Immunology of hydroxypyrrolone

Abstract

The present invention relates to a novel compound of formula (I) and its composition: [Formula 1] TIFF2026513467000023.tif57115[in the formula, X is a halogen, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyl, alkenyloxy, or alkenylcarbonyl; Y is a hydroxyl or alkoxy group; R is phenyl, cyanophenyl, or halogenated phenyl; R 1 [These are alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyloxy, alkenylcarbonyl, phenyl, phenylalkyl, dialkylphenyl, benzyl, or benzylalkyl]. The present invention also relates to the use of compounds of formula (I) and compositions thereof as immunomodulators useful for restoring the adaptive and innate immune systems to healthy baseline ranges. The present invention also relates to the use of compounds of formula (I) and compositions thereof in the treatment of undesirable immune-mediated physiological conditions such as inflammation, viral infections, and cancer, and in other medical applications.

Description

[Technical Field]

[0001] The present invention relates to compositions of 5-hydroxy-5-aryl-pyrrole-2-one, and their use in the treatment of various diseases. [Background technology]

[0002] Several adverse physiological conditions are related to the immune system, for example, to cancer. The immune system consists of the innate immune system and the adaptive immune system. Currently, all known drugs affect both the innate and adaptive immune systems similarly, that is, they either upregulate (upregulate) both or downregulate (downregulate) both. Therefore, drugs act as either immune enhancers or immunosuppressants.

[0003] Standard immunotherapeutic drugs are, in most cases, re-proposed anticancer drugs and immunosuppressants, such as alkylating agents and natural products (e.g., cyclosporine). Furthermore, there is a large class of anti-inflammatory steroids, such as dexamethasone, all of which impair the body's immune response. The time window for treatment is narrow; their use was recommended in Covid-19 SARS-2 but contraindicated in SARS-1. On the other hand, immune stimulators, such as interferon and especially IFN-γ, are generally useful but come with very serious, life-threatening adverse reactions. Therefore, stimulating the immune system can be problematic.

[0004] Immunotherapy is currently emerging in the form of monoclonal antibody therapy, but its costs are generally very high. In contrast, regulating the immune system to a healthy range would enable effective treatment of all immune-related diseases without the serious life-threatening effects associated with immune stimulants, the damage to parts of the body's immune system as in the case of steroids, or the enormous costs associated with monoclonal antibody therapy. Stimulation of the immune system is problematic, as seen with interferon. Therefore, an approach that restores the immune system to a healthy range is needed.

[0005] Compounds of the 5-hydroxy-5-arylpyrrole-2-one class have been reported to act as cholecystokinin (CCK) receptor ligands. Patent Document 1 describes compounds having the core structure of 5-hydroxy-5-arylpyrrole-2-one disclosed therein as having CCK binding activity. Patent Document 1 discloses methods for preparing 15 5-hydroxy-5-arylpyrrole-ones, as well as the binding of these compounds to receptors. However, no immunological studies have been reported for any of the disclosed compounds or their compositions.

[0006] Therefore, there is a huge and unmet need for immunomodulatory agents and their compositions that act as effective treatments for immune-mediated physiological adverse conditions and have beneficial effects on a wide range of diseases and their associated conditions.

[0007] In the selected figures, all applications to immunology in which the immune system is upregulated or downregulated are disclosed in detail. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Indian Patent No. 405278 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Object of the invention The object of the present invention is to provide 5-hydroxy-5-aryl-pyrrole-2-one derivatives and compositions thereof that are useful as immunomodulators.

[0010] Another object of the present invention is to provide 5-hydroxy-5-aryl-pyrrole-2-one derivatives and compositions thereof as agents that act as immunomodulators by modulating both adaptive and innate immunity of the immune system to bring them within healthy ranges.

[0011] Another object of the present invention is to provide 5-hydroxy-5-aryl-pyrrole-2-one derivatives and compositions thereof that are useful as immunomodulators, capable of acting as anti-inflammatory agents, antiviral agents, anticancer agents, and modulators / regulators of the innate and adaptive immune systems (particularly cytotoxic T cells and helper cells).

[0012] Another object of the present invention is to provide 5-hydroxy-5-aryl-pyrrole-2-one derivatives and compositions thereof that are useful for repairing organs such as the lungs, gut, and pancreas. [Means for solving the problem]

[0013] The present disclosure provides that the compounds of 5-hydroxy-5-aryl-pyrrol-2-ones and their compositions disclosed in Indian Patent No. 405278 have additional unexpected clinical benefits as immunomodulators by regulating both the adaptive and innate immunity of the immune system to bring their values within a healthy range. Thereby, 5-hydroxy-5-aryl-pyrrol-2-one is effective in the treatment of a number of physiological harmful conditions including inflammation, viral infections, cancer, blood sugar, etc. This unexpected broad clinical applicability extends to almost the entire range of immune-mediated inflammatory diseases. For example, they have been found to be useful as anti-inflammatory agents, antiviral agents, anticancer agents, and modulators of the innate immune system / adaptive immune system. They have also been found to act as modulators of lymphocytes, particularly cytotoxic T cells, as well as helper T cells. These compounds and their compositions are also useful for organ repair as found in the lungs, intestinal tract, and pancreas. Such additional unexpected clinical benefits of 5-hydroxy-5-aryl-pyrrole also significantly improve the patient outcome.

[0014] One embodiment of the present invention is to provide a pharmaceutical composition comprising a 5-hydroxy-5-aryl-pyrrol-2-one compound of formula (I) and a pharmaceutically acceptable excipient and / or carrier: [Chemical formula] [Wherein, X is halogen, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyl, alkenyloxy, or alkenylcarbonyl, Y is a hydroxy or alkoxy group, R is selected from phenyl, cyanophenyl, or halogenated phenyl, R 1is selected from alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyloxy, alkenylcarbonyl, phenyl, phenylalkyl, dialkylphenyl, benzyl, or benzylalkyl.

[0015] Another embodiment of the present invention provides a pharmaceutical composition, wherein in the above formula, X is selected from H, F, Br, Cl, I, and methyl.

[0016] Another embodiment of the present invention provides a pharmaceutical composition having one of the compounds of the following formula. [Chemical formula]

[0017] Another embodiment of the present invention provides a pharmaceutical composition wherein the therapeutically effective amount of the compound of formula I is in the range of 100 ng / kg to 20 mg / kg.

[0018] Another embodiment of the present invention provides 5-hydroxy-5-aryl-pyrrol-2-one of formula I and its composition, and uses the compound in the preparation of a medicament for the treatment or prevention of inflammation or related conditions.

[0019] Another embodiment of the present invention provides 5-hydroxy-5-aryl-pyrrol-2-compound of formula I and its composition, and uses the compound in the preparation of a medicament for the treatment of pain, immune-mediated physiological conditions (including inflammation or related conditions, pain, fever, pneumonia, viral infections), and particularly for the treatment of inflammation of the intestine, pancreas or lung.

[0020] <Another embodiment of the present invention provides 5-hydroxy-5-aryl-pyrrole-2-one of formula I and compositions thereof, which are used in the preparation of pharmaceuticals for the symptomatic treatment of pneumonia associated with microorganisms (bacteria, particularly Gram-negative microorganisms, fungi) and viral infections (e.g., dengue fever or coronavirus-19 virus infection, hepatitis and multiple sclerosis associated with / unrelated to Epstein-Barr virus).

[0021] Another embodiment of the present invention provides 5-hydroxy-5-aryl-pyrrole-2-one of formula I and compositions thereof, which are used in the preparation of pharmaceuticals for the treatment or prevention of cytokine-mediated inflammation, such as IL-6, or related conditions often referred to as cytokine storms (including sepsis).

[0022] Another embodiment of the present invention provides a 5-hydroxy-5-aryl-pyrrole-2-one of formula I and compositions thereof, the compounds to be used to treat viral diseases including Covid-19, dengue fever, HIV, hepatitis, multiple sclerosis, Lyme disease, and herpes zoster (including pain associated with herpes zoster).

[0023] Another embodiment of the present invention provides 5-hydroxy-5-aryl-pyrrole-2-one of formula I and compositions thereof as highly effective anti-inflammatory agents, even in the presence of potent steroids.

[0024] Novel features and properties of this disclosure are described herein. However, the disclosure itself, as well as its preferred uses, further purposes and advantages, will be best understood by referring to the following description of exemplary embodiments, when read in conjunction with the accompanying drawings. Here, one or more embodiments are described, merely as examples, with reference to the accompanying drawings, where similar reference numerals in the drawings represent similar elements. [Brief explanation of the drawing]

[0025] [Figure 1]This demonstrates an inflammatory pathway involving cytokines, progressing from pain to fever and then to immune-mediated disease. [Figure 2] This graph shows how compounds enhance the anti-pain effect of tramadol. [Figure 3] This graph shows how to determine the anxiolytic properties of Pyrrol 8 compared to standard diazepam. [Figure 4] This graph shows the antidepressant properties of pyrrole 8 compared to desipramine. [Figure 5] This graph shows the results of an antipyretic assay in rats comparing the antipyretic effect of aspirin. [Figure 6] This graph shows how to determine the anti-inflammatory effect in a rat paw edema assay. [Figure 7] This graph shows the survival rates for an analysis of mortality in dengue fever cases with viral illness, comparing the untreated control group with the group treated with pyrrole 5. [Figure 8] This demonstrates the role of pyrrole 5 in stimulating inflammation and lymphocyte production. [Figure 9] This shows CRP levels before and after pyrrole 5 + BC treatment and BC treatment in patients with moderate COVID-19. [Figure 10] This graph shows the IL6 cytokine levels before and after pyrrole 5 + BC treatment and BC treatment in patients with moderate COVID-19. [Figure 11] This graph shows the percentage of lymphocytes before and after pyrrole 5 + BC treatment and BC treatment in patients with moderate COVID-19. [Figure 12] This shows the percentage of neutrophils before and after pyrrole 5 + BC treatment and BC treatment in patients with moderate COVID-19. [Figure 13]This figure illustrates the neutrophil / lymphocyte ratio (NLR) before and after pyrrole 5 + BC treatment and BC treatment in patients with moderate COVID-19. [Figure 14] This study demonstrates the effectiveness of steroid-only and adjuvant pyrrole treatment (5 treatments) in treating blood glucose levels and promoting pancreatic tissue recovery in patients with moderate COVID-19. [Figure 15] This describes the proposed pathway of interaction between pyrrole 5 and the adaptive immune system (T cells) and the innate immune system (neutrophils) in the fight against microbial (bacteria, fungi) and viral invaders. The same MOA may be applicable to cancer. [Figure 16] This shows an increase in CD3T cells in human subjects. [Figure 17] This shows an increase in CD4 T cells and helper T cells in human subjects. [Figure 18] This study shows an increase in CD8 T cells and cytotoxic T cells in human subjects. [Figure 19] This shows the packed cell volume (the percentage of red blood cell volume in the blood) in LPS-induced inflammation in mice. [Figure 20] This shows the changes in polymorphonuclear cells (polymorph) and neutrophils in a mouse LPS model. [Figure 21] This shows the dose range in the LPS model and the percentage of lymphocytes when used in combination with dexamethasone (Dex). [Figure 22] This study compares treated mice with untreated control mice, demonstrating immune-based anticancer activity in lung cancer cells.

[0026] Figures 1–22 illustrate embodiments of the present disclosure for illustrative purposes only. Those skilled in the art will readily recognize from the following description that alternative embodiments of the assemblies, structures, and methods described herein can be adopted without departing from the principles of the present disclosure. [Modes for carrying out the invention]

[0027] According to the present invention, there are provided a pharmaceutical composition comprising a 5-hydroxy-5-aryl-pyrrol-2-one compound of formula (I) and a pharmaceutically acceptable excipient and / or carrier, and the use of the compound: [Chemical formula] [wherein, X is halogen, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyl, alkenyloxy, or alkenylcarbonyl; Y is a hydroxy or alkoxy group; R is phenyl, cyanophenyl, or halogenated phenyl; R 1 is alkyl, branched-chain alkyl, alkenyl, alkynyl, cycloalkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyloxy, alkenylcarbonyl, phenyl, phenylalkyl, dialkylphenyl, benzyl, or benzylalkyl].

[0028] Preferably, the alkyl-containing moiety is C1-C 18 and preferably C1-C 12 . Preferably, the alkenyl-containing moiety and the alkynyl-containing moiety are C2-C 18 and preferably C2-C 12 . Preferred substituents of R 1 are C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, benzyl, cyclohexyl, phenyl, benzyl(C 2-4 )alkyl, or phenyl(C 2-4 )alkyl. Preferably, X is F, Br, Cl, or I.

[0029] It should be understood that formula (I) is intended to encompass all possible isomers, including optical isomers and mixtures thereof (including racemates). It should also be understood that formula (I) is intended to encompass all possible polymorphs, crystals, impurities, N-oxides, esters, hydrates, or any combination thereof. Furthermore, the present invention includes, within its scope, prodrugs of compounds of formula (I). Generally, such prodrugs would be functional derivatives of compounds of formula (I) that can be readily converted into compounds of formula (I) required in living organisms. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed H. Bungaard, Elsevier, 1985.

[0030] The scope of the present invention also extends to salts of the compound of formula (I), in particular physiologically acceptable salts and hydrates.

[0031] pharmaceutically acceptable salts of the compound of formula (I) include, for example, conventional non-toxic salts or quaternary ammonium salts of the compound of formula (I) formed from non-toxic inorganic or organic acids. pharmaceutically acceptable salts of formula (I) also include those formed from bases such as alkali metal or alkaline earth metal hydroxides, or organic bases such as amines or quaternary ammonium hydroxides. Some preferred compounds of formula (I) are listed below. [ka]

[0032] The present invention relates to a pharmaceutical composition for treating a disease, the composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable excipient and / or carrier: [ka] [In the formula, X is a halogen, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyl, alkenyloxy, or alkenylcarbonyl; Y is a hydroxyl or alkoxy group; R is phenyl, cyanophenyl, or halogenated phenyl; R 1 [These are alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyloxy, alkenylcarbonyl, phenyl, phenylalkyl, dialkylphenyl, benzyl, or benzylalkyl.]

[0033] Preferably, the alkyl-containing portion is C1-C 18 Preferably C1~C 12 Preferably, the alkenyl-containing portion and the alkynyl-containing portion are C2-C 18 Preferably C2~C 12 Preferably, R 1 C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkynyl, benzyl, cyclohexyl, phenyl, benzyl (C 2-4 ) alkyl, or phenyl (C 2-4 ) is alkyl. Preferably, X is selected from F, Br, Cl, and I.

[0034] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound having one of the following formulas: [ka]

[0035] According to another aspect of the present invention, the therapeutically effective dose of the compound of formula I is in the range of 100 ng / kg to 20 mg / kg.

[0036] The compounds and compositions according to the present invention may be administered orally, topically, intraperitoneally, or intravenously.

[0037] In another embodiment, the compounds of Formula I according to the present invention and the pharmaceutical compositions thereof are useful in preparing pharmaceuticals for the treatment or prevention of immune-mediated physiological adverse conditions such as inflammation or related conditions, pain, fever, cancer, pneumonia, viral diseases, and blood sugar (diabetes).

[0038] Another embodiment of the present invention provides a compound of formula I and a pharmaceutical composition thereof, using the compound in the preparation of a pharmaceutical for the treatment or prevention of inflammation or related conditions.

[0039] Another embodiment of the present invention provides compounds of formula I and pharmaceutically equivalent compositions thereof, and uses of the compounds in the preparation of pharmaceuticals for the treatment of pain, immune-mediated diseases, and in particular inflammation of the intestines, pancreas, or lungs.

[0040] Another embodiment of the present invention provides compounds of formula I and pharmaceutical compositions thereof, which use the compounds in the preparation of pharmaceuticals for the symptomatic treatment of pneumonia associated with microorganisms (bacteria, particularly Gram-negative microorganisms, fungi) and viral infections (e.g., dengue fever or coronavirus-19 virus infection, hepatitis and multiple sclerosis associated with / unassociated with Epstein-Barr virus).

[0041] Another embodiment of the present invention provides a compound of formula I and a pharmaceutical composition thereof, using the compound in the preparation of a medicament for the treatment or prevention of cytokine-mediated inflammation, such as IL-6, or related conditions often referred to as cytokine storms (including sepsis).

[0042] Another embodiment of the present invention provides compounds of formula I and pharmaceutical compositions thereof, the compounds being used to treat viral diseases including Covid-19, dengue fever, HIV, hepatitis, multiple sclerosis, Lyme disease, and herpes zoster (including pain associated with herpes zoster).

[0043] Another embodiment of the present invention provides a compound of formula I and a pharmaceutical composition thereof, the compound being a highly effective anti-inflammatory agent even in the presence of a potent steroid.

[0044] In another embodiment, the compounds of Formula I and pharmaceutical compositions according to the present invention are useful for preparing pharmaceuticals for the treatment or prevention of inflammatory or related conditions mediated by cytokines such as IL-6.

[0045] In another embodiment, the compounds and pharmaceutical compositions of Formula I according to the present invention are useful for regulating immune function, blood glucose levels, or both.

[0046] In another embodiment, the compound of formula I according to the present invention and its pharmaceutical composition are useful for regulating lymphocytes (particularly cytotoxic T cells).

[0047] In another embodiment, the compounds of formula I according to the present invention and their pharmaceutical compositions are useful for regulating neutrophils and bringing them within a medically acceptable range.

[0048] In another embodiment, the compound of formula I according to the present invention and its pharmaceutical composition are useful for inducing an increase in T cells (particularly CD4 cells or CD8 cells, or both).

[0049] In another aspect, the present invention relates to a method for treating a mammal suffering from a disease or for preventing a mammal at risk of the disease, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a composition thereof to a patient in need.

[0050] In another embodiment, the present invention provides a method for treating a mammal suffering from a disease or for preventing a mammal at risk of the disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound having one of the formulas disclosed above.

[0051] The experimental drug may be administered orally, topically, intraperitoneally, or intravenously.

[0052] According to aspects of the present invention, the disease is an inflammatory or related condition or an immune-mediated disease (e.g., cancer).

[0053] According to another aspect of the present invention, the disease is a viral disease and / or symptoms associated with a viral disease (e.g., pneumonia).

[0054] According to another aspect of the present invention, the viral disease is dengue fever, COVID-19 virus infection, HIV, hepatitis, or multiple sclerosis.

[0055] According to another aspect of the present invention, inflammation is a condition mediated by or associated with cytokines such as IL-6.

[0056] According to another aspect of the present invention, the method is useful for inducing an increase in T cells (particularly CD4 cells or CD8 cells, or both).

[0057] Another aspect of the present invention provides the use of compounds of formula (I) in the treatment or prevention of inflammatory or related conditions mediated by cytokines such as IL-6.

[0058] Another aspect of the present invention provides the use of a compound of formula (I), wherein treatment or prevention comprises administering a therapeutically effective amount of the compound of formula (I) in the range of 100 ng / kg patient body weight to 20 mg / kg patient body weight. Administration may be carried out orally, intraperitoneally, or intravenously.

[0059] Another aspect of the present invention provides the use of a compound of formula (I) or a composition thereof, the compound which can modulate an immune response or blood glucose or both.

[0060] Another aspect of the present invention provides the use of a compound of formula (I) or a composition thereof, the compound which can modulate lymphocytes, including an increase in the total number of lymphocytes (particularly cytotoxic T cells).

[0061] Another aspect of the present invention provides the use of a compound of formula (I) or a composition thereof, wherein the compound can modulate neutrophils, and they restore homeostasis to a medically acceptable range.

[0062] Another aspect of the present invention provides the use of a compound of formula (I) or a composition thereof, the compound which can increase T cells (in particular CD4 or CD8, or both).

[0063] Another aspect of the present invention provides the use of a compound of formula (I) or a composition thereof to enhance the analgesic effect of SE / NE reuptake inhibitors.

[0064] Another aspect of the present invention provides the use of a compound of formula (I) or a composition thereof for enhancing the analgesic effect of opioate.

[0065] Another aspect of the present invention provides the use of a compound of formula (I) or a composition thereof for modulating immune function.

[0066] Figure 1 shows anti-inflammatory analgesics at the interface of pain and inflammation in the therapeutic area. Their efficacy has been widely confirmed in a series of experiments using mice and rats, as well as in a broad range of animal models targeting immunoinflammation, from hot-plate / tail flick to antipyretic assays and ultimately to formalin testing. We propose a possible understanding via the cholinergic pathway, where acetylcholine plays a crucial role, with reports indicating that ACh is involved in chronic pain in addition to immune stimulation of T cells. T cells themselves produce ACh, thus autocrinely, leading directly to a reduction in cytokines. In the spleen, ACH by macrophages and T cells inhibits cytokines (IL-1, 2, 6, 14, 17) on nicotinic acetylcholine receptors. The α7 subunit of the nicotinic acetylcholine receptor is a highly valued molecular pain target. Indirectly, ACH is released from the vagus nerve, shifting the pain threshold lower, particularly in the spinal cord. Interestingly, the dose ranges at which anti-inflammatory activity was observed in the formalin test and analgesic activity in the tail flick / hot plate assay were found to be the same as the dose ranges for immunomodulation.

[0067] Figure 2 shows that the CCK B antagonist (pyrrole 8) did not show a significant enhancement of tramadol. The phenylethyl derivative (pyrrole 5) enhanced the analgesic effect of tramadol fourfold. Similar, but smaller, activity was observed for the cyclopentyl derivative (pyrrole 7). Since tramadol acts via the NA / SE pathway, these crosstalks, in addition to opioid interactions, are of particular therapeutic interest in pain, anxiety, and depression.

[0068] Figure 3 shows that isobutyl derivative 8 at a dose of 0.1 mg / kg exhibited a significant anxiolytic effect similar to that of the standard anxiolytic diazepam at a dose of 1 mg / kg at a dose of 0.5 mg / kg. This CNS effect is unexpected, novel, and useful for creating therapeutic profiling of the molecule.

[0069] Figure 4 shows that isobutyl derivative 8 exhibited superior antidepressant properties compared to the standard antidepressant desipramine at a dose of 10 mg / kg. Within the disclosed comprehensive range, the 0.5 mg dose molecule had a greater effect than standard desipramine in the forced swim test.

[0070] Figure 5 shows data on fever associated with pyrrole 5. Compared to aspirin (200 mg / kg), pyrrole 5 was 20 times more potent at an oral dose of 10 mg / kg. The antipyretic effect was significantly greater than that of the standard drug and was consistent with the anti-inflammatory activity predicted in the nanomolar range. Fever is a direct effect of cytokine release, such as TNF-α and interleukin-6, and these effects are inhibited in a dose-dependent manner over long periods at low drug molecular concentrations.

[0071] Figure 6 shows that in the control group, the formation of paw edema gradually increased within 1 hour, reaching its maximum effect over a period of 3 hours. Animals treated with 200 mg / kg of aspirin showed less paw swelling, and paw volume was significantly smaller than that of the control group at 2 and 3 hours. The anti-inflammatory effect of API Example 5 at 10 mg / kg was superior to that of the group administered 200 mg / kg of aspirin and was significantly greater than the activity of aspirin. API Pyrrole 5 at a dose of 100 mg / kg resulted in an even higher level of anti-inflammatory effect, being 20 times more potent than aspirin. In this rat paw edema assay (induced by carrageenan), the addition of an esterase inhibitor enhanced the anti-inflammatory effect of the test molecule, which may further support the involvement of the cholinergic pathway proposed by the inventors.

[0072] Figure 7 shows that injection of unadapted dengue virus into mice resulted in dose-dependent transient viremia lasting several days, peaking on day 3 post-infection. Elevated levels of the pro-inflammatory cytokine IL-6 were measured, providing experimental evidence of a significant involvement of inflammation. Oral administration of API Example 5 resulted in splenomegaly, reduced levels of pro-inflammatory cytokines, and, most importantly, reduced mortality. The results in mice regarding reduced mortality justify clinical study of this experimental agent in viral diseases where inflammation leads to death. These findings are likely to be observed in this selected model virus, as well as in other viral infections such as COVID-19 and other viruses.

[0073] Figure 8 illustrates the role of pyrrole 5 in stimulating inflammation and lymphocyte production. Molecules within the inclusive range trigger T cell activation via increased calcium ion concentration; and further indirectly induce lymphocyte proliferation via cytokine release. Clinically, in line with the expected effects, lymphocytes were regulated to the median of the healthy reference range in inflamed human subjects.

[0074] Figure 9 shows that CRP levels were high on day 1 in both the pyrrole 5+BC group and the BC group. A significant decrease was observed on day 15 post-treatment, and more importantly, CRP levels decreased by >90% in patients treated with pyrrole 5+BC, demonstrating the anti-inflammatory properties of this compound in human subjects. CRP is an optimal biomarker for monitoring inflammation. Interestingly, a stronger decrease in the CRP marker was observed in humans even in the presence of potent anti-inflammatory steroids such as dexamethasone.

[0075] Figure 10 shows the changes in IL-6 cytokine levels according to the severity of inflammation. The immune response requires the presence of cytokines. Excessive cytokines cause organ damage in the body, as observed in Covid-19 infection. A decrease in cytokines is observed during severe inflammation. Very high IL-6 levels were observed in sepsis, and the higher the value, the stronger the reduction of IL-6 was observed in humans. Low IL-6 levels in the presence of APIs stimulate the immune system to initiate lymphocyte proliferation. Thus, immunomodulators were disclosed for the first time. These immunomodulators are expected to have more therapeutic applications in immune-mediated inflammatory diseases in the future.

[0076] Figure 11 shows that lymphocytes increased from 14% to 27% after treatment with pyrrole 5 + BC, compared to only 14% to 19% with BC alone. Lymphocytes are immune cells needed to fight Covid-19 infection. This doubling in lymphocytes provides more helper T cells and more killer T cells. In advanced HIV-AIDS, the number and percentage of helper T cells tend to move toward zero. Here, and for hepatitis, the increase in helper T cells has been therapeutically proven. In cancer, cytotoxic T cells kill distorted cancer tissue, and this cancer approach with small molecules is first in class. This is a smart therapeutic approach to biologics such as monoclonal antibodies, and these molecules have the potential to replace current antibody-based cancer therapies.

[0077] Figure 12 shows neutrophil levels before and after pyrrole 5 + BC treatment and BC treatment. Higher levels of neutrophils cause NETosis. Pyrrole 5 may reduce the number of neutrophils through the cholinergic inflammatory pathway. The neutrophil percentage decreased from 81% to 65% with pyrrole 5 + BC treatment and increased from 72% to 76% with BC treatment, highlighting the effect of pyrrole 5 on neutropenia. Neutrophils and macrophages are part of the innate immune system, and the reduction here is only intermediate within the healthy range. A reduction to zero, as seen with IL-6 antibody therapy, is not observed. Reducing NETosis is generally important, and especially crucial when inflammation leads to sepsis (and death). Excessive inflammation is effectively suppressed by the disclosed API molecules.

[0078] Figure 13 shows the NLR ratios of the pyrrole 5+BC group and the BC group before and after treatment. NLR is an important indicator of infection or inflammation. The NLR ratio decreased from 8.5 to 2.8 in the pyrrole 5+BC group and from 11.1 to 5.9 in the BC group, indicating better recovery with pyrrole 5. NLR is a useful cellular biomarker for monitoring inflammation. This decrease is highly significant, and the molecule is best in its class at reducing this neutrophil / lymphocyte ratio. This biomarker has been characterized in many reviews, and NLR can be considered a gold standard inflammatory biomarker for a wide range of diseases, from cancer, IBD (inflammatory bowel disease), psoriasis, and RA (rheumatoid arthritis) to pancreatic inflammation, also known as pancreatitis.

[0079] Figure 14 shows a decrease in blood glucose levels in patients treated with Pyrrole 5 + BC, which is highly significant for prediabetic and diabetic patients. Similar to what is observed in the mouse intestines and human lungs, it can be concluded that this drug repaired the pancreatic organ. Type 1 diabetes may be associated with viral infection that irreversibly destroys B cells in the pancreatic organ (and subsequently triggers an immune response). Here, blood glucose levels fully recovered in Covid-19 patients, and this applied to diabetic patients who were diabetic before Covid-19 infection, as well as those who developed diabetes after Covid-19 infection. This organ repair was also observed in the intestines and lungs of Covid-19 patients, who required less oxygen and were discharged from the hospital earlier.

[0080] Figure 15 illustrates the concept of the efficacy of an API (active pharmaceutical ingredient) in Covid-19 infection. Pyrrole 5 was effective in its use in Covid-19 patients as an example of viral infection. This immune modulator stimulated lymphocytes and reduced neutrophils. The reduction in NETosis stopped excessive inflammation and prevented the progression of the inflammatory disease, which would otherwise lead to death via sepsis. For the first time, decoupling (separation) of immunity and inflammation was achieved. For the first time, the innate immune system, including macrophages and neutrophils, was downregulated at the cellular level, while the adaptive immune system, including helper T cells and cytotoxic T cells, was upregulated.

[0081] Polymorphonuclear cells (Polymorphs) are neutrophils, and in humans, a significant decrease in neutrophils was observed when treated with pyrrole 5. Lymphocytes are subdivided into B cells and T cells, also called B lymphocytes and T lymphocytes. T lymphocytes play a crucial role in fighting infection, and T cells include killer T cells and helper T cells as part of an orchestrated immune response.

[0082] Figure 16 is the first example of a detailed analysis of lymphocyte subtypes based on differentiation cluster (CD). Figure 16 shows an increase in CD3 cells. Lymphocytes include B cells and T cells, and the T cell subpopulation was analyzed in particular. CD3 cells are T cells possessing the CD3 marker and are useful for various purposes, such as immunomodulation. Regulatory T cells decreased in response to Covid-19 infection. Adjuvant treatment increased their number back to the healthy range.

[0083] Helper T cells: Helper T cells are targeted by HIV / AIDS infection, and CD4 was analyzed in the clinical laboratory (Figure 17) (CD4 cells = helper T cells). CD4 cells are essential for a regulated immune response and were analyzed. As a result of Covid-19 infection on day 1, the number of CD4 cells was low in the BC group and the adjuvant group (Figure 17). The increase in the adjuvant group was higher in the adjuvant group on day 15 compared to BC alone. Figure 17 shows the changes in helper T cells in humans.

[0084] Cytotoxic T cells: Cytotoxic T cells, or killer T cells, are crucial in the fight against viral infection. Furthermore, Figure 18 shows CD8 T cells before and after treatment. Data for CD8 T cells are plotted in Figure 18. In conclusion, an increase in lymphocytes was observed, particularly in helper T cells and killer T cells. In all hospitalized patients, the number was within the low normal range on day 1, and the number of CD8 cells increased by day 15, with a greater increase in the adjuvant group compared to the BC group.

[0085] In addition to its use against viruses, the application was expanded from viruses to bacteria using a mouse LPS model. A mouse LPS model (inducing pneumonia with lipopolysaccharide (LPS)) was used. LPS is a component of the cell wall of Gram-negative microorganisms. LPS-induced lung damage increased packed cell volume (the percentage of blood volume occupied by red blood cells), which was reduced by the positive control dexamethasone (Figure 19). The efficacy of pyrrole 5 was fully confirmed using this parameter, and its activity was lost when pyrrole 5 was combined with dexamethasone. Here, neutrophils increased from 3% to 13% with LPS treatment and decreased in a dose-dependent manner with the positive controls dexamethasone and PNB-001 / pyrrole 5 (Figure 20). The effect on neutrophils was completely lost when pyrrole 5 was combined with dexamethasone. Again, for this second parameter, adjuvant treatment resulted in loss of activity (Figure 20).

[0086] LPS treatment increased lymphocytes, which decreased with the positive control dexamethasone (Figure 21). Treatment with pyrrole 5 as a monotherapy also increased lymphocytes, with minimal margin of error. The same effects observed in the human MAD Phase 1 trial were uniformly observed across all groups in mice. Here, the organisms were not healthy and were infected with the experimental drug LPS. This effect was smaller with adjuvant treatment (dexamethasone and pyrrole 5) and was lost again at higher doses.

[0087] In addition to its therapeutic applications for viruses and bacteria, this invention discloses the use of hydroxypyrrolone in cancer immunotherapy. To date, the use of hydroxypyrrolone as a CCK antagonist has been reported to inhibit CCK-related cancers by pathway inhibition. This known effect is related to the inhibition of the CCK pathway, a growth factor established only for CCK-related cancers (it does not act on non-CCK-related cancers). Herein lies a novel mode of action for a broad range of molecules that indirectly acts on cancer cells via the immune system by killing cancer cells / tissues with T cells. Thus, all cancers, including non-CCK-related cancers, are eliminated from the organism by immunotherapy. In contrast to the conventional approach of blocking pathways, cancer tissue is phagocytosed by specialized lymphocytes by activating killer cells such as cytotoxic T cells (Figure 22). The tumor is killed by the host's own immune response in the form of cytotoxic killer cells. This effect is achieved not by complex, expensive, and unstable biomolecules (antibodies), but by small molecules that are easily manufactured.

[0088] For the treatment of any immunomodulated physiological condition, the effective dose range is preferably about 100 ng / kg to about 1.0 mg / kg of CCK antagonist, which can be administered orally (po) as a single dose or in divided doses per day (bid). Other routes of administration are also appropriate.

[0089] In effective treatments for the disclosed therapeutic indications, preferably about 0.05 mg / kg to about 10.0 mg / kg of the drug may be administered orally (PO) as a single dose or in divided doses per day (BID). Other routes of administration are also appropriate.

[0090] To directly induce the therapeutic effect, the effective dose range is preferably about 100 ng / kg to about 10 mg / kg via intraperitoneal administration. Oral administration is an alternative route, as are the other routes.

[0091] When directly treating viral infections such as dengue fever and SARS, the effective dose range is preferably about 100 ng / kg to about 1 mg / kg, administered intraperitoneally, orally, or intravenously.

[0092] Regarding cancer immune activity, it responds to low doses, as seen in lung cancer and in Covid-19 patients. The active dose range stimulates cytotoxic T cells that kill cancer and virus-infected cells. This has been studied in Gram-negative bacteria in mice, but it is universal to all types of infection.

[0093] While it is possible to administer the active ingredient (active ingredient) alone as a raw chemical substance, it is preferable to provide it as a pharmaceutical formulation. The formulations of the present invention contain the active ingredient in combination with a pharmaceutically acceptable carrier and optionally other therapeutic components for both veterinary and human medical use. The carrier must be compatible with the other components of the formulation and "acceptable" in the sense that it is not harmful to the recipient.

[0094] The present invention will be further explained by examples.

[0095] The compound of formula (I) can be prepared by the reaction of a appropriately substituted furan-2(5H)-one with the corresponding amine, as described in Indian Patent No. 405278.

[0096] Examples of pyrolone 1–24 were prepared from intermediates, and details of the experiments are included in the selected examples. [Examples]

[0097] Example 1: Preparation of 5-hydroxy-5-aryl-pyrrole-2-one Preparation of 4-chloro-5-hydroxy-5-aryl-1,5-dihydropyrrole-2-one (1-24) The compound was prepared according to the method described in Indian Patent No. 405278, which is briefly outlined below.

[0098] General method: The relevant amine (3-fold excess) was added to a solution of building block (0.7 mol) in ether (10 ml) and stirred on ice for 30 minutes. The mixture was gradually warmed to room temperature (RT). The resulting mixture was poured into 5 ml of water and separated using a separatory funnel. The mixture was washed three times with water. The organic layer was dried on magnesium sulfate and the solvent was removed under vacuum. All compounds yielded an oily solid, which was passed through a column (80% ether, 20% petroleum ether). The resulting fraction was dried under vacuum from the excess solvent to obtain crystals.

[0099] The following active molecules (pyrrole 1-24) were prepared: [ka] [ka] [ka] [ka] [ka]

[0100] Example 2: Mortality rate after dengue virus infection for 4-chloro-5-hydroxy-l-phenethyl-5-phenyl-l,5-dihydropyrrole-2-one (5) Dengue fever is an infectious disease caused by the dengue virus (DENV) and is the most prevalent mosquito-borne viral disease in humans. It occurs in tropical and subtropical regions and threatens an estimated 2.5 billion lives. Expanding urbanization, failure to control the mosquito vectors, and increased long-distance travel are contributing to the continued spread and increase of the disease.

[0101] In most cases, fever and other symptoms subside after 3 to 5 days, but some patients worsen and progress to fatal dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which can have a mortality rate of >20%. There is no vaccine or antiviral treatment for dengue virus infection.

[0102] [Table 1]

[0103] Just one week later, the mortality rate in the control group was 80%, compared to 20% in the treatment group, representing a reduction of over 50% in mortality, which was considered effective (Table 1).

[0104] Inclusion criteria: T, rectal temperature, T > 38°C; the mortality rate for dengue fever in humans is approximately 20%, and viral load was increased in a dose-range exploration study prior to this experiment. Organs were collected from mouse studies, and immunosuppression was not applied in the experiment (Table 2). The mortality rate was set at approximately 80% using a high-dose 2017 dengue virus strain (Table 1). The results are shown in the lower part of Figure 7.

[0105] Example 3: Bioactivity related to viral inflammation The following sections will study the biological activities associated with inflammation. Body temperature will serve as an inclusion criterion for the study, and the preclinical endpoints will be the level of the inflammatory marker IL-6 and spleen size.

[0106] Preparation of ex vivo isolated tissues Inflammatory immune response during dengue virus infection To investigate the effects of dengue virus infection on mice, the inventors examined the degree of inflammatory immune response associated with the severity of symptoms in dengue fever patients.

[0107] A clearly visible marker of a viral infection-induced inflammatory response is splenomegaly, which is also observed in dengue fever patients.

[0108] [Table 2]

[0109] The spleen size increased 35-fold in one week, which is a good marker for monitoring infections resulting from common viral infections (Table 2).

[0110] Pyrrole molecule 5 significantly reduces swelling, and the reduction in splenic swelling is highly correlated with a decrease in mortality.

[0111] In vitro inflammatory marker IL-6 The extent of the inflammatory immune response in dengue virus-infected mice was further investigated by analyzing the levels of pro-inflammatory cytokines.

[0112] Interleukin (IL)-6 is an inflammatory marker and has been reported to be elevated in patients with acute dengue fever infection. Post-infection, levels of pro-inflammatory cytokines increased until day 3, and IL-6 was measured on day 7 at the end of the experiment. Its levels returned to normal two weeks post-infection, when the viral infection was overcome by the host organism. These results correlated with dengue virus infection in humans and mice, confirming a causal relationship between the inflammatory response and dengue virus infection in mice.

[0113] [Table 3]

[0114] Initially, the inflammatory marker IL-6 was low even in the presence of fever, but inflammation increased from day 3 onward, peaking on day 7. This high inflammation correlated with a significant and consistent decrease in survival (Table 3). Pyrrole reduced the inflammatory marker IL-6 by 80%, which was consistent with milder splenic inflammation and a decrease in mortality.

[0115] A dose of 10 mg / kg was effective in three analgesic models, four inflammatory models, and for antipyretic effects. A 10 mg / kg dose of pyrrole 5 is equivalent to a 70 mg dose in humans, which is within the extremely safe range tested in the G1-G4 MAD trials.

[0116] Example 3: Clinical evaluation of pyrrole-5 in patients with moderate COVID-19 RNA viruses also pose a major public health problem worldwide. Well-known RNA viruses include influenza viruses (including avian and porcine isolates), hepatitis C virus (HCV), West Nile virus, SARS-CoV-2 coronavirus, COVID-19, respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV). Vaccines exist only for the influenza virus.

[0117] Therefore, drug therapy is essential to reduce the significant morbidity and mortality rates associated with these viruses. Unfortunately, the number of antiviral drugs is limited, and many of them are not very effective.

[0118] COVID-19, the novel coronavirus infection of 2019, has spread worldwide since the first case was identified in Wuhan, China, in February 2019. COVID-19 spreads through droplets or direct contact, infecting the respiratory system and causing pneumonia. Severe COVID-19 patients develop cytokine storm syndrome, organ failure, and acute respiratory distress syndrome, which can be fatal. Given that neutrophil extracellular traps (NETs) have been reported as important mediators of tissue damage in inflammatory diseases, NETs have been shown to be highly relevant in the pathophysiology of COVID-19. This case study relates to a clinical case.

[0119] NLR is a predictive biomarker for severe infection, and pyrrole 5 is required to stimulate lymphocyte production (Figure 8).

[0120] Methods: This study was conducted at two facilities in India (Study registration number: CTRI / 2020 / 10 / 028423), and effectiveness was evaluated using an 8-score ordinal scale. [Table 4]

[0121] The inclusion criteria for this study are as follows: SARS-CoV-2 infection confirmed by PCR within two days of randomization; patients with pneumonia without signs of severe illness and SpO2 ≤ 94% (in the range of 90-94%) in indoor air; patients with any two of the following signs or symptoms suggestive of COVID-19: fever, cough, dyspnea, or hypoxia; respiratory rate of 24 breaths per minute or more; and radiographic infiltrates confirmed by imaging (chest X-ray).

[0122] Patients were randomly assigned in a 1:1 ratio to two parallel groups: one group received pyrrole 5 along with best clinical care (BC) (pyrrole 5 + BC), and the second group received best clinical care (BC) only.

[0123] The primary efficacy endpoint showed significant improvement from baseline in the pyrrole 5+BC group from day 5 of the study until the end of the study, compared to patients in the BC group who showed improvement from day 8. The mean ordinal scale score was 0.22 in the pyrrole 5+BC group and 1.12 in the BC group, and the mean change in ordinal scale score from baseline to day 15 was statistically significant (P=0.042).

[0124] Patients who received pyrrole 5 + BC had shorter hospital stays compared to those who received BC alone (mean 9.45 vs. 9.80 days). 95% of patients who received pyrrole 5 + BC were discharged by the end of day 15, compared to 75% of patients in the BC group.

[0125] The average duration of oxygen supplementation required in patients in the pyrrole 5+BC group was 5.45 days, while patients in the BC group required oxygen supplementation for a relatively longer period of 7.10 days. Seventeen patients in the pyrrole 5+BC group were weaned off oxygen support on day 14, compared to 13 patients in the BC group (P=0.14).

[0126] CRP and ESR were analyzed as molecular and cellular inflammatory biomarkers, respectively. In the pyrrole 5 + BC group, CRP decreased by over 90%; in the BC group, CRP decreased by less than 80% (Figure 9). This finding is greater than that of any known anti-inflammatory agent.

[0127] The cytokine IL-6 was analyzed as an inflammation or immune marker. A decrease in cytokines was observed during high levels of inflammation, and low levels of IL-6 led to an increase in cytokines, triggering stimulation of the immune system by initiating lymphocyte proliferation (Figure 10).

[0128] Lymphocyte counts increased from 14% to the optimal reference range of 27% in the pyrrole 5 + BC group after 14 days of treatment. The BC group showed a slight increase from 14% to 19%. The change between the adjuvant (pyrrole 5) group and the BC group at day 15 was statistically significant (P=0.032) (Figure 11). Neutrophil / lymphocyte ratio (NLR) is the most relevant Covid-19 biomarker. Patients showed an elevated NLR ratio on day 1 of hospitalization as a result of Covid-19 infection. This ratio decreased from 8.5 to 2.8 in the pyrrole 5 + BC treatment group and from 11.1 to 5.9 in the BC treatment group (Figure 13). The difference between the two groups was statistically significant (P=0.010). The pyrrole 5 + BC treatment group showed a decrease in blood glucose levels (Figure 14).

[0129] Example 4: Evaluation of differentiation antigen group CD in lymphocytes treated with pyrrole 5 Lymphocytes included B cells and T cells, and a subpopulation of T cells was analyzed in particular. CD3 cells are T cells that possess the CD3 marker and are useful for various purposes, such as immunomodulation. Regulatory T cells decreased in response to Covid infection. Adjuvant treatment increased their number back to the healthy range (Figure 16).

[0130] Helper T cells are targets of HIV / AIDS infection, and CD4 counts were analyzed using clinical tests.

[0131] CD4 cells / helper T cells: CD4 cells are essential for an orchestrated immune response and were analyzed. As a result of day 1 of Covid-19 infection, CD4 cell counts were low in both the BC group and the adjuvant-treated group. The increase in CD4 cell count was greater in the adjuvant-treated group at day 15 compared to the BC monotherapy group. (Figure 17)

[0132] Cytotoxic T cells, or killer T cells, are crucial in the fight against viral infection. Before-and-after values ​​for CD8 T cells were plotted (Figure 18). For all hospitalized patients, values ​​were within the low normal range on day 1, and CD8 cell counts increased by day 15, with a greater increase in the adjuvant-treated group compared to the standard group (BC).

[0133] In conclusion, the increase in lymphocytes was most pronounced in the increase of helper T cells and killer T cells.

[0134] Example 5: Bacterial activity / bacterial inflammation / infection in mice using an LPS model LPS derived from Gram-negative organisms was applied to the lungs to induce an inflammatory cascade. The body retaliated by increasing the number of lymphocytes (Figure 21). Notably, this was the first time that inflammation and the immune response were isolated.

[0135] LPS infusion and sampling procedure: Mice anesthetized with ketamine-xylazine (50 mg / kg and 10 mg / kg; intraperitoneal (ip)) were subjected to intratracheal infusion of 50 μl of saline or saline containing LPS (10 μg per mouse) after blunt incision of the neck soft tissue to expose the trachea. At different times (4, 6, 12, and 24 hours) after endotoxin infusion, the animals were sacrificed by ether hyperanesthesia; bronchoalveolar lavage fluid (BALF) was collected by repeatedly and gently rinsing the lung cavity with 600 μl of saline until the total volume was approximately 3 ml, and placed in ice-cold conical plastic tubes. The lungs were then excised and MPO activity was measured. Betamethasone, or vehicle and pyrrole 5 (10, 30, and 100 mg / kg), was orally administered 1 hour before and 6 hours after LPS infusion; 1 hour after the final dose of the standard and test compounds, the animals were sacrificed by ether hyperanesthesia; BALF was collected by repeatedly and gently irrigating the pulmonary cavity with 600 μl of saline until the total volume was approximately 3 ml, and placed in an ice-cold conical plastic tube. The lungs were then removed, and the following activities were measured.

[0136] Here, under immune stimulation with LPS, neutrophils and macrophages decreased (Figure 20). This is a serious problem in sepsis when the body needs to fight off the organism, but cytokine levels must be controlled, and neutrophils constitute part of the neutrophil toxic storm (called a cytokine storm) triggered by cytokines.

[0137] Here, the comprehensive range of molecules reduced inflammation / cytokine storms while fully maintaining the immune response of the adaptive immune system.

[0138] Example 6. Cancer activity mediated by killer T cells Human tumors were transplanted into a mouse model, and their growth was studied based on tumor volume and morphology. The complete experimental details have been repeatedly published previously by Lattmann et al., and are summarized briefly here.

[0139] Human xenotransplantation research: In vivo experiments in mice - Evaluation of antitumor suppression Small cell lung cancer (SCLC) and gastric tumors were transplanted into purebred NMRI mice aged 6-8 weeks from inbred colonies at our facility. The animals were given free access to RM3E feed (Lillco-England) and water. Tumor fragments were 2 × 10⁶. 5 A cube containing cells, approximately 2 mm in size, was subcutaneously transplanted into the groin via a trocar in a volume of 0.2 ml. Tumor-bearing mice were randomized into groups of six animals each, and treatment was initiated approximately 10 days after transplantation, when the tumor had fully established itself.

[0140] The test compound was administered in an appropriate formulation. The effect of chemotherapy was evaluated weekly after transplantation by measuring tumor volume. Mice were sacrificed after drug treatment or when weight loss reached 20% of body weight, and the effect was measured by the difference in tumor volume, as shown below: %[Inhibition] = Treatment volume / Control volume × 100

[0141] In this study, untreated tumors grew exponentially, while the treated group showed suppression of tumor growth by up to 90% (Figure 22).

[0142] Typically, inhibitors of cancer pathways are studied, but here, rather than toxic chemicals or biological agents, the organism's own defense system killed the dysregulated cells. This eliminated the cancerous tissue from the host organism. This effect does not require blockade of pathways, which typically involve very high levels of inhibition that cause drug-related toxicity. Other doses (Figure 22) were tested, and similar curves were obtained over a wide dose range of 1, 3, 10, and 30–100 mg / kg.

Claims

1. A pharmaceutical composition for the treatment of a disease comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable excipient and / or carrier: 【Chemistry 1】 [In the formula, X is a halogen, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyl, alkenyloxy, or alkenylcarbonyl; Y is a hydroxyl or alkoxy group; R is phenyl, cyanophenyl, or halogenated phenyl; R １ [These are alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyloxy, alkenylcarbonyl, phenyl, phenylalkyl, dialkylphenyl, benzyl, or benzylalkyl.]

2. The alkyl-containing portion is C １ ~C １８ And preferably C １ ~C １２ The pharmaceutical composition according to claim 1.

3. The alkenyl-containing moiety and the alkynyl-containing moiety are C ２ to C １８ and preferably are C ２ to C １２ The pharmaceutical composition according to claim 1.

4. R １ C １－６ Alkyl, C １－６ Alkenil, C １－６ Alkynyl, benzyl, cyclohexyl, phenyl, benzyl (C ２－４ ) alkyl, or phenyl (C ２－４ The pharmaceutical composition according to claim 1, wherein the alkyl group is...

5. The pharmaceutical composition according to claim 1, wherein X is selected from F, Br, Cl, and I.

6. A pharmaceutical composition comprising a compound having one of the following formulas in a therapeutically effective amount. 【Chemistry 2】

7. The pharmaceutical composition according to claim 1 or 6, wherein the therapeutically effective dose of the compound of formula I is in the range of 100 ng / kg to 20 mg / kg.

8. A pharmaceutical composition according to any one of claims 1 to 7, which is administered orally, topically, intraperitoneally, or intravenously.

9. A pharmaceutical composition according to claim 1 or 6 for use in the preparation of a pharmaceutical for the treatment or prevention of inflammation or related conditions.

10. A pharmaceutical composition according to claim 1 or 6 for use in the preparation of a pharmaceutical for the treatment of pain, fever, inflammation of the intestines or lungs, or immune-mediated diseases such as cancer.

11. A pharmaceutical composition according to claim 1 or 6 for use in the preparation of a pharmaceutical for the treatment of viral diseases and / or symptomatic treatment of pneumonia associated with viral diseases.

12. The pharmaceutical composition according to claim 11, wherein the viral disease is dengue fever, COVID-19 virus infection, HIV, hepatitis, or multiple sclerosis.

13. A pharmaceutical composition according to claim 1 or 6, for use in the preparation of a pharmaceutical for the treatment or prevention of inflammation or related conditions mediated by cytokines such as IL-6.

14. A pharmaceutical composition according to claim 1 or 6, which is useful for regulating immune function, blood glucose levels, or both.

15. A pharmaceutical composition according to claim 1 or 6, which is useful for regulating lymphocytes, particularly cytotoxic T cells.

16. A pharmaceutical composition according to any one of claims 1 to 6, which is useful for regulating neutrophils and bringing them to a medically acceptable range.

17. A pharmaceutical composition according to any one of claims 1 to 6, which is useful for inducing an increase in T cells, particularly CD4 cells or CD8 cells or both.

18. A method for treating a mammal suffering from a disease or a method for preventing a disease in a mammal at risk, comprising administering a therapeutically effective amount of a compound of formula (I) to a patient in need: 【Transformation 3】 [In the formula, X is a halogen, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyl, alkenyloxy, or alkenylcarbonyl; Y is a hydroxyl or alkoxy group; R is phenyl, cyanophenyl, or halogenated phenyl; R １ [These are alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyloxy, alkenylcarbonyl, phenyl, phenylalkyl, dialkylphenyl, benzyl, or benzylalkyl.]

19. The alkyl-containing portion is C １ ~C １８ And preferably C １ ~C １２ The method according to claim 18.

20. The alkenyl-containing portion and the alkynyl-containing portion are C ２ ~C １８ And preferably C ２ ~C １２ The method according to claim 18.

21. R １ C １－６ Alkyl, C １－６ Alkenil, C １－６ Alkynyl, benzyl, cyclohexyl, phenyl, benzyl (C ２－４ ) alkyl, or phenyl (C ２－４ The method according to claim 18, wherein the alkyl is...

22. The method according to claim 18, wherein X is selected from F, Br, Cl, and I.

23. A method for treating a mammal suffering from a disease or for preventing a mammal at risk of a disease, comprising administering a therapeutically effective amount of a compound having one of the following formulas to a patient in need thereof. 【Chemistry 4】

24. The method according to claim 18 or 23, wherein the administration is carried out via oral, topical, intraperitoneal or intravenous route.

25. The method according to claim 18 or 23, wherein the disease is an inflammatory or related condition.

26. The method according to claim 18 or 23, wherein the disease is an immune-mediated disease such as pain, fever, inflammation of the intestines or lungs, or cancer.

27. The method according to claim 18 or 23, wherein the disease is a viral disease and / or a symptom associated with a viral disease such as pneumonia.

28. The method according to claim 27, wherein the viral disease is dengue fever, COVID-19 virus infection, HIV, hepatitis, or multiple sclerosis.

29. The method according to claim 25, wherein the inflammation is mediated by or associated with cytokines such as IL-6.

30. The method according to claim 18 or 23, which is useful for inducing an increase in T cells, particularly CD4 cells or CD8 cells or both.

31. The method according to claim 18 or 23, wherein the therapeutically effective dose of the compound of formula (I) is in the range of 100 ng / kg patient body weight to 20 mg / kg patient body weight.

32. The method according to claim 31, wherein a therapeutically effective amount of the compound of formula I is administered as a single dose or in divided doses.

33. Use of the compound of formula (I) for the treatment of a disease by administering a therapeutically effective amount of the compound of formula (I) to patients who require treatment of the disease: 【Transformation 5】 [In the formula, X is a halogen, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyl, alkenyloxy, or alkenylcarbonyl; Y is a hydroxyl or alkoxy group; R is phenyl, cyanophenyl, or halogenated phenyl; R １ [These are alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkenyloxy, alkenylcarbonyl, phenyl, phenylalkyl, dialkylphenyl, benzyl, or benzylalkyl.]

34. The alkyl-containing portion is C １ ~C １８ And preferably C １ ~C １２ The use described in claim 33.

35. The alkenyl-containing portion and the alkynyl-containing portion are C ２ ~C １８ And preferably C ２ ~C １２ The use described in claim 33.

36. R １ C １－６ Alkyl, C １－６ Alkenil, C １－６ Alkynyl, benzyl, cyclohexyl, phenyl, benzyl (C ２－４ ) alkyl, or phenyl (C ２－４ The use according to claim 33, wherein the alkyl group is alkyl.

37. The use according to claim 33, wherein X is selected from F, Br, Cl, and I.

38. Use of a compound having one of the following formulas for the treatment of a disease. 【Transformation 6】

39. The use according to claim 33 or 38, wherein the disease is an inflammatory or related condition.

40. The use according to claim 33 or 38, wherein the disease is an immune-mediated disease such as pain, fever, inflammation of the intestines or lungs, or cancer.

41. The use according to claim 33 or 38, wherein the disease is a viral disease and / or a symptom associated with a viral disease such as pneumonia.

42. The use according to claim 41, wherein the viral disease is dengue fever, COVID-19 virus infection, HIV, hepatitis, or multiple sclerosis.

43. The use according to claim 38, for the treatment or prevention of inflammation or related conditions mediated by cytokines such as IL-6.

44. The therapeutically effective dose of the compound of formula (I) is in the range of 100 ng / kg patient body weight to 20 mg / kg patient body weight, as per claim 33 or 38.

45. The use according to claim 33 or 38, wherein the administration is carried out via oral, intraperitoneal, or intravenous route.

46. The use of the compound according to any one of claims 33 to 45, wherein the compound can regulate an immune response, blood glucose levels, or both.

47. The use according to any one of claims 33 to 45, wherein the compound can regulate lymphocytes, including increasing the total number of lymphocytes, particularly cytotoxic T cells.

48. The use according to any one of claims 33 to 45, wherein the compound can regulate neutrophils and bring them within a medically acceptable range.

49. The use of the compound according to any one of claims 33 to 45, wherein the compound can increase T cells, particularly CD4 or CD8 or both.

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