Pharmaceutical Compound
The present application relates to compounds of Formula (I) or a pharmaceutically acceptable salt thereof, compositions thereof, and their use in the treatment and/or prophylaxis of systemic infections, such as the treatment and/or prophylaxis of systemic parasitic and fungal infections, such as malaria, in particular infection by Plasmodium falciparum.
1 . A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-5 alkyl, C 1-5 hydroxyalkyl or C 1 -C 5 haloalkyl;
R 2 is hydrogen or halogen;
X is S, SO, or SO 2 ;
Z is a single bond, —O—, —C═C—, —C═C—CH 2 —NR 3 —CH 2 —, or —(CH 2 ) m —, wherein m is 1, 2 or 3, and wherein R 3 is hydrogen or a C 1-5 alkyl;
R 4 is hydrogen, halogen, —CH 2 F, —CHF 2 , —CF 3 , —OCH 2 F, —OCHF 2 , or —OCF 3 ;
R 5 is —CF 3 , —OCF 3 , —(CH 2 ) q —OH, wherein q is 1, 2, 3, or 4, or R 5 is represented by the following group:
where indicates a binding site to the phenyl ring and wherein W is —O—, or —CH 2 —NR b —Y—CH 2 —, where R b is hydrogen or C 1-5 alkyl, and Y is a single bond or Y is represented by the following group:
where indicates a binding site to the amine and indicates a binding site to the methylene group;
R 6 is —CF 3 , or —OCF 3 ;
R 7 is halogen, —CHF 2 , —CH 2 F, or —CF 3 ; and
a is 0, 1, 2, or 3.
2 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is defined according to Formula Ia:
wherein R 1 -R 3 , X, and Z are as defined in claim 1 ;
R 8 is hydrogen, halogen, —CHF 2 , —CH 2 F, or —CF 3 ;
R 9 is hydrogen, —CF 3 , or —OCF 3 ;
R 10 is hydrogen, —CF 3 , —OCF 3 , C 1 -C 4 alkyl-OH,
where indicates a binding site to the phenyl ring;
R 11 is hydrogen, —CHF 2 , —CH 2 F, —CF 3 ;
R 12 is hydrogen, halogen, —CHF 2 , —CH 2 F, —CF 3 , or —OCF 3 .
3 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is methyl; and/or wherein R 2 is chloro.
4 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X is S.
5 . The compound or pharmaceutically acceptable salt thereof according to any of claim 1 , wherein Z is a single bond.
6 . The compound or pharmaceutically acceptable salt thereof according to claim 1 selected from:
3-chloro-7-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[4,5] thieno[2,3-b]pyridin-4(1H)-one;
sodium 3-chloro-7-[2-fluoro-4-(trifluoromethyl)phenyl]-2-methyl[1]benzothieno [2,3-b]pyridin-4-olate;
3-chloro-7-(2-fluoro-5-(trifluoromethyl)phenyl)-2-methylbenzo[4,5]thieno[2,3-b]pyridin-4(1H)-one;
3-chloro-2-methyl-7-(2-(trifluoromethoxy)phenyl)benzo[4,5]thieno[2,3-b]pyridin-4(1H)-one;
7-(2,4-bis(trifluoromethyl)phenyl)-3-chloro-2-methylbenzo[4,5]thieno[2,3-b]pyridin-4(1H)-one;
3-chloro-7-(4-(hydroxymethyl)phenyl)-2-methylbenzo[4,5]thieno[2,3-b]pyridin-4(1H)-one;
3-chloro-2-methyl-7-(4-((methyl(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)amino)methyl)phenyl)benzo[4,5]thieno[2,3-b]pyridin-4(1H)-one; or
3-chloro-2-methyl-7-(4-((methyl(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)amino)methyl)phenyl)benzo[4,5]thieno[2,3-b]pyridin-4(1H)-one 2,2,2-trifluoroacetate.
7 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is:
8 . A crystalline form of 3-chloro-7-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[4,5] thieno[2,3-b]pyridin-4(1H)-one characterised by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu K α radiation, selected from the group consisting of either:
(i) about 5.2±0.1, 8.6±0.1, 10.5±0.1, 12.5±0.1, 13.5±0.1, 15.6±0.1, 18.8±0.1, 19.7±0.1, 20.9±0.1, 21.9±0.1, and 26.2±0.1 degrees 2θ; or
(ii) about 5.9±0.1, 9.9±0.1, 11.8±0.1, 13.9±0.1, 14.2±0.1, 15.4±0.1, 19.9±0.1, 23.2±0.1, 23.7±0.1, 24.2±0.1, 28.6±0.1, 29.7±0.1, 35.8±0.1 and 35.9±0.1 degrees 2θ.
9 . The crystalline form of claim 8 , wherein the crystalline form is characterised by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1 or FIG. 2 .
10 . The compound or pharmaceutically acceptable salt thereof according to of claim 1 for use in therapy.
11 . A pharmaceutical composition comprising (a) the compound or pharmaceutically acceptable salt thereof according to claim 1 ; and (b) a pharmaceutically acceptable excipient or carrier.
12 . The pharmaceutical composition according to claim 11 , where the pharmaceutical composition is an injectable composition.
13 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , for use in the treatment and/or prophylaxis of a parasitic protozoal infection.
14 . The compound or pharmaceutically acceptable salt thereof according to claim 13 , wherein the parasitic protozoal infection is malaria.
15 . The compound or pharmaceutically acceptable salt thereof according to claim 13 , wherein the parasitic protozoal infection is a Plasmodium falciparum infection.
16 . A method of treating a parasitic protozoal infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 1 .
17 . The method according to claim 16 , wherein the parasitic protozoal infection is malaria.
18 . The method according to claim 16 , wherein the parasitic protozoal infection is a Plasmodium falciparum infection.
19 . (canceled)
20 . (canceled)
21 . (canceled)
22 . A combination of (a) a compound or pharmaceutically acceptable salt thereof according to claim 1 ; and at least one other anti-malarial agent.
23 . The combination according to claim 22 , wherein the at least one other anti-malarial agent is atovaquone, 6-chloro-7-methoxy-2-methyl-3-{4-[4-(trifluoromethoxy)phenoxy]phenyl}quinolin-4(1H)-one, 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one, a pharmaceutically salt thereof, or a combination thereof.
24 . The crystalline form according to claim 8 for use in therapy.
25 . A pharmaceutical composition comprising (a) the crystalline form of claim 8 ; and (b) a pharmaceutically acceptable excipient or carrier.
26 . The crystalline form according to claim 8 , for use in the treatment and/or prophylaxis of a parasitic protozoal infection.
27 . The pharmaceutical composition according to claim 11 , for use in the treatment and/or prophylaxis of a parasitic protozoal infection.
28 . A method of treating a parasitic protozoal infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of the crystalline form of claim 8 .
29 . A method of treating a parasitic protozoal infection in a human in need thereof, comprising administering to the human a therapeutically effective amount of the pharmaceutical composition according to claim 11 .
30 . A combination of (a) the crystalline form according to claim 8 ; and at least one other anti-malarial agent.