Claims
1.
A compound of Formula I:
O
O
Cl
CH3
OCF3
N
H
O
OH
P
HO
O
I
or a salt thereof.
2.
The compound according to claim 1, which is in the form of the free acid.
3.
A salt of the compound according to claim 1, which is a tromethamine salt, a
sodium salt or a potassium salt.
4.
A crystalline solid of the compound or salt thereof according to any of claims
1 to 3.
5.
A compound in the form of the free acid according to claim 4, which is
characterised by one or more of:
a.
an X-ray powder diffraction (XRPD) spectra comprising 2 theta angle
peaks at 5.7, 5.9, 9.7, 11.4, 11.9, 12.9, 15.1, 16.7, 17.2, 21.4, 22.4
degrees to 0.2°;
b.
bands on the FT-Raman spectrum at: 593, 818, 854, 1166, 1215,
1612, 2946, 3076 cm-1 to 4 cm-1;
19
c.
F solid-state NMR peak at (, ppm from CFCl3): -54.5 to 0.2 ppm;
31
d.
P solid-state NMR peaks at (, ppm from 85% H3PO4): -0.3 and -1.4
to 0.2 ppm; and
e.
at least 16 13C solid-state NMR peaks selected from peaks at (, ppm
from tetramethylsilane): 156.5, 155.1, 153.3, 152.8, 149.9, 148.1,
146.1, 145.6, 143.5, 142.5, 135.9, 133.2, 132.5, 131.2, 127.0, 124.5,
122.3, 119.3, 117.6, 116.9, 115.1 and 114.0 to 0.2 ppm.
6.
The compound according to claim 5, characterised by at least two of a to e.
7.
The compound according to claim 5, characterised by all five of a to e.
8.
A tromethamine salt according to claim 4, which is characterised by one or
more of:
a.
b.
c.
d.
and
e.
an X-ray powder diffraction (XRPD) spectra comprising 2 theta angle
peaks at 6.7, 15.3, 17.2, 18.1, 20.2, 21.0, 21.5, 24.8, 27.1 degrees to
0.2°;
bands on the FT-Raman spectrum at: 593, 818, 854, 1166, 1215,
1612, 2946, 3076 cm-1 to 4 cm-1;
19
F solid-state NMR peak at (, ppm from CFCl3): -58.3 to 0.2 ppm;
31
P solid-state NMR peaks at (, ppm from 85% H3PO4): -1.1 to 0.2
ppm;
at least 12 13C solid-state NMR peaks selected from peaks at (, ppm
from tetrmethylsilane): 158.7, 154.9, 147.4, 145.8, 141.2, 133.2, 131.2,
127.9, 127.4, 126.4, 124.2, 122.3, 120.7, 120.1, 117.4 and 114.1 to
0.2 ppm.
9.
The tromethamine salt according to claim 8, characterised by at least two of a
to e.
10.
The tromethamine salt according to claim 8, characterised by all five of a to e.
11.
A sodium salt of the compound according to claim 4, which is a hydrated,
mono-sodium salt which is characterised by one or more of:
a.
an X-ray powder diffraction (XRPD) spectra comprising 2 theta angle
peaks at 11.7, 15.7, 16.3, 18.7, 19.9, 22.5, 24.4, 25.1, 27.9 to 0.2°;
b.
bands on the FT-Raman spectrum at: 598, 816, 847, 1207, 1298,
1616, 2946, 3061 cm-1 to 4 cm-1;
19
a.
F solid-state NMR peak at (, ppm from CFCl3): -56.9 to 0.2 ppm;
31
b.
P solid-state NMR peaks at (, ppm from 85% H3PO4): 4.8 to 0.2
ppm;
and
c.
at least 14 13C solid-state NMR peaks selected from peaks at (, ppm
from tetrmethylsilane): 157.1, 155.4, 147.2, 147.0, 144.1, 142.8,
132.6, 132.0, 128.6, 127.8, 125.4, 124.3, 123.2, 122.3, 120.9, 120.0,
118.0 and 114.0 to 0.4 ppm.
12.
The sodium salt according to claim 11, characterised by at least two of a to e.
13.
The sodium salt according to claim 11, characterised by all five of a to e.
14.
A hydrated, mono-potassium salt of the compound of claim 4 which is
characterized by an X-ray powder diffraction (XRPD) pattern substantially as
shown in Figure 4a, wherein the XRPD pattern is expressed in terms of 2
theta angles and obtained with a diffractometer equipped with a diffracted
beam monochromator using copper K radiation.
15.
A hydrated, mono-potassium salt of the compound of claim 4 which is
characterized by at least two of:
a.
an onset of melting in the range 105.5-109.5 C;
b.
an enthalpy of melting in the range of 78-81 J/g;
c.
a DSC thermogram substantially in accordance with Figure 4b;
and
d.
a TGA thermogram substantially in accordance with Figure 4c.
16.
An anhydrous, mono-potassium salt of the compound of claim 4, which is
characterised by:
a.
an X-ray powder diffraction (XRPD) spectra comprising 2 theta angle
peaks at 5.7, 5.8, 11.3, 11.6, 16.2, 16.6, 18.9, 19.3, 20.9, 22.5 to 0.2;
and/or
b.
bands on the FT-Raman spectrum at: 596, 784, 817, 1161, 1206,
1297, 1615, 2940, 3079 cm-1 to to 4 cm-1.
17.
A compound or a salt thereof according to any preceding claim, for use in
medical therapy.
18.
Use of a compound of Formula I or a salt thereof according to any one of
claims 1 to 16, in the manufacture of a medicament for the treatment of
malaria.
19.
A method for the treatment of malaria comprising administering to a patient
suffering therefrom an effective amount of a compound or salt thereof of any
of claims 1 to 16.
20.
The use according to claim 18 or the method according to claim 19 wherein
malaria is caused by infection with Plasmodium falciparum.
21.
A pharmaceutical composition comprising a compound or a salt thereof
according to any one of claims 1 to 16, and one or more pharmaceutically
acceptable carriers and/or excipients.
22.
The pharmaceutical composition according to claim 21 for parenteral
administration.
23.
The pharmaceutical composition according to claim 21 or claim 22 in the form
of a solid for reconstitution into a liquid dosage form.
24.
A pharmaceutical composition comprising a compound or a salt thereof
according to any one of claims 1 to 3, in the form of a liquid dosage for
injection or infusion, in which the compound or salt is present as a solution in
one or more liquid carriers.
25.
The pharmaceutical composition according to any one of claims 21 to 24
comprising a combination of a compound or a salt thereof according to any
one of claims 1 to 16, and a further active thereapeutic agent.
26.
{5-chloro-6-methyl-4-oxo-3-[4-({4-[(trifluoromethyl)oxy]phenyl}
oxy)phenyl]1,4-dihydro-2-pyridinyl}methyl bis(phenylmethyl) phosphate or a salt thereof.
27.
A method of making the compound according to claim 1 or a salt thereof,
comprising the step of deprotecting {5-chloro-6-methyl-4-oxo-3-[4-({4[(trifluoromethyl)oxy]phenyl}
oxy)phenyl]-1,4-dihydro-2-pyridinyl}methyl
bis(phenylmethyl) phosphate and, optionally, contacting the compound of
claim 1 with a base to form a salt.
28.
A method of claim 27 further comprising the step of combining 3-chloro-6(hydroxymethyl)-2-methyl-5-[4-({4-[(trifluoromethyl)
oxy]phenyl}oxy)phenyl]4(1H)-pyridinone with tetrabenzyl pyrophosphate under conditions in which
the 6-hydroxymethyl group of 3-chloro-6-(hydroxymethyl)-2-methyl-5-[4-({4[(trifluoromethyl) oxy]phenyl}oxy)phenyl]-4(1H)-pyridinone is selectively
phosphorylated
to
form
{5-chloro-6-methyl-4-oxo-3-[4-({4[(trifluoromethyl)oxy]phenyl}oxy)phenyl]-1,4-dihydro-2-pyridinyl}methyl
bis(phenylmethyl) phosphate thereof.
29.
The method according to claim 28, wherein the 6-hydroxymethyl group is
deprotonated in the presence of lithium hydride and a hindered alcohol.