WO2011057262A2 - Treatment of infections with tp receptor antagonists - Google Patents

Abstract

The present invention relates to TP Receptor Antagonists for treatment of infection, Prodrugs and salts of the present pharmaceutical compositions are also provided.

Description

TREATMENT OF INFECTIONS WITH TP RECEPTOR ANTAGONISTS Cross-Reference to Related Applications

This application claims the benefit of and claims priority from U.S. provisional patent application Ser. No. 61/259,297, filed Nov 9, 2009 which is incorporated herein by reference in its entirety.

Field of invention

The present invention relates to treatment of infections, in particular to treatment of infections by administration of TP receptor antagonists.

Background of invention

Thromboxane A2 (TXA2) is an unstable metabolite of arachidonic acid produced by catalysis of cyclooxygenase and thromboxane synthase in various cell types and exerts its actions through one of the prostanoid receptors belonging to the rhodopsin-like G protein coupled receptor super-family, termed TP (thromboxane receptor). It is produced abundantly by platelets upon exposure to injured blood vessels. Because of its potent platelet aggregating and vessel-contracting activities, the functions of TXA2 have been studied mainly in the cardiovascular system.

However, the TP receptor is not only present in the plasma membrane of blood platelets, but also in many other tissues, e.g. vascular endothelial cells, smooth muscle cells of the vasculature and airways, kidney, placenta, lung, heart, uterus, thymus, spleen and monocytes/macrophages. The natural ligands for the TP receptor are TXA2, isoprostanes and some hydroxyeicosatetraenoic acids.

It has recently been found that TP is highly expressed in the spleen and thymus and that the binding activity for TP in thymocytes is comparable to that in platelets (Ushikubi F, Aiba Y, Nakamura K, Namba T, Hirata M, Mazda O, et al. Thromboxane A2 receptor is highly expressed in mouse immature thymocytes and mediates DNA fragmentation and apoptosis. J Exp Med 1993 Nov 1 ; 178(5): 1825-30). In addition, thromboxane synthase is highly expressed in macrophages and dendritic cells, which release TXA2 upon activation. Together these results imply that TXA2 has a function in the immune system. Exposure of dendritic cells to foreign antigens initiates immune response. Dendritic cells take up and process antigens and migrate toward regional lymph nodes, becoming activated and mature. Antigen-loaded mature dendritic cells encounter naive T cells in the lymph nodes and make a physical contact referred to as the immunological synapse, through which antigen presentation and associated signalling occur. The strength, duration and efficiency of this cell-cell adhesion apparently determine the extent of T cell activation and differentiation. Studies in mice deficient in TP have been used to examine the role of TXA2 signalling in the immune system. The results show that TXA2 modulates interaction of dendritic cells and T cells regulate acquired immunity

(Kabashima et al, Nature Immunology, 2003, 4:694-701).

However, when TXA2 is present in excess amounts it seems to lead to impairment of dendritic cell-T cell adhesion, apoptosis of dendritic cells, decreased antigen presentation and T cell proliferation, increased release of TNFa and suppression of

monocyte/macrophage activation.

Additionally, it is known that some pathogens have been shown to induce eicosanoid synthesis in host cells and in particular the synthesis of TXA2. For example, avian flu virus infects macrophages leading to a massive production of TXA2, and Francisella tularensis infected macrophages release eicosanoids and block T cell proliferation.

Kishino J, Hanasaki K, Nagasaki T, Arita H. Kinetic studies on stereospecific recognition by the thromboxane A2/prostaglandin H2 receptor of the antagonist, S-145. Br J

Pharmacol 1991 Aug;103(4): 1883-8; Namba T, Sugimoto Y, Hirata M, Hayashi Y,

Honda A, Watabe A, et al. Mouse thromboxane A2 receptor: cDNA cloning, expression and northern blot analysis. Biochem Biophys Res Commun 1992 May 15;184(3): 1197- 203; Ushikubi F, Aiba Y, Nakamura K, Namba T, Hirata M, Mazda O, et al.

Thromboxane A2 receptor is highly expressed in mouse immature thymocytes and mediates DNA fragmentation and apoptosis. J Exp Med 1993 Nov 1 ; 178(5): 1825-30. Viruses such as Ebola and Lassa viruses, in turn, are known to infect human monocyte- derived dendritic cells and impair their function making them poor stimulators of T cells.

TP receptor antagonists have been suggested for use in the treatment of diseases involving platelet aggregation notably in cardiovascular diseases.

However, there has been no suggestion of the use of TP receptor antagonists the treatment of infections induced either by a virus or a bacterium. Summary of the invention

In a first aspect of the invention is provided a pharmaceutical composition comprising a TP receptor antagonist for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject after administration of the composition.

In a second aspect of the invention is provided a pharmaceutical composition comprising a TP receptor antagonist that is effective as an anti-infective agent in an amount lower than that which would trigger PPARy activity, for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject after administration of the composition.

In a third aspect of the invention is provided a pharmaceutical composition comprising a TP receptor antagonist that is not a PPARy ligand nor one that can trigger PPARy activity, for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject after administration of the composition. In a fourth aspect, the invention provides provided a TP receptor antagonist composition for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject after administration of the composition, wherein where the levels of thromboxane receptor agonists in the subject are raised above normal levels.

In each case of these four aspects of the invention is provided one embodiment comprising a TP receptor antagonist effective as an anti-infective agent in a concentration of between 0.001 nM and 100 μΜ. In a further embodiment, the TP receptor antagonists is provided in a concentration not above 10 micromolar, or not above 5 micromolar, or not above 1 micromolar.

In a second embodiment of these four aspects of the invention, the TP receptor has an IC5₀ in respect of inhibition of binding of a ligand to the TP receptor of at most 10 nM, or at most 5 nM, or at most 1 nM.

In a third embodiment of these four aspects of the invention, the TP receptor devoid of agonistic activity.

Equally in each case of the four aspects of the invention, the invention provides in one embodiment a pharmaceutical composition comprising a TP receptor antagonist selected from Table 1, including their prodrugs, salts, and compositions comprising the compounds, methods and intermediates useful for synthesizing the compounds, and uses and methods of using the compounds. Equally in each case of the four aspects of the invention, the invention provides in one embodiment a pharmaceutical composition comprising a TP receptor antagonist for treatment of an infection by a pathogen, wherein the pathogen is capable of modulating eicosanoid synthesis in a mammalian host.

Equally in each case of the four aspects of the invention, the invention provides in one embodiment a pharmaceutical composition comprising a TP receptor antagonist for treatment of an infection by a pathogen, wherein the pathogen is capable of inducing eicosanoid levels in a mammalian host.

Equally in each case of the four aspects of the invention, the invention provides in one embodiment a pharmaceutical composition comprising a TP receptor antagonist for treatment of an infection by a pathogen, wherein the pathogen is capable of inducing TXA2 levels in a mammalian host.

In yet another embodiment the invention relates to methods for decreasing TNFa levels in an individual in need thereof, the method comprising administering a therapeutically acceptable amount of a TP receptor antagonist to the individual. Not sure

Equally in each case of the four aspects of the invention, the invention provides in one embodiment a pharmaceutical composition comprising a TP receptor antagonist for treatment of an infection by a pathogen, for stimulating dendritic cell dependent proliferation of T-cells in an individual in need thereof.

The pharmaceutical composition according to the invention, wherein the TP receptor antagonist has a Ki in relation to binding to TP receptor in vitro of at most 100 nM, or at the most 50 nM, or at most 30 nM, or at most 10 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.

The pharmaceutical composition according to the invention, wherein the TP receptor antagonist has a Kd in respect of inhibition of TP receptor function of at most 1 μΜ, or at most 500nM, or at most 300nM, or at most 100 nM, 75 nM, 50 nM, 30 nM, 20 nM, 10 nM, preferably at most 5 nM, more preferably at most 1 nM. The pharmaceutical composition, according to the invention, wherein the TP receptor antagonist has an IC5₀ in respect of inhibition of binding of an agonist to human TPa receptor of at the most has an IC50 in respect of inhibition of binding of a ligand to the TP receptor of at most Ι μΜ, or at most 500nM, or at most 300nM, or at most lOOnM or at most 50nM or at most 10 nM, or at most 5 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.

Equally in each case of the four aspects of the invention, the invention provides in one embodiment a pharmaceutical composition comprising a TP receptor antagonist comprising a compound having the 1, 3-dioxane moiety, including its prodrugs, salts, compositions comprising the compound, methods and intermediates useful for synthesizing the compound, and uses and methods of using the compound, the compound having the general formula I:

wherein A is a branched or linear carbon chain of 2 to 7 carbons, each optionally containing 1 or 2 double bonds (each can be cis or trans); wherein W is COOH, OH, NH₂, S0₃H, OSO₃H, -C(0)-Zi- R^p, where Z_x can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like wherein the progroup R^p can be metabolized in vivo to yield the active diaryl 1, 3-dioxane moiety containing drug, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example, or a 1 ,3 dioxolane group linked through the 2 position, or a bioisostere of COOH; wherein Ar is a phenyl, or a 5 or 6 membered heterocyclic aromatic group, such as, but not limited to, 2-pyridine, 3 -pyridine, thiophene, furan, wherein the aromatic or heteroaromatic group can optionally be mono- or poly-substituted with halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, or Z₂-R^p', where Z₂ can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, wherein the progroup R^p can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug; and wherein Ra and Rb are independently hydrogen, 2-6C alkenyl, 1-8C alkyl, optionally with up to three halogeno-substituents, 0-(l-4C)alkyl, (3-7C)cycloalkyl and oxapoly-methylene of 2 to 4 carbon atoms, or wherein Ra and Rb together form polymethylene of 2 to 7 carbon atoms, optionally having one or two (l-4C)alkyl substituents, or an aromatic or heteroaromatic moiety, containing up to 24 C atoms and up to 6 heteroatoms, the aromatic or heteroaromatic moieties comprising fused aromatic and heteroaromatic structures, such as for example a derivative from naphthalene, phenalene, chromen-4-one, indole or quinoline, or comprising two or more aromatic and heteroaromatic structures directly linked together (such as for example derived from biphenyl) or linked together via -X- or -((¾) -X- where X is a heteroatom, such as for example a derivative of phenylamino-phenyl or phenyoxy -phenyl, the aromatic or heteroaromatic structures being optionally mono- or poly-substituted with halogen, nitro, cyano, (1-5C) alkyl, optionally substituted with up to three halogeno-substituents, hydroxyl, 0-(l-4C) alkyl, optionally with up to three halogeno-substituents.

In a further embodiment of the invention is provided a 1, 3-dioxane having the structure:

or a racemic equimolar mixture of both, IV: wherein X is CH or N; wherein Rc is optionally a mono- or poly-substituent of the aromatic or heteroaromatic 6-membered ring (phenyl or pyridinyl) with one or more group from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z₂-R^p', wherein Z₂ is O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, wherein R^p may be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, SO₃H, OSO₃H, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example; or a 1 ,3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S, and where R^p is a progroup such as lower alkyl, ester, amide, and the like wherein the progroup R^p can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug or can be a bioisostere of COOH; and wherein Ra and Rb are independently hydrogen, 2-6C alkenyl, 1-8C alkyl, optionally with up to three halogeno-substituents, 0-(l-4C)alkyl, (3-7C)cycloalkyl and oxapoly-methylene of 2 to 4 carbon atoms, or wherein Ra and Rb together form polymethylene of 2 to 7 carbon atoms, optionally having one or two (l-4C)alkyl substituents, or an aromatic or heteroaromatic moiety, containing up to 24 C atoms and up to 6 heteroatoms, the aromatic or heteroaromatic moieties comprising fused aromatic and heteroaromatic structures, such as for example a derivative from naphthalene, phenalene, chromen-4-one, indole or quinoline, or comprising two or more aromatic and heteroaromatic structures directly linked together (such as for example a derivative from biphenyl) or linked together via -X- or -(CH₂) -X- where X is a heteroatom, such as for example a derivative of phenylamino-phenyl or phenyoxy -phenyl, the aromatic or heteroaromatic structures being optionally mono- or poly-substituted with halogen, nitro, cyano, (1-5C) alkyl, optionally substituted with up to three halogeno-substituents, hydroxyl, 0-(l-4C) alkyl, optionally with up to three halogeno-substituents; and wherein n is equal to 0, 1, 2 or 3.

In yet another embodiment of the invention is provided a 1, 3-dioxane having the structure:

or a racemic equimolar mixture of both, VII: wherein Rc is optionally a mono- or poly-substituent selected from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z₂-R^p', where Z₂ can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, where progroup R^p can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, SO₃H, OSO₃H, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example, or a 1 ,3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S, where R^p is a progroup such as lower alkyl, ester, amide, and the like, where R^p can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug, or a bioisostere of COOH; and wherein Ar is a phenyl moiety optionally mono- or poly substituted with one or more group selected individually and independently from: a linear or branched saturated or unsaturated carbon chain, containing up to 8 carbons, containing optionally up to three halogeno substituents; halogen; branched or linear (l-8C)alkoxy, (1- 4C)alkylenedioxy, cyano, nitro, hydroxyl, (2-6C)alkanoyloxy, (l-6C)alkylthio, (1- 6C)alkanesulphonyl, (l-6C)alkanoylamino and oxapoly-methylene of 2 to 4 carbon atoms.

In another embodiment, the invention provides a 1, 3-dioxane having the structure:

or a racemic equimolar mixture of both, X: wherein Rc is optionally a mono- or poly-substituent selected from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z₂-R^p', where Z₂ can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like which can be metabolized in vivo to yield the active diaryl 1, 3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, S0₃H, OSO₃H, O, N or S or an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example; or a 1,3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, and can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug, or is a bioisostere of COOH; wherein Ar is a phenyl moiety optionally mono- or poly substituted with one or more group selected individually and independently from: a linear or branched saturated or unsaturated carbon chain, containing up to 8 carbons, containing optionally up to three halogeno substituents; halogen; branched or linear (l-8C)alkoxy, (l-4C)alkylenedioxy, cyano, nitro, hydroxyl, (2-6C)alkanoyloxy, (l-6C)alkylthio, (l-6C)alkanesulphonyl, (1- 6C)alkanoylamino and oxapoly-methylene of 2 to 4 carbon atoms; wherein Z is an optional mono- or poly-substitution taken from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, or O-R where R is a lower alkyl group; and wherein X is CH₂, NH, CH₂0 or O.

In a further embodiment, the invention provides a 1, 3-dioxane having the structure:

or

or a racemic equimolar mixture of both, XIII: wherein Rc is optionally a mono- or poly-substituent selected from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z₂-R^p', where Z₂ can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, and can be metabolized in vivo to yield the active diaryl 1, 3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, SO₃H, OSO₃H, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example; or a 1, 3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S, or a bioisostere of COOH; wherein B is a fused bicyclic aromatic or heteroaromatic ring structure optionally mono- or poly substituted with one or more group selected individually and independently from: a linear or branched saturated or unsaturated carbon chain, containing up to 8 carbons, containing optionally up to three halogeno substituents; halogen; branched or linear (l-8C)alkoxy, (l-4C)alkylenedioxy, cyano, nitro, hydroxyl, (2-6C)alkanoyloxy, (l-6C)alkylthio, (l-6C)alkanesulphonyl, (l-6C)alkanoylamino and oxapoly-methylene of 2 to 4 carbon atoms, or a moiety containing a double bond O. In other embodiments, the invention provides compounds selected from:

(Z)-6-((2R,4R,5S)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4-

(Z)-6-((2R,4R,5S)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, tert-butylamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, tert-butylamine salt

(Z)-6-((2R,4R,5S)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4-

(Z)-6-((2R,4R,5S)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, tert-butylamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, tert-butylamine salt

(Z)-methyl 6-((2R,4R,5S)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)- 1 ,3-dioxan-5- yl)hex-4-enoate

(Z)-methyl 6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5- yl)hex-4-enoate

(Z)-6-((2R,4R,5S)-4-(2-acetoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4- enoic acid

and

(Z)-6-((2S,4S,5R)-4-(2-acetoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4-enoic acid

In other embodiments, the invention provides compounds selected from:

(4Z)-6-((2R,4R,5S)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-4-(2-hydroxyphenyl)-l,3- dioxan-5-yl)hex-4-enoic acid

(4Z)-6-((2S,4S,5R)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-4-(2-hydroxyphenyl)-l,3- dioxan-5-yl)hex-4-enoic acid

and

(4Z)-6-((2S,4S,5R)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-4-(2-hydroxyphenyl)-l,3- dioxan-5-yl)hex-4-enoic acid, sodium salt

In further embodiments, the invention provides compounds selected from:

(Z)-6-((2R,4R,5S)-2-(2-(4-methoxyphenoxy)phenyl)-4-(2-hydroxyphenyl)-l,3-dioxan- 5-yl)hex-4-enoic acid

and

(Z)-6-((2S,4S,5R)-2-(2-(4-methoxyphenoxy)phenyl)-4-(2-hydroxyphenyl)-l,3-dioxan- 5-yl)hex-4-enoic acid

In another embodiment, the invention provides a TP receptor antagonist selected from the group consisting of:

4-(2-(benzenesulfonamido)-ethyl)phenoxyacetic acid (CAS number 72131-33-0)

3R-[[(4-fluorophenyl)sulfonyl]amino]-l,2,3,4-tetrahydro-9H-carbazole-9-propanoic

7-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl)-7-phenylheptanoic acid (CAS

-43-7)

3- [(6R)-6-(4-Chlorobenzenesulfonamido)-2-methyl-5,6,7,8-tetrahydronaphthalen-l-yl] propanoic acid (CAS number 165538-40-9)

4-methoxy-N¹,N³-bis((pyridin-3-yl)methyl)benzene-l,3-diamide (CAS number 32828- 81-2)

and (Z)-7-[(lR,2R,3S,5S)-3-hydroxy-5-[(4-phenylphenyl)methoxy]-2-piperidin-l- ylcyclopentyl] hept-4-enoic acid hydrochloride (CAS number 87248-13-3)

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, sodium salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l ,3-dioxan-5-yl)hex-4- enoic acid, potassium salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, calcium salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l ,3-dioxan-5-yl)hex-4- enoic acid, magnesium salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hi enoic acid, ammonium salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydi xyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, lysine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, arginine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, choline salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydiOxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, diethyleneamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, dimethylaminoethanol salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, N-ethylglucamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, N-methylglucamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, 2-amino-2-hydroxymethyl-l,3-propanediol salt

(4Z)-6-((2S,4S,5R)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-4-(2-hydroxyphenyl)-l,3- dioxan-5-yl)hex-4-enoic acid, ammonium salt

(4Z)-6-((2S,4S,5R)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-4-(2-hydroxyphenyl)-l,3- dioxan-5-yl)hex-4-enoic acid, lysine salt

(4Z)-6-((2S,4S,5R)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-4-(2-hydroxyphenyl)-l, dioxan-5-yl)hex-4-enoic acid, 2-amino-2-hydroxymethyl-l,3-propanediol salt

(4Z)-6-((2S,4S,5R)-2-(6-chloro-4-oxo-4H-chromen-3-yl)-4-(2-hydroxyphenyl)-l,3- dioxan-5-yl)hex-4-enoic acid, tert-butylamine salt

(Z)-6-((2S,4S,5R)-4-(2-acetoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4-enoic acid, tert-butylamine salt

(Z)-6-((2S,4S,5R)-4-(2-acetoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4-enoic acid, sodium salt

(Z)-6-((2S,4S,5R)-4-(2-acetoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4-enoic acid, lysine salt

(Z)-6-((2S,4S,5R)-4-(2-methoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, lysine salt

(Z)-6-((2S,4S,5R)-4-(2-methoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, sodium salt

(Z)-6-((2S,4S,5R)-4-(2-methoxyphenyl)-2-(2-chlorophenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, ammonium salt

(Z)-6-((2S,4S,5R)-4-(2-methoxyphenyl)-2-(2-chlorophenyl)- l,3-dioxan-5-yl)hex-4- enoic acid, potassium salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l ,3-dioxan-5-yl)hex-4- enoic acid, calcium salt

(Z)-6-((2S,4S,5R)-2-(2-chloiOphenyl)-4-(2-methoxyphenyl)- l,3-dioxan-5-yl)hex-4- enoic acid, magnesium salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, arginine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, choline salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, diethyleneamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, dimethylaminoethanol salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, N-ethylglucamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, N-methylglucamine salt

(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-methoxyphenyl)-l,3-dioxan-5-yl)hex-4- enoic acid, 2-amino-2-hydroxymethyl-l,3-propanediol salt

In further embodiments of the invention, the TP receptor antagonist is selected from the compounds shown in Table 1.

Table 1 Analogs and Progdrugs of 1,3-dioxanes

In another embodiment of the present invention, the TP receptor agonist is a compound, or a pharmaceutically acceptable salt thereof, shown Table 2.

Table 2 TP Receptor Antagonists

Equally, in one emboment of each of the four aspects of the invention, the pathogen encompassed by the invention is a virus or a bacterium in a human or an animal and the TP receptor antagonist is the compound XVII .

In another embodiment of the invention, the pathogen encompassed by the above is any pathogen shown in Table 4. It would be evident to those skilled in the art that the beneficial results shown herein against certain pathogens would equally apply to a wild types, genetic modifications therefrom, mutations therefrom. In yet another embodiment therefore, the pathogen selected from: a wild type, a genetically modified type therefrom, or a mutation therefrom.

In a further embodiment of the invention is provided a pharmaceutical composition according to the above claims for the treatment of a virus of the family Poxviridae, for example a virus selected from the group consisting of orthopox, parapox (for example orf virus, pseudocowpox or bovine papular stomatitis virus), yatapox (for example tanapox virus or yaba monkey tumor virus) and molluscipox virusses (for example molluscum contagiosum virus (MCV). In another embodiment of the invention a pharmaceutical composition according to the above claims is provided comprising one or more of compounds XVII, XXVI, XXVII, XXI, , XXVIII, 2,3,3a,8b-tetrahydro-2-hydroxy-l-(3-hydroxy-4-methyl-l-octen-6- ynyl)-lH-cyclopenta[b]benzofuran-5-butanoic acid, monosodium salt and (2E)-3-[4- (lH-imidazol-l-ylmethyl)phenyl] acrylic acid, for the treatment of an Ebola infection.

In another embodiment of the invention a pharmaceutical composition according to the above claims is provided for the treatment a hemorrhagic fever virus.

In an embodiment of the invention, the pharmaceutical composition is provided for treatment of one of the family Arenaviridae, Filoviridae, Bunyaviridae, Togaviridae, and Flaviviridae or is selected from the group consisting of Lassa virus, viruses responsible for Argentine, Bolivian, Brazilian or Venezuelan hemorrhagic fevers, Bunvaviridae (for example Hantavirus), Crimean-Congo hemorrhagic fever (CCHF) virus, Rift Valley fever (RVF) virus, Filoviridae (for example Ebola or Marburg viruses), Flaviviridae (for example dengue virus, yellow fever virus, Omsk hemorrhagic fever virus or Kyasanur Forest disease virus) and Lujo virus. In a further embodiment of the invention is provided a pharmaceutical composition according to the above claims comprising compounds XVII and XXI for the treatment of a Rift Valley Fever infection. In a further embodiment of the invention is provided a pharmaceutical composition according to the above claims for the treatment of an Orthopox virus selected from the group consisting of variola virus, vaccinia virus, cowpox virus, monkeypox virus and smallpox, preferably Cowpox. In yet another embodiment of the invention is provided a pharmaceutical composition according to the above claims comprising one of compounds XVII, XXVII and LIII for the treatment of a Cowpox infection.

In another embodiment of the invention is provided a pharmaceutical composition according to the above claims comprising compound XXI for the treatment of a Marburg infection.

In a further embodiment of the invention is provided a pharmaceutical composition according to the above claims for the treatment of an influenza virus.

In a further embodiment of the invention is provided a pharmaceutical composition according to the above claims comprising one of compounds XVII, XXI, XXVII, XXIX, and XXX, for the treatment of where the influenza virus is an H1 1 or H3N2 influenza virus.

In a further embodiment of the invention is provided a pharmaceutical composition according to the above claims comprising compound XXVI I and XVII for the treatment of B. anthracis ox Bacillus cereus. In one embodiment, the inventive pharmaceutical composition reduces the risk of contagion in a subject that has acquired the infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more.

In another embodiment, the pharmaceutical composition of the invention reduces the risk of contagion caused by an infection in an individual at risk of acquiring that infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more. In yet another embodiment, the pharmaceutical compositions of the invention reduces the risk of mortality caused by an infection by the Ebola or Marburg virus in a subject infected by the pathogen by up to 90% or more.

In a further embodiment of the pharmaceutical composition of the invention, the treatment is prophylactic treatment of an infection by a pathogen in an individual in risk of infection by the pathogen and reduces the risk of infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more. In a further embodiment of the pharmaceutical composition of the invention, the treatment reduces the risk of morbidity by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more. In another aspect of the invention is provided a pharmaceutical composition comprising a TP receptor antagonist, wherein the composition has pharmacokinetic profile of the TP antagonist achieving rapid plasma concentrations after oral administration, achieving maximal plasma concentrations after 30 min or less, and wherein the effective plasma concentrations (EC50) should be 0.01 ng/mL up to 1 mg/mL, and wherein the effective plasma concentrations should last for 8 h or more after a single oral application. In another aspect of the invention is provided a skin graft comprising any one or more of compounds listed in Table 2 or of a structure selected from compounds I - CXXVIII, in an amount to treat, reduce or inhibit an infection at the site of the skin graft. In a further aspect of the invention is provided an anti-infective agent comprising any one or more of compounds listed in Table 2 or of a structure selected from compounds I

- CXXVIII, in an amount to treat, reduce or inhibit an infection for provision at the site of a wound, skin graft, scar tissue, internal or external surgical intervention. In another aspect of the invention is provided a method of treatment for an infection from a pathogen in a subject, the method comprising administering to the subject any one or more of compounds listed in Table 2 or of a structure selected from compounds I

- CXXVIII, in an amount sufficient to confer survival against the infection, inhibit, reduce the infection or ameliorate the clinical symptoms in the subject, or to protect the subject against the infection, wherein the pathogen is as disclosed herein.

In yet another aspect of the invention is provided a pharmaceutical composition comprising any one or more of compounds listed in Table 2 or of a structure selected from compounds I - CXXVIII for the manufacture of a medicament for treatment of infections caused by a pathogen, or to confer survival against the infection or to protect the subject against the infection, wherein the pathogen is as disclosed herein.

In a further aspect of the invention is provided a use of any one or more of compounds listed in Table 1 or of a structure selected from compounds I - CXXVIII in the treatment or prophylaxis of an infection caused by a pathogen disclosed herein in a human or animal subject in need of such treatment, comprising administering to the subject an amount of the TP -receptor antagonist sufficient to confer survival against the infection, inhibit or reduce the infection or protect against the infection. In an embodiment, is provided the use as described above in which the treatment or medicament described above is suitable for oral or parenteral administration. In another embodiment, is provided the use as described above in which the treatment or medicament described above is suitable for repeated administration.

Description of Drawings

Figure 1 shows the displacement of the TP receptor antagonist [3H]-SQ-29548 (5 nM) binding at the human TPa with compound XV. Each point is the mean of duplicate determinations. The regression line obtained using the calculated IC5₀ value is shown.

Figure 2A shows the antagonistic effects of compound XVII; filled circles (·): compound XVII is a potent antagonist of the human TP receptor expressed in human recombinant HEK-293 cells; the TP receptor was activated by the presence of U-46619 (30 nM); the regression line obtained is shown. Figure 2B shows its agonistic activity; filled circles (·): compound XVII was shown to be devoid of agonistic activity of the human TP receptor expressed in human recombinant HEK-293 cells; the TP receptor was activated by the presence of U-46619 (30 nM). Figure 3 shows antagonist effect (Figure 3 A) and lack of agonist effect (Figure

3B) of compound XVII on human umbilical artery (HUA) rings. In Figure 3A, filled circles (·) show the antagonist effect of compound XVII; concentration- response inhibition curve to compound XVII obtained on HUA rings pre- constricted with 0.1 μΜ of U-46619; means ± S.E.M. (n=6). In Figure 3B, no agonist effect of compound XVII at concentrations of 0.1 nM - 0.1 mM was observed; concentration-response contraction curves on HUA rings to compound XVII (open circles: o) and U-46619 (a reference TP receptor agonist; filled circles: ·); means ± S.E.M. (n=7).

Figure 4 shows the displacement of the PPARy receptor ligand Rosiglitazone (10 nM) binding at the human PPARy by compound XV. Each point is the mean of duplicate determinations. The regression line obtained is shown. Figure 5 shows the displacement of the TP receptor antagonist [3H]-SQ-29548 (5 nM) binding at the human TPa with compound XXVII. Each point is the mean of duplicate determinations. The regression line obtained using the calculated IC5₀ value is shown.

Figure 6A shows the antagonistic effects of compound XXVIII; filled circles (·): compound XXVIII is a potent antagonist of the human TP receptor expressed in human recombinant HEK-293 cells; the TP receptor was activated by the presence of U-46619 (30 nM); the regression line is shown. Figure 6B shows its agonistic activity; filled circles (·): compound XXVIII was shown to be devoid of agonistic activity of the human TP receptor expressed in human recombinant HEK-293 cells; the TP receptor was activated by the presence of U-46619 (30 nM).

Figure 7 shows the displacement of the PPARy receptor ligand Rosiglitazone (10 nM) binding at the human PPARy by the racemic mixture of compounds XXVI and XXVII. Each point is the mean of duplicate determinations. The regression line obtained is shown.

Figure 8A and Figure 8B show PPARy-LBD transactivation by compound XXXVI. In Figure 8A, activation versus vehicle control (relative units) is shown; bars from left to right: vehicle (DMSO), Rosiglitazone (1 μΜ), compound XXXVI at 0.1, I, and 10 μΜ. In Figure 8B, activation versus positive control (Rosiglitazone: 1 μΜ) is shown; bars from left to right: Rosiglitazone (1 μΜ), compound XXXVI at 0.1, 1, and 10 μΜ.

Figure 9 shows the increase in survival in a lethal mouse model of Ebola in animals treated with compound XVII. Filled circles (·): Vehicle. Filled triangles ( A ): compound XVII. Figure 10 shows increased in survival from 50 to 80% for compound XVII in a lethal mouse model of Ebola with higher dosage regime. Filled circles (·): Vehicle. Open circles and open triangles: compound XVII at 1 and lOmg/kg respectively.

Figure 1 1A and B, respectively, shows efficacy (survival 80%) of compound XVII, and reduction or elimination (zero titers as shown on the right side of the x- axis) of viral titers of liver and spleen in a lethal mouse model of Ebola. In Figure 1 1A, filled circles (·): vehicle; open triangles: compound XVII. In Figure 1 IB, from left to right: vehicle, compound XVII.

Figure 12 shows survival (of 50%) in animals treated with the racemic mixture of compounds XXVI and XXVII versus vehicle in a lethal mouse model of Ebola. Filled circles (·): Vehicle. Filled squares (■): compound racemic mixture of compounds XXVI and XXVII.

Figure 13 demonstrates that increased survival (75%) observed with compound XXXVI in a lethal mouse model of Ebola is via the TP mechanism of action because it is known that compound XXXVI is devoid of PPARy activity. Filled circles (·): Vehicle. Open squares (□): compound XXXVI.

Figure 14A shows survival at 60% beyond 20 days in animals treated with compound XXVIII in in the lethal mouse model of Ebola versus vehicle having no survival after 6 days; and Figure 14B shows viral liver and spleen loads at respectively, low and high dose versus vehicle. In Figure 14A, filled circles (·): vehicle; empty squares and filled squares are compound XXVIII at 1 and lOmg/kg, respectively. In each graph of Figure 14B from left to right, it is shown, vehicle and compound XXVIII at low and high dose respectively.

Figure 15 shows increase in survival with compounds XVII and XXVII evaluated in a mouse model of Cowpox. Filled circles (·): compound XXVII. Open circles (o): compound XVII. Figure 16 Figure 16 shows the increase in survival in animals treated with compound XVII evaluated in a lethal mouse model of Marburg. Filled circles (·): Vehicle. Open triangles: compound XVII.

Figures 17A, B, and C, respectively, show reduction in clinical scores, reduced lung consolidation, and reduction of lung viral titers by vehicle, compound XVII and Oseltamivir (Tamiflu™) in an influenza virus challenge in mice. In Figure 17A, filled circles (·): vehicle; open squares (□): Oseltamivir; open triangles: compound XVII; untreated animals remained healthy throughout the experiment (data not plotted). In Figure 17B, levels of lung consolidation are shown for, from left to right, vehicle, compound XVII, Oseltamivir. In Figure 17C, lung viral titers are shown for, from left to right, vehicle, vehicle no influenza virus challenge, compound XVII, and Oseltamivir.

Figure 18 shows decrease in clinical scores of mice infected with Influenza H3N2 with compound XXVII and Oseltamivir. Filled circles (·): Vehicle. Open squares (□): Oseltamivir. Open circles (o): unchallenged. Filled triangles (A): compound XVII.

Figure 19 shows reduction in lung consolidation in ferrets infected with Influenza H3N2 with compound XVII and Oseltamivir. From left to right: vehicle, compound XVII at 10 mg/kg, compound XVII at 30 mg/kg, Oseltamivir.

Figure 20 shows decrease in clinical scores in mice infected with Influenza H3N2 with compounds XXIX and XXX and Oseltamivir. Filled circles (·): Vehicle. Open squares (□): Oseltamivir. Open diamonds: racemic mixture of compounds XXIX and XXX.

Figure 21 shows reduction in lung viral titers by compound XXVII and

Oseltamivir evaluated in a mouse model of H3N2. From left to right: Vehicle, compound XXVII administered from Day - 1 , compound XXVII administered from lh post challenge, Oseltamivir administered from day -1.

Figure 22 shows efficacy of compound XXVII and Oseltamivir after challenge with Influenza H3N2, evaluated in a mouse model. Filled circles (·): Vehicle.

Open squares (□): Oseltamivir. Filled triangles (A ): compound XXVII.

Figure 23 shows lung viral titers with respect to compound XXVII and

Oseltamivir in a mouse model of H1 1 Influenza. From left to right: Vehicle, compound XXVII administered from day -1, compound XXVII administered from day 0 (lh post challenge), Oseltamivir from day -1.

Figure 24 shows survival with compound XXVII in a mouse model of Anthrax. Filled circles (·): Vehicle. Open diamonds: positive control. Filled triangles (A) and filled squares (■): compound XXVII (at 20 and lOmg/kg, respectively).

Description of the Invention

Definitions

compounds of the invention

"compounds of the invention" refers to compounds encompassed by the various descriptions and structural formulae disclosed herein. The compounds of the invention may be identified by either their chemical structure and/or their chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of the invention may contain one or more chiral centers and/or double bonds and therefore may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), rotamers, enantiomers or diastereomers. Accordingly, when stereochemistry at chiral centers is not specified, the chemical structures depicted herein encompass all possible configurations at those chiral centers including the stereoisomerically pure form (e.g. , geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, with the exception that when only one enantiomer is specified, the structure includes the other enantiomer as well. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds of the invention may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The compounds of the invention may also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶C1. compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N- oxides. In general, the hydrated, solvated and N-oxide forms are within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. Prodrug

"Prodrug" refers to a derivative of an active compound (drug) that undergoes a transformation under the conditions of use, such as within the body, to release an active drug, such being as transformed in vivo to yield a substance of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Such prodrugs are usually, but need not be,

pharmacologically inactive until converted into their active drug form. In the prodrugs of the invention, any available functional moiety may be masked with a progroup to yield a prodrug. Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a progroup (defined below) to form a promoiety or "progroup" which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug. The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, or combination thereof. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.

A wide variety of progroups suitable for masking functional groups in active compounds to yield prodrugs are well-known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vitro to provide the hydroxyl group. An amino functional group may be masked as an amide, imine, phosphinyl, phosphonyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group. A carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art. "Progroup" refers to a type of protecting group that, when used to mask a functional group within an active drug, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use. Solvates

Useful TP receptor antagonists according to the invention also include solvates of any of the aforementioned compounds. As used herein, the term "solvate" means any compound of the invention or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. The solvated forms, including hydrated forms, are equivalent to unsolvated forms and are encompassed within the scope of the present invention. As described herein above preferred TP receptor antagonists according to the invention have a specific stereochemistry as described above. It is preferred that any composition of the invention comprises a substantially enantiomeric pure compound. Accordingly, it is preferred that the TP receptor antagonists of the invention has an optical purity of at least 80%, more preferably at least 90%, even more preferably at least 95%, yet more preferably at least 98%, even more preferably at least 99%, yet more preferably at least 99.5%, yet more preferably at least 99.8%, for example at least 99.9%, such as essentially 100%, for example 100% optical purity.

Salts

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine and the like. Also included are salts of amino acids such as arginates and the like, and salts of organic acids like glucurmic or galactunoric acids and the like (see, e.g., Berge et al, 1977, J. Pharm. Sci. 66: 1-19).

The present invention demonstrates for the first time that TXA2 pathogen-triggered suppression of immune responses is a widespread mechanism, and that drugs that are TP antagonists have a role in prophylaxis and treatment of, for example, hemorrhagic fevers such as those caused by Ebola, Lassa and Marburg viruses, Influenzas, infections caused by intracellular bacterial pathogens such as Anthrax, or in any infection where the levels of thromboxane receptor agonists are raised above normal levels.

The inventors have shown using animal models of Ebola, Marburg, Cowpox, Influenza H1 1 and H3N2 and Anthrax that TP receptor antagonists are useful in reducing mortality and ameliorating symptoms in these animal models of infection. The present invention thus provides thromboxane (TP receptor) antagonists (TP receptor antagonists) as anti-infective compositions for treating pathogen induced infections. Additionally, the present TP antagonists have a role in prophylaxis and treatment of infections where the levels of thromboxane receptor agonists are raised above normal levels.

The invention also discloses a pharmaceutical composition comprising a TP receptor antagonist that is effective as an anti-infective agent in an amount lower than that needed to activate PPARy activity. The TP receptor antagonists are efficacious in treating infection when administered in an amount that is 100-1000 fold lower than the concentration (above 1 micromolar) required to trigger PPARy activity (see Examples below), providing a novel route for the treatment of infection mediated by a TP receptor antagonist that is entirely distinguishable from effects mediated by a PPARy ligand, and in addition, providing a novel route for the treatment of infection mediated by a TP receptor antagonist that is not a PPARy ligand.

The activity of such useful TP receptor antagonist-containing compositions in treating pathogenic infections is shown to be in a clearly PPARy independent manner: 1) compound XXXVI was shown to be devoid of PPARy activity yet still induced good efficacy in the Ebola lethal animal model; and 2) the results obtained with molecules previously described as PPARy ligands, show that efficacy was obtained at doses 100- 1000 lower than those needed to activate PPARy.

Therefore the invention provides a useful TP receptor antagonist that is effective as an anti-infective agent in an amount lower than that which would trigger PPARy activity, for the treatment of an infection in a subject suffering from the infection, the composition conferring survival, reduction of mortality, amelioration of clinical symptoms, or prophylaxis in the subject after administration of the composition.

The binding affinity of a TP receptor antagonist to the human TPa was evaluated in radioactive ligand competition binding studies (see Example 1 and Figure 1) in which it was shown (see Examples 2 and 3) that ligand binds almost exclusively to the TP receptor, and is a highly potent TP receptor antagonist devoid of agonistic activity (see Figures 2A and 2B, Figures 3A and 3B). It is shown in Examples 1 and 4 that data in experiment 1 and experiment 4 show that such TP receptor antagonists have up to greater than 3000-fold higher affinity for the TP receptor than for the PPARy receptor, and bind with a very high affinity to the human TPa receptor while being devoid of agonist activity (see Examples 5, 6 and Figures 5 and 6A, 6B).

The unique mode of action as an anti-infective agent demonstrated by the TP receptor antagonists of the invention, are shown to be devoid of, or unrelated to, PPARy activity (see Examples 7, 8 and Figures 7 and 8A, 8B).

Examples 9-24 demonstrate exemplary TP receptor antagonists, compounds XVII, XXVII, XXVIII, racemate of XXVI and XXVII, racemate of XXIX and XXX, and their salts, in conferring survival, reducing mortality and ameliorating symptoms in animal models of Ebola, Cowpox, Marburg, Influenza, and Anthrax infection.

Examples 9-14 demonstrates efficacy of compounds XVII, XXVI, XXVII, XXXVI and XXVIII in a lethal mouse model of Ebola, showing increased survival of up to 80%, and reduction or elimination of the virus in liver and spleen. It is important to note that in Example 13 we observed increased survival (75%) with compound XXXVI, demonstrating that in a lethal mouse model of Ebola this effectivity is via the TP mechanism of action since it is known that compound XXXVI is devoid of PPARy activity.

Example 15 shows the efficacy of compounds XVII and XXVII in a mouse model of Cowpox infection, showing increased survival. Example 16 shows the efficacy of compound XVII was evaluated in a lethal mouse model of Marburg.

Examples 17- 23 demonstrates increased survival and efficacy of, Oseltamivir

(Tamiflu™) versus compounds XVII , XXIX, XXX and XXVII in mouse models of influenza viruses H3N2 and H1 1 (see Figures 17- 23).

Example 24 demonstrates efficacy of compound XXVII in a mouse model of Anthrax to increase survival between 25 and 45% with respect to vehicle alone which showed no survival past 6 days.

Anti-infective activity has not been tested in the sense of a PK profile, however the inventor believes the pharmacokinetic profile of the TP antagonist should achieve rapid plasma concentrations after oral administration, achieving maximal plasma

concentrations after 30 min or less. Effective plasma concentrations (EC50) should be 0.01 ng/mL or higher, but not over 1 mg/mL Effective plasma concentrations should last for 8, 10 or 12 h or more after a single oral application.

The TP receptor antagonist of the present invention may be any compound capable of binding a TP receptor. In the invention, the TP receptor antagonist is capable of binding a TP receptor, thereby reducing or preferably blocking binding of an agonist to the TP receptor, and thereby reducing or blocking TP receptor signaling. The TP receptor may be the TPa receptor or TPB receptor. The TP receptor may also be a dimer of two TP receptor proteins, for example a homodimer of two TPa receptors, a homodimer of two TPB receptors or a heterodimer of a TPa receptor and a TPB receptor. In one embodiment of the invention, the TP receptor is a human TP receptor, thus the TP receptor may be the human TPa receptor or human TPB receptor. The TP receptor may also be a dimer of two TP receptor proteins, for example a homodimer of two human TPa receptors, a homodimer of two human TPB receptors or a heterodimer of a human TPa receptor and a human TPB receptor. The TP receptor may in various non-limiting embodiments be any of the following: a rat TP receptor and may also be a dimer of two TP receptor proteins, for example a dimer of two rat TP receptors; a rabbit TP receptor or a dimer of two rabbit TP receptors; a ferret TP receptor or a dimer of two ferret TP receptor proteins; a mouse TP receptor; or a dimer of two mouse TP receptors: a dog TP receptor or a dimer of two dog TP receptors; a monkey (non-human primate) TP receptor or a dimer of two monkey (non-human primate) TP receptors.

The TP receptor antagonist of the invention has an IC5₀ in respect of inhibition of binding of a ligand to the TP receptor which is sufficiently low. The IC5₀ is the concentration of drug that inhibits 50% of ligand binding. Thus, in various

embodiments of the invention, the TP receptor antagonist has an IC50 in respect of inhibition of binding of a ligand to the TP receptor of has an IC50 in respect of inhibition of binding of a ligand to the TP receptor of at most Ι μΜ, or at most 500nM, or at most 300nM, or at most ΙΟΟηΜ or at most 50nM or at most 10 nM, or at most 5 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.. The ligand may be any ligand of the TP receptor, such as the TPa receptor. The TP receptor antagonist to be used with the present invention has a Ki in relation to binding to the TP receptor. The Ki is the inhibition constant and the Ki is calculated from the IC5₀ using the Cheng-Prusoff equation: Ki=ICso/(l+([L]/KD), wherein [L] is the concentration of ligand and Kd is its dissociation constant. Thus, in one embodiment of the invention, the TP receptor antagonist has a Ki in relation to binding to TP receptor in vitro of at most ΙμΜ, or at most 500nM, or at most 300nM, or at most 100 nM, at most 50 nM, or at most 30 nM, yet more preferably at the most 10 nM or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.. In certain embodiments of the invention the ligand is a labelled ligand, such as a radio labelled ligand, which facilitates the determination of the ICso and subsequently Ki. In one embodiment the ligand is selected from the group consisting of [³H]-SQ-29548, [¹²⁵I]-PTA-0H and [³H]-(+)-S-145 and the Ki in relation to binding to TPa receptor in vitro is at most has an IC50 in respect of inhibition of binding of a ligand to the TP receptor of at most Ι μΜ, or at most 500nM, or at most 300nM, or at most ΙΟΟηΜ or at most 50nM or at most 10 nM, or at most 5 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM..

The TP receptor antagonist to be used with the present invention has a KB in respect of inhibition of TP receptor function. KB values are determined in functional studies as antagonism either of contractions induced by agonists in isolated tissues, ion fluxes, preferably calcium fluxes, in isolated or culture cells , like HEK-293 cells, or platelet aggregation induced by agonists. In one embodiment, the TP receptor antagonist to be used with the present invention has a KB in respect of inhibition of TP receptor function of at most 100 nM, or at most 50 nM, or at most 30 nM, or at most 15 nM, or at most 10 nM, or at most 10 nM, for example at most 1 nM, or at most 0.1 nM or at most 0.01 nM„ wherein the TP receptor function preferably is either induction of contractions in isolated tissues induced by a TP agonist or platelet aggregation induced by a TP agonist. The TP receptor agonist may be any TP receptor agonist.

The value A2 is generally defined as the concentration of antagonist that makes it necessary to double agonist concentration to elicit the same response. pA2 is -logA2. In one embodiment the TP receptor antagonist according to the invention has a A2 in relation to TP agonist induced contractions in isolated tissues of at the most 100 nM, or at most 50 nM, or at most 30 nM, or at most 15 nM, or at most 10 nM, or at most 10 nM, for example at most 1 nM, or at most 0.1 nM or at most 0.01 nM, In functional and binding studies for determining Ki, Kd, KB and pA2, the isolated tissues used in these studies in include, but are not limited to: human astrocytoma cell/PI, human bladder (detrusor), human bronchus, human immortalized ciliary epithelial cell/PI, human coronary artery, human corpus cavernosum, human hand vein, human internal mammary artery, human lung parenchyma, human platelet aggregation, human platelet (membrane) - binding, human pulmonary artery, human pulmonary vein, human uterine artery, human uterus (non-pregnant), human uterus (pregnant), human saphenous vein, human umbilical artery, human umbilical vein, human embryonic kidney 293 cells (HEK-293 cells), rat aorta, rat lung parenchyma, rat platelet aggregation, rat tail artery, rat trachea, guinea-pig aorta, guinea-pig basilar artery, guinea-pig lung parenchyma, guinea-pig lung strip, guinea-pig trachea, rabbit aorta, rabbit jugular vein, rabbit saphenous vein, pig coronary artery; or dog coronary artery.

Infection

The present invention relates to pathogens listed in Table 3.

Table 3 showing pathogens inducing human and animal infections

Human Diseases

Acinetobacter infections (Acinetobacter baumannii); Actinomycosis (Actinomyces israelii, Actinomyces gerencseriae, Propionibacterium propionicus); AIDS (Acquired immune deficiency syndrome); HIV (Human immunodeficiency virus); Anthrax (Bacillus anthracis); Arcanobacterium haemolyticum infection (Arcanobacterium haemolyticum); Argentine hemorrhagic fever (Junin virus); Aspergillosis (Aspergillus spp.); Astrovirus infection (Astroviridae family); Avian influenza (Influenza A viruses) Bacillus cereus infection (Bacillus cereus); Bacterial vaginosis (Gardnerella vaginalis, Lactobacillus spp., Prevotella spp., Mobiluncus spp., Bacteroides spp.,

Peptostreptococcus spp., Fusobacterium spp., Veillonella spp, Eubacterium spp., Mycoplasma hominis, Ureaplasma urealyticum, Streptococcus viridans, Atopobium vaginae); Bacteroides infection (Bacteroides spp.); BK virus infection (BK virus (human polyomavirus)), Black piedra (Piedraia hortae); Blastocystis hominis infection (Blastocystis hominis); Blastomycosis (Blastomyces dermatitidis); Bolivian

hemorrhagic fever (Machupo virus); Borrelia infection (Borrelia burgdorferi, Borrelia spp.); Brazilian hemorrhagic fever (Sabia Virus); Brucellosis (Brucella abortus, Brucella spp.); Burkholderia infection (Burkholderia cepacia, Burkholderia spp.); Buruli ulcer (Mycobacterium ulcerans); Calicivirus infection ( orovirus and Sapovirus);

Campylobacteriosis (Campylobacter jejuni, Campylobacter coli, Campylobacter spp.); Candidiasis (Candida albicans, Candida spp.); Cat-scratch disease (Bartonella henselae); Cellulitis (Group A Streptococcus spp. and Staphylococcus spp.); Chancroid

(Haemophilus ducreyi); Chickenpox (Varicella zoster virus (VZV)); Chikungunya (Chikungunya virus); Chlamydia infection (Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia spp.); Cholera (Vibrio cholera); Crimean-Congo Hemorrhagic Fever ( airovirus); Chromoblastomycosis (Fonsecaea pedrosoi, Phialophora verrucosa, Cladosporium carrionii, Fonsecaea compacta, Exophiala spp.); Clostridium difficile infection (Clostridium difficile); Coccidioidomycosis (Coccidioides immitis,

Coccidioides posadasii); Colorado tick fever (CTF) (Colorado tick fever virus (CTFV)); Common cold (Rhinoviruses, Coronaviruses); Crimean-Congo hemorrhagic fever (CCHF) (Crimean-Congo hemorrhagic fever virus); Cryptococcosis (Cryptococcus neoformans, Cryptococcus gattii); Cytomegalovirus infection (Cytomegaloviruses); Dengue fever (Dengue viruses (DEN-1, DE -2, DEN-3 and DEN-4) - Flaviviruses); Diphtheria (Corynebacterium diphtheria); Ebola hemorrhagic fever (Ebolavirus (EBOV)); Enterococcus infection (Enterococcus spp.); Enterovirus infections

(Polioviruses, Coxsackievirus (groups A and B), Echoviruses); Epidemic typhus (Rickettsia prowazekii); Erythema infectiosum (Parvovirus B 19); Exanthem subitum (Human herpesvirus 6 (HHV-6), Human herpesvirus 7 (HHV-7));

Entomophthoramycosis (Conidiobolus spp., Basidiobolus spp.); Epstein-Barr Virus Infectious Mononucleosis (Epstein-Barr Virus (EBV)); Erysipeloid (Erysipelothrix rhusiopathiae); Eumycetoma (Madurella mycetomatis, Madurella grisea, Leptosphaeria senegalensis, Leptosphaeria tompkinsii, Acremonium spp., Aspergillus nidulans, Aspergillus flavus, Cylindrocarpon cyanescens, Cylindrocarpon destructans, Fusarium spp., Neotestudina rosatii, Polycytella hominis, Polycytella boydii, Pseudoallescheria boydii, Exophiala jeans elmei, Corynespora cassicola, Curvularia spp., Phialophora verrucosa, Plenodomus auramii, Pyrenochaeta mackinnonii, Pyrenochaeta romeroi); Food poisoning by Clostridium perfringens (Clostridium perfringens); Fusobacterium infection (Fusobacterium spp.); Gas gangrene (Clostridial myonecrosis, Clostridium perfringens, Clostridium spp.); Geotrichosis (Geotrichum candidum); Glanders (Burkholderia mallei); Gonorrhea (Neisseria gonorrhoeae); Granuloma inguinale (Klebsiella granulomatis); Group A streptococcal infection (Streptococcus pyogenes); Group B streptococcal infection (Streptococcus agalactiae); Haemophilus influenzae infection (Haemophilus influenza); Hand, foot and mouth disease (HFMD) (Coxsackie A viruses and Enterovirus 71 (EV-71)); Hantavirus Pulmonary Syndrome

(Hantaviruses (Hantaan, Dobrava, Seoul, Puumala, Sin nombre virus)); Helicobacter pylori infection (Helicobacter pylori); Hemolytic -uremic syndrome (Escherichia coli 0157:H7); Hemorrhagic fever with renal syndromes (Bunyaviridae family viruses); Hendra Virus Disease (Hendra Virus); Hepatitis A (Hepatitis A Virus); Hepatitis B (Hepatitis B Virus); Hepatitis C (Hepatitis C Virus); Hepatitis D (Hepatitis D Virus); Hepatitis E (Hepatitis E Virus); Herpes simplex (Herpes simplex virus 1 and 2 (HSV-1 and HSV-2)); Histoplasmosis (Histoplasma capsulatum); Human bocavirus infection (Human bocavirus); Human ewingii ehrlichiosis (Ehrlichia ewingii); Human granulocytic anaplasmosis (Anaplasma phagocytophilum); Human metapneumovirus infection (Human metapneumovirus); Human monocytic ehrlichiosis (Ehrlichia chaffeensis); Human papillomavirus infection (Human papillomavirus); Human parainfluenza virus infection (Human parainfluenza viruses); Influenza (flu) (Influenza viruses A, B & C); Keratitis (Bacteria: Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes; fungi: Candida albicans, Candida spp.,

Aspergillus spp.; virus: human Herpes simplex virus); Kingella kingae infection (Kingella kingae); Kyasanur Forest disease (Kyasanur forest disease virus); Lassa fever (Lassa viruses); Legionellosis (Legionnaires' disease) (Legionella pneumophila);

Legionellosis (Pontiac fever) (Legionella pneumophila); Leprosy (Mycobacterium leprae, Mycobacterium lepromatosis); Leptospirosis (Leptospira interrogans);

Listeriosis (Listeria monocytogenes); Lyme disease (Lyme borreliosis) (Borrelia burgdorferi, Borrelia spp.); Lymphocytic choriomeningitis (Lymphocytic

choriomeningitis virus); Marburg hemorrhagic fever (Marburg virus); Measles (Measles virus); Melioidosis (Burkholderia pseudomallei); Meningitis (Bacteria: group B streptococci, Escherichia coli (carrying Kl), Listeria monocytogenes, Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type B,

Staphylococcus spp., Pseudomonas spp., Gram negative bacilli, Mycobacterium tuberculosis, Treponema pallidum, Borrelia burgdorferi, Mycoplasma spp.; fungi: Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Candida albicans, Blastomyces dermatitidis, Aspergillus spp.; viruses: Enteroviruses,

Arboviruses, West Nile virus, Mumps virus, human Herpes virus 1, HSV-2, HSV-3, Varicella-Zoster virus, Epstein-Barr virus, Cytomegalovirus, Lymphocytic

choriomeningitis virus, Adenovirus, Measles, HIV); Meningococcal disease (Neisseria meningitides); Microsporidiosis (Enterocytozoon bieneusi, Encephalitozoon hellem, Encephalitozoon intestinalis, Encephalitozoon cuniculi, Pleistophora spp,

Trachipleistophora hominis, Trachipleistophora anthropophthera, Nosema connori, Nosema ocularum, Brachiola vesicularum, Vittaforma corneae, Microsporidium ceylonensis, Microsporidium africanum, Brachiola algerae); Molluscum contagiosum (Molluscum contagiosum virus); Mucormycosis (Rhizopus spp., Mucor spp.,

Rhizomucor spp., Absidia spp., Apophysomyces elegans, Cunninghamella spp.,

Saksenaea vasiformis, Cokeromyces recurvatus, Syncephalastrum racemosum); Mumps (Mumps virus); Murine typhus (Rickettsia typhi); Mycoplasma pneumonia

(Mycoplasma pneumoniae); Neonatal conjunctivitis (Chlamydia trachomatis, Neisseria gonorrhoeae); Nipah Virus Disease (Nipah Virus); Nocardiosis (Nocardia asteroides, Nocardia spp.); Omsk hemorrhagic fever (Omsk hemorrhagic fever virus);

Paracoccidioidomycosis (Paracoccidioides brasiliensis); Pasteurellosis (Pasteurella multocida, Pasteurella spp.); Pelvic inflammatory disease (Chlamydia trachomatis, Neisseria gonorrhoeae, Peptococcus niger, Peptostreptococcus spp., Bacteroides spp., Mycoplasma spp., Ureaplasma spp., Escherichia coli); Pertussis (Whooping cough) (Bordetella pertussis); Plague (Yersinia pestis); Pneumococcal infection (Streptococcus pneumoniae); Pneumocystis pneumonia (Pneumocystis jirovecii); Pneumonia (Bacteria: Streptococcus pneumoniae, Streptococcus spp., Haemophilus influenzae., Moraxella catarrhalis, Legionella pneumophila, Francisella tularensis, Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas (Xanthomonas) maltophilia, Citrobacter freundii, Burkholderia cepacia, Citrobacter koseri, Enterobacter spp., Flavobacterium spp., Enterobacter cloacae, Flavobacterium meningisepticum, Enterobacter

agglomerans, Enterococcus spp.; fungi: Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Candida spp., Aspergillus spp., Mucor spp., Cryptococcus neoformans; viruses: Influenza viruses, Respiratory syncytial viruses, Adenoviruses, Parainfluenza viruses, human Metapneumovirus, Coronaviruses (SARS), Varicella-Zoster virus, Measles virus, Cytomegalovirus, Herpes simplex viruses, Hantaviruses, Swine influenza viruses); Poliomyelitis (Poliovirus); Prevotella infection (Prevotella spp.); Progressive multifocal leukoencephalopathy (JC virus); Psittacosis (Chlamydia psittaci); Q fever (Coxiella burnetii); Rabies (Rabies virus); Rat- bite fever (Streptobacillus moniliformis, Spirillum minus); Rhinosporidiosis

(Rhinosporidium seeberi); Rhinovirus infection (Rhinoviruses); Rickettsial infection (Rickettsia spp.); Rickettsialpox (Rickettsia akari); Rift Valley fever (Rift Valley fever virus); Rocky mountain spotted fever (Rickettsia rickettsia); Rotavirus infection (Rotaviruses); Rubella (Rubella virus); Sabia-associated hemorrhagic fever (Sabia virus); Salmonellosis, Typhoid and Paratyphoid fevers (Salmonella spp.); SARS (Severe Acute Respiratory Syndrome) (SARS coronavirus); Sepsis (Escherichia coli, Klebsiella pneumoniae, Pseudomonas spp., Proteus spp., Streptococcus spp.,

Enterococcus spp., Staphylococcus spp., Bacteroides fragilis, Bacteroides spp., Eubacterium spp., Clostridium spp., anaerobic Streptococcus spp. Candida albicans, Candida spp.); Shigellosis (Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei); Shingles (Herpes zoster) (Varicella zoster virus); Smallpox (Variola major, Variola minor); Sporotrichosis (Sporothrix schenckii); Staphylococcal food poisoning (Staphylococcus aureus, Staphylococcus spp.); Staphylococcal infection (Staphylococcus aureus, Staphylococcus spp.); Syphilis (Treponema pallidum); Tetanus (Lockjaw) (Clostridium tetani); Tick-borne Encephalitis (Tick-borne Encephalitis Virus); Tinea Trichophyton tonsurans, Epidermophyton floccosum, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton spp., Hortaea werneckii,

Malassezia spp.); Tuberculosis (Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium avium, Mycobacterium kansasii); Tularemia (Francisella tularensis); Ureaplasma urealyticum infection (Ureaplasma urealyticum); Venezuelan equine encephalitis (Venezuelan equine encephalitis virus); Venezuelan hemorrhagic fever (Guanarito virus); West Nile Fever (West Nile virus); White piedra (Tinea blanca) (Trichosporon beigelii); Yaws (Treponema pertenue); Yersinia pseudotuberculosis infection (Yersinia pseudotuberculosis); Yersiniosis (Yersinia enterocolitica); Yellow fever (Yellow fever virus); Zygomycosis (Mucororales; Entomophthorales)

Animal Diseases

African horse sickness (Orbivirus); African swine fever (Asfivirus); Atrophic rhinitis of the swine (Pasteurella multocida, Bordetella bronchioseptica); Aujeszky's disease (Herpes virus); Avian chlamydiosis (Chlamydophila psittaci); Avian infectious bronchitis (Coronavirus); Avian infectious laryngotracheitis (gallid Herpesvirus 1); Avian mycoplasmosis (Mycoplasma gallisepticum, Mycoplasma synoviae); Avian tuberculosis (Mycobacterium avium; Mycobacterium genavense); Bacterial kidney disease (Renibacterium salmoninarum); Bluetongue (Bluetongue virus); Border disease (Flaviviruses); Bovine anaplasmosis (Anaplasma spp.); Bovine genital

campylobacteriosis (Campylobacter fetus venerealis or Campylobacter fetus fetus); Bovine tuberculosis (Mycobacterium spp.); Bovine viral diarrhoea (Bovine viral diarrhea virus); Brucellosis in sheep (Brucella melitensis); Brucellosis (Brucella abortus, Brucella melitensis, Brucella suis); Camelpox (Orthopoxviruses);

Campylobacteriosis (Campylobacter jejuni, Campylobacter coli); Caprine

arthritis/encephalitis (CAE virus); Channel catfish virus disease (Ictalurid herpesvirus 1); Classical swine fever (Classical swine fever virus); Contagious agalactia

(Mycoplasma spp.); Contagious bovine pleuropneumonia (Mycoplasma mycoides mycoides); Contagious caprine pleuropneumonia (Mycoplasma biotype F38);

Contagious equine metritis (Taylorella equigenitalis); Crayfish plague (Aphanomyces astaci); Crimean Congo haemorrhagic fever (Crimean Congo haemorrhagic fever virus); Crustacean pathogens (Aphanomyces astaci, Intranuclear bacilliform viruses, Parvo-like viruses, Birnavirus, Reo-like virus, Toti-like virus); Dermatophilosis (Dermatophilus congolensis); Duck virus enteritis (duck Herpes virus); Duck viral hepatitis (Duck hepatitis virus); Enteric septicaemia of the catfish (Edwardsiella ictaluri); Enzootic abortion of ewes (Chlamydophila abortus); Enzootic bovine leukosis (Bovine leukosis virus); Epizootic haematopoietic necrosis (Epizootic hematopoietic necrosis virus);

Epizootic haemorrhagic disease (Arboviruses); Epizootic lymphangitis (Histoplasma capsulatum var. farciminosum); Epizootic ulcerative syndrome (Aphanomyces invadans); Equine encephalomyelitis (Eastern) (Eastern and Western equine

encephalomyelitis viruses); Equine infectious anaemia (Equine infectious anemia virus); Equine influenza (Influenza A virus); Equine rhinopneumonitis (Equid herpesvirus- 1 and -4); Equine viral arteritis (Equine arteritis virus); European foulbrood of honey bees (Melissococcus plutonius); Foot and mouth disease (Foot-and-mouth disease virus); Fowl cholera (Pasteurella multocida); Fowl pox (Avipoxvirus); Fowl typhoid

(Salmonella enterica subsp. Enterica); Glanders (Burkholderia mallei); Gyrodactylosis (Gyrodactylus salaris); Haemorrhagic septicaemia (Pasteurella multocida); Heartwater (Ehrlichia ruminantium); Hendra and Nipah virus diseases (Equine morbillivirus, Nipah virus); Highly pathogenic avian influenza and low pathogenic avian influenza (Avian Influenza virus A); Horse pox (Poxviruses); Infection with Abalone Herpes-like Virus (Abalone herpes-like virus); Infection with Batrachochytrium dendrobatidis

(Batrachochytrium dendrobatidis); Infection with ranavirus (Ranaviruses); Infection with Xenohaliotis californiensis (Xenohaliotis californiensis); Infectious bovine rhinotracheitis/infectious pustular vulvovaginitis (Bovine Herpes virus 1); Infectious bursal disease (Gumboro disease) (Birnavirus); Infectious haematopoietic necrosis (Infectious hematopoietic necrosis virus (IHNV)); Infectious hypodermal and haematopoietic necrosis (Infectious hypodermal and haematopoietic necrosis virus); Infectious myonecrosis (Infectious myonecrosis virus); Infectious salmon anaemia (Infectious salmon anemia virus); Japanese encephalitis (Japanese encephalitis virus);

Koi herpesvirus disease (Carp interstitial nephritis and gill necrosis virus); Leptospirosis (Leptospira irritans); Lumpy skin disease (Capripoxvirus bovis nodularis); Maedi-visna (Visna-Maedi-Virus); Malignant catarrhal fever (Alcelaphine Herpes Virus 1 and Ovine Herpes Virus 2); Marek's disease (Marek's disease virus); Myxomatosis (Myxoma virus); Nairobi sheep disease (Nairobi sheep disease virus); Newcastle disease

(Newcastle-Disease-Virus); Nipah virus encephalitis (Nipha Virus); Oncorhynchus masou virus disease (Salmonid herpes virus type 2); Ovine epididymitis (Brucella ovis); Ovine pulmonary adenomatosis (jaagsiekte sheep retrovirus); Paratuberculosis

(Mycobacterium avium ssp. paratuberculosis); Peste des petits ruminants (Peste des petits ruminants virus (PPRV)); Porcine reproductive and respiratory syndrome (Porcine Reproductive and Respiratory Syndrome Virus); Pullorum disease (Salmonella pullorum); Q fever (Coxiella burnetii); Rabbit haemorrhagic disease (Rabbit haemorrhagic disease virus); Rabies (rabies virus); Red sea bream iridoviral disease (Red sea bream iridovirus); Rift Valley fever (Rift Valley fever virus); Rinderpest (Rinderpest virus); Chicken salmonellosis (Salmonella enteritidis, Salmonella typhimurium); Salmonellosis (Salmonella typhimurium, Salmonella abortusovis, Salmonella spp.); Sheep pox and goat pox (Capripoxvirus); Spherical baculovirosis

(Penaeus monodon-type baculovirus); Spring viraemia of carp (Spring viremia of carp virus); Swine vesicular disease (Swine vesicular disease virus); Taura syndrome (Taura syndrome virus); Tetrahedral baculovirosis (Baculovirus penaei); Transmissible gastroenteritis (Coronaviruses); Tropilaelaps infestation of honey bees (Tropilaelaps clareae, Tropilaelaps koenigerum); Tularemia (Francisella tularensis); Turkey rhinotracheitis (Avian metapneumovirus ); Venezuelan equine encephalomyelitis (Venezuelan equine encephalitis virus); Vesicular stomatitis (Vesicular stomatitis virus); Viral encephalopathy and retinopathy (Fish encephalitis virus); Viral haemorrhagic septicaemia (Viral hemorrhagic septicemia virus); West Nile Fever (West-Nile- Virus); White spot disease (White spot syndrome virus); White tail disease (Macrobrachium rosenbergii nodavirus (primary) and extra small virus (XSV) associated); Yellow head disease (Yellow head virus); Canine parvovirus (Canine parvovirus 2); infection with Canine minute virus (Canine parvovirus 1); infection with Canine coronavirus (Canine coronavirus type IV and type II (CCoV &CRCoV));

Canine distemper (Canine distemper virus); Canine influenza (Influenza virus A);

Infectious canine hepatitis (Canine adenovirus 1); Canine herpesvirus infection (Canine herpes virus); Pseudorabies (Pseudorabies virus); Brucellosis (Brucella canis);

Leptospirosis (Leptospira canicola, Leptospira icterohaemorrhagiae, Leptospira spp.) Lyme disease (Borrelia burgdorferi); Ehrlichiosis (Ehrlichia canis); Rocky Mountain spotted fever (Rickettsia rickettsia); caninen and feline Clostridium infection

(Clostridium perfringes, Clostridium difficile. Clostridium spp.); Kennel cough (Bordetella bronchiseptica); Blastomycosis (Blastomyces dermatitidis); Histoplasmosis (Histoplasma capsulatum); Coccidioidomycosis (Coccidioides immitis); Cryptococcosis (Cryptococcus neoformans) Ringworm (Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes); Sporotrichosis (Sporothrix schenckii); Aspergillosis (Aspergillus fumigatus, Aspergillus spp.); Pythiosis (Pythium insidiosum);

Mucormycosis (Pythium spp., Mucor spp. Rhizopus spp., Absidia spp.; Rhizmucor spp.); Lagenidiosis (proposed Lagenidium caninum, Lagenidium karlingii; Lagenidium spp.); Protothecosis (Prototheca wickerhamii, Prototheca zopfii); Feline viral rhinotracheitis (Feline Herpesvirus- 1); Feline calicivirus infection (Feline calicivirus); Chlamydia felis infection (Chlamydophila felis); Feline panleukopenia (Feline

Panleucopenia virus); Feline leukemia (Feline leukemia virus); Feline

immunodeficiency virus infection (Feline immunodeficiency virus); Feline infectious peritonitis (Feline Infectious Peritonitis Virus); Feline Enteric Coronavirus infection (Feline Enteric Coronavirus); Feline Influenza (Influenza A H5 1 virus)

It is preferred that the pathogen is capable of inducing TXA₂ levels in a mammalian host cell infected by the pathogen.

In particular, the pathogen may be a virus capable of modulating (such as inducing) eicosanoid synthesis in a mammalian host cell infected by the pathogen. Thus, the pathogen may be a virus capable of inducing eicosanoid levels in dendritic cells in a mammal infected by the pathogen.

Alternatively, the pathogen may be a bacteria capable of modulating (such as inducing) eicosanoid synthesis in a mammalian host cell infected by the pathogen. Thus, the pathogen may be a bacterium capable of inducing eicosanoid levels in macrophages in a mammal infected by the bacteria.

Treatment

According to the present invention, treatment may be given either to a subject infected by the pathogen, or may be a subject at risk of acquiring such an infection. Generally, the subject is mammalian, such as a human or animal mammalian.

The treatment may be ameliorating or curative. By curative, it is intended to mean survival from the infection which otherwise in the absence of the treatment causes the subject suffering from the infection to show increasing pathology or even morbidity. In another embodiment of the invention the treatment is prophylactic treatment. Thus, the pharmaceutical compositions described herein may be prepared for prophylactic treatment of an infection by a pathogen in an individual at risk of infection by the pathogen.

In one embodiment of the invention, the pharmaceutical composition is for reducing the risk of contagion caused by the infection or in an individual at risk of acquiring an infection by the pathogen. In relation to epidemic or even pandemic infections causing a high mortality rate, even slight reductions in risk of contagion may be of major importance.

In another embodiment, the pharmaceutical composition reduces the risk of contagion in a subject that has acquired the infection by at least 5%, preferably at least 10%, preferably at least 15%, more preferably at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more.

The pharmaceutical compositions of the invention may also reduce the risk of contagion caused by an infection in an individual at risk of acquiring that infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more.

For example, when the pathogen is Ebola or Marburg virus, the pharmaceutical compositions of the invention may be for reducing the risk of contagion caused by an infection by the Ebola or Marburg virus in a subject infected by the pathogen by up to 90% or more.

Administration of the anti-infective pharmaceutical compositions according to the invention may be only once or administration may be repeated for a number of times. For example, the compositions may be given for a repeatedly with regular intervals, for example in the range of 1 to 5 times daily for in the range of 1 to 100 days, such as in the range of 1 to 50 days, for example in the range of 1 to 25 days, such as in the range of 10 to 16 days. The pharmaceutical compositions may be prepared for any suitable administration route, for example, topical, parenteral, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation. For example, the pharmaceutical compositions of the invention are prepared for oral administration or for intraperitonal administration, such as for oral administration. Similarly, the pharmaceutical compositions of the invention may or may be used at the site of a wound on or in the body, for example as a result of surgery or injury. Equally, the pharmaceutical compositions of the invention may or may be used for an internal infection at the site of a prosthesis.

Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the active compound suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.

The TP receptor antagonist of choice, alone or in combination with other suitable components, can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.

Suitable formulations for rectal administration include, for example, suppositories, which consist of the packaged TP receptor antagonist with a suppository base. Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the compound of choice with a base, including, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocarbons.

Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, by intravenous infusion, orally, topically,

intraperitoneally, intravesically or intrathecally.

The pharmaceutical composition may be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The composition can, if desired, also contain other compatible therapeutic agents, discussed in more detail, below. In therapeutic use, the TP receptor antagonists utilized in the methods of the invention may be administered to subjects at dosage levels suitable to achieve therapeutic benefit. By therapeutic benefit is meant that the administration of compound leads to a beneficial effect in the patient over time. Initial dosages suitable for administration to humans may be determined from in vitro assays or animal models. For example, an initial dosage may be formulated to achieve a serum concentration that includes the IC5₀ of the particular compound being administered, as measured in an in vitro assay. Alternatively, an initial dosage for humans may be based upon dosages found to be effective in animal models of the disease.

EXAMPLES

In the following examples, TP receptor antagonists, and in particular, compounds XVII, XXVII, XXVIII, racemate of XXVI and XXVII, racemate of XXIX and XXX and their salts thereof are described demonstrating survival, reduction of mortality and amelioration of symptoms in animal models of Ebola, Cowpox, Marburg, Influenza, and Anthrax infection.

Example 1

The binding affinity of compound XV to the human TPa was evaluated in radioactive ligand competition binding studies. The radioactively labelled TP receptor antagonist [³H]-SQ-29548 (5 nM) was incubated with compound XV (0.1, 0.3, 1, 3, and 10 nM) and membranes from HEK-293 cells expressing the human TPa receptor for 30 minutes at 25°C. Specific binding was determined to be 93% in the presence of 1 μΜ non- labelled, cold, SQ-29548 ligand, meaning that in this assay the radioactive ligand bound almost exclusively to the TP receptor. The determined IC5₀ for compound XV was 0.84 nM (see Fig. 1) and the inhibition constant (Ki), calculated using the Cheng and Prusoff equation, was 0.5 nM. In conclusion, compound XV binds with very high affinity to the human TPa receptor.

Example 2

The antagonistic effect of compound XVII (a salt form of compound XV) was then evaluated using human recombinant HEK-293 cells expressing the human TP receptor. Intracellular calcium ion flux was measured by fluorimetry. When the TP receptor was activated by the presence of U-46619 (30 nM), compound XVII dose dependency antagonized the response (Figure 2A). The IC5₀ value for compound XVII was 0.56 nM and the calculated Ki was 0.080 nM. This was further confirmed, since in these cells compound XVII (1 nM - 10 μΜ) had no agonist effect at all (Figure 2B). In conclusion, compound XVII was shown to be a highly potent TP receptor antagonist devoid of agonistic activity.

Example 3

The antagonistic effect of compound XVII was then evaluated in functional studies using isolated human umbilical artery (HUA) rings. In one series of experiments, HUA rings were pre-contracted with a submaximal concentration of U-46619 (0.1 μΜ). In the other series of experiments, concentration-response contraction curves to U-46619 (0.1 nM - 1 μΜ) (a reference TP receptor agonist) and to compound XVII (0.1 nM - 100 μΜ) were obtained in the HUA rings. When contraction was induced by activation of the TP receptor by the presence of U-46619 (0.1 μΜ), compound XVII dose dependently antagonized the contractile response. The EC5₀ value was 0.13 ± 0.03 μΜ and the calculated maximal inhibition was 92.39 ± 3.59 % (95% CI: = 85.25 % - 100 %) (Figure 3A). This was further confirmed, since in these cells compound XVII (0.1 nM - 100 μΜ) had no agonist effect at all (Figure 3B). In conclusion, compound XVII was shown to be a highly potent TP receptor antagonist devoid of agonistic activity.

Example 4

The binding affinity of compound XV to the human PPARy receptor was evaluated in radioactive ligand competition binding studies. The radioactively labelled PPARy receptor agonist [³H]-rosiglitazone (10 nM) was incubated with compound XV (0.1, 0.3, 1, 3, 10 and 30 μΜ) and membranes expressing the human PPARy receptor for 120 minutes at 4°C. Specific binding was determined in the presence of 10 μΜ non-labelled, cold, rosiglitazone ligand. The determined IC5₀ in two independent experiments were 4.9 μΜ and 12 μΜ (see Fig. 4) and the inhibition constant (Ki), calculated using the Cheng and Prusoff equation, in the range of 1800 to 4300 nM.

Example 5

The binding affinity of compound XXVII to the human TPa receptor was evaluated in radioactive ligand competition binding studies. The radioactively labelled TP receptor antagonist [³H]-SQ-29548 (5 nM) was incubated with compound XXVII (0.1, 0.3, 1, 3, and 10 nM) and membranes from HEK-293 cells expressing the human TPa receptor for 30 minutes at 25°C. Specific binding was determined to be 93% in the presence of 1 μΜ non-labelled, cold, SQ-29548 ligand, meaning that in this assay the radioactive ligand bound almost exclusively to the TP receptor. The determined IC5₀ for compound XXVII was 0.6 nM and the inhibition constant (Ki), calculated using the Cheng and

Prusoff equation, was 0.4 nM (see Fig. 5). In conclusion, compound XXVII binds with very high affinity to the human TPa receptor.

Example 6

The antagonistic effect of compound XXVII was then evaluated using human recombinant HEK-293 cells expressing the human TP receptor. Intracellular calcium ion flux was measured by fluorimetry. When the TP receptor was activated by the presence of U-46619 (30 nM), the sodium salt of compound XXVII, named compound XXVIII, dose dependently antagonized the response (Figure 6A). The IC5₀ value for compound XXVIII was 0.19 nM and the calculated Ki was 0.028 nM. This was further confirmed, since in these same cells compound XXVIII (1 nM - 10 μΜ) had no agonist effect at all (Figure 6B). In conclusion, compound XXVIII was shown to be a highly potent TP receptor antagonist devoid of agonistic activity.

Example 7

The PPARy activity of a racemic mixture of compounds XXVI and XXVII was also evaluated. The radioactively labelled PPARy receptor agonist [3H]-rosiglitazone (10 nM) was incubated a racemic mixture of compounds XXVI and XXVII (0.1, 0.3, 1, 3, 10 and 30 μΜ) and membranes expressing the human PPARy receptor for 120 minutes at 4°C. Specific binding was determined in the presence of 10 μΜ non-labelled, cold, rosiglitazone ligand. The determined IC50 was 7.4 μΜ (see Fig. 7) and the inhibition constant (Ki), calculated using the Cheng and Prusoff equation, was 2.7 μΜ. These results show that this racemic mixture binds with low affinity to the human PPARy receptor. Thus, even if all the PPARy activity was due to only to compound XXVII, it would still have a more than 1000-fold higher affinity for the TP than for the PPARy receptor. Example 8

Compound XXXVI is a commercially available reference TP receptor antagonist with published Kd values of 0.1 -2.2 nM and pA2 values of 7.5- 10. In order to demonstrate that the anti-infective effect of the TP antagonists is unrelated to any possible PPARy activity, the PPARy activation potential of this compound was evaluated. The results (Figure 8A and 8B) show that while the reference PPARy agonist Rosiglitazone (1 μΜ) caused a 50-60-fold activation over vehicle control (DMSO), the activation by 0.1, 1, and 10 μΜ of compound XXXVI was not significantly different from the vehicle control. Therefore, the reference TP receptor antagonist, compound XXXVI, did not activate PPARy-LBD transactivation.

Example 9

The efficacy of compound XVII was evaluated in a lethal mouse model of Ebola. Ten (10) female Balb/c mice per group were infected with mouse-adapted Ebola Zaire virus (1000 pfu corresponding to 3000 times the LD_5Q) via the intraperitoneal (i.p route) administration on Day 0. The animals were treated with either compound XVII or with the vehicle used to solubilise compound XVII. The latter solution was used as negative control since to date there are no known compounds able to treat Ebola. Treatment at 10 mg/kg was administered i.p. from day -1 to day 8 at every 12 hours. Figure 9 shows the increase in survival in animals treated with compound XVII.

Example 10

The efficacy of compound XVII was then evaluated in the same lethal mouse model of Ebola but using two doses and a longer administration regimen. Ten (10) female Balb/c mice per group were infected with mouse-adapted Ebola Zaire virus (1000 pfu corresponding to 3000 times the LD_5Q) via the intraperitoneal (i.p route) administration on Day 0. The animals were treated with either compound XVII or with the vehicle used to solubilise compound XVII. The latter solution was used as negative control since to date there are no known compounds able to treat Ebola. Treatment at 1 and 10 mg/kg was administered i.p. from day -1 to day 14 at every 12 hours. Figure 10 shows a further increase in survival compared with the first experiment (for the same lOmg/kg there was an increase in survival from 50 to 80%). Example 1 1

The efficacy of compound XVII was evaluated a third time in the lethal mouse model of Ebola but this time viral titers in the liver and spleen were also measured. Ten (10) female Balb/c mice per group were infected via the intraperitoneal (i.p route) with mouse-adapted Ebola Zaire virus (1000 pfu corresponding to 3000 times the LD ) administration on Day 0. The animals were treated with either compound XVII or with the vehicle used to solubilise compound XVII. The latter solution was used as negative control since to date there are no known compounds able to treat Ebola. Treatment at lOmg/kg was administered i.p. from day -1 to day 14 at 9h and 15h intervals. Figure 11 A shows that treatment with compound XVII once more gave 80% increase in survival.

Viral RNA loads in liver and spleen tissues were decreased or abolished in mice challenged with 1000 pfu (3000 x LD5₀) of Ebola virus and treated with compound XVII (Fig 11B).

Example 12

The efficacy of a racemic mixture of compounds XXVI and XXVII was evaluated in the same lethal mouse model of Ebola. Ten (10) female Balb/c mice per group were infected with mouse-adapted Ebola Zaire virus (1000 pfu corresponding to 3000 times the LF>_5o) via the intraperitoneal (i.p route) administration on Day 0. The animals were treated with either a racemic mixture of compounds XXVI and XXVII or with the vehicle used to solubilise them. The latter solution was used as negative control since to date there are no known compounds able to treat Ebola. Treatment at 30mg/kg, i.e. with 15mg/kg of each compound, was administered i.p. from day -1 to day 8 at every 12 hours. Figure 12 shows the increase in survival observed in animals treated with the racemic mixture of compounds XXVI and XXVII.

Example 13

The efficacy of compound XXXVI was also evaluated in the lethal mouse model of Ebola. Ten (10) female Balb/c mice per group were infected with mouse-adapted Ebola Zaire virus (1000 pfu corresponding to 3000 times the LD_5Q) via the intraperitoneal (i.p route) administration on Day 0. The animals were treated with either compound XXXVI or with the vehicle used to solubilise compound XXXVI. The latter solution was used as negative control since to date there are no known compounds able to treat Ebola.

Treatment at 20mg/kg was administered i.p. from day -1 to day 14 at every 12 hours. Figure 13 shows the 75% increase in survival in animals treated with compound XXXVI. It is important to note that compound XXXVI is devoid of PPARy activity and therefore this data clearly demonstrates that the increased in survival is via the TP mechanism of action.

Example 14

The efficacy of compound XXVIII was also evaluated in the lethal mouse model of Ebola. Ten (10) female Balb/c mice per group were infected via the intraperitoneal (i.p route) with mouse-adapted Ebola Zaire virus (1000 pfu corresponding to 3000 times the LD_5o) administered on Day 0. The animals were treated with either compound XXVIII or with the vehicle used to solubilise compound XXVIII. The latter solution was used as negative control since to date there are no known compounds able to treat Ebola.

Treatment at 1 and lOmg/kg was administered i.p. from day -1 to day 14 at 9h and 15h intervals. Figure 14A shows the increase in survival in animals treated with compound XXVIII.

The viral RNA loads in liver and spleen tissues were also evaluated in this experiment. In animals treated with compound XXVIII, the viral loads decreased very significantly (see Figure 14B).

Example 15

The efficacy of compounds XVII and XXVII was evaluated in a mouse model of Cowpox. Ten 10 female BALB/c mice per group were infected via the i.p route with

7

Cowpox (Brighton) virus (10 pfu/mouse corresponding to 100 LD ) administered on

Day 0. The animals were treated with either compound XVII at 20mg/kg or with compound XXVII at 6mg/kg. Treatments were administered by oral gavage (p.o.) from day -1 to day 8 at 7 and 17 hour intervals. Figure 15 shows the increase in survival in animals treated with either molecule.

Example 16

The efficacy of compound XVII was evaluated in a lethal mouse model of Marburg. Six (6) female Balb/c mice per group (5 in the vehicle group) were infected, via the i.p route, with mouse-adapted Marburg virus (lOOO pfu corresponding to 2000 times the LD_5o) administered on Day 0. The animals were treated with either compound XVII or with the vehicle used to solubilise compound XVII. Treatment at 20mg/kg was administered i.p. from day -1 to day 14 at every 12 hours. Figure 16 shows the increase in survival in animals treated with compound XVII.

Example 17

The efficacy of compound XVII was evaluated in a mouse model of Influenza H3N2. Ten (10) female BALB/c mice per group were infected with Influenza

(A/Panama/2007/99 H3N2) virus (5xl0⁶ pfu/mouse) by intranasal administration on Day 0. The animals were treated with either compound XVII (5 mg/kg), with the vehicle used to solubilise compound XVII, or with Oseltamivir (Tamiflu) (20 mg/kg) that was used as positive control. One group was left unchallenged as an additional control. Treatment was administered by oral gavage once daily from day - 1 to day 3. Clinical signs were scored according to the following system: 0: no clinical signs; 1 : slight starry coat or hunched posture; 2: starry coat plus hunched posture, and 3: starry coat plus hunched posture and laboured breathing. Figure 17A shows the reduction in clinical scores observed for left to right, vehicle, compound XVII, and Oseltamivir .

The lungs of infected mice showed signs of viral damage leading to hemorrhage, necrosis and immune cell infiltration leading to lung consolidation. Together, these changes resulted in areas of the lung acquiring plum coloration, which were scored on a semi-quantitative scale (percentage of lung affected by viral damage). Figure 17B shows the reduction in lung consolidation observed at termination, on Day 10, in animals treated with either Oseltamivir or compound XVII compared to vehicle treated animals. Lung consolidation was lower in animal treated with compound XVII than with Oseltamivir.

The viral loads in the lungs were also evaluated in this experiment. Animals from satellite groups (n=4 per group) were sacrificed on day 3 post challenge and the lung viral titre assessed by plaque assay using MDCK cells. Lung viral titre was reduced more by compound XVII treatment than by oseltamivir (Figure 17C).

Example 18

The efficacy of compound XVII, when administered after the influenza challenge, was also evaluated in the mouse model of H3N2_Influenza. Ten (10) female BALB/c mice per group were infected with Influenza (A/Panama/2007/99 H3N2) virus (5xl0⁶ pfu/mouse) by intranasal administration on Day 0. The animals were treated with either compound XVII (5 mg/kg), with the vehicle used to solubilise compound XVII, or with Oseltamivir (20 mg/kg) that was used as positive control. One group was left unchallenged as an additional control. Treatment was administered by oral gavage twice daily from day 1 after the Influenza virus challenge and continued until day 7. Clinical signs were scored according to the following system: 0: no clinical signs; 1 : slight starry coat or hunched posture; 2: starry coat plus hunched posture, and 3 : starry coat plus hunched posture and laboured breathing. Figure 18 shows the decrease in clinical scores observed.

Example 19

The efficacy of compound XVII was evaluated in a second animal model of influenza, the ferret model of H3N2_Influenza. Six (6) female Fitch ferrets per group were infected

4

with Influenza (A/Victoria/75 H3N2) virus (10 pfu/ferret) by intranasal administration on Day 0. The animals were treated with either compound XVII (10 mg/kg or 30 mg/kg), with the vehicle used to solubilise compound XVII, or with Oseltamivir (Tamiflu) (20 mg/kg) that was used as positive control. Treatment was administered by oral gavage once daily from day -1 until day 7. The lungs of infected ferrets showed signs of viral damage leading to hemorrhage, necrosis and immune cell infiltration. Together, these changes resulted in areas of the lung acquiring plum coloration, which were scored on a semi-quantitative scale. As shown in Figure 19, treatment with compound XVII decreased lung consolidation better than treatment with Oseltamivir.

Example 20

The efficacy of the racemic mixture of compounds XXIX and XXX was also evaluated in the mouse model of H3N2 Influenza. Ten (10) female BALB/c mice per group were infected with Influenza (A/Panama/2007/99 H3N2) virus (5xl0⁶ pfu/mouse) by intranasal administration on Day 0. The animals were treated with either the racemic mixture of compounds XXIX and XXX (10 mg/kg which is equivalent to 5mg/kg of each compound), with the vehicle used to solubilise the racemic mixture of compounds XXIX and XXX, or with Oseltamivir (Tamiflu) (20 mg/kg) that was used as positive control. Treatment was administered by oral gavage once daily from day - 1 to day 3. Clinical signs were scored according to the following system: 0: no clinical signs; 1 : slight starry coat or hunched posture; 2: starry coat plus hunched posture, and 3: starry coat plus hunched posture and laboured breathing. The racemic mixture of compounds XXIX and XXX decreased the clinical scores as shown in Figure 20.

Example 21

The efficacy of compound XXVII was also evaluated in a mouse model of H3N2 Influenza. Ten (10) female BALB/c mice per group were infected with Influenza

(A/Panama/2007/99 H3N2) virus (5xl0⁶ pfu/mouse) by intranasal administration on Day 0. The animals were treated with either compound XXVII (lOmg/kg), with the vehicle used to solubilise compound XXVII, or with Oseltamivir (Tamiflu) (20 mg/kg) that was used as positive control. Treatment was administered by oral gavage once daily from day -1 (prophylactic treatment) or day 0 (1 hour post viral challenge) until day 7. Figure 21 shows the decrease in lung viral titers observed with both compound XXVII when administered prophylactically or in treatment mode.

Example 22

The efficacy of compound XXVII, when administered starting 1 day after challenge with Influenza H3N2, was also evaluated in a mouse model. Ten (10) female BALB/c mice per group were infected with Influenza (A/Panama/2007/99 H3N2) virus (5xl0⁶ pfu/mouse) by intranasal administration on Day 0. The animals were treated with either compound XXVII (6mg/kg), with the vehicle used to solubilise compound XXVII, or with Oseltamivir (Tamiflu) (20 mg/kg) that was used as positive control. Treatment was administered by oral gavage once daily from day 1 post Influenza challenge until day 7. Clinical signs were scored according to the following system: 0: no clinical signs; 1 : slight starry coat or hunched posture; 2: starry coat plus hunched posture, and 3: starry coat plus hunched posture and laboured breathing. As shown in Figure 22, compound XXVII decreased clinical scores similarly well to Oseltamivir.

Example 23

The efficacy of compound XXVII was evaluated in a mouse model of a second type of influenza - the H1 1 Influenza or swine flu. Ten (10) female BALB/c mice per group were infected with Influenza (A/Puerto Rico/8/34 H1N1) virus (5xl0⁶ pfu/mouse) by intranasal administration on Day 0. The animals were treated with either compound XXVII (10 mg/kg), with the vehicle used to solubilise compound XXVII, or with Oseltamivir (20 mg/kg) that was used as positive control. Treatment was administered by oral gavage once daily from day -1 or day 0 (1 h post challenge) until day 7. The treatment with XXVII decreased the lung viral titers as efficiently as Oseltamivir (Figure 23).

Example 24

The efficacy of compound XXVII was evaluated in a mouse model of Anthrax, an intracellular bacterial pathogen. Seven (7) C57B1/6 mice per group (N=5 for negative

6

control) were infected with Bacillus anthracis (Sterne, BA34F2) (10 spores/mouse corresponding to 1 times LD_5Q) by intranasal administration on Day 0. The animals were treated with either compound XXVII (10 or 20 mg/kg), with the vehicle used to solubilise compound XXVII, or positive control. Treatment was administered by oral gavage once daily from day -1 until day 14. Figure 24 shows the increase in survival in animals treated with compound XXVII compared to vehicle treated animals.

Claims

1. A pharmaceutical composition comprising a TP receptor antagonist for

prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject after administration of the composition.

2. A pharmaceutical composition comprising a TP receptor antagonist that is

effective as an anti-infective agent for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject, wherein the the TP receptor antagonist is present in a concentration lower than that which would trigger PPARy activity.

3. A pharmaceutical composition comprising a TP receptor antagonist that is not a PPARy ligand, nor one that can trigger PPARy activity, for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject.

4. A pharmaceutical composition comprising a TP receptor antagonist for

prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject, wherein the levels of thromboxane receptor agonists in the subject are raised above normal levels.

5. The pharmaceutical composition of any of the above claims, wherein the concentration of the TP receptor antagonist is in an amount of between 0.001 nM and 100 μΜ.

6. The pharmaceutical composition of any of the above claims, wherein the

concentration of the TP receptor antagonist is not above 1 micromolar.

7. The pharmaceutical composition of any of the above claims, wherein the

concentration of the TP receptor antagonist is not above 5 micromolar.

8. The pharmaceutical composition of any of the above claims, wherein the

concentration of the TP receptor antagonist is 5-10 micromolar.

9. The pharmaceutical composition of any of the above claims, wherein the TP receptor antagonist has an IC5₀ in respect of inhibition of binding of a ligand to the TP receptor of at most ΙμΜ, or at most 500nM, or at most 300nM, or at most lOOnM or at most 50nM or at most 10 nM, or at most 5 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.

10. The pharmaceutical composition of any of the above claims, wherein the TP receptor is devoid of agonistic activity.

1 1. The pharmaceutical composition any of the above claims for stimulating

dendritic cell dependent proliferation of T-cells in a subject in need thereof.

12. The pharmaceutical composition any of the above claims, wherein the TP

receptor antagonist has a Ki in relation to binding to TP receptor in vitro of Ι μΜ, or at most 500nM, or at most 300nM, or at most 100 nM, or at most 50 nM, or at most 30 nM, or at most 10 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.

13. The pharmaceutical composition any of the above claims, wherein the TP

receptor antagonist has a Kd in respect of inhibition of TP receptor function of of ΙμΜ, or at most 500nM, or at most 300nM, or at most 100 nM, or at most 50 nM, or at most 30 nM, or at most 10 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.

14. The pharmaceutical composition any of the above claims, wherein the TP

receptor antagonist has an IC5₀ in respect of inhibition of binding of an agonist to human TPa receptor of at most 300 nM, 200 nM, 100 nM, or at most 50 nM, or at most 30 nM, or at most 10 nM, or at most 1 nM, or at most 0.5 nM or at most 0.1 nM, or at most 0.05 nM, or at most 0.01 nM.

15. The pharmaceutical composition of any of the above claims, wherein the TP receptor antagonist is selected from any of compounds I - CXXVIII, and the compounds shown in Table 1 and Table 2, including their prodrugs, salts, and compositions comprising the compounds.

16. The pharmaceutical composition any of the above claims comprising a

compound having the 1, 3-dioxane moiety, including its prodrugs, salts, compositions comprising the compound, methods and intermediates useful for synthesizing the compound, and uses and methods of using the compound, the compound having the general formula I:

wherein A is a branched or linear carbon chain of 2 to 7 carbons, each optionally containing 1 or 2 double bonds (each can be cis or trans); wherein W is COOH, OH, NH₂, S0₃H, OSO₃H, -C(0)-Z_!- R^p, where Z_x can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like wherein the progroup R^p can be metabolized in vivo to yield the active diaryl 1,3- dioxane moiety containing drug, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or N¾, for example, or a 1 ,3 dioxolane group linked through the 2 position, or a bioisostere of COOH; wherein Ar is a phenyl, or a 5 or 6 membered heterocyclic aromatic group, such as, but not limited to, 2-pyridine, 3-pyridine, thiophene, furan, wherein the aromatic or heteroaromatic group can optionally be mono- or poly-substituted with halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, or Z₂-R^p', where Z2 can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, wherein the progroup R^p can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug; and wherein Ra and Rb are independently hydrogen, 2-6C alkenyl, 1-8C alkyl, optionally with up to three halogeno-substituents, 0-(l-4C)alkyl, (3-7C)cycloalkyl and oxapoly-methylene of 2 to 4 carbon atoms, or wherein Ra and Rb together form polymethylene of 2 to 7 carbon atoms, optionally having one or two (l-4C)alkyl substituents, or an aromatic or heteroaromatic moiety, containing up to 24 C atoms and up to 6 heteroatoms, the aromatic or heteroaromatic moieties comprising fused aromatic and heteroaromatic structures, such as for example a derivative from naphthalene, phenalene, chromen-4-one, indole or quinoline, or comprising two or more aromatic and heteroaromatic structures directly linked together (such as for example derived from biphenyl) or linked together via -X- or -(CH₂) -X- where X is a heteroatom, such as for example a derivative of phenyl-amino phenyl or phenyoxy -phenyl, the aromatic or heteroaromatic structures being optionally mono- or poly-substituted with halogen, nitro, cyano, (1-5C) alkyl, optionally substituted with up to three halogeno-substituents, hydroxyl, 0-(l-4C) alkyl, optionally with up to three halogeno-substituents.

17. The pharmaceutical composition of any of the above claims, comprising a 1, 3- dioxane having the structure:

or

or a racemic equimolar mixture of both, IV: wherein X is CH or N; wherein Rc is optionally mono- or poly-substitution of the aromatic or

heteroaromatic 6-membered ring ring (phenyl or pyridinyl) with one or more groups selected from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z₂-R^p', wherein Z₂ is O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, wherein R^p may be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, SO₃H, OSO₃H, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example; or a 1,3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S, and where R^p is a progroup such as lower alkyl, ester, amide, and the like wherein the progroup R^p can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug or can be a bioisostere of COOH; and wherein Ra and Rb are independently hydrogen, 2-6C alkenyl, 1-8C alkyl, optionally with up to three halogeno-substituents, 0-(l-4C)alkyl, (3-7C)cycloalkyl and oxapoly-methylene of 2 to 4 carbon atoms, or wherein Ra and Rb together form polymethylene of 2 to 7 carbon atoms, optionally having one or two (l-4C)alkyl substituents, or an aromatic or heteroaromatic moiety, containing up to 24 C atoms and up to 6 heteroatoms, the aromatic or heteroaromatic moieties comprising fused aromatic and heteroaromatic structures, such as for example a derivative from naphthalene, phenalene, chromen-4-one, indole or quinoline, or comprising two or more aromatic and heteroaromatic structures directly linked together (such as for example a derivative from biphenyl) or linked together via -X- or -((¾) -X- where X is a heteroatom, such as for example a derivative of phenylamino phenyl or phenyoxy -phenyl, the aromatic or heteroaromatic structures being optionally mono- or poly-substituted with halogen, nitro, cyano, (1-5C) alkyl, optionally substituted with up to three halogeno-substituents, hydroxyl, 0-(l-4C) alkyl, optionally with up to three halogeno-substituents; and wherein n is equal to 0, 1 , 2 or 3.

18. The pharmaceutical composition any of the above claims, comprising a 1, 3-dioxane having the structure:

or a racemic equimolar mixture of both, VII: wherein Rc is optionally a mono- or poly-substitutuent selected from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z2-R^p', where Z2 can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, where progroup R^p can be metabolized in vivo to yield the active diaryl 1, 3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, SO₃H, OSO₃H, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example, or a 1 ,3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S, where R^p is a progroup such as lower alkyl, ester, amide, and the like, where R^p can be metabolized in vivo to yield the active diaryl 1, 3-dioxane moiety containing drug, or a bioisostere of COOH; and wherein Ar is a phenyl moiety optionally mono- or poly substituted with one or more group selected individually and independently from: a linear or branched saturated or unsaturated carbon chain, containing up to 8 carbons, containing optionally up to three halogeno substituents; halogen; branched or linear (l-8C)alkoxy, (1-

4C)alkylenedioxy, cyano, nitro, hydroxyl, (2-6C)alkanoyloxy, (l-6C)alkylthio, (1- 6C)alkanesulphonyl, (l-6C)alkanoylamino and oxapoly-methylene of 2 to 4 carbon atoms.

19. The pharmaceutical composition any of the above claims, comprising a 1, 3-dioxane having the structure:

or a racemic equimolar mixture of both, X: wherein Rc is optionally a mono- or poly-substituent selected from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z₂-R^p', where Z₂ can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like which can be metabolized in vivo to yield the active diaryl 1, 3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, S0₃H, OS0₃H, O, N or S or an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example; or a 1,3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, and can be metabolized in vivo to yield the active diaryl 1,3-dioxane moiety containing drug, or is a bioisostere of COOH; wherein Ar is a phenyl moiety optionally mono- or poly substituted with one or more group selected individually and independently from: a linear or branched saturated or unsaturated carbon chain, containing up to 8 carbons, containing optionally up to three halogeno substituents; halogen; branched or linear (l-8C)alkoxy, (l-4C)alkylenedioxy, cyano, nitro, hydroxyl, (2-6C)alkanoyloxy, (l-6C)alkylthio, (l-6C)alkanesulphonyl, (1- 6C)alkanoylamino and oxapoly-methylene of 2 to 4 carbon atoms; wherein Z is an optional mono- or poly-substitution taken from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, or O-R where R is a lower alkyl group; and wherein X is CH₂, NH, CH₂0 or O.

20. The pharmaceutical composition any of the above claims, comprising a 1, 3-dioxane having the structure:

or

or a racemic equimolar mixture of both, XIII: wherein Rc is optionally a mono- or poly-substituent selected from halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, and/or with Z₂-R^p', where Z₂ can be O, N or S and where R^p is a progroup such as lower alkyl, ester, amide, and the like, and can be metabolized in vivo to yield the active diaryl 1, 3-dioxane moiety containing drug; wherein Y is COOH, OH, NH₂, SO₃H, OSO₃H, an aromatic group such as, but not limited to, phenyl, 1- or 2-naphthyl, pyridine, furan, 2-methylpyridine, optionally substituted with COOH, OH or NH₂, for example; or a 1, 3 dioxolane group linked through the 2 position, or -C(0)-Zi-Rp, where Zi can be O, N or S, or a bioisostere of COOH; wherein B is a fused bicyclic aromatic or heteroaromatic ring structure optionally mono- or poly substituted with one or more group selected individually and independently from: a linear or branched saturated or unsaturated carbon chain, containing up to 8 carbons, containing optionally up to three halogeno substituents; halogen; branched or linear (l-8C)alkoxy, (l-4C)alkylenedioxy, cyano, nitro, hydroxyl, (2-6C)alkanoyloxy, (l-6C)alkylthio, (l-6C)alkanesulphonyl, (l-6C)alkanoylamino and oxapoly-methylene of 2 to 4 carbon atoms, or a moiety containing a double bond O.

21. The pharmaceutical composition any of the above claims, wherein the pathogen is one selected from those shown in Table 3.

22. The pharmaceutical composition any of the above claims, wherein the pathogen is a wild type, a genetically modified wild type, or a mutation of the wild type.

23. The pharmaceutical composition any of the above claims, wherein the pathogen selected from a virus of the family Poxviridae, for example a virus selected from the group consisting of orthopox, parapox (for example orf virus, pseudocowpox or bovine papular stomatitis virus), yatapox (for example tanapox virus or yaba monkey tumor virus) and molluscipox virusses (for example molluscum contagiosum virus (MCV).

24. The pharmaceutical composition any of the above claims, wherein the pathogen is capable of modulating eicosanoid levels.

25. The pharmaceutical composition of any of the above claims, wherein the

pathogen is capable of inducing eicosanoid levels.

26. The pharmaceutical composition of any of the above claims, wherein the

pathogen is capable of inducing TXA₂ levels.

27. The pharmaceutical composition of any of the above claims, wherein the

pathogen is a virus or a bacterium and the TP receptor antagonist is XVII.

28. The pharmaceutical composition any of the above claims, wherein the pathogen is one or more of the family Arenaviridae, Filoviridae, Bunyaviridae,

Togaviridae, and Flaviviridae or is selected from the group consisting of Lassa virus, viruses responsible for Argentine, Bolivian, Brazilian or Venezuelan hemorrhagic fevers, Bunvaviridae (for example Hantavirus), Crimean-Congo hemorrhagic fever (CCHF) virus, Rift Valley fever (RVF) virus, Filoviridae (for example Ebola or Marburg viruses), Flaviviridae (for example dengue virus, yellow fever virus, Omsk hemorrhagic fever virus or Kyasanur Forest disease virus) and Lujo virus.

29. The pharmaceutical composition any of the above claims, wherein the pathogen is a hemorrhagic fever virus.

30. The pharmaceutical composition any of the above claims, wherein the pathogen is Rift Valley Fever and the TP receptor antagonist is compound XVII or XXI.

31. The pharmaceutical composition any of the above claims, wherein the pathogen is an Ebola virus.

32. The pharmaceutical composition any of the above claims, wherein the pathogen is Ebola and the TP receptor antagonist comprises one or more of compounds XVII, XXVI, XXVII, XXI, , XXVIII, 2,3,3a,8b-tetrahydro-2-hydroxy-l-(3- hydroxy-4-methyl- 1 -octen-6-ynyl)- 1 H-cyclopenta[b]benzofuran-5-butanoic acid, monosodium salt and (2E)-3-[4-(lH-imidazol-l-ylmethyl)phenyl]acrylic acid.

33. The pharmaceutical composition any of the above claims, wherein treatment is for an infection induced by an Orthopox virus selected from the group consistin| of variola virus, vaccinia virus, cowpox virus, monkeypox virus and smallpox, preferably Cowpox.

34. The pharmaceutical composition any of the above claims, wherein the pathogen is Cowpox, and the TP receptor antagonist comprises one of compounds XVII, XXVII and LIII.

35. The pharmaceutical composition of any of the above claims, wherein the

pathogen is an influenza virus.

36. The pharmaceutical composition of any of the above claims, wherein the

influenza virus is an H1 1 or H3N2 influenza virus.

37. The pharmaceutical composition of any of the above claims, wherein the

pathogen is an H1 1 or H3N2 influenza virus, and the TP receptor antagonist is one of compounds XVII, XXI, XXVII, XXIX, and XXX.

38. The pharmaceutical composition of any of the above claims, wherein the pathogen is an intracellular bacterial pathogen.

39. The pharmaceutical composition of any of the above claims, wherein the

pathogen is of B. anthracis or Bacillus cereus.

40. The pharmaceutical composition of any of the above claims, wherein the

pathogen is Bacillus anthracis and the TP receptor is compound XVII or XXVII.

41. The pharmaceutical composition of any of the above claims, wherein the

pharmaceutical composition reduces the risk of contagion by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more.

42. The pharmaceutical composition of any of the above claims, wherein the

pharmaceutical composition of the invention reduces the risk of contagion caused by an infection induced by the pathogen in an individual at risk of acquiring that infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more.

43. The pharmaceutical composition of any of the above claims, wherein the

pharmaceutical composition of the invention reduces the risk of mortality caused by an infection induced by an Ebola or Marburg virus in a subject infected by the pathogen, the risk reduced by up to 90% or more.

44. The pharmaceutical composition of any of the above claims, for prophylactic treatment of an infection induced by a pathogen in a subject at risk of infection by the pathogen and reduces the risk of infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more.

45. The pharmaceutical composition of any of the above claims, for reducing the risk of morbidity by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more.

46. The pharmaceutical composition of any of the above claims, comprising a TP receptor antagonist, wherein the composition has pharmacokinetic profile of the TP antagonist achieving rapid plasma concentrations after oral administration, achieving maximal plasma concentrations after 30 min or less, and wherein the effective plasma concentrations (EC50) should be 0.01 ng/niL up to 10 mg/mL, and wherein the effective plasma concentrations should last for 4 h or more after a single oral application.

47. The pharmaceutical compositions of the above claims and uses thereof, wherein the treatment or medicament is suitable for oral or parenteral administration.

48. The pharmaceutical compositions of the above claims and uses thereof,, wherein the treatment or medicament is suitable for repeated administration.

49. A method of treating an infection induced by a pathogen listed in Table 3 for use in human or veterinary medicine, the pathogen being any one or more pathogen, the method comprising administering to a subject in need one or more of compounds I - CXXVIII, or one or more of the TP receptor antagonists selected from Tables 1 and 2, in an amount sufficient to confer survival against the infection, inhibit, reduce the infection or ameliorate clinical symptoms, or to protect against the infection, optionally with one or more pharmaceutical carriers or excipients.

50. The method of claim 45 for treating Rift Valley Fever in a subject, the method comprising administering to a subject in need an effective amount of the TP receptor antagonists compound XXI.

51. The method of claim 45 for treating Ebola in a subject, the method comprising administering to a subject in need, the method comprising administering an effective amount of one of the TP receptor antagonist compounds XXVI, XXVII, XXI, , XXVIII, 2,3,3a,8b-tetrahydro-2-hydroxy-l-(3-hydroxy-4-methyl- l-octen-6-ynyl)-lH-cyclopenta[b]benzofuran-5-butanoic acid, monosodium salt and (2E)-3-[4-(lH-imidazol-l-ylmethyl)phenyl]acrylic acid.

52. The method of claim 45 for treating Cowpox in a subject, the method

comprising administering an effective amount of one of the TP receptor antagonists compounds XXVII and LIU.

53. The method of claim 45 for treating an H1N1 or H3N2 influenza virus in a subject, the method comprising administering an effective amount of one of the TP receptor antagonists compounds XXI, XXVII, XXIX, and XXX.

54. The method of claim 45 for treating Bacillus anthracis in a subject, the method comprising administering an effective amount of the TP receptor compound XXVII.

55. A pharmaceutical composition comprising any one or more of compounds listed in Table 1 or 2, or of a structure selected from compounds I - CXXVIII for the manufacture of a medicament for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject

56. A use of any one or more of compounds listed in Table 1 or Table 2 or one of compounds I - CXXVIII for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the compound conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject.

57. A skin graft comprising any one or more of compounds listed in Table 1

one of compounds I - CXXVIII, in an amount to treat, reduce or inhibit a pathogenic infection as described herein at the site of the skin graft for use in human or veterinary medicine for the treatment or prophylaxis of conditions induced by or exacerbated by the pathogen, optionally with one or more pharmaceutical carriers or excipients.

58. An anti-infective agent comprising any one or more of compounds listed in Table 1 or 2 or one of compounds I - CXXVIII, in an amount to treat, reduce or inhibit or for prophylaxis of an infection induced by or exacerbated by the pathogen for provision at the site of a wound, skin graft, scar tissue, internal or external surgical intervention for use in human or veterinary medicine, optionally with one or more pharmaceutical carriers or excipients.