METHODS AND PHARMACEUTICAL COMPOSITIONS OF THROMBOXANE A2 RECEPTOR ANTAGONIST FOR THE TREATMENT OF COVID-19

Abstract

The present invention is related to the use of thromboxane A2 receptor antagonists (e.g., 3-[2-[[(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid (Ifetroban), or one, or a mixture of more than one pharmaceutically acceptable salts thereof) in the treatment of SARS-CoV-2 infection in humans, and pharmaceutical compositions for the same comprising thromboxane A2 receptor antagonists (e.g., ifetroban) in an effective amount to treat and/or prevent conditions resulting from such infection.

Claims

1. A method of treating COVID-19, comprising administering a therapeutically effective amount of a thromboxane A2 receptor antagonist to a patient suffering from SARS-CoV-2 infection and/or COVID-19 symptoms.

2. The method of claim 1, wherein the COVID-19 patient is treated by administering the thromboxane A2 antagonist in an outpatient, inpatient and/or convalescent phase.

3. The method of claim 2, wherein the thromboxane A2 receptor antagonist is selected from the group of 3-[2-[[(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid (Ifetroban), or one, or a mixture of more than one pharmaceutically acceptable salts thereof.

4. The method of claim 2, wherein the thromboxane A2 receptor antagonist is 3-[2-[[(1S,2R,3 S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid, monosodium salt (Ifetroban Sodium).

5. The method of claim 1, wherein the thromboxane A2 receptor antagonist is administered either orally, intranasally, by inhalation, rectally, vaginally, sublingually, buccally, parenterally, or transdermally, or any combination thereof.

6. The method of claim 2, wherein the thromboxane A2 receptor antagonist is administered prophylactically to prevent development of respiratory failure in an outpatient or inpatient stage.

7. The method of claim 2, wherein the thromboxane A2 receptor antagonist is administered to treat and prevent progression of pulmonary fibrosis in the patient.

8. The method of claim 2, wherein the therapeutically effective amount is from about 10 mg to about 1,500 mg, per day.

9. The method of claim 2, wherein the therapeutically effective amount is from about 10 mg to about 500 mg per day, and the thromboxane A2 receptor antagonist is administered parenterally.

10. The method of claim 2, wherein the therapeutically effective amount is from about 50 mg to about 1,500 mg per day, and the thromboxane A2 receptor antagonist is administered orally.

11. A method of treating pulmonary dysfunction in a human patient suffering from COVID-19, comprising chronically administering a therapeutically effective amount of a thromboxane A2 receptor antagonist to the human patient.

12. The method of claim 11, wherein the therapeutically effective amount is from about 10 mg to about 1,500 mg, per day.

13. The method of claim 11, wherein the thromboxane A2 receptor antagonist is selected from the group of 3-[2-[[(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid (Ifetroban), or one, or a mixture of more than one pharmaceutically acceptable salts thereof.

14. The method of claim 11, wherein the thromboxane A2 receptor antagonist is 3-[2-[[(1 S,2R,3 S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid, monosodium salt (Ifetroban Sodium).

15. The method of claim 13, wherein the therapeutically effective amount is from about 50 mg to about 250 mg per day, and the ifetroban is administered orally.

16. The method of claim 11, wherein the pulmonary dysfunction is pulmonary capillary hypertension.

17. The method of claim 11, wherein the pulmonary dysfunction is pulmonary edema.

18. The method of claim 11, wherein the pulmonary dysfunction is pulmonary fibrosis.

19. The method of claim 11, wherein the pulmonary dysfunction is thrombotic microangiopathy.

20. The method of claim 2, wherein the COVID-19 patient is a person less than 60 years of age, lacking a history of thrombosis, and is administered the thromboxane A2 antagonist to prevent or treat large vessel thrombotic angiopathy.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0020] In accordance with the above stated background, it is believed that administration of a therapeutically effective amount of a TP receptor antagonist to a subject(s) or patient(s) in need thereof can treat pulmonary dysfunction associated with SARS-CoV-2 infection or COVID-19. The phrase “therapeutically effective amount” refers to that amount of a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, whether the subject is fasted or fed, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0021] The TP receptor is a G protein-coupled receptor spanning membranes located in platelets, immune cells, smooth muscle, endothelial cells, fibroblasts, and cardiomyocytes, and its sustained activation may have deleterious consequences in the lungs. For example, a gain-of-function mutation in TBXA2R, the human TP receptor gene, was identified in Phenome-Wide Association Studies (PheWAS) because this mutation associated with a higher-than-normal incidence of metastatic cancers as well as pulmonary heart disease, pulmonary hypertension, primary pulmonary hypertension, and lung transplantation. (Pulley, Jerome et al. 2018, Werfel, Hicks et al. 2020)

[0022] West has shown that blockade of the TP receptor with ifetroban dramatically decreases right ventricular fibrosis and improves cardiac function in a pressure-overload model of pulmonary arterial hypertension (West, Voss et al. 2016) and in a model of Duchenne muscular dystrophy (West, Galindo et al. 2019).

[0023] In hospitalized COVID-19 patients, synthesis of TxA2, evidenced by the plasma concentration of TxB2, is strongly correlated with mortality. (Barrett, Lee et al. 2020) Critically ill patients suffering from COVID-19 may be diagnosed with adult respiratory distress syndrome (ARDS) characterized by pulmonary edema resulting from lung injury, increased lung vascular permeability, and fluid accumulation in terminal airways. However, the cardiopulmonary dynamics in COVID-19 are subtly different from typical ARDS in the following ways: “pulmonary vascular resistance of COVID-19 patients was normal, similar to that of control subjects [1.6 (1.1-2.5) vs. 1.6 (0.9-2.0) WU, P=0.343], and lower than reported in ARDS patients (P<0.01). Pulmonary hypertension was present in 76% of COVID-19 patients and in 19% of control subjects (P<0.001), and it was always post-capillary. Pulmonary artery wedge pressure was higher in COVID-19 than in ARDS patients, and inversely related to lung compliance (r=−0.46, P=0.038).” (Caravita, Baratto et al. 2020) Note that pulmonary hypertension in COVID-19 patients is post-capillary as reflected in higher pulmonary artery wedge pressure (an estimate of pulmonary capillary blood pressure) and inversely related to lung compliance—higher lung stiffness largely due to pulmonary edema. TP receptor dependent post-capillary pulmonary hypertension can result from selective pulmonary venoconstriction which raises pulmonary artery wedge pressure. (Wakerlin, Finn et al. 1995) COVID-19 post-mortem lung tissue revealed platelet aggregates obstructing the microvasculature. (Ackermann, Verleden et al. 2020) The mediator(s) responsible for lung pathology in COVID-19 patients is unknown, but increased TxA2 synthesis and resulting platelet aggregation, pulmonary venoconstriction, and increased vascular endothelial permeability are consistent with a major causative role of TxA2 and TP receptor activation.

[0024] In SARS-CoV-2 mediated lung injury, higher pulmonary capillary pressure, due to post-capillary pulmonary hypertension, can greatly exaggerate lung fluid accumulation, overwhelm lymphatic drainage of lung water, and cause pulmonary edema. Elevated TxA2 and TP receptor activation in the pulmonary circulation are known to cause pulmonary hypertension due to selective pulmonary venoconstriction (i.e., contraction of post-capillary pulmonary venules and veins) which elevates pulmonary capillary blood pressure. (Yoshimura, Tod et al. 1989) Treatment of COVID-19 with a TP receptor antagonist like ifetroban may lower elevated pulmonary capillary pressure, reduce pulmonary edema, improve lung mechanics, shorten hospital stay and improve survival. Early treatment of SARS-CoV-2 infection with ifetroban may prevent development of post-capillary pulmonary hypertension, pulmonary edema and lung stiffness.

[0025] Elevated pulmonary capillary pressure promotes lung fluid accumulation, which may be greatly exaggerated when pulmonary vascular permeability is increased. The stable TxA2 mimetic, U-46,619 (9,11-dideoxy-9α, 11α-methanoepoxy prostaglandin F2α), activates TP receptors. In preclinical studies, U-16,619 infusion strongly increased plasma fluid and protein accumulation in the lung, and this effect was completely blocked by a TP receptor antagonist, SQ29548. Smaller TP receptor dependent increases in plasma fluid and protein accumulation were seen in the heart and kidneys. The authors concluded: “The present findings demonstrate that TxA2 receptor activation acutely increased hematocrit, probably by inducing a shift of plasma fluid from the vascular compartment toward the interstitium. This hypothesis was confirmed in studies using Evans blue dye as a reliable marker of albumin extravasation; the results demonstrate the existence of organ-specific increases in microvascular shift of albumin and possibly other proteins.” (Bertolino, Valentin et al. 1995) These effects on transvascular fluid and protein flux require not only an increase in capillary blood pressure but also increases in vascular permeability.

[0026] In patients with acute lung injury, TP receptor blockade with ifetroban reduced pulmonary capillary pressure by selectively relaxing pulmonary veins and decreasing post-capillary resistance. (Schuster, Kozlowski et al. 2001) In COVID-19 patients with coronavirus-mediated lung injury, TP receptor dependent pulmonary venoconstriction will aggravate lung fluid accumulation and exaggerate pulmonary edema, and this life-threatening disease process may be improved by TP receptor blockade with ifetroban.

[0027] Lung injury provocations trigger release of TxA2, and inhibition of TxA2 synthesis or activity ameliorates many but not all these early lung injury responses (e.g., pulmonary hypertension, hypoxemia, pulmonary edema). In particular, TP receptor blockade with ifetroban (also known as SQ34451 and BMS-180291) or closely related 7-oxabicyclo[2.2.1] heptane compounds (i.e., SQ29548, SQ28668 and SQ30741) inhibited lung injury-associated pulmonary hypertension, hypoxemia, and pulmonary edema (Schumacher, Adams et al. 1987, Kuhl, Bolds et al. 1988, Klausner, Paterson et al. 1989, Sandberg, Edberg et al. 1994, Smith, Murphy et al. 1994, Thies, Corbin et al. 1996, Quinn and Slotman 1999, Collins, Blum et al. 2001, Kobayashi, Horikami et al. 2016).

[0028] COVID-19 patients exhibit shortness of breath and low arterial blood oxygen saturation due to pulmonary edema, bronchoconstriction and reduced compliance of the lung as well as mismatching of ventilation and perfusion in alveolar gas exchange units. The cause of hypoxemia in COVID-19 is complex and not completely understood. In an animal model of lung injury following bacterial infection (i.e., sepsis), TP receptor blockade with ifetroban ameliorated systemic and pulmonary vasoconstriction and significantly increased arterial and tissue oxygenation compared with septic controls. (Quinn and Slotman 1999) A similar mitigation of hypoxemia with ifetroban may be seen in COVID-19 patients.

[0029] Isoprostanes (e.g., 8-iso-PGF2α and 8-iso-PGE2) are similar in structure to prostaglandins and also activate TP receptors (Acquaviva, Vecchio et al. 2013); however, they are produced non-enzymatically, by a pathway different from PGH2 and TxA2, following attack by oxygen-derived free radicals on phospholipids containing an esterified arachidonate moiety. The free isoprostane is released from the oxidized phospholipid by phospholipase A2. Free isoprostanes are TP receptor activators produced by mechanisms independent of cyclooxygenase and TxA synthase and are, therefore, insensitive to non-steroidal anti-inflammatory drugs and TxA synthase inhibitors. Isoprostanes are of particular interest because their synthesis is triggered by oxidative stress, their TP-receptor dependent effects are blocked by ifetroban and other TP receptor antagonists, and they are released in patients with acute lung injury or ARDS. (Carpenter, Price et al. 1998; Nanji, Liong et al. 2013; West, Voss et al. 2016)

[0030] Many COVID-19 patients develop pulmonary fibrosis, especially if they survive following mechanical ventilation and intensive care. Long-term symptoms of COVID-19 are like those caused by idiopathic pulmonary fibrosis including cough, dyspnea, and fatigue. At this time, there is COVID-19 autopsy evidence of diffuse alveolar damage (DAD) progressing to fibrosis. The authors conclude, “While we observed fibrosing DAD in fatal cases, whether or not surviving patients are at risk for developing pulmonary fibrosis and the frequency of this complication will require further clinical and radiological follow-up studies.” (Li, Wu et al. 2021)

[0031] The pathogenesis of pulmonary fibrosis has been modeled and found to be triggered by generation of free isoprostanes. 8-Iso-PGF2α activates TP receptors which leads to activation of latent TGFβ, a known mediator of fibroproliferative disorders. In the bleomycin model of pulmonary fibrosis, ifetroban blocked development of fibrosis. (Suzuki, Kropski et al. 2021) In convalescent COVID-19 patients, prevention and treatment of COVID-19-related pulmonary fibrosis is expected to become a public health problem, and effective treatment will employ a clinically effective dose regimen of TP receptor antagonist, such as ifetroban.

[0032] The most recognized biological effect of TxA2 and TP receptor activation is platelet-dependent thrombosis. Ifetroban and other TP receptor antagonists block TxA2-mediated thrombosis. Chronic hypoxia in mice produced pulmonary hypertension and pulmonary intravascular thrombosis, both of which were potentiated in COX-2 knock-out mice and prevented by treatment with ifetroban. (Cathcart, Tamosiuniene et al. 2008). In patients hospitalized with COVID-19 in a large New York City health system, thrombotic events occurred in 16.0%. Among 829 COVID-19 ICU patients, 29.4% had a thrombotic event (13.6% venous and 18.6% arterial). Among 2,505 COVID-19 non-ICU patients, 11.5% had a thrombotic event (3.6% venous and 8.4% arterial). Rates of thrombotic events in patients with COVID-19 were substantially higher than with other lung injury hospitalizations (5.9% prevalence of thrombotic events during the 2009 influenza pandemic). (Bilaloglu, Aphinyanaphongs et al. 2020) In addition to platelet-mediated thrombosis, blood coagulation initiated by expression of tissue factor on endothelial cells and monocytes can be triggered by TxA2 and TP receptor activation. (Bode, Mackman 2014) Thus, strong TP receptor signaling in pulmonary venules, platelets, monocytes and endothelial cells in the SARS-CoV-2 damaged pulmonary circulation creates an unusual prothrombotic state that is mitigated by TP receptor blockade, especially with an effective dose regimen of ifetroban.

[0033] In accordance with the present invention, it is believed that increased isoprostane signaling through the TP receptor contributes to pulmonary fibrosis in COVID-19, and thus treatment with ifetroban, an orally active TP receptor antagonist, will halt the progression of pulmonary fibrosis, improve lung function tests, and enable more complete recovery from COVID-19.

[0034] The term “TP receptor antagonist” as used herein refers to a compound that inhibits the expression or activity of a TP receptor by at least or at least about 30%, 50%, 60%, 75%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% in a standard bioassay or in vivo or ex vivo when used in a therapeutically effective dose. In certain embodiments, a TP receptor antagonist inhibits binding of TxA2 to the receptor. TP receptor antagonists include competitive antagonists (i.e., antagonists that compete with an agonist for receptor occupancy) and noncompetitive antagonists. TP receptor antagonists include antibodies to the receptor. The antibodies may be monoclonal. They may be human or humanized antibodies. TP receptor antagonists may be molecules that prevent expression of the receptor with silencing RNA (i.e., siRNA) technology. TP receptor antagonists also include TxA synthase inhibitors that have both TP receptor antagonist activity and TxA synthase inhibitor activity.

[0035] TP Receptor Antagonist

[0036] The discovery and development of TP receptor antagonists has been an objective of many pharmaceutical companies for approximately 40 years. Certain individual compounds identified by these companies, either with or without concomitant TxA2 synthase inhibitory activity, include ifetroban (SQ34451; BMS-180291; Bristol-Myers Squibb), SQ29548 (BMS), SQ28668 (BMS), SQ30741 (BMS), AA-2414 (Abbott), R68070 (Janssen), BAY u 3405 (Bayer), picotamide (Sandoz), terbogrel (BI),L670596 (Merck), L655240 (Merck), ICI-192605 (Zeneca), ICI-185282 (Zeneca),ICI-159995 (Zeneca), SKF-88046 (Smith-Kline), EP-092 (U. Edinburgh), NTP-42 (ATXA), S-1452 (Shionogi), GR32191B (Glaxo), and S-18886 (Servier). Preclinical pharmacology has established that this class of compounds has effective antithrombotic activity obtained by inhibition of the prostaglandin endoperoxide and TxA2 pathway. These compounds also prevent vasoconstriction induced by TxA2 and other eicosanoids including certain isoprostanes that act on the TP receptor within vascular beds, and thus may be beneficial for use in preventing and/or treating pulmonary hypertension, fibroprolifereative disorders, hepatorenal syndrome and/or hepatic encephalopathy.

[0037] Suitable TP receptor antagonists for use in the present invention may include, for example, but are not limited to small molecules such as ifetroban {BMS; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid; or IUPAC nomenclature: 3-[2-[[(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid}, as well as others described in U.S. Patent Application Publication No. 2009/0012115, the disclosure of which is hereby incorporated by reference in its entirety.

[0038] Additional TP receptor antagonists suitable for use herein are also described in U.S. Pat. No. 4,839,384 (Ogletree); U.S. Pat. No. 5,066,480 (Ogletree, et al.); U.S. Pat. No. 5,100,889 (Misra, et al.); U.S. Pat. No. 5,312,818 (Rubin, et al.); U.S. Pat. No. 5,399,725 (Poss, et al.); and U.S. Pat. No. 6,509,348 (Ogletree), the disclosures of which are hereby incorporated by reference in their entireties.

[0039] These may include, but are not limited to: [0040] Interphenylene 7-oxabicyclo-heptyl substituted heterocyclic amide prostaglandin analogs as disclosed in U.S. Pat. No. 5,100,889, including: [0041] [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexylbutyl) amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid (SQ 33,961), or esters or salts thereof; [0042] [1S-(1α,2α,3α,4α)]-2-[[3-[4[[[(4-chloro-phenyl)-butyl] amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid or esters, or salts thereof; [0043] [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo]2.2.1 ]hept-2-yl] benzene acetic acid, or esters or salts thereof; [0044] [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexyl-butyl) amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]acetic acid, or esters or salts thereof; [0045] [1S-(1α,2α,3α,4α)]-2-[3-[4-[[(7, 7-dimethyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoic acid, or esters or salts thereof; [0046] 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs as disclosed in U.S. Pat. No. 5,100,889, issued Mar. 31, 1992, including: [0047] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(4-cyclohexylbutyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0048] [1S-(1α,2α (Z), 3α,4α)]-6-[3-4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0049] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(4-cyclohexyl-butyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0050] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[(1-pyrrolidinyl)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0051] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[(cyclohexyl-amino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexenoic acid or esters or salts thereof; [0052] 1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(2-cyclohexyl-ethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0053] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[[2-(4-chloro-phenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0054] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(4-chlorophenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0055] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[[4-(4-chloro-phenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1] hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0056] [1S-(1α,2α (Z), 3α,4α)]-6-[3-4-[[-(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters, or salts thereof; [0057] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0058] [1S-(1α,2α (Z), 3α,4α)]-6-[3[4-[(propylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0059] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(4-butylphenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0060] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo(2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0061] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-(phenylsulfonyl)-4-hexenamide; [0062] [1S-[1α,2α (Z), 3α,4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-N-(methyl sulfonyl)- 7-oxabicyclo[2-2.1]hept-2-yl]-4-hexenamide; [0063] [1S-(1α,2α (Z), 3α,4α)]-7-[3[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo(2.2.1]hept-2-yl]-5-heptenoic acid, or esters or salts thereof; [0064] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid or esters or salts thereof; [0065] [1 S-[1α,2α,3α,4α]-6-[3-[4-[[(7, 7-dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0066] [1S-(1α,2α (E), 3α,4α)]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid; [0067] 1 S-(1α,2α,3α,4α)-3-[4-[[(4-(cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptane-2-hexanoic acid or esters or salts thereof; [0068] [1S-(1α,2α (Z), 3α,4α)]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof; [0069] 7-oxabicycloheptane and 7-oxabicycloheptene compounds disclosed in U.S. Pat. No. 4,537,981 to Snitman et al, the disclosure of which is hereby incorporated by reference in its entirety, such as: [0070] [1S-(1α,2α (Z), 3α (1E,3S*,4R*),4α)]]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 29,548); [0071] the 7-oxabicycloheptane substituted aminoprostaglandin analogs disclosed in U.S. Pat. No. 4,416,896 to Nakane et al, the disclosure of which is hereby incorporated by reference in its entirety, such as: [0072] [1S-(1α,2α (Z), 3α,4α)]-7-[3-[[2-(phenylamino)carbonyl]-hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; [0073] the 7-oxabicycloheptane substituted diamide prostaglandin analogs disclosed in U.S. Pat. No. 4,663,336 to Nakane et al, the disclosure of which is hereby incorporated by reference in its entirety, such as: [0074] [1S-[1α,2α (Z), 3α,4α]]-7-[3-[[[[(1 oxoheptyl)amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid and the corresponding tetrazole, and [0075] [1S-[1α,2α (Z), 3α,4α]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)-amino]acetyl]amino]methyl]-7-oxabicyclo]2.2.1]hept-2-yl]-5-heptenoic acid; [0076] 7-oxabicycloheptane imidazole prostaglandin analogs as disclosed in U.S. Pat. No. 4,977,174, the disclosure of which is hereby incorporated by reference in its entirety, such as: [0077] [1S-[1α,2α (Z), 3α,4α]]-6-[3-[[4-(4-cyclohexyl-1-hydroxybutyl)-1 H-imidazole-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; [0078] [1S-[1α,2α (Z), 3α,4α]]-6-3-[[4-(3-cyclohexyl-propyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; [0079] [1S-[1α,2α (Z), 3α,4α]]-6-[3-[[4-cyclohexyl-1-oxobutyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; [0080] 1S-[1α,2α (Z), 3α,4α]]-6[3-(1H-imidazol-1-ylmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester; or [0081] [1S-[1α,2α (Z), 3α,4α]]-6-[3-[[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-1-yl]methyl-7-oxabicyclo-[2.2.1]-hept-2-yl]-4-hexenoic acid, or its methyl ester; [0082] The phenoxyalkyl carboxylic acids disclosed in U.S. Pat. No. 4,258,058 to Witte et al, the disclosure of which is hereby incorporated by reference in its entirety, including:

[0083] BM 13.177: 2[4-[2-(benzenesulfonamido)ethyl]phenoxy]acetic acid (sulotroban, Boehringer Mannheim);

[0084] The sulphonamidophenyl carboxylic acids disclosed in U.S. Pat. No. 4,443,477 to Witte et al, the disclosure of which is hereby incorporated by reference in its entirety, including:

[0085] BM 13.505: 2-[4-[2-[(4-chlorophenyl)sulfonylamino]ethyl]phenyl]acetic acid (daltroban, Boehringer Mannheim);

[0086] The arylthioalkylphenyl carboxylic acids disclosed in U.S. Pat. No. 4,752,616, the disclosure of which is hereby incorporated by reference in its entirety, including 4-(3-((4-chlorophenyl)sulfonyl)propyl)benzene acetic acid.

[0087] Other examples of thromboxane A2 receptor antagonists suitable for use herein include, but are not limited to: [0088] R68070: 5-[(E)-[pyridin-3-yl-[3-(trifluoromethyl)phenyl]methylidene]amino]oxypentanoic acid (ridogrel, Janssen), [0089] L670596: (—)6,8-difluoro-9-p-methylsulfonylbenzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (Merck), [0090] L655240: 3-[1-[(4-chlorophenyl)methyl]-5-fluoro-3-methyl-2-indolyl]-2,2-dimethylpropanoic acid (Merck-Frosst), [0091] ICI-192,605: 4(Z)-6-[(2,4,5-cis)2-chloropheny 1)-4-(2-hydroxyphenyl)-1,3-dioxan yl]hexenoic acid (ICI, Zeneca), [0092] ICI-185282: (Z)-7-[(2S,4S,5R)-4-(2-hydroxyphenyl)-2-(trifluoromethyl)-1,3-dioxan-5-yl]hept-5-enoic acid (ICI, Zeneca), [0093] ICI-159995: 5(Z)-7-[2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl]heptanoic acid (ICI, Zeneca), [0094] SKF-88046: N,N′-bis[7-(3-chlorobenzeneaminosulfonyl)-1,2,3,4-tetrahydro-isoquinolyl]disulfonylimide (Smith Kline), [0095] EP-092: (Z,2-endo-3-oxo)-7-(3-acetyl-2-bicyclo[2.2.1]heptyl-5-hepta-3Z-enoic acid, 4-phenyl-thiosemicarbazone (Univ. Edinburgh), [0096] AH-23848: (E)-7-[2-morpholin-4-yl-3-oxo-5-[(4-phenylphenyl)methoxy]cyclopentyl]hept-4-enoic acid (Glaxo), [0097] GR-32,191B: (Z)-7-[(1R,2R,3 S,5S)-3-hydroxy-5-[(4-phenylphenyl)methoxy]-2-piperidin-1-ylcyclopentyl]hept-4-enoic acid (vapiprost; Glaxo), [0098] BAY u 3405: 3-[[(4-fluorophenyl)-sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid; (ramatroban; Bayer), [0099] ONO-3708: ((1S,2S,3S,5R)-3-((R)-2-cyclopentyl-2-hydroxyacetamido)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)hept-5-enoic acid (ONO), [0100] S-1452: (Z)-7-[(1R,2S,3S,4S)-3-(benzenesulfonamido)-2-bicyclo[2.2.1]heptanyl]hept-5-enoic acid (domitroban, Anboxan®, Shionogi), [0101] S-18886: 3-[(6R)-6-[(4-chlorophenyl)sulfonylamino]-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoic acid (terutroban, Servier), [0102] AA-2414: 7-phenyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)heptanoic acid (seratrodast, Abbott), [0103] NTP-42: 1-tert-butyl-3-[5-cyano-2-[3-[4-(difluoromethoxy)phenyl]phenoxy]phenyl]sulfonylurea (ATXA Therapeutics), [0104] Picotamide: 4-methoxy-1-N,3-N-bis(pyridin-3-ylmethyl)benzene-1,3-dicarboxamide (Sandoz), [0105] Linotroban: 5(2-(phenylsulfonylamino)ethyl)-thienyloxy-acetic acid (Nycomed),

[0106] The preferred TP receptor antagonist of the present invention is ifetroban or any pharmaceutically acceptable salts thereof. In certain preferred embodiments the preferred TP receptor antagonist is ifetroban sodium (known chemically as 3-[2-[[(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid, monosodium salt.

[0107] Methods of Treatment

[0108] In certain embodiments of the present invention there is provided a method of treating and/or ameliorating COVID-19 in a patient or patient population by administration of a therapeutically effective amount of a TP receptor antagonist to a patient(s) in need thereof. The administration of a therapeutically effective amount of a TP receptor antagonist may be accomplished via any therapeutically useful route of administration, including but not limited to orally, intranasally, by inhalation, rectally, vaginally, sublingually, buccally, parenterally, or transdermally.

[0109] In certain preferred embodiments, the TP receptor antagonist is administered orally. In certain further embodiments, the TP receptor antagonist is administered by parenteral injection. In certain further embodiments, the TP receptor antagonist is administered by inhalation directly to the lungs. In certain preferred embodiments, the plasma concentrations of TP receptor antagonists range from about 0.1 ng/mL to about 10,000 ng/mL. Preferably, the plasma concentration of TP receptor antagonists range from about 1 ng/mL to about 1,000 ng/mL. When the TP receptor antagonist is ifetroban, the desired plasma concentration for treatment of COVID-19 in certain embodiments should be greater than about 10 ng/mL (ifetroban free acid). Some therapeutic effects of TP receptor antagonist, e.g., ifetroban, may be seen at concentrations of greater than about 1 ng/mL. The dose administered should be adjusted according to age, weight and condition of the patient, fed or fasted state, as well as the route of administration, dosage form and regimen and the desired result.

[0110] In order to obtain the desired plasma concentration of TP receptor antagonists for the treatment of COVID-19 patients, daily doses of the TP receptor antagonists preferably range from about 0.1 mg to about 5,000 mg. In certain preferred embodiments, the TP receptor antagonist is administered on a chronic basis. Daily doses may range from about 1 mg to about 1,000 mg; about 10 mg to about 1,000 mg; about 50 mg to about 250 mg; about 100 mg to about 500 mg; about 200 mg to about 500 mg; about 300 mg to about 500 mg; or from about 400 mg to about 500 mg per day. In certain preferred embodiments where the animal is a human patient, the therapeutically effective amount is from about 50 mg to about 2,000 mg per day, or from about 10 mg to 250 mg per day, or from about 200 mg to about 1,000 mg per day, and certain embodiments more preferably from about 50 to about 500 mg per day, or from about 100 mg to about 500 mg per day.

[0111] The daily dose may be administered in divided doses or in one bolus or unit dose or in multiple dosages administered concurrently. In this regard, the ifetroban may be administered orally, intranasally, by inhalation, rectally, vaginally, sublingually, buccally, parenterally, or transdermally. In certain preferred embodiments, the pharmaceutical composition described above, the therapeutically effective amount is from about 10 mg to about 300 mg ifetroban (or a pharmaceutically acceptable salt thereof) per day. In certain preferred embodiments, the therapeutically effective amount is from about 50 to about 250 mg per day, and in certain embodiments from about 150 mg to about 350 mg per day will produce therapeutically effective plasma levels of ifetroban free acid for the treatment COVID-19. In certain preferred embodiments, a daily dose of ifetroban sodium from about 10 mg to about 250 mg (ifetroban free acid amounts) will produce therapeutically effective plasma levels of ifetroban free acid for the treatment of COVID-19.

[0112] Preferably, the therapeutically effective plasma concentration of TP receptor antagonists ranges from about 1 ng/mL to about 1,000 ng/mL for the treatment of COVID-19. When the TP receptor antagonist is ifetroban, the desired plasma concentration for providing an inhibitory effect versus TP receptor activation, and thus a reduction of platelet activation should be greater than about 10 ng/mL (ifetroban free acid). Some inhibitory effects of TP receptor antagonist, e.g., ifetroban, may be seen at concentrations of greater than about 1 ng/mL.

[0113] The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result. However, in order to obtain the desired plasma concentration of TP receptor antagonists, daily doses of the TP receptor antagonists ranging from about 1 mg to about 5000 mg should be administered. Preferably, the daily dose of TP receptor antagonists ranges from about 1 mg to about 1000 mg; about 10 mg to about 1000 mg; about 50 mg to about 500 mg; about 100 mg to about 500 mg; about 200 mg to about 500 mg; about 300 mg to about 500 mg; and about 400 mg to about 500 mg per day. In certain preferred embodiments, a daily dose of ifetroban sodium from about 10 mg to about 250 mg (ifetroban free acid amounts) will produce effective plasma levels of ifetroban free acid.

[0114] Pharmaceutical Compositions

[0115] The TP receptor antagonists of the present invention may be administered by any pharmaceutically effective route. For example, the TP receptor antagonists may be formulated in a manner such that they can be administered orally, intranasally, by inhalation, rectally, vaginally, sublingually, buccally, parenterally, or transdermally, and, thus, be formulated accordingly.

[0116] In certain embodiments, the TP receptor antagonists may be formulated in a pharmaceutically acceptable oral dosage form. Oral dosage forms may include, but are not limited to, oral solid dosage forms and oral liquid dosage forms. Oral solid dosage forms may include, but are not limited to, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres and any combinations thereof. These oral solid dosage forms may be formulated as immediate release, controlled release, sustained (extended) release or modified release formulations. The oral solid dosage forms of the present invention may also contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.

[0117] Depending on the desired release profile, the oral solid dosage forms of the present invention may contain a suitable amount of controlled-release agents, extended-release agents, or modified-release agents.

[0118] Oral liquid dosage forms include, but are not limited to, solutions, emulsions, suspensions, and syrups. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms. For example, water, glycerin, simple syrup, alcohol and combinations thereof. In certain embodiments of the present invention, the TP receptor antagonists may be formulated into a dosage form suitable for parenteral use. For example, the dosage form may be a lyophilized powder, a solution, suspension (e.g., depot suspension). In other embodiments, the TP receptor antagonists may be formulated into a topical dosage form such as, but not limited to, a patch, a gel, a paste, a cream, an emulsion, liniment, balm, lotion, and ointment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0119] The following examples are not meant to be limiting and represent certain embodiments of the present invention.

Example I

[0120] In this example, ifetroban sodium tablets are prepared with the following ingredients listed in Table 1:

TABLE-US-00001 TABLE 1 Ingredients Percent by weight Na salt of Ifetroban 35 Mannitol 50 Microcrystalline Cellulose 8.0 Crospovidone 3.0 Magnesium Oxide 2.0 Magnesium Stearate 1.5 Colloidal Silica 0.3

[0121] The sodium salt of ifetroban, magnesium oxide, mannitol, microcrystalline cellulose, and crospovidone is mixed together for about 2 to about 10 minutes employing a suitable mixer. The resulting mixture is passed through a #12 to #40 mesh size screen. Thereafter, magnesium stearate and colloidal silica are added and mixing is continued for about 1 to about 3 minutes. The resulting homogeneous mixture is then compressed into tablets each containing 35 mg, ifetroban sodium salt.

Example II

[0122] In this example, 1,000 tablets each containing 400 mg of Ifetroban sodium are produced from the following ingredients listed in Table 2:

TABLE-US-00002 TABLE 2 Ingredients Amount Na salt of Ifetroban 400 gm Corn Starch 50 g Gelatin 7.5 g Microcrystalline Cellulose (Avicel) 25 g Magnesium Stearate 2.5 g

Example III

[0123] An injectable solution of ifetroban sodium is prepared for intravenous use with the following ingredients listed in Table 3:

TABLE-US-00003 TABLE 3 Ingredients Amount Ifetroban Sodium 2500 mg Methyl Paraben 5 mg Propyl Paraben 1 mg Sodium Chloride 25,000 mg Water for injection, q.s. 5 liters

[0124] The sodium salt of ifetroban, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are then closed with pre-sterilized rubber closures. Each vial contains a concentration of 75 mg of active ingredient per 150 mL of solution.

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[0167] While the present invention has been described in its preferred embodiments, it is to be understood that the words which have been used are words of description rather than of limitation and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the invention in its broader aspects. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the spirit of the invention. The inventor further requires that the scope accorded their claims be in accordance with the broadest possible construction available under the law as it exists on the date of filing hereof (and of the application from which this application obtains priority, if any) and that no narrowing of the scope of the appended claims be allowed due to subsequent changes in the law, as such a narrowing would constitute an ex post facto adjudication, and a taking without due process or just compensation.