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3-beta-D-ribofuranosylthiazolo[4,5-d]pyridimine nucleosides and uses thereof

An alkyl and aryl technology, applied to 3-β-D-ribofuranosyl thiazolo[4,5-d]pyrimidine nucleosides and their application fields, can solve the problems of undescribed, difficult, low solubility and the like

Inactive Publication Date: 2007-05-16
ANDADYS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the ability of D-guanosine analogs such as 7-thio-8-oxoguanosine to directly regulate type 1 or type 2 cytokines in T cells is not effective or has not been described
[0007] Furthermore, oral administration of many purine nucleoside analogs is known to face difficulties due to poor absorption, low solubility, or degradation in the digestive tract due to acidic or alkaline conditions or the action of enzymes and / or a combination of these phenomena

Method used

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  • 3-beta-D-ribofuranosylthiazolo[4,5-d]pyridimine nucleosides and uses thereof
  • 3-beta-D-ribofuranosylthiazolo[4,5-d]pyridimine nucleosides and uses thereof
  • 3-beta-D-ribofuranosylthiazolo[4,5-d]pyridimine nucleosides and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] Example 1: 5-amino-3-(5'-O-L-valyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7-dione dihydrochloride ( 3)

[0190]

[0191] Step 1: Preparation of 5-amino-3-(2',3'-O-isopropylidene-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7-dione

[0192] Inhomogeneity of 1 (5.37 g, 17.0 mmol, prepared following the procedure given in US 5,041,426 (Example 2), which is incorporated by reference in its entirety) in acetone (40 mL) contained in a 250 mL Morton flask at room temperature 2,2-DMP (6.26 mL, 50.9 mmol), DMSO (6.6 mL) and MeSO were added sequentially to the mixture 3 H (220 μL, 3.39 mmol). The reaction mixture was stirred vigorously and became homogeneous and golden yellow as the diol was consumed. TLC analysis after 6 hours (SiO 2 , 10% MeOH-CHCl 3 ) shows that the reaction is complete. Undissolved solids were removed by gravity filtration using fluted Whatman type 1 filter paper. After this time the filtrate was poured into 10 volumes of ice water (-400 mL)...

Embodiment 2

[0201] Example 2: 5-amino-3-(5'-O-L-isoleucyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7-dione 3 / 2 salt Salt (5)

[0202]

[0203] Step 1: 5-amino-3-(2',3'-O-isopropylidene-5'-N-tert-butoxycarbonyl-L-isoleucyl)-β-D-ribofuranosyl)- Preparation of Thiazolo[4,5-d]pyrimidine-2,7-dione (6)

[0204] In a manner similar to step 2 of Example 1, from 5-amino-3-(2',3'-O-isopropylidene-β-D-ribofuranosyl)-thiazolo[4,5-d] Preparation of 5-amino-3-(2',3'-O-isopropylidene-5'-N- tert-butoxycarbonyl-L-isoleucyl)-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione 6, 93% yield as off-white foam :

[0205] 1 HNMR (400MHz, d 6 -DMSO) δ 11.29 (s, 1H), 7.09 (d, J=8.0, 1H), 7.02 (br s, 1H), 6.02 (s, 1H), 5.28 (d, J=6.2, 1H), 5.06 (br s, 1H), 4.16-4.22 (m, 2H), 3.85 (dd, J = 8.0, 6.6, 1H), 1.68 (br s, 1H), 1.47 (s, 3H), 1.34 (s, 9H) , 1.29(s, 3H), 0.71-0.89(m, 5H).

[0206] Step 2: 5-amino-3-(5'-O-L-isoleucyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7-dione dihydrochloride ( ...

Embodiment 3

[0209] Example 3: 5-amino-3-(5'-O-[α-L-tert-butylglycyl]-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2, 7-diketone hydrochloride (8)

[0210]

[0211] Step 1: 5-Amino-3-(2',3'-O-isopropylidene-5'-N-tert-butoxycarbonyl-[α-L-tert-butylglycyl]-β-D- Preparation of Ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione (9)

[0212]In a manner similar to Example 1, step 2, from 5-amino-3-(2,3-O-isopropylidene-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidinone -2,7-Diketone 2 and N-α-L-tert-butoxyglycine to prepare 5-amino-3-(2',3'-O-isopropylidene-5'-N-tert-butoxycarbonyl -[α-L-tert-butylglycyl]-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione 10, 66% yield, off-white Foam:

[0213] 1 h

[0214] NMR (400MHz, d 6 -DMSO) δ11.28 (br s, 1H), 6.70-7.40 (m, 3H), 6.02 (s, 1H), 5.30 (d, J=6.2, 1H), 5.05 (br s, 1H), 4.17- 4.24(m, 3H), 3.77(d, J=8.4, 1H), 1.47(s, 3H), 1.33(s, 9H), 1.29(s, 3H), 0.85(s, 9H).

[0215] Step 2: 5-amino-3-(5'-O-[α-L-tert-butylglycyl]-β-D-ribofuranosyl)-th...

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Abstract

The invention is directed to 3-ss-D-ribofuranosylthiazolo[4,5-d]pyridimine nucleosides and pharmaceutical compositions containing such compounds that have immunomodulatory activity. The invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating diseases and disorders described herein, by administering effective amounts of such compounds.

Description

[0001] This application is filed as a PCT International Application in the names of Devron R. Averett, Stephen E. Webber, Joseph R. Lennox, Erik J. Rueden, and David L. Clark, all citizens and ordinarily resident in the United States on June 7, 2004 resident. field of invention [0002] The present invention relates to 3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine nucleosides with immunomodulatory activity and pharmaceutical compositions containing such compounds. The invention also relates to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating the diseases and conditions described herein by administering an effective amount of such compounds. Background of the invention [0003] In recent decades, considerable effort has been devoted to investigating possible therapeutic applications of D- and L-purine nucleoside analogs. A number of nucleoside analogs are currently marketed as antivirals, including HIV reverse transcriptase in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/24A61K31/7052A61P37/02
CPCC07H19/24A61P1/16A61P31/12A61P31/14A61P35/00A61P35/02A61P37/00A61P37/02
Inventor D·R·阿维雷特S·E·韦伯J·R·列诺克斯E·J·鲁顿D·L·克拉克A·X·项
Owner ANDADYS PHARMA INC
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