Purine derivative compounds for medical use

1. A method for the treatment of a disease characterized by a reduction in macrophages-mediated bacterial killing, comprising the administration to a patient in need thereof of a compound of formula (I):

or pharmaceutically acceptable salts thereof,

wherein

A is N or CH,

B is N, O, or S,

R 1 is

H,

a (C 1 -C 4 )alkyl group,

a methyl(C 3 -C 6 )cycloalkyl group, or

a (C 3 -C 6 )cycloalkyl group,

R 2 is

an aryl, said aryl group being optionally substituted by an halogen atom, an hydroxyl group, a methoxy group or an identical or different aryl group or a heteroaryl group,

an arylmethyl group, an aryl group of said arylmethyl group being optionally substituted with one to three groups, or

a methylheteroaryl group,

R 3 is

absent when B is O or S, or is

H or a (C 1 -C 4 )alkyl group when B is N,

R 4 is a (C 1 -C 5 )alkyl group or a (C 3 -C 4 )cycloalkyl group, each group bearing a carboxylic acid group, and said (C 1 -C 5 )alkyl group or (C 3 -C 4 )cycloalkyl group being optionally substituted by a hydroxyl group, a halogen group or a methoxy group, and

when B is N, R 3 and R 4 can together form a 5- or 6-membered heterocycle substituted by a carboxylic acid group, and optionally substituted by a halogen atom, a hydroxyl group, a methoxy group or a hydroxymethyl group, or alternatively substituted by an ethylic acid,

or pharmaceutically acceptable salts thereof,

wherein the disease characterized by a reduction in macrophage-mediated bacterial killing is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, tuberculosis, and a disease involving pulmonary microbial infection selected from the group consisting of an infection by a bacterium from the genus Haemophilus, Pseudomonas, Burkholderia, Staphylococcus, Mycobacterium, Prevotella, Veillonella, Propionibacterium, Actinomyces, Streptococcus , and Legionnella.

2. The method according to claim 1 , wherein the group NHR 2 of the compound of formula (I) is selected from the group consisting of:

3. The method according to claim 1 , wherein B is N and the group NR 3 R 4 is selected from the group consisting of:

or alternatively B is O and OR 4 is selected from the group consisting of:

4. The method according to claim 1 , wherein R 1 represents isopropyl, R 2 represents a benzyl group, R 3 represents a hydrogen atom and R 4 represents a 1-carboxypropan-1-yl group, in the (R) or (S) form or in the form of a racemic mixture thereof.

5. The method according to claim 1 , wherein the compound of formula (I) is (2R)-2-[[9-isopropyl-6-(phenylmethylamino)purin-2-yl]amino]butanoic acid.

6. The method according to claim 1 , wherein the disease characterized by a reduction in macrophage-mediated bacterial killing is a disease involving pulmonary microbial infection selected from the group consisting of an infection by a bacterium from the genus Haemophilus, Pseudomonas, Burkholderia, Staphylococcus, Mycobacterium, Prevotella, Veillonella, Propionibacterium, Actinomyces, Streptococcus , and Legionnella.

7. The method according to claim 1 , wherein the disease characterized by a reduction in macrophage-mediated bacterial killing is cystic fibrosis.

8. The method according to claim 1 , wherein the compound of formula (I) is orally administered in an amount of about 1 to 500 mg.

9. The method according to claim 1 , wherein administration of a compound of formula (I) is administered by aerosol, in an amount from about 1 to about 100 mg per inhalation.

10. A compound selected from the group consisting of (3R)-3-[[6-(benzylamino)-9-isopropyl-purin-2-yl]amino]butanoic acid and (2S)-2-[[6-(benzylamino)-9-isopropyl-purin-2-yl]amino]-3-hydroxy-propanoic acid.

11. The method according to claim 1 , comprising administration to the patient in need thereof the compound of formula (I) in the form of a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

12. The method according to claim 11 , wherein the pharmaceutical composition is administered by oral, systemic, parenteral, or intra-pulmonary administration.

13. The method according to claim 11 , wherein the pharmaceutical composition further comprises an additional agent selected from the group consisting of mucolytic agent, bronchodilator, an anti-inflammatory agent, and an anti-infective agent.

14. A method for identifying a patient with an increased likelihood of responding to a compound of formula (I), wherein the patient has been diagnosed with or is at increased risk of developing a pulmonary disease, said method comprising:

a) providing isolated macrophages from said individual;

b) incubating said macrophages with a microorganism able to provoke a pulmonary disease;

c) providing to said macrophages an effective amount of the compound of formula (I); and

d) assessing the abilities of said macrophages to kill said microorganism,

wherein the compound of formula (I) is:

or pharmaceutically acceptable salts thereof

wherein

A is N or CH,

B is N, O, or S,

R 1 is

H,

a (C 1 -C 4 )alkyl group,

a methyl(C 3 -C 6 )cycloalkyl group, or

a (C 3 -C 6 )cycloalkyl group,

R 2 is

an aryl, said aryl group being optionally substituted by an halogen atom, an hydroxyl group, a methoxy group or an identical or different aryl group or a heteroaryl group,

an arylmethyl group, an aryl group of said arylmethyl group being optionally substituted with one to three groups, or

a methylheteroaryl group,

R 3 is

absent when B is O or S, or is

H or a (C 1 -C 4 )alkyl group when B is N,

R 4 is a (C 1 -C 5 )alkyl group or a (C 3 -C 4 )cycloalkyl group, each group bearing a carboxylic acid group, and said (C 1 -C 5 )alkyl group or (C 3 -C 4 )cycloalkyl group being optionally substituted by a hydroxyl group, a halogen group or a methoxy group, and

when B is N, R 3 and R 4 can together form a 5- or 6-membered heterocycle substituted by a carboxylic acid group, and optionally substituted by a halogen atom, a hydroxyl group, a methoxy group or a hydroxymethyl group, or alternatively substituted by an ethylic acid or pharmaceutically acceptable salts thereof.

15. The method according to claim 1 , wherein the disease involving pulmonary microbial infection is selected from the group consisting of an infection by Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia cepacia, Haemophilus influenza, Mycobacterium absessus , and Mycobacterium tuberculosis.

16. The method according to claim 1 , wherein the group that substitutes the benzyl of R 2 is selected from the group consisting of a (C 1 -C 3 )alkyl group, a OH, a OMe, or a halogen group.

17. The method according to claim 12 , wherein the intra-pulmonary administration consists of an intra-bronchial or an intra-alveolar administration.

18. The method according to claim 13 , wherein the anti-infective agent is selected from the group consisting of an antibiotic and a bacteriophage.

19. The method according to claim 1 , wherein the group that substitutes the aryl group of the arylmethyl group of R 2 is selected from the group consisting of a (C 1 -C 3 )alkyl group, a OH, a OMe, or a halogen group.

20. The method according to claim 14 , wherein the group that substitutes the aryl group of the arylmethyl group of R 2 is selected from the group consisting of a (C 1 -C 3 )alkyl group, a OH, a OMe, or a halogen group.