Acyl- or acyloxymethyl-allopurinol prodrugs

• US 4,694,006 A
• Filed: 02/26/1985
• Issued: 09/15/1987
• Est. Priority Date: 06/30/1983
• Status: Expired due to Fees

• Current Assignee: A/S Gea
• Original Assignee: A/S Gea
• Inventors: Falch, Erik, Bundgaard, Hans
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): Noel, M.
• Application Number:
  US06/711,583
• Time in Patent Office: 931 Days
• Field of Search: 544/262, 544/243, 544/302, 514/258
• US Class Current: 514/262.1
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Compounds of the formula Ia and Ib ##STR1## are prodrugs of allopurinol and have i.a. a much higher solubility in water and/or a higher lipophilicity than allopurinol, which makes such compounds useful for oral, parenteral and rectal administration to a warm-blooded animal such as a human. Such compounds will after administration be converted into allopurinol.

Claims

1. A compound of the formula Ia or Ib ##STR60## wherein R₁ is a group of the formula II ##STR61## wherein R₃ is C_1-8 alkyl;

C_1-4 alkyl monosubstituted with chloro or bromo;

phenyl;

phenyl substituted with 1-3 substituents selected from chloro, bromo, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, acetoxy, or phenoxy;

phenyl C_1-4 alkyl in which the phenyl group may be substituted with 1-3 substituents selected from chloro, bromo, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, acetoxy or phenoxy;

or phenyl C_1-4 alkenyl in which the phenyl group may be substituted with 1-3 substituents selected from chloro, bromo, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, acetoxy, or phenoxy;

or R₃ is an aromatic 5- or 6-membered heterocyclic ring selected from pyridinyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, furanyl and pyrimidinyl; and

A is a single bond or a group of the formula IIa ##STR62## wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein R₆ and R₇ are the same or different and each represent hydrogen or have the same meaning as R₃ as defined above;

or R₁ is a group of the formula III ##STR63## wherein R₈ and R₉ are the same or different and each represent hydrogen or have the same meaning as R₃ as defined above;

or R₈ and R₉ together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring selected from piperidinyl, imidazolyl, pyrazolyl and piperazinyl;

Y is a group of the formula IIIa ##STR64## wherein n is an integer from 1 to 5; and

A, R₆, and R₇ are as defined above;

or R₁ is a group of the formula IV ##STR65## wherein A is as defined above and R'"'"'₃ has the same meaning as R₃ defined above, with the proviso that R'"'"'₃ is not ethyl when A is a bond;

or R₁ is a group of the formula VII ##STR66## wherein n and A are as defined above, and R₁₃ is hydroxy or a group of the formula --NR₈ R₉ wherein R₈ and R₉ are as defined above;

R₂ is any of the groups II, III, IV and VII as defined above with the proviso that A solely is the group IIa as defined above; and

R₅ is hydrogen or has the same meaning as R₂ as defined above, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R₁ and R₅ are the same;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2, wherein R₁ and R₅ are groups of the formulas II or III, wherein A is a group of formula IIa and Y is a group of formula IIIa;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, wherein R₅ is hydrogen and R₁ is a group of the formulas II, III, IV or VII;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4, wherein R₁ is a group of the formulas II or III wherein Y is a group of formula IIIa or VII;

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5, wherein A is a group of formula IIa;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6, wherein R₁ is a group of the formula III wherein A is a group of formula IIa and Y is a group of formula IIIa;

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 7, wherein R₁ is N,N-dimethylglycyloxymethyl, N,N-diethylglycyloxymethyl, N,N-dipropylglycyloxymethyl, N,N-dimethylalanyloxymethyl, N,N-diethylalanyloxymethyl, phenylalanyloxymethyl, phenylglycyloxymethyl, or leucyloxymethyl;

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1, wherein R₂ and R₅ are the same;

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 9, wherein R₂ and R₅ are groups of the formula III wherein A is a group of formula IIa and Y is a group of formula IIIa;

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1, wherein R₅ is hydrogen and R₂ is a group of the formula II wherein A is a group of formula IIa;

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1, selected from the group consisting of 1-(butyryloxymethyl)allopurinol, 1-(N,N-dimethylglycyloxymethyl)allopurinol, 1-(N,N-diethylglycyloxymethyl)allopurinol, 1-(N,N-dipropylglycyloxymethyl)allopurinol, 1-(DL-N,N-dimethylalanyloxymethyl)allopurinol, 1-(DL-N,N-diethylalanyloxymethyl)allopurinol, 1-(L-phenylalanyloxymethyl)allopurinol, 1-(L-leucyloxymethyl)allopurinol, 1-(L-valyloxymethyl)allopurinol and 1-(DL-N,N-dimethylphenylalanyloxymethyl)allopurinol;

or a pharmaceutically acceptable salt thereof.

14. A method for treating and preventing hyperuricemic states comprising administering an amount effective in lowering the level of uric acid, of a compound according to any one of claims 1-12 to a warm-blooded animal.

13. A pharmaceutical composition for rectal, parenteral, or oral use in the prevention and treatment of hyperuricemic states such as gout comprising a pharmaceutically acceptable carrier or excipient in combination with a compound of the formula I'"'"'a or Ib ##STR67## wherein R₁ is a group of the formula II ##STR68## wherein R₃ is C_1-8 alkyl;

C_1-4 alkyl monosubstituted with chloro or bromo;

phenyl;

phenyl substituted with 1-3 substituents selected from chloro, bromo, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, acetoxy, or phenoxy;

phenyl C_1-4 alkyl in which the phenyl group may be substituted with 1-3 substituents selected from chloro, bromo, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, acetoxy or phenoxy;

or phenyl C_1-4 alkenyl in which the phenyl group may be substituted with 1-3 substituents selected from chloro, bromo, C_1-4 alkyl, hydroxy, C_1-4 alkoxy, acetoxy, or phenoxy;

or R₃ is an aromatic 5- or 6-membered heterocyclic ring selected from pyridinyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, isothiazolyl, furanyl and pyrimidinyl; and

A is a single bond or a group of the formula IIa ##STR69## wherein the carbon atom is attached to the nitrogen atom of the parent ring system, and wherein R₆ and R₇ are the same or different and each represent hydrogen or have the same meaning as R₃ as defined above;

or R₁ is a group of the formula III ##STR70## wherein R₈ and R₉ are the same or different and each represent hydrogen or have the same meaning as R₃ as defined above;

or R₈ and R₉ together with the adjacent nitrogen form a 5- or 6-membered heterocyclic ring selected from piperidinyl, imidazolyl, pyrazolyl and piperazinyl;

Y is a group of the formula IIIa ##STR71## wherein n is an integer from 1 to 5; and

A, R₆, and R₇ are as defined above;

or R₁ is a group of the formula IV ##STR72## wherein A is as defined above and R'"'"'₃ has the same meaning as R₃ defined above;

or R₁ is a group of the formula VII ##STR73## wherein n and A are as defined above, and R₁₃ is hydroxy or a group of the formula --NR₈ R₉ wherein R₈ and R₉ are as defined above;

R₂ is any of the groups II, III, IV, and VII as defined above with the proviso that A solely is the group IIa as defined above; and

R₅ is hydrogen or has the same meaning as R₂ as defined above;

or a pharmaceutically acceptable salt thereof.

15. A method for treating and preventing hyperuricemic states comprising administering an amount effective in lowering the level of uric acid of the composition of claim 13 to a warm-blooded animal.

16. The method of claim 15, wherein said composition is administered orally.

17. The method of claim 15, wherein said composition is administered rectally.