COMPOSITIONS FOR LOCAL APPLICATION AND METHODS OF THEIR APPLICATION

Claims

1. A composition for topical use comprising a compound of formula I or a pharmaceutically acceptable salt thereof Where R1 is C1-C3 alkyl, preferably methyl or ethyl, more preferably ethyl; R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H; R3 is C1-C4 alkyl, preferably ethyl or propyl, more preferably n-propyl; R4 is C1-C6 alkyl, preferably ethyl or propyl, more preferably n-propyl; R5 is SO2NR 13 R 14 , while R 13 and R 14 together with the nitrogen atom to which they are attached, form a heterocyclic ring, wherein said heterocyclic ring is selected from piperidine and piperazine, wherein said heterocyclic ring contains as a substituent at least one R15 , and at the same time the specified R 15 independently selected from C1-C6 alkyl, optionally containing OH, ONO2 as a substituent, wherein at least one of R 15 contains at least one ONO2 fragment; wherein said topical composition comprises said compound of formula I, preferably said compound 1, in an amount of from about 0.0001% (w / v) to about 0.05% (w / v).

2. The topical composition of claim 1, wherein R1 is methyl or ethyl; R2 is H; R3 is ethyl or n-propyl; and R4 is ethyl or n-propyl.

3. A topical composition according to claim 1 or 2, wherein R1 is ethyl; R2 is H; R3 is n-propyl; and R4 is n-propyl.

4. A topical composition according to any one of claims 1 to 3, wherein said compound of formula I is a compound selected from And 5. A topical composition according to any one of claims 1 to 3, wherein said compound of formula I is a compound selected from (1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4,4-diyl)bis(ethane-2,1-diyl)dinitrate (1); 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate (2); 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate (3); 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)propyl nitrate (4); (R)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyldinite); (S)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyldinite); ((2R,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diethyl-dinyl)2is); ((2S,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diethyl-din8)bis); 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentanyl (dinitra-dyl-); and 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-2-hydroxypropan-1,3-diyl dinitrate (10).

6. A topical composition according to any one of claims 1 to 5, wherein said compound of formula I is compound 1 or compound 2, and wherein said compound of formula I is preferably compound 1 7. The composition of any one of claims 1 to 6, wherein said compound of formula I, preferably said compound 1, is present in said topical composition in an amount of from about 0.0001% (w / v) to about 0.02% (w / v), preferably from about 0.0002% (w / v) to about 0.02% (w / v), and more preferably from about 0.0002% (w / v) to about 0.01% (w / v).

8. The composition of any one of claims 1 to 7, wherein said compound of formula I, preferably said compound 1, is present in said topical composition in an amount of from about 0.0002% (w / v) to about 0.008% (w / v), preferably from about 0.0002% (w / v) to about 0.006% (w / v), and even more preferably from about 0.0002% (w / v) to about 0.005% (w / v), and even more preferably from about 0.0002% (w / v) to about 0.004% (w / v).

9. A topical composition according to any one of the preceding claims, wherein said topical composition comprises at least one solvent, wherein said solvent is selected from the group consisting of PEG-400, PEG-350, PEG-240, ethanol, 2-(2-ethoxyethoxy)ethanol, glycerol, propylene glycol, polypropylene glycol, poloxamer 407, poloxamer 188, water and mixtures thereof.

10. A topical composition according to any one of claims 1-8, wherein said topical composition comprises a combination of solvents, wherein said combination of solvents comprises PEG-400 and ethanol.

11. A topical composition according to any one of the preceding claims, wherein said compound of formula I is compound 1, And wherein said topical composition comprises said compound 1 in a concentration of from about 1.5 μM to about 300 μM, preferably from about 3 μM to about 200 μM, more preferably from about 5 μM to about 100 μM; and wherein said topical composition comprises a solvent; and wherein said solvent is a combination of PEG-400 and ethanol, and wherein the ratio (v / v) of said PEG-400 and ethanol is from about 60:40 to 75:25, preferably from about 65:35 to 75:25, more preferably from about 68:32 to 72:28, and even more preferably about 70:30; or wherein said solvent is a combination of PEG-400, ethanol, 2-(2-ethoxyethoxy)ethanol and water, wherein the ratio (v / v) of said PEG-400:ethanol:2-(2-ethoxyethoxy)ethanol:water is from about 5:20:5:30 to 15:40:15:70, preferably from about 8:25:8:40 to about 12:35:12:60, and more preferably about 10:30:10:

50.

12. A topical composition according to any one of claims 1-11 for use in a method for the topical treatment of a disease or disorder mediated by PDE5 activity and / or NO-associated endothelial dysfunction, preferably a disease or lesion of the skin mediated by PDE5 activity and / or NO-associated endothelial dysfunction, in a subject, preferably a human.

13. A topical composition according to any one of claims 1-11 for use in a method of locally treating a disease or disorder in a subject, preferably a human, wherein said local treatment for the disease or disorder is selected from (a) treatment of skin disease, preferably steroid-induced skin aging or skin atrophy; (b) treatment of erectile dysfunction; (c) preventing or treating hair loss, or (d) stimulating hair growth through (i) inducing anagen of hair follicles; (ii) stimulation of melanogenesis; (iii) increasing the number of hair follicles; (iv) increasing skin thickness; (v) stimulation of angiogenesis; (vi) proliferation of cells in the outer root sheath; and / or (vii) increasing blood flow to the hair follicle.

14. A topical composition according to claim 12 or 13, wherein said topical treatment of said disease or disorder is the prevention or treatment of hair loss, wherein said hair loss is alopecia, and wherein said alopecia is preferably androgenetic alopecia (AGA) or chemotherapy-induced alopecia (CIA) or alopecia areata.

15. A topical composition according to claim 12 or 13, wherein said topical treatment of said disease or disorder stimulates hair growth by (i) inducing anagen of hair follicles; (ii) stimulation of melanogenesis; (iii) increasing the number of hair follicles; (iv) increasing skin thickness; (v) stimulation of angiogenesis; (vi) proliferation of cells in the outer root sheath; and / or (vii) increasing blood flow to the hair follicle.