Nucleoside analogs

• US 5,726,174 A
• Filed: 06/07/1995
• Issued: 03/10/1998
• Est. Priority Date: 05/15/1989
• Status: Expired due to Term

• Current Assignee: Institute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I., REGA Stichting VZW
• Original Assignee: Institute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I., REGA Stichting VZW
• Inventors: Kim, Choung Un, Luh, Bing Uh, Martin, John C., Misco, Peter F.
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US08/488,338
• Time in Patent Office: 1,007 Days
• Field of Search: 544/244, 546/23
• US Class Current: 544/244
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/32 Nitrogen atom
• CPC Class Codes: C07D 473/40 with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Provided are compounds of the following formulae:

A phosphonomethoxymethyoxymethyl purine/pyridimidine derivative of the formula ##STR1## wherein X and X'"'"' are the same or different and are hydrogen or alkyl. R and R'"'"' are the same or different and are hydrogen, alkyl, hydroxyalkyl or alkanoyl and

B is a purine or pyrimidine base.

A compound of formula (II) or (VIII) ##STR2## wherein the broken line is an optional bond; X, R and X'"'"' are the same or different and are H or alkyl with 1 to 6 carbon atoms;

wherein in the compound of formula (II), Y and Z are the same or different and are H; OH; alkyl having 1 to 6 carbon atoms; alkyl having 1 to 6 carbon atoms which is substituted with halogen, hydroxy, amino or azido; or Y and Z are taken together to form an oxygen atom or a methylene group; or Y is taken together with X'"'"' to complete a cyclic phosphonate having the structure of formula (III) ##STR3## wherein R^b is H or OH; wherein in the compound of formula (VIII), Y is halogen, phenylthio or phenylseleno;

wherein in the compound of formula (II), B is hypoxanthine, xanthine, guanine, 8-bromoguanine, 8-chloroguanine, 8-methylguanine, 8-thioguanine, 3-deazaguanine, purine, 2-aminopurine, 2,6-diaminopurine, adenine or 3-deazaadenine, any one of which is substituted at the 9-position;

and, wherein in the compound of formula (III) or (VIII), B is hypoxanthine, xanthine, guanine, 8-bromoguanine, 8-chloroguanine, 8-methylguanine, 8-thioguanine, 3-deazaguanine, purine, 2-aminopurine, 2,6-diaminopurine, adenine, 3-deazaadenine, 8-aminoguanine, 8-hydrazinoguanine or 8-hydroxyguanine, any one of which is substituted at the 9-position; and the pharmaceutically acceptable salts thereof.

Claims

1. A compound of formula (II) or (VIII) ##STR101## wherein the broken line is an optional bond;

X, R and X'"'"' are the same or different and are H or alkyl with 1 to 6 carbon atoms;

wherein in the compound of formula (II), Y and Z are the same or different and are H;

OH;

alkyl having 1 to 6 carbon atoms;

alkyl having 1 to 6 carbon atoms which is substituted with halogen, hydroxy, amino or azido;

or when the optional double bond is not present, Y and Z are taken together to form an oxygen atom or a methylene group ##STR102## wherein in the compound of formula (VIII), Y is halogen, phenylthio or phenylseleno;

wherein in the compound of formula (II), B is hypoxanthine, xanthine, guanine, 8-bromoguanine, 8-chloroguanine, 8-methylguanine, 8-thioguanine, 3-deazaguanine, purine, 2-aminopurine, 2,6-diaminopurine, adenine, or 3-deazaadenine any one of which is substituted at the 9-position;

and, wherein in the compound of formula (VIII), B is hypoxanthine, xanthine, guanine, 8-bromoguanine, 8-chloroguanine, 8-methylguanine, 8-thioguanine, 3-deazaguanine, purine, 2-aminopurine, 2,6-diaminopurine, adenine, 3-deazaadenine, 8-aminoguanine, 8-hydrazinoguanine or 8-hydroxyguanine, any one of which is substituted at the 9-position; and

the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 having the structure of formula (II).

3. The compound of claim 2 wherein Y and Z are H.

4. The compound of claim 2 wherein Y and Z independently are H;

alkyl having 1 to 6 carbon atoms;

OH;

or alkyl having 1 to 6 carbon atoms substituted by halogen, hydroxy or azido.

5. The compound of claim 4 wherein Z is H.

6. The compound of claim 2 wherein B is guanine, 2,6-diaminopurine, 8-bromoguanine, 8-chloroguanine, 8-methylguanine, 8-thioguanine or 3-deazaguanine.

7. The compound of claim 6 wherein B is guanine, 2,6-diaminopurine, 8-bromoguanine, 8-chloroguanine, 8-methylguanine or 8-thioguanine.

8. The compound of claim 2 wherein B is adenine, 2-aminopurine or 3-deazaadenine.

9. The compound of claim 8 wherein B is adenine.

10. The compound of claim 2 wherein the broken line is a bond.

11. The compound of claim 2 which is:

(a) 1- 2,3-dideoxy-2,3-didehydro-4-β

-(methylphosphono)methoxy-β

-D-erythrofuranosyl!adenine;

(b) 1- 2,3-dideoxy-2,3-didehydro-4-β

-methylphosphono)methoxy-β

-D-erythrofuranosyl!guanine;

(c) 1- 4-β

-(dimethylphosphono)methoxy-β

-D-erythrofuranosyl!adenine;

(d) 1- 4-β

-(dimethylphosphono)methoxy-β

-D-erythrofuranosyl!guanine;

(e) 1- 4-β

-(methylphosphono)methoxy-β

-D-erythrofuranosyl!adenine;

(f) 1- 4-β

-(methylphosphono)methoxy-β

-D-erythrofuranosyl!guanine;

(g) 1- 4-β

-(phosphonomethoxy-β

-D-erythrofuranosyl)adenine!1- 4-.beta.-(phosphonomethoxy-β

-D-erythrofuranosyl!adenine;

(h) 1- 2-deoxy-4-β

-(diethylphosphono)methoxy-β

-D-erythrofuranosyl!adenine;

(i) 1- 2-deoxy-4-β

(diethylphosphono)methoxy-β

-D-erythrofuranosyl!guanine;

(j) 1- 2-deoxy-4-β

-phosphonomethoxy-β

-D-erythrofuranosyl)adenine!1- 2-deoxy-4-β

-phosphonomethoxy-β

-D-erythrofuranosyl!adenine;

(k) 1- 2-deoxy-4-β

-phosphonomethoxy-β

-D-erythrofuranosyl)guanine!1- 2-deoxy-4-β

-phosphonomethoxy-β

-D-erythrofuranosyl!guanine;

(l) 1-(2-deoxy-4-β

-(methylphosphono)methoxy-β

-D-erythrofuranosyl!adenine.

12. The compound of claim 2 wherein Y and Z are H and the broken line is a bond.

13. The compound of claim 1 wherein B is substituted at its 9-position.

14. The compound of claim 2 wherein Y and Z are OH and the broken line is not a bond.

15. The compound of claim 2 wherein Y and Z are H and the broken line is not a bond.

16. The compound of claim 2 wherein Y is OH, Z is H and the broken line is not a bond.

17. The compound of claim 1 wherein Y is halogen, Z is H and the broken line is a bond.

18. A compound having the structure ##STR103##