Precursor medicine of acyclic nucleoside phosphonic acid

A technology of prodrugs and drugs, which is applied in the fields of compounds of group 5/15 elements of the periodic table, pharmaceutical formulations, medical preparations containing active ingredients, etc. Constructs, low levels of carnitine, etc.

Active Publication Date: 2007-06-27
广东京豪生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with (R)-PMPA, the prodrug (R)-(POC) 2 -The bioavailability of PMPA is significantly improved, and the bioavailability of PMPA administered orally to dogs can reach 30%; but human oral (R)-(POC) 2 - The bioavailability of PMPA (25%) is much lower than that of similar drug adefovir dipivoxil (59%), and (R)-(POC) 2 - Bioavailability of PMPA is affected by food
[0006] U.S. Patent No. 5,663,159 discloses a series of prodrugs of bis(alkanoyloxymethoxy) acyclic nucleoside phosphonates, but this patent does not relate to the handcrafts including (R)-PMPA and (R)-PMPDAP. sex isomer
[0007] Literature (Shaw JP, et al.Pharmaceutical Research 1997; 14:1824-1829.) reported that (R)-bis-[(pivaloyloxy)-methoxy]-PMPA((R)-(POM) 2 -PMPA) has a ratio (R)-(POC) 2 -Higher oral bioavailability of PMPA; however, due to (R)-(POM) 2 The combination of pivalic acid and coenzyme A, the hydrolyzate of PMPA in the body, cannot be metabolized by the oxidative pathway, and is easy to accumulate in the cell, causing toxicity (Brass EP.Pharmacological Review, 2002; 54:589-598.), therefore, ( R)-(POM) 2 -PMPA was significantly more cytotoxic than (R)-(POC) 2 -PMPA (Robbins BL, et al.Antimicrobial Agents and Chemotherapy 1998; 42:612-617.), long-term use of prodrugs containing pivalic acid will cause low levels of carnitine in plasma (Abrahamson K, et al.Biochem.Med .Metab.Biol.1994;52:18-21.)

Method used

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  • Precursor medicine of acyclic nucleoside phosphonic acid
  • Precursor medicine of acyclic nucleoside phosphonic acid
  • Precursor medicine of acyclic nucleoside phosphonic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Embodiment 1 (R)-9-{2-[bis-(isobutyryloxymethoxy)-phosphonomethoxy]-propyl}-adenine (I 1 ) preparation

[0018] 1.1 Synthesis of (R)-1-chloro-2-propanol

[0019] Add 208 g of (R)-lactate methyl ester to 1200 ml of dimethylformamide, cool in an ice bath, add 96 g of 60% sodium hydride in batches under stirring, and react with stirring for 1 hour. Then 408 g of benzyl bromide was added dropwise, and after the drop was completed, the mixture was stirred under ice bath for 4 hours, and continued to stir at room temperature for 48 hours. DMF was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography, eluting with ethyl acetate:petroleum ether (1:9), and the desired components were collected and evaporated to dryness under reduced pressure to obtain 191 g of an oily liquid.

[0020] Dissolve 186 grams of the product from the previous step in 1200 ml of anhydrous tetrahydrofuran, place in an ice bath, add 60 grams of lithium alum...

Embodiment 2

[0035] Example 2 (R)-9-{2-[bis-(isovaleryloxymethoxy)-phosphonomethoxy]-propyl}-adenine (I 2 ) preparation

[0036] Referring to the method of Example 1.6, chloromethyl isovalerate was prepared by reacting isovaleryl chloride instead of isobutyryl chloride with thionyl chloride and paraformaldehyde.

[0037] With reference to the method of Example 1.7, (R)-PMPA reacts with chloromethyl isovalerate to obtain target compound I 2 . Elemental Analysis C 21 h 34 N 5 o 8 Calculated P value (%): C48.93, H6.65, N13.59; measured value (%): C49.03, H6.42, N13.41.

Embodiment 3

[0038] Example 3 (R)-9-{2-[bis-(2-methylbutyryloxymethoxy)-phosphonomethoxy]-propyl}-adenine (I 3 ) preparation

[0039] Referring to the method of Example 1.6, chloromethyl 2-methylbutyrate was prepared by reacting 2-methylbutyryl chloride instead of isobutyryl chloride with thionyl chloride and paraformaldehyde.

[0040] Referring to the method of Example 1.7, (R)-PMPA reacted with 2-methyl chloromethyl butyrate to obtain target compound I 3 . Elemental Analysis C 21 h 34 N 5 o 8 Calculated P value (%): C48.93, H6.65, N13.59; measured value (%): C48.79, H6.20, N13.85.

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Abstract

The present invention provides new (R)-PMPA or (R)-PMPDAP precursor medicine as shown in the expression.

Description

technical field [0001] The present invention relates to novel (R)-9-[2-(phosphonomethoxy)propyl]-adenine and (R)-9-[2-(phosphonomethoxy)propyl]-2, Prodrugs of 6-diaminopurine and non-toxic pharmaceutically acceptable salts thereof. Background technique [0002] Diseases caused by viral infections such as viral hepatitis and AIDS are major diseases that threaten human health. Although the research on antiviral drugs has made important progress, some clinically effective antiviral drugs have been found. For example, interferon, lamivudine, adefovir dipivoxil, and entecavir are used to treat hepatitis B, and zidovudine, stavudine, nevirapine, and indinavir are used to treat AIDS. However, these compounds also have many side effects; and when used for a long time, the virus will mutate and develop drug resistance. Therefore, new antiviral drugs with better pharmacological properties are also needed. [0003] (R)-9-[2-(Phosphonomethoxy)propyl]-adenine {(R)-9-[2-(Phosphonometh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P31/18
Inventor 杨兆新房建山
Owner 广东京豪生物制药有限公司
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