N-(3-fluoro-2-phosphonylmethoxypropyl) derivatives of purine and pyrimidine heterocyclic bases, their preparation and use

• US 5,733,896 A
• Filed: 03/18/1994
• Issued: 03/31/1998
• Est. Priority Date: 04/24/1990
• 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: Balzarini, Jan, De Clercq, Erik, Jindrich, Jindrich, Holy, Antonin
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US08/210,255
• Time in Patent Office: 1,474 Days
• Field of Search: 544/243, 544/244, 514/81, 514/86, 546/23
• US Class Current: 514/81
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• 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

Abstract

N-(3-Fluoro-2-phosphonylmethoxypropyl) derivatives of purine and pyrimidine heterocyclic bases, method of producing them and their use as active principles of drugs.

The invention relates to suppression of multiplication of viruses, particularly retroviruses, by application of the new compounds, N-(3-fluoro-2-phosphonylmethoxypropyl) derivatives of purine and pyrimidine heterocyclic bases. These compounds are obtained by the reaction of the N-(3-fluoro-2-hydroxypropyl) derivatives of purine and pyrimidine heterocyclic bases with diesters of p-toluenesulfonyloxymethylphosphonic acid in the presence of sodium hydride.

Claims

1. A compound of formula I ##STR8## wherein R'"'"' is H or alkyl and B is a purin-9-yl base of formula VIIa ##STR9## wherein R⁵ and R⁶ are independently hydrogen, halogen, amino, hydrazino, hydroxylamine, azido, aroylamino, hydroxy, alkoxy, mercapto, alkylmercapto or C_1-4 alkyl, and R⁷ is hydrogen, halogen, hydroxy, alkoxy, mercapto, alkylthio, amino or aroylamino, the 1-deaza, 3-deaza, 7-deaza, 2-aza or 8-aza analogues thereof, as the racemate or the (R) or (S) optical isomers thereof, or the pharmaceutically acceptable salts thereof with alkali metals, ammonia or amines.

5. The compound of claim 1 which is the (R) optical isomer.

6. The compound of claim 1 wherein B is adenine or guanine.

7. The compound of claim 1 wherein B is a 3-deaza, 7-deaza, or 8-aza purin-9-yl base.

8. The compound of claim 1 wherein R⁵ and R⁶ independently are hydrogen, halogen, amino, hydrazino, hydroxylamine, azido, aroylamino, hydroxyl, alkoxy, mercapto or alkylmercapto,

R^Z is hydrogen or halogen, and

the aza or deaza analogues are the 3-deaza, 7-deaza or 8-aza analogues.

10. The compound of claim 8, wherein R⁵ and R⁶ independently are hydrogen, halogen, amino, hydrazino, hydroxylamine, aroylamino, hydroxyl, mercapto or alkoxy, R⁷ is hydrogen and the aza or deaza analogue is 3-deaza.

11. The compound of claim 10 wherein R⁵ and R⁶ independently are hydrogen, halogen, amino or hydroxyl and the aza or deaza analogue is 3-deaza.

12. The compound of claim 11 wherein B is 3-deazaadenine.

13. The compound of claim 1 wherein B is not a 1-deaza, 3-deaza, 7-deaza, 2-aza or 8-aza analogue.

14. The compound of claim 13 wherein R⁷ is hydrogen.

2. A method of using a compound of formula II, ##STR10## wherein B'"'"' is a purin-9-yl base or a protected form thereof, comprising the steps of;

(a) reacting said compound with a dialkyl p-toluenesulfonyloxymethyl phosphonate of the formula

space="preserve" listing-type="equation">-- CH.sub.3 C.sub.6 H.sub.4 SO.sub.2 OCH.sub.2 P(O)(OR.sup.1).sub.2 Formula III

wherein R¹ is alkyl (1-3 C), in the presence of demethylformamide sodium hydride,

(b) removing by methanalysis or acid hydrolysis the protection group on protected heterocyclic base B'"'"',

(c) and isolating compounds of formula IV ##STR11## wherein B is a purin-9-yl base, (d) reacting the compound of formula IV with bromotrimethylsilane or iodotrimethylsilane in an aprotic solvent, and after removal of the solvent treating the reaction mixture with water or buffer solutions and isolating the compounds of formula I ##STR12##

9. The method of claim 2 wherein R¹ is 2-propyl.

3. A compound of formula ##STR13## wherein, R¹ is H or alkyl, and B is a purin-9-yl base of formula VIIa ##STR14## wherein R⁵ and R⁶ are independently hydrogen, halogen, amino, hydrazino, hydroxylamine, azido, hydroxy, alkoxy, mercapto, alkylmercapto or C_1-4 alkyl, and R⁷ is hydrogen, halogen, hydroxy, alkoxy, mercapto, amino or alkylthio, the 1-deaza, 3-deaza, 7-deaza, 2-aza or 8-aza analogues thereof, the (R) or (S) optical isomers thereof, or the pharmaceutically acceptable salts thereof with alkali metals, ammonia or amines, provided however, that R⁶ or R⁷ are omitted in the case of the 2-aza or 8-aza analogues, respectively, and R⁵, R⁶ or R⁷ also may be protected amino wherein the protecting group protects an amino group of the Formula VII base during condensation of base of formula VII ##STR15## with di(2-propyl) p-toluene-sulfonyloxymethylphosphonate and sodium hydride in dimethylformamide.

4. A method of suppressing multiplication of retroviruses in a host, comprising administering to the host a therapeutically effective amount of a compound of formula I ##STR16## wherein B is a purin-9-yl base of formula VIIa ##STR17## wherein R⁵ and R⁶ are independently hydrogen, halogen, amino, hydrazino, hydroxylamine, azido, aroylamino, hydroxy, alkoxy, mercapto, alkylmercapto or C_1-4 alkyl, and R⁷ is hydrogen, halogen, hydroxy, alkoxy, mercapto, amino or aroylamino, the 1-deaza, 3-deaza, 7-deaza, 2-aza or 8-aza analogues thereof, the (R) or (S) optical isomers thereof, or the pharmaceutically acceptable salts thereof with alkali metals, ammonia or amines, provided, however, that R⁵ and R⁶ are not both hydroxyl, and if R⁶ is hydrogen then R⁵ is not hydroxyl.

15. A method according to claim 4, wherein the host is a mammal.

16. A method according to claim 4, wherein the host is mammalian cell.