Lipids that reduce lung damage, improve lung function, and lower pro-inflammatory cytokines.

Abstract

A method of treating a disease or condition caused by elevated levels of inflammatory cytokines, comprising administering to a subject a compound of formula (I), wherein R 1 is C1-C 20 R is a branched or unbranched hydrocarbon; 3 is (II); R 4 is H or a pharma- ceutically acceptable cation; R 5 is a C1-C substituted or unsubstituted group; 10 R is a branched or unbranched hydrocarbon; 6 is optionally substituted C1-C 10 R is a branched or unbranched hydrocarbon; 7 is C0-C 20 R is a branched or unbranched hydrocarbon; 8 is H or C0-C 20 X is a direct bond, CH2, O, or NH; Y is a direct bond, CH2, O, or NH; and each asymmetric center is independently R, S, or racemic. [Formula 1] JPEG2024505225000044.jpg6689 [Case 2] JPEG2024505225000045.jpg57130

Description

[Technical Field]

[0001] Cross-reference of related applications This PCT international application claims priority to U.S. Provisional Patent Application No. 63 / 143,511, filed on 29 January 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention generally relates to compositions and methods for reducing pro-inflammatory cytokines, and to the field of treatment for disease symptoms caused by pro-inflammatory cytokines, including lung injury, pulmonary dysfunction, and / or acute respiratory distress syndrome (ARDS).

[0003] Specification of research funded by the federal government none. [Background technology]

[0004] Many medical conditions and states involve pro-inflammatory cytokines, such as sepsis, Alzheimer's disease, traumatic brain injury, Ebola, arthritis, and other situations where reducing pro-inflammatory cytokines may be beneficial. While not limiting the scope of this invention, its background is explained in relation to acute respiratory distress syndrome (ARDS).

[0005] One example of a disease involving pro-inflammatory cytokines is acute respiratory distress syndrome (ARDS), a highly fatal, violent inflammatory process in the lungs characterized by severe hypoxemia following acute lung injury. The etiologies of ARDS include sepsis, pneumonia, acute pancreatitis, inhalation of chemicals or fumes, aspiration of gastric contents, traumatic shock, chemotherapy toxicity, or viral diseases, such as COVID-19 (Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. NEJM. 2017 Aug 10;377(6):562-72, Dushianthan A, Grocott MP, Postle AD, Cusack R. Acute respiratory distress syndrome and acute lung injury. PMJ. 2011 Sep 1;87(1031):612-22, Confalonieri M, Salton F, Fabiano F. Acute respiratory distress syndrome. ERR. 2017 Jun 30;26(144):160116, Kirch C, Blot F, Fizazi K, Raynard B, Theodore C, Nitenberg G. Acute respiratory distress syndrome after chemotherapy for lung metastases from non-seminomatous germ-cell tumors. SCC. 2003 Sep 1;11(9):575-80, Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med.(2020 Apr 1;8(4):420-2, Grasselli G, Tonetti T, Protti A, Langer T, Girardis M, Bellani G, Laffey J, Carrafiello G, Carsana L, Rizzuto C, Zanella A. Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study. Lancet Respir Med. 2020 Dec 1;8(12):1201-8). Hypoxemia secondary to cardiogenic pulmonary edema is excluded from the diagnosis of ARDS. In patients with ARDS, lung damage may begin several hours or days after the initial injury, accompanied by alveolar damage and extensive edema in the lungs, which are revealed by diffuse infiltration on chest radiographs. After 7-10 days, lung damage may progress to fibrosis (Spadaro S, Park M, Turrini C, Tunstall T, Thwaites R, Mauri T, Ragazzi R, Ruggeri P, Hansel TT, Caramori G, Volta CA. Biomarkers for acute respiratory distress syndrome and prospects for personalized medicine. J Inflamm. 2019 Dec 1;16(1):1, Ware LB, Matthay MA. The acute respiratory distress syndrome. NEJM. 2000 May 4;342(18):1334-49). In patients with ARDS lung injury, the PaO2 / FiO2 ratio (arterial oxygen partial pressure / inspired oxygen fraction), which indicates the degree to which the patients' lungs can take in oxygen, is decreased. P. A A decrease in the O2 / FiO2 value indicates worsening lung damage.

[0006] An increase in neutrophils is prominently observed in bronchoalveolar lavage fluid (BALF) from ARDS patients, and these cells are important for the progression of the disease (Juss JK, House D, Amour A, Begg M, Herre J, Storisteanu DM, Hoenderdos K, Bradley G, Lennon M, Summers C, Hessel EM. Acute respiratory distress syndrome neutrophils have a distinct phenotype and are resistant to phosphoinositide 3-kinase inhibition. Am J Respir Crit Care Med. 2016 Oct 15;194(8):961-73; Matute-Bello G, Liles WC, RADELLA F, Steinberg KP, Ruzinski JT, Jonas M, Chi EY, Hudson LD, Martin TR. Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med.) 1997 Dec 1;156(6):1969-77, Windsor AC, Mullen PG, Fowler AA, Sugerman HJ. Role of the neutrophil in adult respiratory distress syndrome. BJS. 1993 Jan;80(1):10-7).Neutrophil levels and neutrophil-to-lymphocyte ratios are prognostic indicators in this patient (Wang Y, Ju M, Chen C, Yang D, Hou D, Tang X, Zhu X, Zhang D, Wang L, Ji S, Jiang J. Neutrophil-to-lymphocyte ratio as a prognostic marker in acute respiratory distress syndrome patients: a retrospective study. J Thorac Dis. 2018 Jan;10(1):273, Ma A, Cheng J, Yang J, Dong M, Liao X, Kang Y. Neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ARDS in severe COVID-19 patients. Crit Care. 2020 Dec;24(1):1-4), and neutrophil deficiency in animal models may partially reduce lung injury (Williams AE, Chambers RC. The mercurial nature of neutrophils: still an enigma in ARDS?. Am J Physiol Lung Cell Mol. 2014 Feb 1;306(3):L217-30). Neutrophils that migrate to the lungs in response to pneumonia trigger the release of pro-inflammatory cytokines. This leads to an inflammatory cascade and increased lung damage (Scott BN, Kubes P. Death to the neutrophil! A resolution for acute respiratory distress syndrome?. Eur Respir J. 2018;52:1801274, Yang SC, Tsai YF, Pan YL, Hwang TL. Understanding the role of neutrophils in acute respiratory distress syndrome. Biomed J. 2020 Sep 10).Neutrophils are known to stimulate the secretion of interleukins (IL), in particular, and this is known to correlate with the severity of ARDS lung injury (Rebetz J, Semple JW, Kapur R. The pathogenic involvement of neutrophils in acute respiratory distress syndrome and transfusion-related acute lung injury. Transfus Med Hemother. 2018;45(5):290-8). The secreted cytokines then replenish the lungs with additional neutrophils (Chen K, Kolls JK. Innate Lymphoid Cells and Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2016 Feb 15;193(4):350-2). In a recent review (September 2020), Yang et al. reported that prominent cytokines, such as interleukins, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and granulocyte colony-stimulating factor (G-CSF), are significantly increased in the lungs (Yang SC, Tsai YF, Pan YL, Hwang TL. Understanding the role of neutrophils in acute respiratory distress syndrome. Biomed J. 2020 Sep 10).Others have also reported that these cytokines are particularly important in causing severe inflammation and serious illness (Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A. Inflammatory cytokines in the BAL of patients with ARDS: persistent elevation over time predicts poor outcome. Chest. 1995 Nov 1;108(5):1303-14, Preira P, Forel JM, Robert P, Negre P, Biarnes-Pelicot M, Xeridat F, Bongrand P, Papazian L, Theodoly O. The leukocyte-stiffening property of plasma in early acute respiratory distress syndrome (ARDS) revealed by a microfluidic single-cell study: the role of cytokines and protection with antibodies. Crit Care. 2015 Dec 1;20(1):8, Wilson JG, Simpson LJ, Ferreira AM, Rustagi A, Roque J, Asuni A, Ranganath T, Grant PM, Subramanian A, Rosenberg-Hasson Y, Maecker HT. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. MedRxiv. 2020 Jan 1). This data in patients has been confirmed in various animal models.For example, in a mouse ARDS model, IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17, vascular endothelial growth factor (VEGF), INF-γ, monocyte chemoattract protein-1 (MCP-1, CCL-2), keratinocyte-derived chemokine (KC, CXCL-1), macrophage inflammatory protein-1α (MIP-1α, CCL-3), and interferon gamma-induced protein 10 (IP-10, CXCL-10) all showed significant increases after 18 hours (Juskewitch JE, Knudsen BE, Platt JL, Nath KA, Knutson KL, Brunn GJ, Grande JP). LPS-induced murine systemic inflammation is driven by parenchymal cell activation and exclusively predicted by early MCP-1 plasma levels. Am J Pathol. 2012 Jan 1;180(1):32-40).Furthermore, when necessary, mechanical ventilation is known to cause further lung injury and further inflammation (Spadaro S, Park M, Turrini C, Tunstall T, Thwaites R, Mauri T, Ragazzi R, Ruggeri P, Hansel TT, Caramori G, Volta CA. Biomarkers for acute respiratory distress syndrome and prospects for personalised medicine. J Inflamm. 2019 Dec 1;16(1):1, Ware LB, Matthay MA. The acute respiratory distress syndrome. NEJM. 2000 May 4;342(18):1334-49, Henderson WR, Chen L, Amato MB, Brochard LJ. Fifty years of research in ARDS. Respiratory mechanics in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017 Oct 1;196(7):822-33). Suppression of inflammation is the key to treating this disease.

Prior Art Documents

Non-Patent Documents

[0007]

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[0008] What is needed are novel compositions and methods for the prevention and treatment of ARDS. [Means for solving the problem]

[0009] In one embodiment, the present invention is a method for treating a disease or condition caused by an increase in the level of inflammatory cytokines, 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-Dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG), or DMPC / DMPG, Lysophosphatidylglycerol comprising at least one of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine, or ercoyl-lysophosphatidylcholine, Alternatively, containing the compound of formula I,

[0010] [ka]

[0011] During the ceremony, R 1 This is a C1-C molecule having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 2 This is a C1-C molecule having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 3 teeth,

[0012] [ka]

[0013] and is R 4 is H or a pharmaceutically acceptable cation, a cation that forms a salt by incorporating the pharmaceutically acceptable cation; R 5 is a C1-C optionally substituted with one or more groups selected from OH, OAc, OMe, NH2, NHAc, NHMe, N(Me)2, SH, CN, COOH, CONH2, Cl, Br, and I 10 branched or unbranched hydrocarbon; R 6 is a C1-C optionally substituted with one or more groups selected from OH, OAc, OMe, NH2, NHAc, NHMe, N(Me)2, SH, CN, COOH, CONH2, Cl, Br, and I 10 branched or unbranched hydrocarbon; R 7 is a C0-C branched or unbranched hydrocarbon having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double bonds and triple bonds; R 20 branched or unbranched hydrocarbon; R 8 is H, or a C0-C branched or unbranched hydrocarbon having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double bonds and triple bonds; X is a direct bond, CH2, O, or NH; Y is a direct bond, CH2, O, or NH; each chiral center is independently R, S, or racemic, including the method. In one aspect, the disease or condition caused by an increase in the level of an inflammatory cytokine is pulmonary inflammation, pulmonary distress, or pulmonary insufficiency. In another aspect, the pulmonary disease includes at least one of bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, bronchitis, chronic or acute bronchoconstriction, acute respiratory distress syndrome, acute lung injury, cytokine storm, or bronchiectasis. In another aspect, R 20 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. In another aspect, the compound is selected from at least one of the following. 4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. In another aspect, the compound is selected from at least one of the following.

[0014] [ka] JPEG0007836103000004.jpg162136JPEG0007836103000005.jpg122134

[0015] In another embodiment, the compound is a single substance, a solvate, a hydrate, crystals, an amorphous solid, a liquid, or an oil. In another embodiment, the compound is administered at least once, once daily, twice daily, or three times daily. In another embodiment, the compound is administered at doses of 0.1, 1, 2, 3, 4, 5, 6, 7, 89, 10, 15, 20, 25, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 255, 250, 300, 400, or 500 mg / kg. In another embodiment, the composition is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, buffers, or salts. In another embodiment, the compound is formulated into a pharmaceutical composition adapted for oral, intravenous, nasal, pulmonary, alveolar, enteral, parenteral, or topical administration. In another embodiment, the composition is formulated in the form of an aerosol, a sprayer, or an inhaler. In another embodiment, the method further comprises one or more polymers, salts, or buffers. In another embodiment, the method further comprises additional therapeutic agents selected from the group consisting of corticosteroids, bronchodilators, anticholinergics, vasodilators, diuretics, antihypertensives, acetazolamide, antibiotics, antivirals, immunosuppressants, and surfactants. In another embodiment, the subject is a child or an adult human, or a child or an adult animal. In another embodiment, the compound is as follows:

[0016] [ka]

[0017] In another embodiment, the present invention relates to a method for treating pneumonia, pulmonary distress, or pulmonary failure, 1,2-Dimiristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-Dimiristoyl-sn-glycero-3-phosphoglycerol (DMPG), or DMPC / DMPG, Lysophosphatidylglycerol comprising at least one of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine, or ercoyl-lysophosphatidylcholine, Alternatively, containing the compound of formula I,

[0018] [ka]

[0019] During the ceremony, R 1 This is a C1-C molecule having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 2 This is a C1-C molecule having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 3 teeth,

[0020] [ka]

[0021] And, R 4 R is H or a pharmaceutically acceptable cation, which is a cation into which a salt is formed by incorporating the pharmaceutically acceptable cation; 5C1-C may be substituted with one or more groups selected from OH, OAc, OMe, NH2, NHAc, NHMe, N(Me)2, SH, CN, COOH, CONH2, Cl, Br, and I. 10 It is a branched or unbranched hydrocarbon; R 6 C1-C may be substituted with one or more groups selected from OH, OAc, OMe, NH2, NHAc, NHMe, N(Me)2, SH, CN, COOH, CONH2, Cl, Br, and I. 10 It is a branched or unbranched hydrocarbon; R 7 C0-C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 8 This is a C0-C molecule having H, or 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 The method comprises a branched or unbranched hydrocarbon; X is a direct bond, CH2, O, or NH; Y is a direct bond, CH2, O, or NH; and each chiral center is independently R, S, or racemic. In one embodiment, the lung disease includes at least one of bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, bronchitis, chronic or acute bronchoconstriction, acute respiratory distress syndrome, acute lung injury, cytokine storm, or bronchiectasis. In another embodiment, R 4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. In another embodiment, the compound is selected from at least one of the following:

[0022] [ka] JPEG0007836103000010.jpg166140JPEG0007836103000011.jpg122133

[0023] In another embodiment, the compound is a single substance, a solvate, a hydrate, crystals, an amorphous solid, a liquid, or an oil. In another embodiment, the compound is administered at least once, once daily, twice daily, or three times daily. In another embodiment, the compound is administered at doses of 0.1, 1, 2, 3, 4, 5, 6, 7, 89, 10, 15, 20, 25, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 255, 250, 300, 400, or 500 mg / kg. In another embodiment, the composition is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, buffers, or salts. In another embodiment, the compound is formulated into a pharmaceutical composition adapted for oral, intravenous, nasal, pulmonary, alveolar, enteral, parenteral, or topical administration. In another embodiment, the composition is formulated in the form of an aerosol, a sprayer, or an inhaler. In another embodiment, the method further comprises one or more polymers, salts, or buffers. In another embodiment, the method further comprises additional therapeutic agents selected from the group consisting of corticosteroids, bronchodilators, anticholinergics, vasodilators, diuretics, antihypertensives, acetazolamide, antibiotics, antivirals, immunosuppressants, and surfactants. In another embodiment, the subject is a child or an adult human, or a child or an adult animal. In another embodiment, the compound is as follows:

[0024] [ka]

[0025] In another embodiment, the present invention provides a method for preventing or treating pneumonia, pulmonary distress, or pulmonary failure, wherein a therapeutically effective amount is administered to a subject in need thereof. 1,2-Dimiristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-Dimiristoyl-sn-glycero-3-phosphoglycerol (DMPG), or DMPC / DMPG, Lysophosphatidylglycerol comprising at least one of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine, or ercoyl-lysophosphatidylcholine, Alternatively, the administration may include administering a compound of formula (I), or its stereoisomer, enantiomer, tautomer, or pharmaceutically acceptable salt thereof.

[0026] [ka]

[0027] During the ceremony, R 1 This is a C1-C molecule having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 2 This is a C1-C molecule having 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 3 teeth,

[0028] [ka]

[0029] And, R 4 R is H or a pharmaceutically acceptable cation, which is a cation into which a salt is formed by incorporating the pharmaceutically acceptable cation; 5C1-C may be substituted with one or more groups selected from OH, OAc, OMe, NH2, NHAc, NHMe, N(Me)2, SH, CN, COOH, CONH2, Cl, Br, and I. 10 It is a branched or unbranched hydrocarbon; R 6 C1-C may be substituted with one or more groups selected from OH, OAc, OMe, NH2, NHAc, NHMe, N(Me)2, SH, CN, COOH, CONH2, Cl, Br, and I. 10 It is a branched or unbranched hydrocarbon; R 7 C0-C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 It is a branched or unbranched hydrocarbon; R 8 This is a C0-C molecule having H, or 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. 20 The method comprises a branched or unbranched hydrocarbon; X is a direct bond, CH2, O, or NH; Y is a direct bond, CH2, O, or NH; and each chiral center is independently R, S, or racemic. In one embodiment, the lung disease includes at least one of bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, bronchitis, chronic or acute bronchoconstriction, acute respiratory distress syndrome, acute lung injury, cytokine storm, or bronchiectasis. In one embodiment, R 4 is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium. In another embodiment, the compound is selected from at least one of the following:

[0030] [ka] JPEG0007836103000016.jpg163140JPEG0007836103000017.jpg125131

[0031] In another embodiment, the compound is a single substance, a solvate, a hydrate, crystals, an amorphous solid, a liquid, or an oil. In another embodiment, the compound is administered at least once, once daily, twice daily, or three times daily. In another embodiment, the compound is administered at doses of 0.1, 1, 2, 3, 4, 5, 6, 7, 89, 10, 15, 20, 25, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 255, 250, 300, 400, or 500 mg / kg. In another embodiment, the composition is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, buffers, or salts. In another embodiment, the compound is formulated into a pharmaceutical composition adapted for oral, intravenous, nasal, pulmonary, alveolar, enteral, parenteral, or topical administration. In another embodiment, the composition is formulated in the form of an aerosol, a sprayer, or an inhaler. In another embodiment, the method further comprises one or more polymers, salts, or buffers. In another embodiment, the method further comprises additional therapeutic agents selected from the group consisting of corticosteroids, bronchodilators, anticholinergics, vasodilators, diuretics, antihypertensives, acetazolamide, antibiotics, antivirals, immunosuppressants, and surfactants. In another embodiment, the subject is a child or an adult human, or a child or an adult animal. In another embodiment, the compound is as follows:

[0032] [ka]

[0033] In another embodiment, the method further includes the step of identifying subjects who require treatment for pneumonia, pulmonary distress, or pulmonary failure prior to treatment. [Brief explanation of the drawing]

[0034] For a more complete understanding of the features and advantages of the present invention, a detailed description of the invention will be provided hereby with reference to the accompanying drawings. [Figure 1]Figure 1A shows that weight loss was significantly reduced at 48 and 72 hours after LPS treatment in animals treated with SPPCT-800, and Figure 1B shows that the lung weight / body weight ratio decreased. [Figure 2] Figures 2A-2E show (Figure 2A): blood oxygen level, (Figure 2B): inspiratory time, (Figure 2C): expiratory time, (Figure 2D): respiratory rate, and (Figure 2E): pulmonary congestion index. Red circles = mice treated with SPPCT-800, black circles = mice treated with LPS and a medium, and white circles = untreated mice. [Figure 3] Figures 3A-3N show the lung injury score at 24 hours (Figure 3A); tissue structure in Siamese mice at 24 hours (Figure 3B+C); tissue structure in mice given LPS+ media at 24 hours (Figure 3D+E); tissue structure in mice given SPPCT-800 as prophylaxis at 24 hours (Figure 3F+G); lung injury score at 72 hours (Figure 3H); tissue structure in Siamese mice at 72 hours (Figure 3I+J); tissue structure in mice given LPS+ media at 72 hours (Figure 3K+L); and tissue structure in mice given SPPCT-800 at 72 hours (Figure 3M+N). [Figure 4] Figures 4A-4C show the protein content in BALF after 24 hours when SPPCT-800 was administered 1.5 hours before LPS administration, and when SPPCT-800 was administered 3 hours after LPS administration, respectively. Figure 4B shows the protein content in BALF after 24 hours, and Figure 4C shows the total number of cells in BALF after 24 hours. [Modes for carrying out the invention]

[0035] While various embodiments of the present invention will be discussed in detail below regarding their preparation and use, it should be understood that the present invention provides many applicable inventive concepts that can be implemented in a wide range of specific circumstances. The specific embodiments discussed herein are merely illustrative of specific methods of preparing and using the present invention and do not limit the scope of the invention.

[0036] To facilitate understanding of the present invention, several terms are defined below. Terms as defined herein have meanings generally understood by those skilled in the art related to the present invention. Terms such as "a," "an," and "the" are not intended to refer only to singular items, but include general classes for which specific examples may be used for illustrative purposes. Terms herein are used to describe specific embodiments of the present invention, but their use is not intended to limit the invention except as outlined in the claims.

[0037] As used herein, the term "in vivo" refers to being inside the body. As used in this application, the term "in vitro" is understood to refer to an operation performed in a non-viable system.

[0038] As used herein, the term “treatment” means, in particular, the treatment of any condition referred to herein in a patient exhibiting symptoms of a disease or disorder.

[0039] As used herein, the terms “treatment” or “to treat” refer to any administration of the compounds of the present invention and include (i) inhibiting the disease in a subject experiencing or exhibiting the pathophysiology or overall symptoms of the disease (i.e., preventing further development of the pathophysiology and / or overall symptoms), or (ii) relieving the disease in a subject experiencing or exhibiting the pathophysiology or overall symptoms of the disease (i.e., restoring the pathophysiology and / or overall symptoms). The term “to control” includes preventing, treating, eradicating, relieving, or otherwise reducing the severity of the condition being controlled.

[0040] As used herein, the terms “effective dose” or “therapeutic dose” mean the amount of the compound of interest that elicits a biological or medical response in a tissue, system, animal, or human, as determined by researchers, veterinarians, physicians, or other clinicians.

[0041] As used herein, the terms “administration of” or “administering” the compound should be understood to mean administering the compound of the present invention to an individual in need of treatment in a form that can be introduced into the body of that individual in a therapeutically useful form and amount, for example, but not limited to, oral administration forms such as tablets, capsules, syrups, suspensions, etc.; injectable administration forms such as IV, IM, or IP, etc.; transdermal administration forms such as creams, jellies, powders, or patches; oral administration forms such as inhalation powders, sprays, suspensions, etc.; and rectal suppositories.

[0042] As used herein, the term "intravenous administration" includes injection and other forms of intravenous administration.

[0043] Where used herein, the term “pharmaceutically acceptable” means that a carrier, diluent, or excipient is compatible with the other components of the formulation and is not harmful to its recipient.

[0044] The dosage units for the use of the lipid of formula (I) of the present invention may be a single compound or a mixture thereof with other compounds. The compounds may be mixed together and may form ionic bonds or even covalent bonds. The lipid of the present invention may be administered orally, intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, and all forms of use are well known to those skilled in the pharmaceutical art. Depending on the specific site or method of delivery, various forms of administration, such as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions, may be used to administer the lipid of the present invention to patients requiring treatment for lung diseases, including, but not limited to, bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, bronchitis, chronic or acute bronchoconstriction, acute respiratory distress syndrome, acute lung injury, cytokine storm, or bronchiectasis. The lipid may also be administered as one of the known salt forms.

[0045] Lipids of formula (I) are typically administered in mixtures with appropriate pharmaceutically acceptable salts, buffers, diluents, expanders, excipients, and / or carriers (collectively referred to herein as pharmaceutically acceptable carriers or carrier materials) selected to conform to conventional pharmaceutically practice based on the intended dosage form. Depending on the optimal administration site, the lipids may be formulated to provide the maximum and / or consistent dose in specific forms for, for example, oral, rectal, topical, intravenous injection, or parenteral administration. Lipids may be administered alone, but are usually provided in the form of stable salts mixed with a pharmaceutically acceptable carrier. The carrier may be solid or liquid, depending on the type and / or site of administration selected.

[0046] The techniques and compositions for producing useful dosage forms using the present invention are referenced in the following references: Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2007; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000, and its latest edition; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, These are described in one or more of the 1999 editions, all of which are incorporated by reference, and similar related portions are incorporated herein by reference.

[0047] For example, lipids may be included in the tablets. The tablets may contain, for example, suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers, and / or melting agents. For example, oral administration may be in the form of tablets, gel caps, caplets, or capsules, and the active drug component may be combined with a pharmaceutically acceptable, non-toxic, inert carrier, such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, or mixtures thereof. Suitable binders for use with the present invention include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic rubbers (e.g., acacia, tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, wax, etc. Lubricants for use in the present invention include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and mixtures thereof. Disintegrants include starch, methylcellulose, agar, bentonite, xanthan gum, and mixtures thereof.

[0048] Lipids may be administered in the form of liposomes, for example, small monolayer vesicles, large monolayer vesicles, and multilayer vesicles, whether charged or uncharged. The liposomes may contain one or more of the following: phospholipids (e.g., cholesterol), stearylamines, and / or phosphatidylcholine, or mixtures thereof.

[0049] The lipid of formula (I) may also be conjugated with one or more soluble, biodegradable, and biocompatible polymers as a drug carrier or prodrug. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamidophenol, or polyethylene oxide-polylysine substituted with palmitoyl residues, and mixtures thereof. Furthermore, the lipid may be conjugated with one or more biodegradable polymers to achieve controlled release of the lipid. Examples of biodegradable polymers for use in the present invention include polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacylates, and crosslinked or amphiphilic block copolymers of hydrogels, and mixtures thereof.

[0050] In one embodiment, the gelatin capsule (gel cap) may contain a lipid and powdered carrier of formula (I), such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Tablets may be prepared using a similar diluent. Both tablets and capsules may be manufactured as immediate-release, mixed-release, or sustained-release formulations to provide a range of drug release over a period of several minutes to several hours. The tablets may be sugar-coated or film-coated to mask unpleasant tastes and protect the tablets from the air. Enteric coatings may be used to provide selective disintegration, for example, in the gastrointestinal tract.

[0051] For oral administration in liquid form, the oral drug component may be combined with any pharmaceutically acceptable, non-toxic, inert carrier for oral use, such as ethanol, glycerol, or water. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols, or other organic solvents containing esters, emulsions, syrups, or elixirs, solutions and / or suspensions reconstituted from suspensions, non-foaming granules, and effervescent formulations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and fluxes, or mixtures thereof.

[0052] Liquid formulations for oral administration may also contain colorants and flavorings to improve patient tolerance and thus improve adherence to the administration plan. Generally, water, suitable oils, physiological saline, aqueous dextrose (e.g., glucose, lactose, and related sugar solutions), and glycols (e.g., propylene glycol or polyethylene glycol) may be used as suitable carriers for parenteral solutions. Parenteral solutions generally contain a water-soluble salt of the active ingredient, a suitable stabilizer, and a buffer salt if necessary. Antioxidants, such as sodium bisulfite, sodium sulfite, and / or ascorbic acid, are suitable stabilizers, either alone or in combination. Citric acid and its salts, as well as sodium EDTA, may also be included to improve stability. In addition, parenteral solutions may contain pharmaceutically acceptable preservatives, such as benzalkonium chloride, methyl or propylparaben, and / or chlorobutanol. Appropriate pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, a standard reference text in this field published by Mack Publishing Company, and the relevant portions are incorporated herein by reference.

[0053] For direct delivery to the nasal cavity, sinuses, mouth, pharynx, esophagus, trachea, lungs, and alveoli, lipids may also be delivered in intranasal form by using a suitable intranasal medium. For skin and transdermal delivery, lipids may be delivered using lotions, creams, oils, elixirs, serums, transdermal patches, etc., as is well known to those skilled in the art. Parenteral and intravenous forms may also include pharmaceutically acceptable salts and / or inorganic substances, as well as other materials, such as buffered isotonic solutions, to adapt them to injection or the type of delivery system of choice. Examples of pharmaceutically useful forms of administration for lipids include the following:

[0054] Capsules. Capsules may be prepared by filling each of two standard rigid gelatin capsules with 10 to 500 milligrams of the active ingredient powder, 5 to 150 milligrams of lactose, 5 to 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

[0055] Soft gelatin capsules. A mixture of active ingredients is dissolved in a digestible oil, such as soybean oil, cottonseed oil, or olive oil. The active ingredients are prepared and injected into gelatin using a volumetric pump to form soft gelatin capsules containing, for example, 100 to 500 milligrams of the active ingredients. The capsules are washed and dried.

[0056] Tablets. Numerous tablets are prepared by conventional procedures so that the dosage unit contains 100-500 milligrams of the active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.8 milligrams of lactose. Appropriate coatings may be applied to improve palatability or delay absorption.

[0057] To provide effervescent tablets, appropriate amounts of, for example, monosodium citrate and sodium bicarbonate are blended together, then roll-compressed in the absence of water to form flakes, and then crushed to produce granules. The granules are then combined with active ingredients, drugs and / or salts thereof, conventional beading or fillers, and any sweeteners, flavorings, and lubricants.

[0058] Injectable solution. A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in deionized water and mixing it with, for example, up to 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized, for example, by ultrafiltration.

[0059] Suspension. Each 5 ml aqueous suspension is prepared for oral administration, containing 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of United States Pharmacopeia sorbitol solution, and 0.025 ml of vanillin.

[0060] For mini-tablets, the active ingredient is compressed to a hardness in the range of 6–12 kN / cm. The hardness of the final tablet is influenced by the linear roller compressive strength used in the preparation of the granules, which is affected, for example, by the particle size of monosodium bicarbonate and sodium bicarbonate. For smaller particle sizes, a linear roller compressive strength of approximately 15–20 kN / cm may be used.

[0061] Kit. The present invention also includes, for example, a pharmaceutical kit useful for the treatment of cancer, the kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of lipid. Such a kit may further include, if desired, one or more of various conventional pharmaceutical kit components, as will be readily apparent to those skilled in the art, e.g., one or more containers containing one or more pharmaceutically acceptable carriers, additional containers, etc. The kit may also include instructions for use, guidelines for administration, and / or guidelines for mixing the components, printed either as an insert or a label indicating the amount of component to be administered. While the specified materials and conditions are important in carrying out the present invention, it should be understood that unspecified materials and conditions are not excluded unless they prevent the realization of the benefits of the present invention.

[0062] Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols, or other organic solvents containing esters, emulsions, syrups, or elixirs, solutions and / or suspensions reconstituted from suspensions, non-effervescent granules, and effervescent formulations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms may contain flavoring agents and coloring agents. Parenteral and intravenous forms may also contain inorganics and other materials to adapt them to injection or the type of selected delivery system. [Examples]

[0063] To investigate the role of the lipid of the present invention, e.g., SPPCT-800, as a treatment for ARDS, the inventors used a mouse LPS model to measure histological changes, lung and body weight, oxygen blood saturation and other pulmonary function parameters, BALF protein and cell count, and pro-inflammatory cytokine levels in plasma and BALF.

[0064] C57Bl6 / N mice were obtained from Charles River Laboratories (Montreal, Quebec). Male mice weighing 20-25g were used throughout the study. Animals were housed under specific pathogen-free conditions, and all experiments were approved by the Institutional Animal Care and Use Committee (IPST_SL20200402-1). Animal studies are reported in accordance with AAALAC guidelines.

[0065] All delivered mice were kept for a one-week acclimatization period before any experiments were conducted. A maximum of two mice were housed per cage, under a 12-hour light / 12-hour dark cycle, at a temperature of approximately 20–22°C and humidity of 40–60%. Food and water were freely available. Each mouse cage was either blinded to a different treatment according to the experimental design or maintained as a control group. While the individuals conducting the experiments were not blinded to their treatment, data analysis and experiments were blinded in other ways to avoid bias.

[0066] In the ARDS group, mice were administered Escherichia coli O111:B4 lipopolysaccharide (50 μg in 0.05 mL of physiological saline, it), while in the control group, animals were administered physiological saline (0.05 mL, it) by drip infusion. For intratracheal infusion, mice were slightly anesthetized with isoflurane.

[0067] Lipid SPPCT-800 was dissolved in water (low dose - 2 mg / ml; high dose - 20 mg / ml). Two treatment methods were used in the 24-hour study. Mice received either a single dose of SPPCT-800 (200 mg / kg per gastric tube feeding) as prophylaxis (30 minutes before LPS infusion) or a single dose of either 20 mg / kg or 200 mg / kg as treatment (3 hours after LPS infusion). In the 72-hour study, mice received a total of eight SPPCT-800 (200 mg / kg) treatments, starting 3 hours after LPS infusion. Disease progression in mice was assessed by evaluating lung function, blood oxygen saturation, and body weight changes. On the final day of each study (24 hours or 72 hours), cytokine levels in plasma and BALF were measured, and histopathological evaluations were performed.

[0068] The chemical formula is [C 42 H 78 O 12 The SPPCT-800 of [P]2Mg is as follows:

[0069] [ka]

[0070] Other compounds for use with the present invention generally include, together with phospholipids and phosphatidylglycerol, the following compounds, for example, 1,2-dimiristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimiristoyl-sn-glycero-3-phosphoglycerol (DMPG), or DMPC / DMPG liposomes. In one embodiment, lysophosphatidylglycerol comprises at least one of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine, or ercoyl-lysophosphatidylcholine, and one or more of the following.

[0071] [ka] JPEG0007836103000021.jpg145136JPEG0007836103000022.jpg86132

[0072] Respiratory function. All mice were introduced into a plethysmography chamber environment. After an acclimatization period, functional respiratory parameters were examined using whole-body plethysmography (VivoFlow, SCIREQ, Montreal, Canada) at 0 hours (baseline), 24 hours after LPS infusion, and 48 and 72 hours after LPS infusion. Each measurement was performed on mice placed alone in an unrestrained whole-body plethysmography (WBP) chamber for measuring respiratory function. WBP tracing allowed for the determination of specific information regarding respiratory patterns and the extraction of important information related to the development of inflammation. The functional respiratory parameters analyzed included respiratory rate, PenH (pulmonary congestion index), and inspiratory / expiratory time measurements. PenH was used as an indicator of edema, inflammation, and congestion (bronchial limitation) (Lomask M. Further exploration of the Penh parameter. Toxicol Pathol. 2006 Jun 15;57:13-20).

[0073] Arterial oxygen saturation (SpO2) was recorded in conscious mice at 0 hours (baseline), 24 hours after LPS administration, and 48 and 72 hours after LPS administration. SpO2 was read from a pulse oximeter (STARR Life Sciences MouseOx Plus system, Oakmont, Pennsylvania) equipped with a mouse collar probe attached to the carotid artery level. Saturation values ​​were measured as a percentage (%).

[0074] Cell classification in BALF. The left lung was clamped while injecting 0.9 mL of 1X cold PBS and 3 × 300 μL of 1X protease inhibitor (SigmaFast®) solution to allow collection of bronchoalveolar lavage fluid (BALF) from the right lobe of the lung. Protein assay was performed according to the manufacturer's instructions for use, BCA Protein Assay (Pierce®-#23227). Briefly, a dilution ratio of 5 was used (1 part BALF: 4 parts 1X PBS). 10 μL of the diluted sample was added to the microplate wells. 200 μL of working reagent was added to each well. The plate was covered and incubated at 37°C for 30 minutes. After the cooling period, the absorbance at 562 nm was rapidly measured using a monochromatic spectrophotometer (SpectraMAX® plus-Molecular Devices). The total BALF protein content was reported by multiplying the protein concentration by the dilution factor, and then by the sum of the collected BALF volumes.

[0075] Multiplex analysis of mediators. The inventors quantified 31 different mediators in BALF and plasma using Discovery Assay® (Mouse Cytokine and Chemokine Array 31-Plex (MD31), Eve Technologies Corp., Calgary, Alberta, Canada). Multiplex assays were performed at Eve Technologies using the Bio-Plex® 200 system (Bio-Rad Laboratories, Inc., Hercules, California, USA) and the Milliplex Mouse Cytokine / Chemokine kit (Millipore, St. Charles, Missouri, USA), following the Eve Tech protocol. The 31 analytes included eotaxin, G-CSF, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IP-10, KC, LIF, MCP-1, M-CSF, MIG, MIP-1α, MIP-1β, MIP-2, RANTES, TNFα, and VEGF. The assay sensitivity for these markers ranged from 0.1 pg / mL to 33.3 pg / mL. Individual analytes and details of other assays are available on the Eve Technologies website and in the Milliplex protocol.

[0076] Histopathological evaluation. The lung airway was washed with 0.9% NaCl, and the left lobe was inflated using a 10 mL syringe fitted with a rounded-tip needle (23G) and filled with fixative (10% NBF). The lung was gently inflated with fixative (10% NBF) at a pressure of 20 cmH2O until the lobe was fully, uniformly, and consistently expanded (ensuring that the fixative did not seep through the lung surface). This resulted in optimal airway dilation without causing tissue damage. The left lobe was kept in the fixative for 48 hours, the 10% NBF was replaced with PBS, and the tissue was stored at 4°C. The left lung was embedded in a paraffin block and sliced ​​into two longitudinal sections 5 μm thick, with each section spaced 50 μm apart in the center of the lung. After tissue embedding and mounting, the two sections were stained with hematoxylin and eosin (H&E). Blinded histologists assessed alveolar septa, lung structure, and general morphology of inflammation according to a general scoring system described and adopted by Matute-Bello, et al. (Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol. 2008 Sep;295(3):L379-99; Aeffner F, Bolon B, Davis IC. Mouse models of acute respiratory distress syndrome: a review of analytical approaches, pathologic features, and common measurements. Toxicol Pathol. 2015 Dec;43(8):1074-92).

[0077] Statistical analysis. Results are expressed as mean ± SEM. Comparisons were performed using GraphPad Prism Software version 8.0 (San Diego, California, USA) on normally distributed data, employing ANOVA followed by Fisher's post-hoc test, to evaluate differences between LPS+ media groups. A p-value less than 0.05 was considered statistically significant. *The symbol indicates the difference for Siamese animals, and the symbol # indicates the difference for the LPS+ media group. * P<0.05, ** P<0.01, *** P < 0.001 (where # means P < 0.05, ##P < 0.01, and ###P < 0.001).

[0078] SPPCT-800 was effective against ARDS in all three types of trials. The best results were seen in the 72-hour trial. This is thought to be due to the fact that mice were given a cumulative dose of 1600 mg / kg over three days in the 72-hour trial, which is eight times the single "high dose" (200 mg / kg) used in the 24-hour trial. However, the positive effects of SPPCT-800 may not be fully observed in the 24-hour trial.

[0079] Physiological and respiratory parameters. An important measure of treatment effectiveness is the degree to which it reduces weight loss in animals with ARDS. At 24 hours, both LPS mice and LPS mice treated with SPPCT-800 showed a greater weight loss compared to Siamese mice, and there was no protective effect from SPPCT-800 at that time (14% weight loss with SPPCT-800 compared to 12% with LPS alone). At 48 hours, weight loss stabilized at 14% in the SPPCT-800 group, but reached 20% in the untreated LPS group (P<0.05). Importantly, at 72 hours, weight loss was reduced to 8% in the SPPCT-800 group compared to 18% in the untreated LPS group (P<0.05) (Figure 1A). SPPCT-800 also tended to reduce lung weight in animals sacrificed at 72 hours (P=0.1100). Therefore, SPPCT-800 significantly reduced the lung index (lung weight / body weight × 100; P<0.05) and the wet lung weight / dry lung ratio (Figure 1B). Another important measure in ARDS patients is the maintenance of sufficient levels of oxygen in arterial blood. In this 72-hour trial, SpO2 levels were maintained in the SPPCT-800 group compared to the untreated LPS group, although this result was not statistically significant. Improvements after SPPCT-800 treatment were also observed in lung function tests at all measurement times. Significant decreases in inspiratory time and pulmonary congestion index (PenH) were observed at 24 hours (P<0.001), and significant decreases in expiratory time and PenH were observed at 48 hours (P<0.001) (Figure 2).

[0080] Lung inflammation. Histological analysis performed at an early stage of 24 hours showed that SPPCT-800 could reduce LPS-induced lung injury. SPPCT-800 administered as a prophylactic agent 30 minutes prior to LPS administration significantly reduced the lung injury score. When mice were given LPS alone, the lung injury score at 24 hours was 1.4, but when SPPCT-800 was administered prophylactically, it was only 0.3 (P<0.01) (Figure 3A). The lung injury score also decreased at 72 hours. In mice treated with multiple doses of SPPCT-800, the score decreased to 2.2 compared to a score of 3.0 in mice that did not receive SPPCT-800 (Figure 3H). Histological changes are also shown in Figure 3. A single dose of SPPCT-800 administered as a preventative measure significantly reduced BALF protein content (P<0.05), providing evidence that inflammation can be reduced as early as 24 hours after LPS injection. At 72 hours, mice treated with multiple doses of SPPCT-800 showed a significant decrease in BALF protein levels, as well as decreases in total BALF cell count (P=0.1714) and BALF neutrophil count (P=0.1493), but these were not statistically significant (Figure 4).

[0081] Pro-inflammatory cytokines. Following treatment with SPPCT-800, dramatic reductions in tested pro-inflammatory cytokines were observed in both plasma and BALF at 24 and 72 hours (see Tables 1 and 2). Significant reductions in TNF-α, INF-γ, G-CSF, GM-CSF, interleukin, VEGF, MCP-1, KC, and MIP-1α were observed in all three mouse groups in the single-dose 24-hour study (200 mg / mL prophylaxis, 20 mg / mL treatment, 200 mg / mL treatment) and the repeated-dose 72-hour study. For example, the highly important cytokine TNF-α was significantly reduced by SPPCT-800 at 24 hours in plasma in all three single-dose groups (P<0.001) and in BALF (P=0.0959). Similarly, in the 72-hour study, TNF-α levels were significantly reduced in plasma (P<0.05) and BALF (P=0.0613).

[0082] [Table 1] JPEG0007836103000024.jpg230170

[0083] [Table 2] JPEG0007836103000026.jpg236170

[0084] SPPCT-800 significantly reduced the levels of another important cytokine, IFN-γ, in plasma (P<0.01 in all three groups) and BALF (P<0.001) in all three single-dose groups over 24 hours in all mouse populations. The significant reduction in IFN-γ levels was also observed in both plasma and BALF at 72 hours.

[0085] GM-CSF, which is thought to trigger the secretion of neutrophils, monocytes, and other cells, and therefore play a major role in causing lung damage in ARDS patients, SPPCT-800 A significant decrease was observed in all mice treated with SPPCT-800. At 24 hours, all three mouse groups (200 mg / kg prophylaxis, 20 mg / kg treatment, and 200 mg / kg treatment) showed a highly significant decrease in GM-CSF induced by SPPCT-800 in both plasma and BALF (P<0.001). Similarly, at 72 hours, a significant decrease in GM-CSF was observed in both plasma (P<0.01) and BALF (P<0.001).

[0086] Of the 15 interleukins tested, a significant reduction with SPPCT-800 was consistently observed in 14 of them. Over 24 hours, IL-1β, IL-2 (P<0.05), IL-3 (P=0.0859 in the 200mg treatment group), IL-4, IL-5 (P<0.05), IL-6 (P=0.0624), IL-7, IL-9 (P<0.001), IL-10 (P=0.0767 in the prevention group), IL-12 (p 40) (P=0.1101 in the prevention group), IL-12 (p 70), IL-13 (P<0.001), IL-15, and IL-17 were significantly reduced. SPPCT-800 did not reduce plasma IL-1α levels in any of the mouse groups over 24 hours. With the exception of IL-6, similar large decreases in these interleukins were observed in BALF at 24 hours, with significant decreases in IL-1β, IL-2 (P<0.001), IL-3 (P<0.001), IL-4 (P<0.05), IL-5 (P<0.01), IL-7 (P<0.001), IL-9 (P<0.01), IL-10 (P<0.01), IL-12 (p40) (P<0.001), IL-12 (p70) (P<0.01), IL-13 (P<0.001), and IL-15 (P<0.001). Significant results were also observed in plasma and BALF at 72 hours. SPPCT-800 also inhibited G-CSF, VEGF, KC, LIF (leukemia inhibitory factor), LIX (LPS-induced CXC chemokine 5), and M-CSF (macrophage colony stimulating factor) in plasma and BALF. MCP-1 was inhibited by SPPCT-800 in plasma at 24 hours and in both plasma and BALF at 72 hours. Inhibitory effects on MIP-1α and MIP1-β (macrophage inflammatory protein 1-β) were observed in both plasma and BALF at 24 hours, and in plasma at 72 hours.RANTES (Regulated on Activation, Normal T cell Expressed and Secreted; CCL5) was suppressed in plasma at both 24-hour and 72-hour intervals, but not in BALF. MIG (monokine induced by human interferon), IP10, and the eosinophil chemotactic protein eotaxin were significantly suppressed by SPPCT-800 in either plasma or BALF, but not in both, resulting in mixed findings.

[0087] This invention demonstrates that the protective and therapeutic effects of the lipid of the present invention, e.g., SPPCT-800, against ARDS have been shown by multiple measures. Mice treated with this drug showed reduced lung injury and definite clinical improvement, as evidenced by reduced weight loss, improved pulmonary function tests and oxygen saturation levels, and better lung injury scores. Protein content and neutrophil count in BALF decreased. Correspondingly, SPPCT-800In animals treated with this treatment, inflammation was greatly suppressed. Interferon-γ, central to the ability to inhibit TNF-α, a key cytokine decisive in the pathogenesis of numerous diseases, and indoleamine 2,3-dioxygenase (Sordillo LA, Sordillo PP. Optical spectroscopy of tryptophan metabolites in neurodegenerative disease. In: Alfano RR, Shi L, eds. Neurophotonics and Biomedical Spectroscopy. Elsevier; 2019: 137-157), as well as almost all interleukins, were significantly suppressed. Levels of VEGF, which is thought to play a major role in the large-scale lung injury and pulmonary edema seen in ARDS, were also significantly reduced (Barratt S, Medford AR, Millar AB. Vascular endothelial growth factor in acute lung injury and acute respiratory distress syndrome. Respiration. 2014;87(4):329-42).It is used to stimulate neutrophils in patients undergoing chemotherapy, but it can induce ARDS-like syndrome (Kudlak K, DeMuro JP, Hanna AF, Brem H. Acute lung injury following the use of granulocyte-macrophage colony-stimulating factor. Int J Crit Illn Inj Sci. 2013 Oct;3(4):279, Inokuchi R, Manabe H, Ohta F, Nakamura K, Nakajima S, Yahagi N. Granulocyte colony-stimulating factor-producing lung cancer and acute respiratory distress syndrome. Clin Respir J. 2015 Apr;9(2):250-2, Takatsuka H, ​​Takemoto Y, Mori A, Okamoto T, Kanamaru A, Kakishita E. Common features in the onset of ARDS after administration of granulocyte colony-stimulating factor. Chest. 2002 May 1;121(5):1716-20, Rhee CK, Kang JY, Kim YH, Kim JW, Yoon HK, Kim SC, Kwon SS, Kim YK, Kim KH, Moon HS, Park SH. Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies. Crit Care. 2009 Dec 1;13(6):R173), G-CSF and GM-CSF were also dramatically suppressed.

[0088] Increased inflammation is associated with cancer (Sordillo PP, Sordillo LA. Glioblastoma cell-induced immunosuppression causing chemoresistance. In: Massoud and Paulmurugan Eds, Glioblastoma Resistance to Chemotherapy: Molecular mechanisms and innovative reversal strategies. Elsevier, Cambridge, MA (in press), Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019 Jul 16;51(1):27-41), Parkinson's disease (Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol. 2008 Sep;295(3):L379-99), and coronary heart disease (Sordillo PP, Sordillo DC, Helson L. The prolonged QT Interval: role of pro-inflammatory cytokines). Reactive oxygen species and the ceramide and sphingosine-1 phosphate pathways. In Vivo. 2015 Nov 1;29(6):619-36, Stanciu AE. Cytokines in heart failure. In: Advances in clinical chemistry 2019 Jan 1 (Vol. 93, pp. 63-113). This is a decisive part of the development of many diseases, including Elsevier.While many brain injuries following neurological trauma are caused by a large-scale accumulation of cytokines in the brain (Sordillo PP, Sordillo LA, Helson L. Bifunctional role of pro-inflammatory cytokines after traumatic brain injury. Brain Inj. 2016 Jul 28;30(9):1043-53), ARDS can similarly be considered as a large-scale accumulation of cytokines in the lungs. Sepsis itself can be interpreted as a systemic inflammatory process caused by systemic infection. Therefore, several trials of cytokine-suppressing drugs are being conducted in ARDS patients. Clinical trials using anti-inflammatory drugs have yielded ambiguous results, and many of these drugs cause additional toxicity in patients (Dushianthan A, Grocott MP, Postle AD, Cusack R. Acute respiratory distress syndrome and acute lung injury. PMJ. 2011 Sep 1;87(1031):612-22, Koh Y. Update in acute respiratory distress syndrome. J Intensive Care Med. 2014 Dec;2(1):1-6, Boyle AJ, Mac Sweeney R, McAuley DF. Pharmacological treatments in ARDS; a state-of-the-art update. BMC Med. 2013 Dec 1;11(1):166, Patel VJ, Biswas Roy S, Mehta HJ, Joo M, Sadikot RT. Alternative and natural therapies for acute lung injury and acute respiratory distress syndrome. BioMed Res Int. 2018 May 16;2018).While corticosteroids are the most commonly used treatment for ARDS, many new therapies, including antiviral drugs, have been introduced to treat some patients with ARDS secondary to COVID-19. To reiterate, treatment with corticosteroids is controversial, has not been proven to increase survival, and exposes patients to numerous additional risks, such as severe hyperglycemia, hypokalemia, gastrointestinal bleeding, severe hypertension, and fungal or bacterial infections (Villar J, Ferrando C, Martinez D, Ambros A, Munoz T, Soler JA, Aguilar G, Alba F, Gonzalez-Higueras E, Conesa LA, Martin-Rodriguez C. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar 1;8(3):267-76, Zhang Z, Chen L, Ni H. The effectiveness of Corticosteroids on mortality in patients with acute respiratory distress syndrome or acute lung injury: a secondary analysis. Sci Rep. 2015 Dec 2;5:17654, Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002 Oct 1;96(1):23-43).

[0089] The chemical formula is [C 42 H 78 O 12SPPCT-800, containing 2Mg of [P], is an orally administered white crystalline powder. It exhibits detectable activity after a single dose of 1 mg / kg and is non-toxic at a maximum daily dose of 800 mg / kg. This study demonstrated that a single dose of 200 mg / kg of SPPCT-800 administered 30 minutes prior to LPS loading significantly reduced severe lung injury by suppressing inflammation in an in vivo mouse LPS ARDS model. Furthermore, this model demonstrated that therapeutic doses of SPPCT-800 are effective in treating ARDS and reducing lung injury.

[0090] Any embodiment discussed herein can be implemented with respect to any method, kit, reagent, or composition of the present invention, and vice versa. Furthermore, compositions of the present invention can be used to achieve the methods of the present invention.

[0091] It will be understood that the specific embodiments described herein are illustrative and not limit the invention. The main features of the invention can be used in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or confirm by simple routine experimental methods, numerous equivalents of the specific procedures described herein. Such equivalents are considered to be within the scope of the invention and are encompassed by the claims.

[0092] All publications and patent applications referenced herein represent the level of skill of a person skilled in the art to which the present invention pertains. All publications and patent applications are incorporated herein by reference to the same extent as each separate publication or patent application is explicitly and separately indicated to be incorporated by reference.

[0093] Where used in the claims and / or specification with the term “comprising,” the use of the words “a” or “an” may mean “one,” but also coincide with the meanings of “one or two or more,” “at least one,” and “one or more than one.” Where used in the claims with the term “or” is used to mean “and / or,” unless it is explicitly indicated to refer only to substitutes, or the substitutes are mutually exclusive; however, this disclosure supports the definitions of substitutes only and “and / or.” Throughout this application, the term “about” is used to indicate that a value includes variations in the inherent errors of the apparatus, methods, or other devices used to determine the value, or variations that exist between the subjects of study.

[0094] As used herein and in the claims, the words “comprising” (and any form of comprising, e.g., “comprise” and “comprises”), “having” (and any form of having, e.g., “have” and “has”), “including” (and any form of including, e.g., “includes” and “include”), or “containing” (and any form of containing, e.g., “contains” and “contain”) are inclusive or non-exclusive and do not exclude additional undescribed elements or method steps. In any embodiment of the compositions and methods presented herein, “comprising” may be replaced with “consisting essentially of” or “consisting of.” As used herein, the phrase “consisting essentially of” requires an integer or step that does not significantly affect the character or function of the claimed invention. Where used herein, the term “become” is used to indicate the existence of only the described integer (e.g., feature, element, property, characteristic, step of a method / process, or limitation) or group of integers (e.g., feature, element, property, characteristic, step of a method / process, or limitation).

[0095] Where used herein, the term “or any combination thereof” refers to all permutations and combinations of the items listed before the term. For example, “A, B, C, or any combination thereof” is intended to include A, B, C, AB, AC, BC, or ABC, and, where the order is important in a particular context, at least one of BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing this example, combinations containing repetitions of one or more items or terms are explicitly included, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc. Those skilled in the art will understand that, unless particularly evident from the context, there is typically no limit to the number of items or terms in any combination.

[0096] Where used herein, approximate terms, such as, but not limited to, “about,” “substantial,” or “substantially,” when modified in this way, refer to a state that, while not necessarily absolute or complete, would be considered sufficiently close to one that a person skilled in the art would justify designating such a state as existing. The degree to which the description may vary depends on the magnitude of the change and whether a person skilled in the art would still perceive the modified feature as still possessing the required properties and capabilities of the unmodified feature. As previously stated, generally, numerical values ​​modified by approximate terms such as “about” in this specification may vary by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12, or 15% from the stated value.

[0097] Furthermore, section headings in this specification are provided to be consistent with the recommendation of Section 1.77 of Volume 37 of the Code of Federal Regulations, or otherwise to provide systematic guidance. These headings are not intended to limit or characterize any invention described in any claims that may be published in this disclosure. Specifically, and as an example, even if a heading refers to “Field of Invention,” the claims thereof should not be limited by the words under this heading that describe the so-called technical field. Furthermore, the description of the technology in the “Background Art” section should not be interpreted as acknowledging that the technology is prior art to any invention in this disclosure. The “Summary” should also not be considered to characterize the invention described in the published claims. Furthermore, no singular reference to “invention” in this disclosure should be used to argue that this disclosure contains only a single novel feature. Multiple inventions may be described in accordance with the limitations of multiple claims published in this disclosure, and such claims may define and protect inventions and their equivalents. In all examples, such claims should be considered on a basis of their true value in light of this disclosure and should not be limited by the headings set forth herein.

[0098] All compositions and / or methods disclosed and claimed herein can be prepared and performed without excessive experimentation in light of this disclosure. Although the compositions and methods of the present invention are described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations can be applied to the compositions and / or methods described herein, as well as to the steps or order of the steps of the method, without departing from the concept, spirit, and scope of the invention. All such similar substitutions and modifications that are apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the invention as defined by the appended claims.

[0099] In interpreting the claims attached herein, and for the benefit of the Patent Office and any reader of any patent published in this application, the applicants hereby note that, unless the terms “means for” or “steps for” are explicitly used in a particular claim, they do not intend to apply any provision of Section 112, paragraph 6, Section 112, paragraph (f), or equivalents existing as of the filing date of this application to any of the attached claims.

[0100] For each claim, each dependent claim may be dependent on both an independent claim and each of the preceding dependent claims of all the claims, insofar as the preceding claim provides a suitable antecedent for the term or element of the claim. (References) 1. Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. NEJM. 2017 Aug 10;377(6):562-72 2. Dushianthan A, Grocott MP, Postle AD, Cusack R. Acute respiratory distress syndrome and acute lung injury. PMJ. 2011 Sep 1;87(1031):612-22 3. Confalonieri M, Salton F, Fabiano F. Acute respiratory distress syndrome. ERR. 2017 Jun 30;26(144):160116 4. Kirch C, Blot F, Fizazi K, Raynard B, Theodore C, Nitenberg G. Acute respiratory distress syndrome after chemotherapy for lung metastases from non-seminomatous germ-cell tumors. SCC. 2003 Sep 1;11(9):575-80 5. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr 1;8(4):420-2 6. Grasselli G, Tonetti T, Protti A, Langer T, Girardis M, Bellani G, Laffey J, Carrafiello G, Carsana L, Rizzuto C, Zanella A. Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study. Lancet Respir Med. 2020 Dec 1;8(12):1201-8 7. Spadaro S, Park M, Turrini C, Tunstall T, Thwaites R, Mauri T, Ragazzi R, Ruggeri P, Hansel TT, Caramori G, Volta CA. Biomarkers for acute respiratory distress syndrome and prospects for personalised medicine. J Inflamm. 2019 Dec 1;16(1):1 8. Ware LB, Matthay MA. The acute respiratory distress syndrome. NEJM. 2000 May 4;342(18):1334-49 9. Juss JK, House D, Amour A, Begg M, Herre J, Storisteanu DM, Hoenderdos K, Bradley G, Lennon M, Summers C, Hessel EM. Acute respiratory distress syndrome neutrophils have a distinct phenotype and are resistant to phosphoinositide 3-kinase inhibition. Am J Respir Crit Care Med. 2016 Oct 15;194(8):961-73 10. Matute-Bello G, Liles WC, RADELLA F, Steinberg KP, Ruzinski JT, Jonas M, Chi EY, Hudson LD, Martin TR. Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997 Dec 1;156(6):1969-77 11. Windsor AC, Mullen PG, Fowler AA, Sugerman HJ. Role of the neutrophil in adult respiratory distress syndrome. BJS. 1993 Jan;80(1):10-7 12. Wang Y, Ju M, Chen C, Yang D, Hou D, Tang X, Zhu X, Zhang D, Wang L, Ji S, Jiang J. Neutrophil-to-lymphocyte ratio as a prognostic marker in acute respiratory distress syndrome patients: a retrospective study. J Thorac Dis. 2018 Jan;10(1):273 13. Ma A, Cheng J, Yang J, Dong M, Liao X, Kang Y. Neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ARDS in severe COVID-19 patients. Crit Care. 2020 Dec;24(1):1-4 14. Williams AE, Chambers RC. The mercurial nature of neutrophils: still an enigma in ARDS?. Am J Physiol Lung Cell Mol. 2014 Feb 1;306(3):L217-30 15. Scott BN, Kubes P. Death to the neutrophil! A resolution for acute respiratory distress syndrome?. Eur Respir J. 2018;52:1801274 16. Yang SC, Tsai YF, Pan YL, Hwang TL. Understanding the role of neutrophils in acute respiratory distress syndrome. Biomed J. 2020 Sep 10 17. Rebetz J, Semple JW, Kapur R. The pathogenic involvement of neutrophils in acute respiratory distress syndrome and transfusion-related acute lung injury. Transfus Med Hemother. 2018;45(5):290-8 18. Chen K, Kolls JK. Innate Lymphoid Cells and Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2016 Feb 15;193(4):350-2 19. Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A. Inflammatory cytokines in the BAL of patients with ARDS: persistent elevation over time predicts poor outcome. Chest. 1995 Nov 1;108(5):1303-14 20. Preira P, Forel JM, Robert P, Negre P, Biarnes-Pelicot M, Xeridat F, Bongrand P, Papazian L, Theodoly O. The leukocyte-stiffening property of plasma in early acute respiratory distress syndrome (ARDS) revealed by a microfluidic single-cell study: the role of cytokines and protection with antibodies. Crit Care. 2015 Dec 1;20(1):8 21. Wilson JG, Simpson LJ, Ferreira AM, Rustagi A, Roque J, Asuni A, Ranganath T, Grant PM, Subramanian A, Rosenberg-Hasson Y, Maecker HT. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. MedRxiv. 2020 Jan 1 22. Juskewitch JE, Knudsen BE, Platt JL, Nath KA, Knutson KL, Brunn GJ, Grande JP. LPS-induced murine systemic inflammation is driven by parenchymal cell activation and exclusively predicted by early MCP-1 plasma levels. Am J Pathol. 2012 Jan 1;180(1):32-40 23. Henderson WR, Chen L, Amato MB, Brochard LJ. Fifty years of research in ARDS. Respiratory mechanics in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017 Oct 1;196(7):822-33 24. Lomask M. Further exploration of the Penh parameter. Toxicol Pathol. 2006 Jun 15;57:13-20 25. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol. 2008 Sep;295(3):L379-99 26. Aeffner F, Bolon B, Davis IC. Mouse models of acute respiratory distress syndrome: a review of analytical approaches, pathologic features, and common measurements. Toxicol Pathol. 2015 Dec;43(8):1074-92 27. Sordillo LA, Sordillo PP. Optical spectroscopy of tryptophan metabolites in neurodegenerative disease. In: Alfano RR, Shi L, eds. Neurophotonics and Biomedical Spectroscopy. Elsevier; 2019: 137-157 28. Barratt S, Medford AR, Millar AB. Vascular endothelial growth factor in acute lung injury and acute respiratory distress syndrome. Respiration. 2014;87(4):329-42 29. Kudlak K, DeMuro JP, Hanna AF, Brem H. Acute lung injury following the use of granulocyte-macrophage colony-stimulating factor. Int J Crit Illn Inj Sci. 2013 Oct;3(4):279 30. Inokuchi R, Manabe H, Ohta F, Nakamura K, Nakajima S, Yahagi N. Granulocyte colony-stimulating factor-producing lung cancer and acute respiratory distress syndrome. Clin Respir J. 2015 Apr;9(2):250-2 31. Takatsuka H, Takemoto Y, Mori A, Okamoto T, Kanamaru A, Kakishita E. Common features in the onset of ARDS after administration of granulocyte colony-stimulating factor. Chest. 2002 May 1;121(5):1716-20 32. Rhee CK, Kang JY, Kim YH, Kim JW, Yoon HK, Kim SC, Kwon SS, Kim YK, Kim KH, Moon HS, Park SH. Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies. Crit Care. 2009 Dec 1;13(6):R173 33. Sordillo PP, Sordillo LA. Glioblastoma cell-induced immunosuppression causing chemoresistance. In: Massoud and Paulmurugan Eds, Glioblastoma Resistance to Chemotherapy: Molecular mechanisms and innovative reversal strategies,. Elsevier, Cambridge, MA (in press) 34. 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Claims

1. A pharmaceutical composition for treating a lung disease or condition caused by elevated levels of inflammatory cytokines, selected from at least one of bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, bronchitis, chronic or acute bronchoconstriction, acute respiratory distress syndrome, acute lung injury, cytokine storm, bronchiectasis, pneumonia, lung distress, or lung failure, comprising a compound of formula I, 【Chemistry 1】 Including, in the formula, R １ C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. １ -C ２０ It is a branched or unbranched hydrocarbon; R ２ C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. １ -C ２０ It is a branched or unbranched hydrocarbon; R ３ teeth, 【Chemistry 2】 And; R ４ is H or a pharmaceutically acceptable cation, wherein a salt is formed by incorporating the pharmaceutically acceptable cation; R ５ is a branched or unbranched hydrocarbon of C ２ -C which may be substituted with one or more groups selected from OH, OAc, OMe, NH ２ , NHAc, NHMe, N(Me) ２ , SH, CN, COOH, CONH １ -, Cl, Br, and I; １０ ​ R ６ OH, OAc, OMe, NH ２ , NHAc, NHMe, N(Me) ２ , SH, CN, COOH, CONH ２ C may be substituted with one or more groups selected from Cl, Br, and I. １ -C １０ It is a branched or unbranched hydrocarbon; R ７ C1-C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double bonds and triple bonds. ２０ It is a branched or unbranched hydrocarbon; R ８ This is a C1-C molecule having H, or 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double bonds and triple bonds. ２０ It is a branched or unbranched hydrocarbon; X is a direct bond, CH ２ , O, or NH; Y is a direct bond, CH ２ , O, or NH; The pharmaceutical composition wherein each chiral center is independently R, S, or racemic.

2. R ４ The pharmaceutical composition according to claim 1, wherein the element is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium, or tetraalkylammonium.

3. The compound is 【Transformation 3】 【change】 【change】 A pharmaceutical composition according to claim 1, selected from at least one of the following.

4. The compound is a single substance, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil; The compound is administered at least once, once a day, twice a day, or three times a day; The compound is administered at a dose of 0.1, 1, 2, 3, 4, 5, 6, 7, 89, 10, 15, 20, 25, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 255, 250, 300, 400, or 500 mg / kg; The compound is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, buffers, or salts; The composition is formulated into an aerosol, a sprayer, or a suction device; and, The composition is formulated in doses for children or adults in humans, or for children or adults in animals; A pharmaceutical composition according to claim 1, which satisfies at least one of the following conditions.

5. The pharmaceutical composition according to claim 1, further comprising an additional therapeutic agent selected from the group consisting of corticosteroids, bronchodilators, anticholinergics, vasodilators, diuretics, antihypertensives, acetazolamide, antibiotics, antivirals, immunosuppressants, and surfactants.

6. The compound is 【Chemistry 4】 The pharmaceutical composition according to claim 1.

7. The compound is formulated into a pharmaceutical composition for the treatment of pneumonia, pulmonary distress, or pulmonary failure, and the compound is 【Transformation 5】 【change】 【change】 【Transformation 6】 A pharmaceutical composition according to claim 1, selected from at least one of the following.

8. The compound is 【Transformation 7】 The pharmaceutical composition according to claim 1.

9. A pharmaceutical composition for treating a lung disease or condition caused by elevated levels of inflammatory cytokines, selected from at least one of bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, bronchitis, chronic or acute bronchoconstriction, acute respiratory distress syndrome, acute lung injury, cytokine storm, bronchiectasis, pneumonia, lung distress, or lung failure, The compound of formula (I), or its stereoisomers, enantiomers, tautomers, or pharmaceutically acceptable salts, 【Transformation 8】 During the ceremony, R １ C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. １ -C ２０ It is a branched or unbranched hydrocarbon; R ２ C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double and triple bonds. １ -C ２０ It is a branched or unbranched hydrocarbon; R ３ teeth, 【Chemistry 9】 And; R ４ is H or a pharmaceutically acceptable cation, wherein a salt is formed by incorporating the pharmaceutically acceptable cation; R ５ OH, OAc, OMe, NH ２ , NHAc, NHMe, N(Me) ２ , SH, CN, COOH, CONH ２ C may be substituted with one or more groups selected from Cl, Br, and I. １ -C １０ It is a branched or unbranched hydrocarbon; R ６ OH, OAc, OMe, NH ２ , NHAc, NHMe, N(Me) ２ , SH, CN, COOH, CONH ２ C may be substituted with one or more groups selected from Cl, Br, and I. １ -C １０ It is a branched or unbranched hydrocarbon; R ７ C1-C has 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double bonds and triple bonds. ２０ It is a branched or unbranched hydrocarbon; R ８ This is a C1-C molecule having H, or 0 to 10 double bonds, 0 to 10 triple bonds, or a combination of 0 to 10 double bonds and triple bonds. ２０ It is a branched or unbranched hydrocarbon; X is a direct bond, CH ２ , O, or NH; Y is a direct bond, CH ２ , O, or NH; Each chiral center is independently R, S, or racemic. The aforementioned pharmaceutical composition.

10. The compound is 【Chemistry 10】 【change】 【change】 【Chemistry 11】 A pharmaceutical composition according to claim 9, selected from at least one of the following.

11. The compound is 【Chemistry 12】 The pharmaceutical composition according to claim 9.

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