Pyrrolo[2,3-d]pyrimidine nucleoside analogs

Details Pyrrolo[2,3-d]pyrimidine nucleoside analogs Pyrrolo[2,3-d]pyrimidine nucleoside analogs

2001-02-28

2004-12-14

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S049000, C536S027200, C544S280000

Reexamination Certificate

active

06831069

ABSTRACT:

FIELD OF THE INVENTION
The field of the invention is nucleoside analogs.
BACKGROUND OF THE INVENTION
Nucleoside analogs have long been used as antimetabolites for treatment of cancers and viral infections. After entry into the cell, nucleoside analogs are frequently phosphorylated by nucleoside salvage pathways, in which the analogs are typically phosphorylated to the corresponding mono-, di-, and triphosphates. Among other intracellular destinations, triphosphorylated nucleoside analogs often are used as substrate for DNA or RNA polymerases and consequently incorporated into DNA or RNA. Where triphosphorylated nucleoside analogs are strong polymerase inhibitors, they may induce premature termination of a nascent nucleic acid molecule. Where triphosphorylated nucleoside analogs are incorporated into nucleic acid replicates or transcripts, gene expression or disruption of function may result.
On a more cellular level, the nucleoside analogs can also interfere with the cell cycle, and especially desirable effects of nucleoside analogs include induction of apoptosis of cancer cells. Furthermore, nucleoside analogs are also known to modulate certain immune responses.
Various nucleoside analogs with relatively potent anti-cancer activity are known in the art. For example, known drugs include thymidylate synthase inhibitors such as 5-fluorouridine, adenosine deaminase inhibitors, including 2-chloroadenosine, and neplanocin A, which is an inhibitor of S-adenosylhomocysteine hydrolase. However, all or almost all of the known nucleoside analogs also imply a threat to normal mammalian cells, primarily because these nucleoside analog's lack adequate selectivity between normal cells and tumor cells. Unfortunately, lack of adequate selectivity is frequently associated with severe side effects, and therefore often limits the potential of such analog therapeutics.
Although there are various nucleoside analogs known in the art, all or almost all of them, suffer from one or more disadvantages. Therefore, there is still a need to provide improved methods and compositions for nucleoside analogs.
SUMMARY OF THE INVENTION
The present invention is directed to nucleoside analogs with modifications on the sugar moieties of the pyrrolo[2,3-d]pyrimidine nucleoside analogs, which can significantly reduce the toxicity of the nucleoside analogs to the mammalian cells while they also provide significant cytotoxicity to cancer cells. These modifications include but are not limited to substitutions at the C4′ and C5′ positions of ribofuranose moieties. The present invention also demonstrates that certain pyrrolo[2,3-d]pyrimidine nucleoside analogs have desired immunomodulation effects, including enhancement of Type 1 cytokines such as IL-2 and suppression of Type 2 cytokines such as IL-4. These immunomodulation properties can be useful in anticancer, antiviral and autoimmune diseases, treating inflammation and preventing graft rejection.
In one aspect of the inventive subject matter, the nucleoside analog is a pyrrolo[2,3]-pyrimidine nucleoside having a structure according to the formula (I):
wherein A is O, S, or CH2; X is H, NH
2
or OH; Y is H, halogen or NH
2
; Z is selected from the group consisting of H, halogen, R, OH, OR, SH, SR, NH
2
, NHR, NR
2
, CN, C(O)NH
2
, COOH, COOR, CH
2
NH
2
, C(═NOH)NH
2
, and C(═NH)NH
2
, where R is alkyl, alkenyl, alkynyl, or aralkyl; R
2
and R
3
are independently selected from the group consisting of H, F, and OH; R
4
is selected from the group consisting of a hydrogen, an alkyl, an alkenyl, an alkynyl, and an aralkyl, wherein R
4
optionally has at least one of a heteroatom and a functional group; R
5
is H, OH, OP(O)(OH)
2
, P(O)(OH)
2
, OP(O)(OR′)
2
, or P(O)(OR′)
2
, wherein R′ is a masking group; and R
5′
is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, and an aralkyl, wherein R
5′
has at least two carbon atoms, and optionally has at least one of a heteroatom and a functional group.
In another aspect of the inventive subject matter, the nucleoside analog is a pyrrolo[2,3d]pyrimidine nucleoside having a structure according to the formula (II):
wherein Z is CN, C(O)NH
2
, C(═NH)NH
2
, or C(═NOH)NH
2
and R
4
and R
5′
are independently selected from the group consisting of a hydrogen, an alkyl, an alkenyl, an alkynyl, and an aralkyl, wherein R
4
and R
5′
, independently and optionally contain at least one of a heteroatom and a functional group; with the proviso that R
4
and R
5′
are not together hydrogen.
In a further aspect of the inventive subject matter, the nucleoside analog is a pyrrolo[2,3]pyrimidine nucleoside having a structure according to the formula (III), which may advantageously be in a salt form (e.g., an HCl salt):
In still further aspects of the inventive subject matter, contemplated compounds are utilized to inhibit tumor growth or to modulate Type 1 and Type 2 cytokine, chemokine production, and in treatment of autoimmune diseases. It is further contemplated that compounds according to the inventive subject matter may be used in the treatment of any condition which responds positively to administration of the compound, and a pharmaceutical composition may comprise contemplated compounds (where appropriate in a prodrug form) or a pharmaceutically acceptable ester or salt thereof admixed with at least one pharmaceutically acceptable carrier.
Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings.


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