IP Library › Granted Patent US 6,921,777

Granted Patent B2

US 6,921,777 · App. 10/192,651 · Granted Jul 26, 2005

Heteroethynylenic compounds and pharmaceutical and cosmetic compositions containing them

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Quick Facts

Patent No.: US 6,921,777
App. No.: 10/192,651
Granted: Jul 26, 2005
Kind: B2

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Abstract

The invention relates to novel heteroethynylenic compounds having the general formula (I): as well as to the use of these compounds in pharmaceutical compositions intended for use in human or veterinary medicine (dermatological, rheumatic, respiratory, cardiovascular and ophthalmological complaints in particular), or alternatively in cosmetic compositions.

Claims (151)

1. A method for the treatment of dermatological symptoms associated with a keratinization disorder, said method comprising administering to an individual in need of said treatment, a therapeutically effective amount of a compound sufficient to treat the dermatological symptoms, the compound having the formula:

wherein:

Y represents a divalent radical which has the formula

R 4 represents a hydrogen atom, a lower alkyl radical, a radical OR 12 , a methoxymethoxy or methoxyethoxymethoxy radical or a halogen atom;

R′ 4 represents a hydrogen atom or a halogen atom;

each of R 7 and R 8 , which are identical or different, represents a hydrogen atom, a lower alkyl radical or a phenyl radical;

R 12 represents a hydrogen atom, a lower alkyl radical, a phenyl radical, a benzyl radical or a monohydroxyalkyl radical; and

R 14 represents a hydrogen atom or a lower alkyl radical;

or a salt or optical or geometrical isomer thereof.

2. A method according to claim 1 , wherein —Se—Y—COOR 14 in the compound of formula (I) has the formula

or is a methyl or ethyl ester thereof.

3. A method according to claim 2 wherein —Se—Y—COOR 14 in the compound of formula (I) has the formula

or is a methyl or ethyl ester thereof.

4. A method according to claim 3 , wherein R 4 in the compound of formula (I) is hydrogen, methyl, hydroxy, propoxy, hexyloxy, benzyloxy, methoxymethoxy, 2-methoxyethoxymethoxy or 5-hydroxypentyloxy.

5. A method according to claim 3 , wherein R′ 4 in the compound of formula (I) is hydrogen.

6. A method according to claim 2 , wherein R 4 in the compound of formula (I) is hydrogen, methyl, hydroxy, propoxy, hexyloxy, benzyloxy, methoxymethoxy, 2-methoxyethoxymethoxy or 5-hydroxypentyloxy.

7. A method according to claim 2 , wherein R′ 4 in the compound of formula (I) is hydrogen.

8. A method according to claim 1 , wherein R4 in the compound of formula (I) is hydrogen, methyl, hydroxy, propoxy, hexyloxyl, benzyloxy, methoxymethoxy, 2-methoxyethoxymethoxy or 5-hydroxypentyloxy.

9. A method according to claim 8 , wherein R′ 4 in the compound of formula (I) is hydrogen.

10. A method according to claim 1 , wherein R′ 4 in the compound of formula (I) is hydrogen.

11. The method according to claim 1 , wherein the compound of formula (I) is administered enterally or topically.

12. The method according to claim 1 , wherein the compound of formula (I) is administered topically.

13. The method according to claim 1 , wherein the keratinization disorder is a differentiation or proliferation disorder.

14. The method according to claim 13 , wherein the disorder is acne.

15. The method according to claim 1 , wherein the keratinization disorder has an inflammatory and/or immunoallergic component.

16. The method according to claim 15 , wherein the disorder is psoriasis.

17. The method according to claim 1 , wherein the compound of formula (I) is administered in the form of tablets, gelatin capsules, suger-coated tablets, syrups, suspensions or lotions, solutions, powders, granules, emulsions, microspheres or nanospheres, polymeric or lipid vesicles, ointments, creams, milks, salves, impregnated pads, sprays, gels or hydrogels.

18. The method according to claim 1 , wherein the compound of formula (I) is administered in a daily dose of from about 0.01 mg/kg to 100 mg/kg of body weight, in 1 to 3 doses.

19. The method according to claim 1 , wherein the compound of formula (I) is administered topically in a composition comprising 0.001% to 5% by weight of the compound.

20. A method for the treatment of dermatological symptoms associated with a keratinization disorder, said method comprising administering to an individual in need of said treatment, a therapeutically effective amount of a compound sufficient to treat the dermatological symptoms, the compound being selected from the group consisting of:

(a) 3-methyl-5-(50,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(b) 3-methyl-5-(5,6,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(d) 3-propyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(e) 5-(4-benzyloxy-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid;

(f) 5-(4-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid;

(g) 3-methyl-5-(5,5,8 8-tetramethyl-3-hexyloxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-ynoic acid;

(h) 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthaten-2-ylselenyl)pent-2-en-4-ynoic acid;

(i) 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)3-phenylpent-2-en-4-ynoic acid;

(j) 5-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid;

(k) 5-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid;

(l) 5-[3-(2-methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yfselenyl]-3-methylpent-2-en-4-ynoic acid;

(m) ethyl 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate;

(n) ethyl 3-methyl-5-(3,5,5,8,8-pentamethyl-5 6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate;

(o) ethyl 5-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate;

(p) ethyl 5-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate;

(q) ethyl 5-(4-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate;

(r) 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(s) ethyl 3-methyl-5-(5,5,8,8-tetramethyl-3-hexyloxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate;

(t) ethyl 3-methyl-5-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate;

(u) ethyl 3-methyl-5-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate;

(v) ethyl 5-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoate;

(w) methyl 5-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoate;

(x) ethyl 5-[3-(2-methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoate; and

(y) ethyl 5-[3-(5-hydroxypentyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoate.

21. A method according to claim 20 , wherein the compound is selected from the group consisting of:

(a) 3-methyl-5-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(b) 3-methyl-5-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(d) 3-propyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(e) 5-(4-benzyloxy-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid;

(f) 5-(4-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid;

(g) 3-methyl-5-(5,5,8,8-tetramethyl-3-hexyloxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-ynoic acid

(h) 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic aciid;

(i) 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenlyl)-3-phenylpent-2-en-4-ynoic acid;

(j) 5-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid;

(k) 5-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid;

(l) 5-[3-(2-methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoic acid; and

(m) 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid.

22. The method according to claim 20 , wherein the compound of formula (I) is administered enterally or topically.

23. The method according to claim 20 , wherein the compound of formula (I) is administered topically.

24. The method according to claim 20 , wherein the keratinization disorder is a differentiation or proliferation disorder.

25. The method according to claim 24 , wherein the disorder is acne.

26. The method according to claim 20 , wherein the keratinization disorder has an inflammatory and/or immunoallergic component.

27. The method according to claim 26 , wherein the disorder is psoriasis.

28. A method for the treatment of dermatological symptoms associated with a keratinization disorder, said method comprising administering to an individual in need of said treatment, a therapeutically effective amount of a compound sufficient to treat the dermatological symptoms, the compound being selected from the group consisting of:

(a) 3-methyl-5-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(b) 3-methyl-5-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid; and

29. The method according to claim 28 , wherein the compound of formula (I) is administered enterally or topically.

30. The method according to claim 28 , wherein the compound of formula (I) is administered topically.

31. The method according to claim 28 , wherein the keratinization disorder is a differentiation or proliferation disorder.

32. The method according to claim 31 , wherein the disorder is acne.

33. The method according to claim 28 , wherein the keratinization disorder has an inflammatory and/or immunoallergic component.

34. The method according to claim 33 , wherein the disorder is psoriasis.

35. A method for the treatment of physiologically dry or acne-prone skin or of signs of light-induced or chronological ageing of the skin, said method comprising topically administering to an individual in need of said treatment, a therapeutically effective amount of a compound sufficient to treat physiologically dry or acne-prone skin or signs of light-induced or chronological ageing of the skin, the compound having the formula:

wherein:

Y represents a divalent radical which has the formula

R 4 represents a hydrogen atom, a lower alkyl radical, a radical OR 12 , a methoxymethoxy or methoxyethoxymethoxy radical or a halogen atom;

R′ 4 represents a hydrogen atom or a halogen atom;

each of R 7 and R 8 , which are identical or different, represents a hydrogen atom, a lower alkyl radical or a phenyl radical;

R 12 represents a hydrogen atom, a lower alkyl radical, a phenyl radical, a benzyl radical or a monohydroxyalkyl radical; and

R 14 represents a hydrogen atom or a lower alkyl radical;

or a salt or optical or geometrical isomer thereof.

36. A method according to claim 35 , wherein —Se—Y—COOR 14 in the compound of formula (I) has the formula

or is a methyl or ethyl ester thereof.

37. A method according to claim 36 , wherein —Se—Y—COOR 14 in the compound of formula (I) has the formula

or is a methyl or ethyl ester thereof.

38. A method according to claim 37 , wherein R 4 in the compound of formula (I) is hydrogen, methyl, hydroxy, propoxy, hexyloxy, benzyloxy, methoxymethoxy, 2-methoxyethoxymethoxy or 5-hydroxypentyloxy.

39. A method according to claim 37 , wherein R′ 4 in the compound of formula (I) is hydrogen.

40. A method according to claim 36 , wherein R 4 in the compound of formula (I) is hydrogen, methyl, hydroxy, propoxy, hexyloxy, benzyloxy, methoxymethoxy, 2-methoxyethoxymethoxy or 5-hydroxypentyloxy.

41. A method according to claim 36 , wherein R′ 4 in the compound of formula (I) is hydrogen.

42. A method according to claim 35 , wherein R 4 in the compound of formula (I) is hydrogen, methyl, hydroxy, propoxy, hexyloxyl, benzyloxy, methoxymethoxy, 2-methoxyethoxymethoxy or 5-hydroxypentyloxy.

43. A method according to claim 37 , wherein R′ 4 in the compound of formula (I) is hydrogen.

44. A method according to claim 35 , wherein R′ 4 in the compound of formula (I) is hydrogen.

45. The method according to claim 35 , wherein the compound of formula (I) is administered in the form of a cream, lotion, gel, microspheres or nanospheres, polymeric or lipid vesicles, soap or shampoo.

46. The method according to claim 35 , wherein the compound of formula (I) is administered in a composition comprising 0.001% to 3% by weight of the compound.

47. A method for the treatment of physiologically dry or acne-prone skin or of signs of light-induced or chronological ageing of the skin, said method comprising topically administering to an individual in need of said treatment, a therapeutically effective amount of a compound sufficient to treat physiologically dry or acne-prone skin or signs of light-induced or chronological ageing of the skin, the compound being selected from the group consisting of:

(a) 3-methyl-5-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(b) 3-methyl-5-(5,5,8,8-tetramethyl-4-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(d) 3-propyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(e) 5-(4-benzyloxy-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid;

(f) 5-(4-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid;

(g) 3-methyl-5-(5,5,8,8-tetramethyl-3-hexyloxy-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-ynoic acid;

(h) 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoic acid;

(i) 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahyd ronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid;

(j) 5-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-phenylpent-2-en-4-ynoic acid;

(k) 5-(3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-3-methylpent-2-en-4-ynoic acid;

(l) 5-[3-(2-methoxyethoxymethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl]-3-methylpent-2-en-4-ynoic acid;

(m) ethyl 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate;

(n) ethyl 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)pent-2-en-4-ynoate;