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3-beta-D-Ribofuranosylthiazalo [4-5-d] pyrimidine nucleosides and uses thereof

a technology of pyrimidine and d-guanosine, which is applied in the field of 3dribofuranosylthiazolo4, 5dpyrimidine nucleosides, can solve the problems of poor absorption, difficulty in oral administration of many purine nucleoside analogs, and ineffectiveness of d-guanosine analogs such as 7-thio-8-oxoguanosine to modulate type 1 or type 2 cytok

Inactive Publication Date: 2008-04-17
ANDADYS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0020] In another aspect of the invention, Formula I compounds are utilized to treat bacterial, fungal, and protozoal infections in mammals by administering to the mammal a therapeutically effective amount of the compounds. The full range of pathogenic microorganisms is contemplated to be treatable by the compounds of the present invention, including without limitation those organisms that are resistant to antibiotics. The ability of Formula I compounds to activate multiple components of the immune system bypasses resistance mechanisms commonly found to reduce susceptibility to antibiotics, and thus treatment of infections in a mammal caused by such resistant microorganisms by Formula I compounds is a particular utility of the present invention.
[0024] In a preferred aspect of the invention, a pharmaceutical composition comprising a therapeutically effective amount of a compound according to Formula I provides for improved oral availability and administration as an immunomodulator. In another preferred aspect of the invention, a pharmaceutical composition comprising a therapeutically effective amount of a compound according to Formula I provides for masking the active structure as the agent passes through lymphoid tissue lining the stomach, thereby minimizing activation of this tissue and allowing for improved oral tolerability.

Problems solved by technology

However, the ability of the D-guanosine analogs such as 7-thio-8-oxoguanosine to modulate Type 1 or Type 2 cytokines directly in T cells was ineffective or had not been described.
Moreover, it is known that the oral administration of many purine nucleoside analogs are subject to difficulties arising from poor absorption, poor solubility, or degradation in the digestive tract as a result of acidic or alkaline conditions or the action of enzymes, and / or combinations of these phenomena.

Method used

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  • 3-beta-D-Ribofuranosylthiazalo [4-5-d] pyrimidine nucleosides and uses thereof
  • 3-beta-D-Ribofuranosylthiazalo [4-5-d] pyrimidine nucleosides and uses thereof
  • 3-beta-D-Ribofuranosylthiazalo [4-5-d] pyrimidine nucleosides and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 3

5-Amino-3-(5′-O-[α-L-tert-butylglycinyl]-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7-dione Hydrochloride (8)

[0108]

Step 1: Preparation of 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 (9)

[0109] In a manner similar to Step 2 of Example 1, 5-Amino-3-(2′,3′-O-isopropylidene-5′-N-tert-butoxycarbonyl-[α-L-tert-butylglycinyl]-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione 10 was prepared in a yield of 66% from 5-Amino-3-(2,3-O-isopropylidene-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidinone-2,7-dione 2 and N-α-L-tert-butoxyglycine as an off-white foam: 1H NMR (400 MHz, d6-DMSO) δ 11.28 (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).

Step 2: Preparation of 5-Amino-3-(5′-O-[α-L-tert-butylglycyl]-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione (8)

[0110] In...

example 4

5-Amino-3-(5′-O-[α-L-N-methylvalinyl]-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7-dione Hydrochloride (11)

[0111]

Step 1: Preparation of 5-Amino-3-(2′,3′-O-isopropylidene-5′-N-tert-butoxycarbonyl-[α-L-N-methylvalinyl]-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione (12)

[0112] In a manner similar to Step 2 of Example 1, 5-Amino-3-(2′,3′-O-isopropylidene-5′-N-tert-butoxycarbonyl-[α-L-N-methylvalinyl]-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione 12 was prepared in a yield of 63% from 5-Amino-3-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidine-2,7-dione 2 and N-tert-butoxy-L-N-methylvaline 13 as an off-white foam: 1H NMR (400 MHz, d6-DMSO) rotameric carbamate δ 11.28 (br s, 1H), 7.00 (br s, 2H), 6.02 (s, 1H), 5.27 (d, J=6.6, 1H), 5.04 (br s, 1H), 4.14-4.28 (m, 3H), 3.91 (d, J=9.5, 1H), 2.79 (br s, 3H), 2.09 (br s, 1H), 1.46 (s, 3H), 1.36 (s, 4.5H), 1.32 (s, 4.5H), 1.28 (s, 3H), 0.78-0.89 (m, 6H).

Step 2: 5-Amino-3-(5′-O-[α-L-N-methylvalinyl]-β-D-r...

example 5

5-Amino-3-β-D-ribofuranosyl-7-methoxy-thiazolo[4,5-d]pyrimidin-2-one (14)

[0115] Anhydrous 1 (2.0 g, 6.3 mmol) was dissolved in dry pyridine under an argon atmosphere. The solution was cooled to 0° C., whereupon TFAA (13.3 g, 63 mmol) was added dropwise to the mixture. After five minutes, the reaction was placed in a 60° C. oil bath for 1.5 h, and was monitored by TLC (SiO2, 20% MeOH—CHCl3) for the formation of the pyridinium cation. The 0.2 Rf starting material was converted to a baseline spot that underwent blue fluorescence upon exposure to 254 nm UV light. Upon conversion to the activated intermediate, freshly made sodium methoxide (1.8 g Na, 78 mmol, 300 ml methanol) solution was added to the reaction at 0° C. The reaction was allowed to warm to room temperature and progress for two days. The mixture was then quenched with 1M NH4Cl (100 mL), and extracted with a 25% IPA-CHCl3 (5×100 mL). The crude material was filtered through a silica gel plug, and then concentrated to afford ...

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Abstract

The invention is directed to 3-β-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 a continuation of co-pending U.S. patent application Ser. No. 11 / 080,449, filed on Mar. 16, 2005, which is a divisional of U.S. patent application Ser. No. 10 / 305,061 filed Nov. 27, 2002, which claims the benefit of U.S. Provisional Patent Application No. 60 / 333,460 filed on Nov. 27, 2001. The entire contents of these applications are hereby incorporated by reference.FIELD OF THE INVENTION [0002] The invention is directed to 3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine 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. BACKGROUND OF THE INVENTION [0003] The last few decades have seen significant efforts expended in exploring possible therapeutic uses of D- and L-purine nucleosi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519A61K31/7052A61K31/708A61P37/02C07HC07H19/24
CPCC07H19/24A61K31/519A61P31/12A61P33/02A61P35/00A61P37/02Y02A50/30C07H19/167C07H19/22
Inventor AVERETT, DEVRONWEBBER, STEPHENLENNOX, JOSEPHRUEDEN, ERIK
Owner ANDADYS PHARMA INC
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