2-fluorinated riboses and arabinoses and methods of use and synthesis

Patent metadata

Field	Value
Publication number	US-9790252-B2
Application number	US-201013381587-A
Country	US
Kind code	B2
Filing date	Jul 1, 2010
Priority date	Jul 1, 2009
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

Disclosed are halogenated 2-deoxy-lactone, 2′-deoxy-nucleosides, and derivatives thereof, for example, a compound of formula (I). Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one compound or salt of the invention, and a method of treating a disorder is selected from the group consisting of an abnormal cellular proliferation, a viral infection, and an autoimmune disorder.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein R 1 is selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted acyloxy, trialkylsilyl, optionally substituted alkyl, optionally substituted alkylaryl, phosphate, diphosphate, triphosphate,

R 2 is selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted acyloxy, trialkylsilyl, optionally substituted alkyl, and optionally substituted alkylaryl, phosphate, diphosphate, triphosphate,

X, Y, and Z are O,
R 3 and R 4 are both F or Cl,
n is 1 or 2,
R 8 and R 16 are selected from the group consisting of hydrogen, COR 19 , B(OR 20 ) 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, F, Cl, Br, I, CF 3 , optionally substituted alkoxy, NO 2 , optionally substituted alkylthio, optionally substituted amino, optionally substituted acylthio, hydroxy, mercapto, and optionally substituted thioamido,
R 19 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, hydroxy, alkoxy, and aryloxy,
R 20 is hydrogen or C 1 -C 6 alkyl,
each of R 5 , R 6 , R 7 , R 9 , R 13 , R 14 , R 15 , and R 17 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, F, Cl, Br, I, CF 3 , optionally substituted alkoxy, optionally substituted aryl, NO 2 , optionally substituted alkylthio, optionally substituted amino, optionally substituted acylamino, optionally substituted arylamino, optionally substituted acylthio, optionally substituted acyl, optionally substituted acyloxy, hydroxy, mercapto, and optionally substituted thioamido, or any of R 5 and R 6 taken together, R 6 and R 7 taken together, R 13 and R 14 taken together, or R 14 and R 15 taken together, form a 5- or 6-membered saturated or unsaturated ring,
R 10 and R 18 are independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted acyloxy, trialkylsilyl, optionally substituted alkyl, optionally substituted alkylaryl, phosphate, diphosphate, and triphosphate,
R 11 and R 12 are independently selected from the group consisting of hydrogen, F, Cl, Br, and I,
R 23 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, and
X − is an anion,
or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein R 8 is CONH 2 and wherein R 5 , R 6 , R 7 , and R 9 are hydrogen.

3. The compound or salt of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, phosphate, diphosphate, and triphosphate.

4. The compound or salt of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, phosphate, diphosphate, and triphosphate, R 3 is Cl, and R 4 is hydrogen.

5. A pharmaceutical composition comprising (a) a compound of claim 1 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

6. A compound of formula (I):

wherein (a) R 1 is hydrogen and R 2 is selected from the group consisting of

or (b) wherein R 1 is selected from the group consisting of

and R 2 is hydrogen,
X, Y, and Z are O,
R 3 and R 4 are independently selected from the group consisting of hydrogen, F, Cl, Br, and I, with the proviso that R 3 and R 4 are not both hydrogen,
n is 1 or 2,
R 8 is selected from the group consisting of hydrogen, COR 19 , B(OR 2 ) 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, F, Cl, Br, I, CF 3 , optionally substituted alkoxy, NO 2 , optionally substituted alkylthio, optionally substituted amino, optionally substituted acylthio, hydroxy, mercapto, and optionally substituted thioamido,
R 19 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, hydroxy, alkoxy, and aryloxy,
R 20 is hydrogen or C 1 -C 6 alkyl,
each of R 5 , R 6 , R 7 , R 9 , R 13 , R 14 , R 15 , and R 17 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, F, Cl, Br, I, CF 3 , optionally substituted alkoxy, optionally substituted aryl, NO 2 , optionally substituted alkylthio, optionally substituted amino, optionally substituted acylamino, optionally substituted arylamino, optionally substituted acylthio, optionally substituted acyl, optionally substituted acyloxy, hydroxy, mercapto, and optionally substituted thioamido, or any of R 5 and R 6 taken together, R 6 and R 7 taken together, R 13 and R 14 taken together, or R 14 and R 15 taken together, form a 5- or 6-membered saturated or unsaturated ring,
R 10 and R 18 are independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted acyloxy, trialkylsilyl, optionally substituted alkyl, optionally substituted alkylaryl, phosphate, diphosphate, and triphosphate,
R 11 and R 12 are independently selected from the group consisting of hydrogen, F, Cl, Br, and I,
R 23 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, and
X − is an anion,
or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound of claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. A polymer comprising as a monomeric unit a compound of formula (I):

wherein R 1 is selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted acyloxy, trialkylsilyl, optionally substituted alkyl, optionally substituted alkylaryl, phosphate, diphosphate, triphosphate,

R 2 is selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted acyloxy, trialkylsilyl, optionally substituted alkyl, and optionally substituted alkylaryl, phosphate, diphosphate, triphosphate,

Assignees

• Sauve Anthony A
• Cen Yana
• Univ Cornell

Inventors

• Sauve Anthony A
• Cen Yana

Classifications

• C07H19/06

  Pyrimidine radicals · CPC title

• C07H23/00 Primary

  Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12 (esters with inorganic acids C07H11/00) · CPC title

• C07H19/12

  Triazine radicals · CPC title

• C07H19/16

  Purine radicals · CPC title

• C07H19/056

  Triazole or tetrazole radicals · CPC title