Benzodiazepine derivatives and pharmaceutical compositions containing them

1. A method of treating an RSV infection in a patient, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein:

R 1 represents C 1-6 alkyl, aryl or heteroaryl;

R 2 represents hydrogen or C 1-6 alkyl;

each R 3 is the same or different and represents halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano, —CO 2 R′, —CONR′R″, —NH—CO—R′, —S(O)R′, —S(O) 2 R′, —NH—S(O) 2 R′, —S(O)NR′R″ or —S(O) 2 NR′R″, wherein each R′ and R″ is the same or different and represents hydrogen or C 1-6 alkyl;

n is from 0 to 3;

R 4 represents hydrogen or C 1-6 alkyl;

R 5 represents C 1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)-, heterocyclyl-(C 1-6 alkyl)-, aryl-(C 1-6 hydroxyalkyl)-, heteroaryl-(C 1-6 hydroxyalkyl)-, carbocyclyl-(C 1-6 hydroxyalkyl)-, heterocyclyl-C 1-6 hydroxyalkyl)-, aryl-C(O)—C(O)—, heteroaryl-C(O)—C(O)—, carbocyclyl-C(O)—C(O)—, heterocyclyl-C(O)—C(O)— or —XR 6 ;

X represents —CO—, —S(O)— or —S(O) 2 —; and

R 6 represents C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)-, heterocyclyl-(C 1-6 alkyl)-, aryl-(C 1-6 alkyl)—O—, heteroaryl-(C 1-6 alkyl)-O—, carbocyclyl-(C 1-6 alkyl)-O—, heterocyclyl-(C 1-6 alkyl)-O— or —NR′R″ wherein each R′ and R″ is the same or different and represents hydrogen, C 1-6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)- or heterocyclyl-(C 1-6 alkyl)-.

2. A method according to claim 1 wherein:

each R 3 is the same or different and represents halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano, —CO 2 R′, —CONR′R″, —NH—CO—R′, —S(O)R′, —S(O) 2 R′, —NH—S(O) 2 R′ or —S(O)NR′R″, wherein each R′ and R″ is the same or different and represents hydrogen or C 1-6 alkyl;

R 5 represents C 1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)-, heterocyclyl-(C 1-6 alkyl)- or —XR 6 ;

X represents —CO—, —S(O)— or —S(O) 2 —; and

R 6 represents C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)-, heterocyclyl-(C 1-6 alkyl)- or —NR′R″ wherein each R′ and R″ is the same or different and represents hydrogen, C 1-6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl-(C 1-6 alkyl)- or heteroaryl-(C 1-6 alkyl).

3. A method according to claim 1 , wherein R 1 is C 1-2 alkyl or aryl.

4. A method according to claim 1 , wherein R 2 is hydrogen.

5. A method according to claim 1 , wherein R 3 is halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, mono(C 1-4 alkyl)amino or di(C 1-4 alkyl)amino.

6. A method according to claim 5 , wherein R 3 is fluorine, chlorine, bromine, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 alkylthio, C 1-2 haloalkyl, C 1-2 haloalkoxy, amino, mono(C 1-2 alkyl)amino or di(C 1-2 alkyl)amino.

7. A method according to claim 1 , wherein R 4 is hydrogen or C 1-2 alkyl.

8. A method according to claim 1 , wherein R 5 is C 1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-4 alkyl)-, heteroaryl-(C 1-4 alkyl)-, carbocyclyl-C 1-4 alkyl)-, heterocyclyl-(C 1-4 alkyl)-, aryl-C(O)—C(O)—, heteroaryl-C(O)—C(O)— or —XR 6 .

9. A method according to claim 8 , wherein R 5 is C 1-4 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, phenyl-(C 1-2 alkyl)-, heteroaryl-(C 1-2 alkyl)-phenyl-C(O)—C(O)—, heteroaryl-C(O)—C(O)— or —XR 6 .

10. A method according to claim 9 , wherein R 5 is C 1-4 alkyl, phenyl, thienyl, furanyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydrobenzofuranyl, phenyl-CH 2 —, furanyl-CH 2 —, phenyl-C(O)—C(O)—, thienyl-C(O)—C(O)— or XR 6 .

11. A method according to claim 1 wherein X is —CO— or —S(O) 2 —.

12. A method according to claim 1 wherein, when R 6 is a group —NR′R″ wherein each R′ and R″ is the same or different and represents hydrogen, C 1-4 alkyl, aryl, carbocyclyl, heterocyclyl, aryl-(C 1-4 alkyl)- or heteroaryl-(C 1-4 alkyl)-.

13. A method according to claim 12 , wherein when R 6 is a group —NR′R″ each R′ and R″ is the same or different and represents hydrogen, C 1-4 alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-CH 2 —.

14. A method according to claim 13 , wherein when R 6 is a group —NR′R″ and one of R′ and R″ is hydrogen.

15. A method according to claim 1 wherein R 6 is C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-4 alkyl)-, heteroaryl-(C 1-4 alkyl)-, carbocyclyl-(C 1-4 alkyl)-, heterocyclyl-(C 1-4 alkyl)-, aryl-(C 1-4 hydroxyalkyl)-, heteroaryl-(C 1-4 hydroxyalkyl)-, carbocyclyl-(C 1-4 hydroxyalkyl)-, heterocyclyl-(C 1-4 hydroxyalkyl)-, aryl-(C 1-4 alkyl)-O—, heteroaryl-(C 1-4 alkyl)-O—, carbocyclyl-(C 1-4 alkyl)-O—, heterocyclyl-(C 1-4 alkyl)-O— or —NR′R″.

16. A method according to claim 15 , wherein R 6 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, phenyl-(C 1-2 alkyl)-, phenyl-(C 1-2 alkyl)-O—, heteroaryl-C 1-2 alkyl)-, phenyl-(C 1-2 hydroxyalkyl)-, heteroaryl-(C 1-2 hydroxyalkyl)- or —NR′R″.

17. A method according to claim 16 , wherein R 6 is C 1-4 alkyl, C 1-4 alkoxy, phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl, indolyl, thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuranyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, phenyl-(C 1-2 alkyl)-, phenyl-CH 2 —CH(OH)—, phenyl-CH(OH)—CH 2 —, phenyl-(C 1-2 alkyl)-O—, 1H-benzo[d]imidazol-2(3H)-onyl or —NR′R″.

18. A method according to claim 1 , wherein the compound of formula (I) is a compound of formula (Ia):

wherein:

R 1 is phenyl or methyl;

R 3 is methyl or chlorine;

n is 0 or 1;

R 4 is hydrogen or methyl;

R 5 is phenyl-CH 2 —, furanyl-CH 2 —, thienyl-C(O)—C(O)— or —XR 6 ;

X is —CO— or —S(O) 2 —; and

R 6 is C 1-4 alkyl, C 1-4 alkoxy, phenyl, naphthyl, dihydrobenzofuranyl, benzodioxinyl, 9H-fluoren-9-onyl, indolyl, thienyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuranyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, phenyl-(C 1 - 2 alkyl)-, phenyl-CH 2 —CH(OH)—, phenyl-CH(OH)—CH 2 —, phenyl-(C 1-2 alkyl)-O—, 1H-benzo[d]imidazol-2(3H)-onyl or —NR′R″ wherein each R′ and R″ is the same or different and represents hydrogen, C 1-4 alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH 2 )—,

the phenyl moiety in the group R′ being unsubstituted or substituted by a single fluorine, chlorine, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 alkylthio, C 1-2 haloalkyl or C 1-2 haloalkoxy substituent;

the aryl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, iodine, C 1-4 alkyl, C 2-4 acyl, hydroxy, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, mono(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, nitro, —CO 2 R′, —S(O) 2 R′ and —S(O) 2 NH 2 , wherein R′ represents C 1-2 alkyl;

the heteroaryl moieties in the groups R 5 and R 6 being unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, C 1-2 alkyl, C 1-2 haloalkyl and di(C 1-2 alkyl)amino; and

the heterocyclyl and carbocyclyl moieties in the R 6 group being unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and nitro.

19. A method according to claim 1 , wherein the patient is a child under two years of age.

20. A method according to claim 19 wherein said child suffers from chronic lung disease.

21. A method according to claim 1 wherein the patient is an infant less than six years of age who was born after 32 weeks of gestation or less.

22. A method according to claim 1 , wherein the benzodiazepine derivative or salt thereof is administered intranasally or intrabronchially.

23. A method according to claim 1 , wherein an anti-inflammatory compound or an anti-influenza compound is further administered to the patient.

24. A method according to claim 23 wherein the anti-inflammatory compound is budesonide or fluticasone.

25. A method according to claim 23 wherein the anti-inflammatory compound is a leukotriene antagonist, phosphodiesterase 4 inhibitor or TNF alpha inhibitor.

26. A method according to claim 23 wherein the anti-inflammatory compound is an interleukin 8 or interleukin 9 inhibitor.

27. A method according to claim 1 , wherein the compound is (S)-1 -(2-Fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro- 1H-benzo[e][1,4]diazepin-3-yl)-urea.