WO1996016663B1

WO1996016663B1 - Thionophosphate derivatives, process for their preparation and pharmaceutical compositions containing them

Info

Publication number: WO1996016663B1
Application number: PCT/US1995/015199
Authority: WO
Filing date: 1995-11-13
Publication date: 1996-08-08
Anticipated expiration: 1997-05-28

Abstract

The invention relates to a compound of formula (I) in which X1 and X2 each independently represents an oxygen or nitrogen atom; p, m and n are each independently an integer of at least 2; R, R1 and R2 each independently represents a hydrogen atom; a halogen atom; an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group R3O in which R3 is hydrogen atom, an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted acyl or optionally substituted aryl or heteroaryl; a group R4O(O)C in which R4 is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group -SR5 in which R5 is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group -NR6R7 in which R6 and R7 each independently represents a hydrogen atom, an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted acyl; or an optionally substituted phosphate ester group. The invention also relates to processes for the preparation of compounds of the formula and to pharmaceutical compositions containing the same.

Claims

AMENDED CLAIMS

[received by the International Bureau on 21 June 1996 (21.06.96); original claims 1, 20 and 26 amended; remaining claims unchanged (4 pages)]

1. A compound of the formula

H S Xι-<CH2)_m_Rι R—<CH₂)_P N—P 2-(CH2)n—R₂ in which

Xi and X₂ each independently represents an oxygen or amino group;

p, m and n are each independently an integer of at least 2;

R, Ri and R₂ each independently represents a hydrogen atom; a halogen atom; an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group -OR₃ in which R₃ is hydrogen atom, an optionally substituted straight- chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted acyl; a group -C(0)OR₄ in which R_t is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group -SR₅ in which R₅ is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group -NR₆Rτ in which R₆ and R-? each independently represents a hydrogen atom, an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted acyl; or an optionally substituted phosphate ester group; provided that:

(1) Xi and X₂ are both an oxygen atom, then R cannot be -NR₆R-,;

(2) Xi and X₂ are both an oxygen atom and Ri or R₂ a haloalkyl group, then m>5 or n>5 respectively;

(3) Xi and X₂ are both -NH then Ri or R₂ or R₃ cannot be -SH;

AMENDED SHEET (ARTICLE 19) (4) Xi and X₂ are both -NH and Ri or R₂ haloalkyl group then m>5 or n>5, respectively;

(5) X_x is different from X₂ then for X, as -NH , n, p>5 or at least one thereof is different from the two others.

2. A compound according to claim 1 in which X,, and X₂ both represent an oxygen atom.

3. A compound according to claim 1 or claim 2 in which each of p, m and n is 2.

4. A compound according to any one of claims 1 to 3 in which R, and R₂ both represent an alkyl radical.

5. A compound according to any one of claims 1 to 4 is which R represents an alkyl radical.

6. A compound according to any one of claims 1 to 4 in which R represents a hydroxyl group.

7. A compound according to any one of claim 1 to 4 in which R represents a carboxyl group.

8. A compound according to claim 5 being N-butylamido diethyl- thionophosphate.

9. A compound according to claim 6 being 2-hydroxyamido diethylthiono-phosphate.

AMENDED SHEET (ARTICLE 19)

38 15. A process according to claim 11 or 12 in which the amine of formula III is beta-alanine.

16. A pharmaceutical composition comprising as active ingredient at least one compound of formula I in a suitable pharmaceutically acceptable carrier or diluent.

17.- A pharmaceutical composition according to claim 16 comprising as active ingredient the compound of claim 8.

18. A pharmaceutical composition according to claim 16 comprising as active ingredient the compound of claim 9.

19. A pharmaceutical composition according to claim 16 comprising as active ingredient the compound of claim 10.

20. A pharmaceutical composition according to any one of claims 16 to 19 for preventing and/or treating oxidative damage associated with inflammatory disorders, atherosclerosis, post-ischemic brain and muscle damage, traumatic shock, degenerative brain diseases, skin disorders, septic shock, lung diseases, radiation damage, particularly skin and eye damage, eye diseases, malignant diseases, tissue natural deterioration, and poisonings by xanobiotics which produce reactive oxygen species.

21. A pharmaceutical composition according to any one of claims 16 to 20 in dosage unit form.

AMENDED SHEET (ARTICLE 19) 22. A pharmaceutical composition according to any one of claims 16 to 20 in an ointment or cream base.

23. A pharmaceutical composition according to any one of claims 16 to 20 in aerosol form.

24. A pharmaceutical composition according to any one of claims 16 to 20 in the form of eye drops.

25. A method of preventing and/or treating oxidative damage in a patient in need of such treatment by administering to said patient a therapeutically effective amount of at least one compound of formula I or of a pharmaceutical composition according to claim 16.

26. A method according to claim 25 for preventing and/or treating oxidative damage associated with inflammatory disorders, atherosclerosis, post-ische ic brain and muscle damage, traumatic shock, degenerative brain diseases, skin disorders, septic shock, lung diseases, radiation damage, particularly skin and eye damage, eye diseases, malignant diseases, tissue natural deterioration and poisonings by xanobiotics which produce reactive oxygen species.

27. An antioxidative additive comprising as active ingredient at least one compound of formula I in a suitable carrier or diluent.

AMENDED SHEET (ARTICLE 19) STATEMENT UNDER ARTICLE 19

Claim l has been amended to exclude compounds disclosed in the prior art:

U.S. Patent No. 3,057,955 discloses phosphoramido-thiate derivatives which contain a halo-lower alkyl residue. These compounds are toxic and cannot be used, as in the present invention, for treating and/or preventing oxidative damages.

U.S. Patent No. 3,251,675 discloses phosphordiamidothioateε acting as parasiticides for the control of insects and particularly as plant growth control agents for the modification of the growth and the killing of many plants. Again, there is the need for lower alkyl residues which seems to contribute to the toxic behavior of the compounds. U.S. Patent No. 3,531,550 claims compounds in which the R residue is selected from a group not containing hydrogen. The hydrogen possibility is mentioned in the description but is absent from the claims, thus, Applicants may claim a selection over the compounds claimed in this patent.

U.S. Patent No. 3,702,332 relates to agricultural pesticides. U.S. Patent No. 3,597,476 relates to resins which are fire-retardant and U.S. Patent No. 3,337,656 relates to herbicides and pesticides. Thus, all these three U.S. patents disclose different compounds with different use. None of the compounds in the cited references may be used in a pharmaceutical form for preventing and/or treating oxidative damage in humans.

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