ESTERS OF HYDROXY-BENZOIC ACIDS FOR USE IN THE TREATMENT OF RHINOVIRUS

Abstract

The present invention provides ester derivatives of hydroxybenzoic acid for use in the treatment or prevention of a rhinovirus infection in a mammal wherein R represents a C.sub.1-10 alkyl group, X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 independently represent H or OH and wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 is OH.

Claims

1. A method for the treatment or prevention of a rhinovirus infection in a mammal comprising administering to said mammal a compound of formula I: ##STR00005## wherein: R represents a C.sub.1-10 alkyl group; X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 independently represent H or OH; and and wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 is OH.

2. A method according to claim 1 wherein the mammal is human.

3. A method according to claim 1 wherein the infection is in the upper respiratory tract.

4. A method according to claim 3 wherein the infection is a common cold.

5. A method according to claim 1 wherein the rhinovirus is human rhinovirus.

6. A method according to claim 5 wherein the rhinovirus is Type A, Type B or Type C.

7-10. (canceled)

11. A method according to claim 1 wherein R represents an unsubstituted alkyl group.

12. A method according to claim 1 wherein R represents a C.sub.1-8 alkyl group, for example a C.sub.1-6 alkyl group, a C.sub.1-5 alkyl group, a C.sub.1-4 alkyl group, a C.sub.1-3 alkyl group, a C.sub.1-2 alkyl group or a C.sub.1 alkyl group.

13. A method according to claim 1 wherein R represents a methyl group, an ethyl group, a propyl group or a butyl group.

14. A method according to claim 1 wherein R represents (CH.sub.2).sub.nCH.sub.3, wherein n is an integer between 0 and 3.

15. A method according to claim 1 wherein R represents (CH.sub.2).sub.2CH.sub.3.

16. A method according to claim 1 wherein the compound is an alkyl ester of a monohydroxybenzoic acid, for example an alkyl ester of 2-hydroxybenzoic acid (salicylic acid), 3-hydroxybenzoic acid or 4-hydroxybenzoic acid.

17. (canceled)

18. A method according to claim 1 wherein the compound is an alkyl ester of a dihydroxybenzoic acid, for example an alkyl ester of 2,3-hydroxybenzoic acid, 2,4-hydroxybenzoic acid, 2,5-hydroxybenzoic acid or 2,6-hydroxybenzoic acid.

19. A method according to claim 1 wherein the compound is an alkyl ester of a trihydroxybenzoic acid, for example an alkyl ester of 3,4,5-trihydroxybenzoic acid (gallic acid) or 2,4,6-trihydroxybenzoic acid (phloro-glucinol carboxylic acid).

20. A method according to claim 1 wherein the compound is an alkyl ester of a tetrahydroxybenzoic acid or pentahydroxybenzoic acid.

21-22. (canceled)

23. A method according to claim 1 wherein the compound is provided in a form suitable for delivery to the mucosa of the mouth and/or pharynx.

24-25. (canceled)

26. A method according to claim 1 wherein the compound is for use in combination with a polypeptide having protease activity.

27-51. (canceled)

52. A method according to claim 1 wherein the compound is for use in combination with one or more additional active agents.

53. A method according to claim 52 wherein the additional active agents are selected from the group consisting of antimicrobial agents (including antibiotics, antiviral agents and anti-fungal agents), anti-inflammatory agents (including steroids and non-steroidal anti-inflammatory agents) and antiseptic agents.

54. (canceled)

55. A method of preparing a medicament comprising a compound of formula I: ##STR00006## wherein: R represents a C.sub.1-10 alkyl group; X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 independently represent H or OH; and and wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 is OH.

56-65. (canceled)

Description

[0251] Preferred, non-limiting examples which embody certain aspects of the invention will now be described, with reference to the following figures:

[0252] FIG. 1. Schematic representation of assay protocol

[0253] FIG. 2. Effect of pre-treatment only with benzoic acid 4-hydroxy propyl ester (placebo) and PBS negative control (PBS) on rhinovirus RV16 titre.

[0254] FIG. 3. Effect of combined pre-treatment and post-treatment with benzoic acid 4-hydroxy propyl ester (placebo) and PBS negative control (PBS) on rhinovirus RV16 titre.

EXAMPLES

[0255] Materials & Methods

[0256] Test Formulation

TABLE-US-00026 Component Amount (w/w %) Purified water 99.68 Disodium phosphate dihydrate 0.047 Sodium dihydrogen 0.101 phosphate monohydrate Benzoic acid 4-hydroxy propyl ester 0.03 (propagin; propyl paraben; N-propyl-p-hydroxy-benzoate) Sucrelose, 98% 0.06 Menthol, 99% 0.0042 Ethanol, 96% 0.08 6 M HCI (used to adjust 6 M NaOH solution to pH 6.4)

[0257] Assay Protocol [0258] BEAS-2B cells were seeded into 12 well plates at 1.710.sup.5 cells per well and left to grow for 24 h in 10% foetal calf serum (FCS) containing RPMI medium [0259] BEAS-2B cells were then placed into 2% FCS containing RPMI medium [0260] Placebo was sprayed into a 10 mL universal tube, and this was used to produce dilutions of 1/2, 1/5 and 1/10 in 2% FCS containing RPMI medium. [0261] Phosphate buffered saline (PBS) pH7.4, was used as a comparison (negative control) and diluted in the same way. [0262] 1 mL per well was added onto each well and incubated for 90 mins (pre-treatment) [0263] The supernatant containing test formulation or PBS was removed, and BEAS-2B cells were then infected with MOI of 1 RV16, at room temperature for 1 h with shaking. [0264] RV16 was washed off 3 in 2% FCS containing RPMI medium [0265] For pre-treatment, 2% FCS containing medium was then added 1 mL per well. [0266] For pre- and post-treatment, the test formulation and PBS control were diluted fresh as above and added 1 mL per well. [0267] Cells were incubated for 48 h and then supernatants frozen at 20 C. [0268] Supernatants were thawed and serially diluted 10-fold and used in titration of HeLa cells in replicates of 8, using standard lab protocols. All plates were read at 4 days post-infection [0269] See FIG. 1

[0270] Results [0271] BEAS-2B cells exhibited no obvious deleterious effects following pre-treatment, or pre- and post-treatment, with the test formulation and PBS control at any dilution [0272] Pre-treatment only appeared to have had no effect on RV16 titre (see FIG. 2) [0273] For pre- and post-treatment, the test formulation at 1/2 dilution reduced RV16 titre by 98.5% (see FIG. 3) [0274] The test formulation at 1/5 dilution reduced RV16 titre by 68% [0275] No effect was seen at 1/10 dilution of the test formulation.

CONCLUSIONS

[0276] The data indicate that the test formulation inhibits rhinovirus replication