Piperidine derivatives as human papilloma virus inhibitors
The present disclosure is directed to antiviral compounds directed against the papilloma virus, to pharmaceutical compositions containing them, to their preparation method and synthesis intermediates, as well as to their use for treating or preventing an infection by the papilloma virus. The present method thus provides an efficient way of treating patients that have lesions associated with an infection by the papilloma virus.
1. A method for treating an infection by HPV 6 or HPV 11 papilloma virus comprising the administration to a patient in need thereof of an efficient quantity of a compound of formula (I):
as well as their stereoisomers,
wherein:
G 1 is a bond, methylene (—CH 2 —), or ethylene (—CH 2 CH 2 —),
G 2 is a
group, the N(R) moiety being bound to the nitrogen carrying the groups B and AG 1 , wherein:
R is H,
W is O and
G is methylene (—CH 2 —),
R 1 is O—CH 3 , and R 2 is H, Br, F or Cl, at the 5-position,
R 3 is C(═O)OH, wherein R 3 is at the 1 position,
A ring is a phenyl, further substituted at the 4-, or at the 3-, or at both the 3- and 4-positions,
and
B ring is a phenyl substituted at the 2- (or 6-) position with piperdin-1-yl; this phenyl is also substituted in the other of the 6- (or 2-) positions with a methyl, or is H,
as well as their pharmaceutically acceptable salts.
2. The method according to claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
1) 5-bromo-2-methoxy-4-[N′-(4-methoxy-phenyl)-N′-2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
2) 5-bromo-2-methoxy-4-[N′-(2-piperidin-1-yl-phenyl)-N′-(4-trifluoromethoxy-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
3) 5-bromo-2-methoxy-4-[N′-(3-methoxy-benzyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
4) 4-[N′-(4-benzyloxy-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride
5) 5-bromo-4-{N′-[4-(4-fluoro-phenoxy)-phenyl]-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoic acid hydrochloride
6) 5-bromo-2-methoxy-4-{N′-[2-(4-methoxy-phenyl)-ethyl]-N′-2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-benzoic acid hydrochloride
7) 5-bromo-2-methoxy-4-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoic acid hydrochloride
7a) Methyl 5-bromo-2-methoxy-4-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoate
8) 5-bromo-2-methoxy-4-[N′-(4-methoxy-benzyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
9) 5-bromo-4-[N′-(4-cyclohexyl-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoic acid hydrochloride
10) 5-bromo-2-methoxy-4-[N′-(2-methyl-6-piperidin-1-yl-phenyl)-N′-(4-trifluoromethoxy-phenyl)-hydrazino-carbonylmethyl]-benzoic acid hydrochloride
11) 5-bromo-2-methoxy-4-[N′-(4′-methoxy-biphenyl-4-yl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
12) 5-bromo-4-[N′-(4-cyclohexyloxy-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoic acid hydrochloride
13) 5-bromo-2-methoxy-4-[N′-(4-phenoxy-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
14) 5-bromo-4-{N′-[4-(4-chloro-phenoxy)-phenyl]-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoic acid hydrochloride
15) 4-{N′-[4-(4-fluoro-phenoxy)-phenyl]-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoic acid hydrochloride
16) 5-bromo-4-{N′-[4-(4-fluoro-phenoxy)-phenyl]-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl}-2-methoxy-benzoic acid hydrochloride
16a) Methyl 5-bromo-4-{N′-[4-(4-fluoro-phenoxy)-phenyl]-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl}-2-methoxy-benzoate
17) 4-[N′-(4-benzyl-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride
18) 4-[N′-(4-bromo-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoic acid hydrochloride
19) 4-[N′-(3′-acetyl-biphenyl-4-yl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoic acid hydrochloride
20) 4-[N′-(4′-acetyl-biphenyl-4-yl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoic acid hydrochloride
21) 5-bromo-2-methoxy-4-[N′-(3-phenoxy)-phenyl]-N′-(2 piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
22) 5-bromo-2-methoxy-4-[N′-(4-phenylsulfanyl)-phenyl]-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride
23) 4-[N′-(4-benzenesulfonyl-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy -benzoic acid hydrochloride
24) 4-[N′-(4-benzenesulfinyl-phenyl)-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride
25) 2-methoxy-4-{(E)-2-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoic acid hydrochloride
26) 5-bromo-2-methoxy-4-{(E)-2-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoic acid hydrochloride
27) 4-[N′-(4-benzyl-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrainocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride
28) 5-bromo-2-methoxy-4-[N′-(4′-methoxy-biphenyl-4-yl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl]-benzoic acid hydrochloride
29) 4-[N′-(acetylamino-methyl)-phenyl]-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride
30) 4-[N′-(4-benzoyl)-phenyl]-N′-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride
31) 5-bromo-4-[N′-(4-cyano-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoic acid hydrochloride
32) 4-[N′-(4′-acetyl-biphenyl-4-yl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride; and
33) 5-bromo-2-methoxy-4-[N′-(4′-methoxy-2-methyl-biphenyl-4-yl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride.
3. The method according to claim 1 , wherein the patient has a lesion associated with an infection by the papilloma virus.
4. The method according to claim 1 , wherein the patient has an ano-genital wart, a laryngeal, conjunctive or buccal papilloma, or an epithelial lesion.
5. The method according to claim 4 , wherein said ano-genital wart is an acuminated condyloma or a plane condyloma.
6. The method according to claim 1 , wherein said epithelial lesion is selected from the group consisting of a recurrent respiratory papillomatosis, a low grade or high grade intra-epithelial neoplasia, a bowenoid papulosis, a wart, an epidermodysplasia verruciformis, a carcinoma, and a lesion associated with the papilloma virus.
7. The method according to claim 6 , wherein said wart is selected from the group consisting of a verruca vulgaris, a verruca plantaris, a myrmecia wart, a surface wart and a verruca plana.
8. The method according to claim 6 , wherein said carcinoma is an ano-genital carcinoma.