a major disease that seriously endangers human health and is a common multiple chronic disease. Chronic nephritis,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/40C07F9/6558C07F9/655A61K31/662A61K31/675A61K31/665A61P37/02A61P37/06A61P37/08A61P13/12A61P25/00A61P17/06A61P19/04A61P19/02A61P3/10A61P21/04A61P17/00
Inventor 张永祥杨日芳周文霞肖智勇赵如胜陈少辉恽榴红程军平赵利枝王艳芳
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A