Purine L-nucleosides, analogs and uses thereof

• US 6,479,463 B1
• Filed: 06/16/2000
• Issued: 11/12/2002
• Est. Priority Date: 10/16/1996
• Status: Expired due to Term

• Current Assignee: ICN Pharmaceuticals, Inc (Bausch Health Cos., Inc.)
• Original Assignee: ICN Pharmaceuticals, Inc (Bausch Health Cos., Inc.)
• Inventors: Wang, Guangyi, Tam, Robert, Averett, Devron
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): CRANE, LAWRENCE E
• Application Number:
  US09/595,364
• Time in Patent Office: 879 Days
• Field of Search: 514/43, 514/45-48, 536/26.23, 536/26.26, 536/26.7, 536/27.13, 536/27.14, 536/27.6, 536/27.8, 536/27.81
• US Class Current: 514/43
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

Novel purine L-nucleoside compounds are disclosed, in which both the purine rings and the sugar are either modified, functionalized or both. The novel compounds or pharmaceutically acceptable esters or salts thereof may be used in pharmaceutical compositions, and such compositions may be used to treat an infection, an infestation, a neoplasm, or an autoimmune disease. The novel compounds may also be used to modulate aspects of the immune system, including modulation of Th1 and Th2.

Claims

1. A compound consisting of either an 8-substituted α

-L-guanosine analog according to Formula 1-A or an 8-substituted β

-L-guanosine analog according to Formula 1-A′

;

wherein X is selected from the group consisting of H, R, F, Cl, Br, I, N₃, —

CN, —

OR, —

SR, —

NR₂, —

NHNH₂, —

NHOH, —

CHO, —

CONH₂, —

COOR, and -L-A;

where R is selected from the group consisting of alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, and sulfonyl;

L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl; and

A is selected from the group consisting of H, —

OR′

, —

SR′

, —

NR′

₂, —

NHNH′

₂, —

CHO, —

COOR′

, and —

CONR′

₂, where R′

is selected from the group consisting of H, Me, Et, allyl, acetyl, and —

COCF₃;

Y is selected from the group consisting of H, R, F, Cl, Br, I, N₃, CN, OR, SR, and NR₂, where R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, and sulfonyl;

Z is N or CH; and

R₁, R₂, and R₃ are independently selected from H, —

OH, —

OAc, —

OBz, and —

OP(O₂)OH;

with the provisos that when X is a halogen, H, OH, SH or NH₂, and/or Y is a halogen, H, OH, SH or NH₂, then R₂ and/or R₃ cannot be H;

when R₁ and R₂ are OH, X and Y are not H; and

when R₁ and R₂ are H, X and Y are not H, and Y is not NH₂.

2. A compound consisting of either a 7-substituted-8-oxo-α

-L-guanosine analog according to Formula 1-B or a 7-substituted-8-oxo-β

-L-guanosine analog according to Formula 1-B′

;

wherein X is selected from the group consisting of H, R, —

NH₂, —

CHO, —

COOR, and -L-A, where R is selected from the group consisting of alkyl, alkenyl, alkynyl, and aralkyl;

L is a linker and selected from alkyl, alkenyl, alkynyl, and aralkyl;

A is selected from the group consisting of H, F, Cl, Br, I, —

OR′

, —

SR′

, —

NR′

₂, —

NHNH₂, —

NHOH, N₃, —

CHO, —

CONH₂, —

COOR′

, and —

, where R′

is selected from the group consisting of Me, Et, allyl, acetyl, and —

COCF₃;

Y is selected from the group consisting of H, R, F, Cl, Br, I, N₃, —

CN, —

OR, —

SR, and —

NR₂, where R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, and sulfonyl;

Z is N or CH; and

R₁, R₂, and R₃ are independently selected from the group consisting of H, —

OH, —

OAc, —

OBz, and —

OP(O₂)OH;

with the proviso that where R₁, R₂, and R₃ are OH, then Z is not N, Y is not NH₂, and X is not propyl.

5. A pharmaceutical composition comprising a compound according to any one of claims 2 or 3, or a pharmaceutically acceptable ester or salt thereof, admixed with at least one pharmaceutically acceptable carrier.

3. A compound consisting of either a 7-deaza-8-aza-7-α

-L-guanosine analog according to Formula 1-D or a 7-deaza-8-aza-7-β

-L-guanosine analog according to Formula 1-D′

;

wherein X is selected from the group consisting of H, R, F, Cl, Br, I, N₃, —

CN, —

OR, —

SR, —

NR₂, —

NHNH₂, —

NHOH, —

CHO, —

CONH₂, —

COOR, and -L-A;

where R is selected from the group consisting of alkyl, alkenyl, alkynyl, and aralkyl, acetyl, acyl, and sulfonyl;

L is a linker and selected from the group consisting of alkyl, alkenyl, alkynyl, and aralkyl; and

A;

is selected from the group consisting of H, —

OR′

, SR′

, —

NR′

₂, —

NHNH₂, —

CHO, —

COOR′

, —

CONR′

₂, where R′

is selected from the group consisting of H, Me, Et, allyl, acetyl, and —

COCF₃;

Y is selected from the group consisting of H, R, F, Cl, Br, I, N₃, —

CN, —

OR, —

SR, and —

NR₂, where R is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, and sulfonyl;

Z is N or CH; and

R₁, R₂, and R₃ are independently selected from the group consisting of H, —

OH, —

OAc, —

OBz, and —

OP(O₂)OH.

4. A compound consisting of either a thiazolopyrimidine α

-L-nucleoside according to Formula 1-E or a thiazolopyrimidine β

-L-nucleoside according to Formula 1-E′

;

wherein X₁ is selected from the group consisting of O, S, ═

NH, ═

NNH₂, ═

NHOH, ═

NR where R is selected from the group consisting of alkyl, alkyenyl, alkynyl, aralkyl, and acyl;

X₂ is S, O, or Se;

Y is selected from the group consisting of H, R, F, Cl, Br, I, N₃, —

CN, —

OR, —

SR, and —

NR₂, where R is selected from H, alkyl, alkenyl, alkynyl, aralkyl, acetyl, acyl, and sulfonyl;

Z is N or CH; and

R₁, R₂, and R₃ are independently selected from the group consisting of H, —

OH, —

OAc, —

OBz, and —

OP(O₂)OH.